The functional role of GABA and glycine in monaural and binaural processing in the inferior colliculus of horseshoe bats.
The functional role of GABA and glycine in monaural and binaural signal analysis was studied in single unit recordings from the central nucleus of the inferior colliculus (IC) of horseshoe bats (Rhinolophus rouxi) employing microiontophoresis of the putative neurotransmitters and their antagonists bicuculline and strychnine. Most neurons were inhibited by GABA (98%; N = 107) and glycine (92%; N = 118). Both neurotransmitters appear involved in several functional contexts, but to different degrees. Bicuculline-induced increases of discharge activity (99% of cells; N = 191) were accompanied by changes of temporal response patterns in 35% of neurons distributed throughout the IC. Strychnine enhanced activity in only 53% of neurons (N = 147); cells exhibiting response pattern changes were rare (9%) and confined to greater recording depths. In individual cells, the effects of both antagonists could markedly differ, suggesting a differential supply by GABAergic and glycinergic networks. Bicuculline changed the shape of the excitatory tuning curve by antagonizing lateral inhibition at neighboring frequencies and/or inhibition at high stimulation levels. Such effects were rarely observed with strychnine. Binaural response properties of single units were influenced either by antagonization of inhibition mediated by ipsilateral stimulation (bicuculline) or by changing the strength of the main excitatory input (bicuculline and strychnine).


Routes of transmission of hepatitis C virus in an endemic rural area of Japan. Molecular epidemiologic study of hepatitis C virus infection.
We conducted an epidemiological study to investigate the routes of transmission of hepatitis C virus (HCV) infection in an area endemic for HCV. Subjects were the 857 adult inhabitants of K area, Japan. The prevalence of antibody to HCV (anti-HCV) was 26.3%. The HCV genotype 1b was the most prevalent (89.3%) among the anti-HCV positive subjects. Molecular evolutionary analysis, based on the nucleotide sequences of the HCV core region from 23 participants with type 1b, showed that the isolates were distributed into more than 1 group. Multivariate regression analysis demonstrated that an age over 40 years, a history of blood transfusion, the presence of antibody to hepatitis B core antigen (anti-HBc), or a history of surgery were each independently associated with the presence of anti-HCV. No significant differences in the presence of anti-HCV prevalence were observed between the wives of men positive for anti-HCV (33.3%) and age-matched women (36.4%), or between the husbands of women positive for anti-HCV (36.4%) and age-matched men (38.3%), from the same area. Findings suggest that the various strains of HCV type 1b were transmitted via medical procedures, not by the intrafamilial route.


Acute Ischemic Priapism: An AUA/SMSNA Guideline.
Priapism is a persistent penile erection that continues hours beyond, or is unrelated to, sexual stimulation and results in a prolonged and uncontrolled erection. Given its time-dependent and progressive nature, priapism is a situation that both urologists and emergency medicine practitioners must be familiar with and comfortable managing. Acute ischemic priapism, characterized by little or no cavernous blood flow and abnormal cavernous blood gases (ie, hypoxic, hypercarbic, acidotic) represents a medical emergency and may lead to cavernosal fibrosis and subsequent erectile dysfunction. A comprehensive search of the literature was performed by Emergency Care Research Institute for articles published between January 1, 1960 and May 1, 2020. Searches identified 2948 potentially relevant articles, and 2516 of these were excluded at the title or abstract level for not meeting inclusion criteria for any key question. Full texts for the remaining 432 articles were reviewed, and ultimately 137 unique articles were included in the report. This Guideline was developed to inform clinicians on the proper diagnosis and surgical and non-surgical treatment of patients with acute ischemic priapism. This Guideline addresses the role of imaging, adjunctive laboratory testing, early involvement of urologists when presenting to the emergency room, discussion of conservative therapies, enhanced data for patient counseling on risks of erectile dysfunction and surgical complications, specific recommendations on intracavernosal phenylephrine with or without irrigation, the inclusion of novel surgical techniques (eg, tunneling), and early penile prosthesis placement. All patients with priapism should be evaluated emergently to identify the sub-type of priapism (acute ischemic versus non-ischemic) and those with an acute ischemic event should be provided early intervention. Treatment of the acute ischemic patient must be based on patient objectives, available resources, and clinician experience. As such, a single pathway for managing the condition is oversimplified and no longer appropriate. Using a diversified approach, some men may be treated with intracavernosal injections of phenylephrine alone, others with aspiration/irrigation or distal shunting, and some may undergo non-emergent placement of a penile prosthesis.


[Homeopathy: a field of work for the veterinarian].
It is generally known that Homeopathy and other so-called alternative methods of treatment have recently been gaining acceptance. The profession of lay animal practitioner is no longer a rarity in Switzerland. For some, alternative medicine is one phenomenon among others in a saturated health market and thrives on the fact that classical medicine does not yet extend to all areas. For others, the search for alternatives corresponds to a justified demand by the practitioners and denotes an extension of the medical disciplines. The Workshop for Veterinary Acupuncture and Homeopathy (AGVAH) was founded several years ago by veterinarians in Switzerland. It represents the professional interests of its members and upholds their right to practice these forms of therapy. The ensuing debate between classical and alternative medicine questions not only the basis of Homeopathy and similar forms of medicine, but also that of scientific thought. The realization that any scientific approach has its limits can open a door to deeper understanding of traditional occidental medicine.


Transforming growth factor-alpha: identification in bovine corpus luteum by immunohistochemistry and northern blot analysis.
Transforming growth factor-alpha (TGF-alpha), a product of the thecal cells, has potent mitogenic and steroidogenic influences on cells within the ovarian follicle. Whether TGF-alpha continues to be produced in those follicles that go on to ovulate and form a corpus luteum is currently under investigation. In the present study, TGF-alpha was localized in the bovine corpus luteum by means of immunoperoxidase staining using a monoclonal antibody for TGF-alpha that does not cross-react with epidermal growth factor. In corpora lutea from the mid-luteal phase of the cycle TGF-alpha staining was found predominantly in the large luteal cells. Northern blot analysis using a human TGF-alpha cDNA probe hybridized to the 4.5-4.8 kb TGF-alpha transcript in RNA from the corpus luteum. These studies provide new evidence that TGF-alpha, a potent paracrine regulator within the ovarian follicle, continues to be expressed in the corpus luteum.


Practical guidance for CD management involving treatment of botulinum toxin: a consensus statement.
Cervical dystonia is a neurological movement disorder causing abnormal posture of the head. It may be accompanied by involuntary movements which are sometimes tremulous. The condition has marked effects on patients' self-image, and adversely affects quality of life, social relationships and employment. Botulinum neurotoxin (BoNT) is the treatment of choice for CD and its efficacy and safety have been extensively studied in clinical trials. However, current guidelines do not provide enough practical information for physicians who wish to use this valuable treatment in a real-life setting. In addition, patients and physicians may have different perceptions of what successful treatment outcomes should be. Consequently, an international group of expert neurologists, experienced in BoNT treatment, met to review the literature and pool their extensive clinical experience to give practical guidance about treatment of CD with BoNT. Eight topic headings were considered: the place of BoNT within CD treatment options; patient perspectives and desires for treatment; assessment and goal setting; starting treatment with BoNT-A; follow-up sessions; management of side effects; management of non-response; switching between different BoNT products. One rapporteur took responsibility for summarising the current literature for each topic, while the consensus statements were developed by the entire expert group. These statements are presented here along with a discussion of the background information.


The serosal mesothelium is a major source of smooth muscle cells of the gut vasculature.
Most internal organs are situated in a coelomic cavity and are covered by a mesothelium. During heart development, epicardial cells (a mesothelium) move to and over the heart, undergo epithelial-mesenchymal transition (EMT), and subsequently differentiate into endothelial and vascular smooth muscle cells. This is thought to be a unique process in blood vessel formation. Still, structural and developmental similarities between the heart and gut led us to test the hypothesis that a conserved or related mechanism may regulate blood vessel development to the gut, which, similar to the heart, is housed in a coelomic cavity. By using a combination of molecular genetics, vital dye fate mapping, organ culture and immunohistochemistry, we demonstrate that the serosal mesothelium is the major source of vasculogenic cells in developing mouse gut. Our studies show that the gut is initially devoid of a mesothelium but that serosal mesothelial cells expressing the Wilm's tumor protein (Wt1) move to and over the gut. Subsequently, a subset of these cells undergoes EMT and migrates throughout the gut. Using Wt1-Cre genetic lineage marking of serosal cells and their progeny, we demonstrate that these cells differentiate to smooth muscle of all major blood vessels in the mesenteries and gut. Our data reveal a conserved mechanism in blood vessel formation to coelomic organs, and have major implications for our understanding of vertebrate organogenesis and vascular deficiencies of the gut.


Primary structure, distribution, and effects on motility of CGRP in the intestine of the cod Gadus morhua.
Calcitonin gene-related peptide (CGRP) was isolated from an extract of the intestine of the cod Gadus morhua. The primary structure of this 37-amino acid peptide was established as follows: ACNTA TCVTH RLADF LSRSG GIGNS NFVPT NVGSK AF-NH2. The peptide shows close structural similarities to other nonmammalian (3-4 amino acid substitutions) and mammalian (5-8 amino acid substitutions) CGRPs, and it contains the two residues Asp14 and Phe15 that seem to be characteristic for CGRP in nonmammalian vertebrates. Cod CGRP (10(-9)-10(-7) M) inhibited the motility of spontaneously active ring preparations from the cod intestine and was significantly (P < 0.05) more potent than rat alpha-CGRP. Neither prostaglandins nor nitric oxide is involved in the inhibitory response produced by cod CGRP, and the lack of effect of tetrodotoxin suggests an action of CGRP on receptors on the intestinal smooth muscle cells. The competitive CGRP antagonist human alpha-CGRP-(8-37) significantly (P < 0.05) reduced the response to cod CGRP. Immunohistochemistry demonstrated CGRP-immunoreactive neurons intrinsic to the intestine, and a dense innervation with immunoreactive nerve fibers was observed in the myenteric plexus and the circular muscle layer. Myotomy studies show that CGRP-containing nerves project orally and anally in the myenteric plexus, whereas nerve fibers in the circular muscle layer project mainly anally, indicating a role for CGRP in descending inhibitory pathways of the cod intestine.


Anticonvulsants for Psychiatric Disorders in Children and Adolescents: A Systematic Review of Their Efficacy.
Aim: Anticonvulsant medications are frequently used in clinical practice to treat psychiatric disorders in children and adolescents, but the evidence for their efficacy is uncertain. We conducted a systematic review of published randomized controlled trials (RCT) that assessed the psychiatric benefit of anticonvulsants in patients under 18 years of age. Method: The Medline, Scopus, Web of Science, and ClinicalTrials.gov databases were systematically searched for peer-reviewed primary publications of RCTs with a minimum of 10 patients per treatment arm through December 2017. Results: Out of 355 identified non-duplicative publications, 24 met the inclusion criteria. Most RCTs were to treat bipolar disorder (n = 12) or manage recurrent aggression (n = 9). Few (n = 3) had both a multisite design and adequate statistical power. Valproate was the most frequently studied anticonvulsant (n = 15). Out of three placebo-controlled RCTs of valproate in bipolar disorder, none showed efficacy. In four RCTs, valproate was inferior to the antipsychotic risperidone. In several small, single-site RCTs, valproate and sulthiame were better than placebo for the management of recurrent aggression. Conclusions: Currently available RCTs do not support the efficacy of anticonvulsants as mood stabilizers in children. There is some preliminary evidence from small RCTs of the efficacy of some anticonvulsants in the control of aggression and behavioral dyscontrol in conduct disorder, autism, and intellectual disability.


Diffuse pulmonary alveolar hemorrhage after bone marrow transplantation: radiographic findings in 39 patients.
Diffuse alveolar hemorrhage is a life-threatening complication after bone marrow transplantation. We investigated the radiographic abnormalities that occurred in 39 transplantation patients with a diagnosis of diffuse alveolar hemorrhage and correlated the findings with the patients' clinical course. The initial radiographic abnormalities after diffuse alveolar hemorrhage developed an average of 11 days after bone marrow transplantation, and the radiographic abnormalities preceded the clinical diagnosis by an average of 3 days. Twenty-seven patients initially had bilateral radiographic abnormalities; 10 initially had unilateral abnormalities (seven in the right lung, three in the left lung). Two patients had normal chest radiographs throughout their clinical course. All 37 patients with radiographic abnormalities had abnormalities involving the central portion of the lung, primarily the middle and lower lung zones. The initial radiographic pattern was interstitial in 27 and alveolar in 10. In 24 patients, radiographic abnormalities were initially judged to be mild; three were severe from the onset. Radiographic abnormalities rapidly worsened in most patients over 6 days. In 30 patients, diffuse bilateral radiographic abnormalities involving all lung zones developed. Eleven patients persisted in having only interstitial radiographic abnormalities; 26 had a confluent alveolar pattern. At the height of radiographic abnormalities, 27 cases were judged to be severe, and only one case was judged to be mild. The mortality rate in patients with diffuse alveolar hemorrhage was 77%. The radiographic abnormalities of diffuse alveolar hemorrhage are nonspecific and usually precede the clinical diagnosis. The clinical course after hemorrhage is short, often resulting in death.


Diagnosis of pulmonary disease in human immunodeficiency virus infection: role of transbronchial biopsy and bronchoalveolar lavage.
The value of transbronchial biopsy and bronchoalveolar lavage was assessed in the diagnosis of pulmonary disease in patients infected with the human immunodeficiency virus (HIV). Seventy four transbronchial biopsy and 66 bronchoalveolar lavage specimens (60 paired specimens) from 80 examinations in 64 patients were reviewed. Pneumocystis carinii was the most common pathogen isolated (43 patients). Bronchoalveolar lavage was superior to transbronchial biopsy for the diagnosis of this pathogen, the sensitivities being 90% and 56%. Cytomegalovirus was identified three times by lavage and once by transbronchial biopsy. Neither method detected Kaposi's sarcoma in the one patient shown to have it by open lung biopsy. The complication rate in a concurrent study of bronchoscopy with transbronchial biopsy in 74 consecutive HIV positive patients was 22%. This study does not support the use of transbronchial biopsy in these patients.


A Streamlined CyTOF Workflow To Facilitate Standardized Multi-Site Immune Profiling of COVID-19 Patients.
Mass cytometry (CyTOF) represents one of the most powerful tools in immune phenotyping, allowing high throughput quantification of over 40 single parameters at single-cell resolution. However, wide deployment of CyTOF-based immune phenotyping studies are limited by complex experimental workflows and the need for specialized CyTOF equipment and technical expertise. Furthermore, differences in cell isolation and enrichment protocols, antibody reagent preparation, sample staining and data acquisition protocols can all introduce technical variation that can potentially confound integrative analyses of large data-sets of samples processed across multiple labs. Here, we present a streamlined whole blood CyTOF workflow which addresses many of these sources of experimental variation and facilitates wider adoption of CyTOF immune monitoring across sites with limited technical expertise or sample-processing resources or equipment. Our workflow utilizes commercially available reagents including the Fluidigm MaxPar Direct Immune Profiling Assay (MDIPA), a dry tube 30-marker immunophenotyping panel, and SmartTube Proteomic Stabilizer, which allows for simple and reliable fixation and cryopreservation of whole blood samples. We validate a workflow that allows for streamlined staining of whole blood samples with minimal processing requirements or expertise at the site of sample collection, followed by shipment to a central CyTOF core facility for batched downstream processing and data acquisition. We further demonstrate the application of this workflow to characterize immune responses in a cohort of hospitalized COVID-19 patients, highlighting key disease-associated changes in immune cell frequency and phenotype.


Highly Luminescent Water-Dispersible NIR-Emitting Wurtzite CuInS2/ZnS Core/Shell Colloidal Quantum Dots.
Copper indium sulfide (CIS) quantum dots (QDs) are attractive as labels for biomedical imaging, since they have large absorption coefficients across a broad spectral range, size- and composition-tunable photoluminescence from the visible to the near-infrared, and low toxicity. However, the application of NIR-emitting CIS QDs is still hindered by large size and shape dispersions and low photoluminescence quantum yields (PLQYs). In this work, we develop an efficient pathway to synthesize highly luminescent NIR-emitting wurtzite CIS/ZnS QDs, starting from template Cu2-x S nanocrystals (NCs), which are converted by topotactic partial Cu+ for In3+ exchange into CIS NCs. These NCs are subsequently used as cores for the overgrowth of ZnS shells (≤1 nm thick). The CIS/ZnS core/shell QDs exhibit PL tunability from the first to the second NIR window (750-1100 nm), with PLQYs ranging from 75% (at 820 nm) to 25% (at 1050 nm), and can be readily transferred to water upon exchange of the native ligands for mercaptoundecanoic acid. The resulting water-dispersible CIS/ZnS QDs possess good colloidal stability over at least 6 months and PLQYs ranging from 39% (at 820 nm) to 6% (at 1050 nm). These PLQYs are superior to those of commonly available water-soluble NIR-fluorophores (dyes and QDs), making the hydrophilic CIS/ZnS QDs developed in this work promising candidates for further application as NIR emitters in bioimaging. The hydrophobic CIS/ZnS QDs obtained immediately after the ZnS shelling are also attractive as fluorophores in luminescent solar concentrators.


Attributions and Attitudes of Mothers and Fathers in the Philippines.
OBJECTIVE.: This paper investigates the mean level and within-family similarities and differences in Filipino mothers' and fathers' attributions about success and failure in caregiving situations, and their progressive and authoritarian parenting attitudes. DESIGN.: Both mothers and fathers in 95 families in metropolitan Manila completed interviews. RESULTS.: Controlling for parents' age, education, and possible social desirability bias, there was a significant gender difference in modernity of attitudes, with mothers exhibiting higher levels of modernity than fathers. There was a strong correlation in mothers' and fathers' authoritarian attitudes and moderate correlations in modernity of attitudes. There were neither parent gender effects nor concordance in the attributions of mothers and fathers. CONCLUSIONS.: Cultural explanations are presented to account for the findings, specifically the sociocultural values that foster traditional attitudes favoring parental authority and child obedience, and the differences in gender and family roles of Filipino mothers and fathers.


Fine specificities of autoantibodies directed against the Ro, La, Sm, RNP, and Jo-1 proteins defined by two-dimensional gel electrophoresis and immunoblotting.
Although useful for specific purposes, immunofluorescence, precipitation in agarose gels, and the m.w. estimation of RNA or proteins immunoprecipitated from transformed cells often provide partial or ambiguous definition of autoantibody specificity. We have analyzed organ and cell extracts by one-and two-dimensional electrophoresis together with Western blotting to define the fine specificities of antibodies to the ribonucleoprotein (RNP) antigens Ro, La, Sm, RNP and Jo-1. One-dimensional analysis identified the Ro protein as a 57 kilodalton (kd) protein, although many anti-Ro sera also react with a 50 kd protein. La antisera react with 50 and 43 kd proteins. The 50 kd La protein readily breaks down into 43, 25, and smaller immunoreactive cleavage products. Partial proteolysis of Ro and La proteins in human spleen extracts produces similar immunoreactive products, providing evidence for a common structure. The major immunoreactive Sm antigens defined by human polyclonal antisera and a mouse monoclonal antiserum were doublets of 25/26 and 16/18 kd, whereas anti-RNP sera reacted with a protein of 68 kd. Most Sm-RNP antisera contained antibodies reactive with additional proteins, especially when whole cell extracts were used as a source of antigens. Two-dimensional analysis provided characteristic maps of the antigens. Ro and La were acidic, and La showed a unique set of acidic charge isomers at 50 and 43 kd. Anti-Sm antibodies reacted with discrete dots corresponding to both the acidic and basic regions of the first-dimension (charge) gels, whereas the RNP antigen showed a series of basic charge isomers of 68 kd. Many anti-Sm-RNP sera reacted with other closely spaced proteins of a similar charge and size to the Sm and RNP antigens, suggesting antibody cross-reactivity or reactivity with closely related functional proteins. Although Jo-1 had the same m.w. as the undegraded La antigen, the fingerprints were quite distinctive on two-dimensional electrophoresis. The results of this study indicate how the source and preparation of antigen extracts, as well as protein degradation, influence the m.w. determinations of soluble protein antigens. With these factors taken into account, two-dimensional fractionation with immunoblotting provides a highly discriminating, sensitive, and reproducible method of analysis of autoantibody specificity. This technique can be used to standardize reference antisera and to study protein antigens in normal and abnormal cell and tissue extracts, and could lead to new or more precise correlations with clinical disease.


Effect of colchicine on cell membrane and on biopterin transport in Crithidia fasciculata.
Incorporation of 14C-labeled biopterin into Crithidia fasciculata was inhibited by 1 mM colchicine or lumicolchicine. These substance do not penetrate the cell membrane, hence they cannot interact with the subpellicular microtubules. In view of this, interference of colchicine with biopterin transport must occur on the outer surface of the cell membrane. Binding of colchicine to Crithidia was not temperature-dependent and did not exhibit saturation kinetics. These facts exclude a binding as in the case of tubulin, or similar proteins which may be present in the membrane. The results suggest an inhibition reflecting steric hindrance of the biopterin carrier system.


Regulation of alveolar epithelial cell ICAM-1 expression by cell shape and cell-cell interactions.
In normal lung, intercellular adhesion molecule 1 (ICAM-1) is expressed at high levels on thin type I alveolar epithelial cells, but is minimally expressed on cuboidal type II cells. ICAM-1 is induced in primary culture on tissue culture-treated plastic as type II cells undergo transition toward a type I cell-like phenotype. We hypothesized that alveolar epithelial cell expression of ICAM-1 might be regulated in part by signals that influence the state of differentiation of these cells. We found that rat type II cells that were cultured as aggregates of cuboidal cells on a hydrated basement membrane gel (Matrigel) or on floating type I collagen gels, expressed markedly less ICAM-1 protein and mRNA compared with cells that had spread on plastic. In contrast, type II cells that had spread as monolayers on dishes coated with basement membrane proteins in planar configuration demonstrated ICAM-1 expression comparable to that of cells on plastic alone. Thus regulation of alveolar epithelial cell expression of this immunologically important adhesion molecule involves complex spatial interactions of the cells with the basement membrane and other epithelial cells.


[Experimental and clinical studies on the effect of sodium dodecylbenzene sulfonate in in vitro killing Demodex and in treating demodicidosis].
To observe the effect of sodium dodecylbenzene sulfonate (SDBS) in killing Demodex in vitro and in the treatment of demodicidosis. (1) The experiment of in vitro killing Demodex with 1% and 2% SDBS was conducted. (2) A clinical trial was carried out to evaluate the therapeutic effect in the treatment of demodicidosis with 2% SDBS and 2% metronidazole emulsion. Patients with demodicidosis were randomly divided into trial and control groups (31 cases each). They were treated with 2% SDBS ointment and 2% metronidazole ointment twice a day in the early morning and evening respectively for eight weeks consecutively. Inflammatory lesions of face, Demodex infestation and scores of erythema were measured to evaluate the effect before and after treatment. (3) Follow-up was carried out for two months to evaluate the effect and side effects after 8 weeks' treatment. (1) 2% SDBS killed all Demodex in vitro after 5 h, there was significant difference between the 2% SDBS and 2% metronidazole (69.4%), or between SDBS and peanut oil (9.1%) (P < 0.05). There was no significant difference in killing Demodex folliculorum and Demodex brevis with 2% SDBS. (2) Clinical observation showed that there was a significant difference in facial inflammatory lesions, Demodex infestation and scores of erythema before and after treatment with 2% SDBS (P < 0.05). The effective rate was 87.1%, 65.5% in 2% SDBS group and 2% metronidazole group respectively, with a significant difference between the two groups (P < 0.05). Follow up showed same results. (3) A slight burning sensation was the only side-effect in 3 cases with 2% SDBS ointment. Sodium dodecylbenzene sulfonate has the effect of in vitro killing Demodex and is highly effective in the treatment of demodicidosis.


Mechanoafferent neurons innervating tail of Aplysia. II. Modulation by sensitizing stimulation.
The tail-withdrawal reflex of Aplysia can be sensitized by weak stimulation of a site outside the site used to test the reflex or by repeatedly stimulating the test site itself. The sensitization of tail-withdrawal responses is associated with enhanced activation of the tail motor neurons and heterosynaptic facilitation of the monosynaptic connections between the tail sensory neurons and tail motor neurons. This synaptic facilitation can occur under conditions in which neither posttetanic potentiation nor generalized changes in postsynaptic input resistance contribute to the facilitation. In addition to producing monosynaptic excitatory postsynaptic potentials (EPSPs), action potentials in tail sensory neurons often recruit longer latency polysynaptic input to the tail motor neurons during sensitization. Strong, noxious tail shock similar in intensity to that used previously for sensitization and aversive classical conditioning of other responses in Aplysia produces more heterosynaptic facilitation than does weak sensitizing stimulation. Heterosynaptic facilitation builds up progressively with multiple trials and lasts for hours. Very strong shocks to the tail can change the response characteristics of tail sensory neurons so that a prolonged, regenerative burst of spikes is elicited by a brief intracellular depolarizing pulse. This bursting response produced by sensitizing stimulation has not been described previously in Aplysia sensory neurons and can greatly amplify the synaptic input to tail motor neurons from the sensory neurons. In addition, strong shocks to the tail increase the duration and magnitude of individual sensory neuron action potentials. Sensitizing tail stimulation usually produces long-lasting depolarization of the tail motor neurons and often long-lasting hyperpolarization of the tail sensory neurons. The tail motor and sensory neurons show both increases and decreases of input resistance following sensitizing stimulation. However, the small, occasional increases in input resistance of the motor neuron are insufficient to explain the heterosynaptic facilitation produced by sensitizing stimulation. Serotonin (5-HT) application can mimic many of the effects of sensitizing tail shock, including facilitation of both tail withdrawal and the monosynaptic connections between tail sensory and motor neurons, hyperpolarizing and depolarizing responses in the tail sensory neurons, and an increase in the duration and magnitude of the sensory neuron action potential. In the nearly isolated sensory neuron soma, 5-HT usually produces a slow, decreased conductance depolarizing response, suggesting that the 5-HT-induced hyperpolarizing response see


Hsp60 peptide therapy of NOD mouse diabetes induces a Th2 cytokine burst and downregulates autoimmunity to various beta-cell antigens.
A peptide of the human 60-kDa heat-shock protein (hsp60), designated p277, was found to be useful as a therapeutic agent to arrest the autoimmune process responsible for diabetes in nonobese diabetic (NOD) mice. The effectiveness of peptide treatment was associated with the induction of peptide-specific antibodies of the IgG1 but not of the IgG2a isotype, suggesting the possibility that a Th2-type response may have been induced. We now report that the effectiveness of p277 treatment is associated with the transient activation of anti-p277 splenic T-cells that produce the Th2 cytokines interleukin-4 (IL-4) and IL-10. The Th2 response to p277 was associated with reduced Th1-type autoimmunity to hsp60 and to two other target antigens associated with diabetes: GAD and insulin. The Th2 shift appeared to be relatively specific; spontaneous T-cell reactivity to a bacterial antigen peptide remained in the Th1 mode in the p277-treated mice. Moreover, treatment with the bacterial peptide did not induce a change in cytokine profile, and it did not affect progression of the disease. Thus, effective peptide treatment of the diabetogenic process associated with the induction of antibodies may be explained by selective and transient activation of Th2 autoimmune reactivity.


Angiosarcoma in the small intestine. Apropos of a particular case.
Presentation of a case of small intestine primary angiosarcoma in a 70-year-old male. There is question of an extremely rare tumor in the gastrointestinal tract. Its symptomatology is similar to that of other tumors in the small intestine. An immunohistochemical study is usually essential for its anatomopathological diagnosis. The diagnosis is generally arrived at in its advanced stages, and that makes for a bad prognosis. The bibliography has been revised from this case on.


Specific in vivo knockdown of protein function by intrabodies.
Intracellular antibodies (intrabodies) are recombinant antibody fragments that bind to target proteins expressed inside of the same living cell producing the antibodies. The molecules are commonly used to study the function of the target proteins (i.e., their antigens). The intrabody technology is an attractive alternative to the generation of gene-targeted knockout animals, and complements knockdown techniques such as RNAi, miRNA and small molecule inhibitors, by-passing various limitations and disadvantages of these methods. The advantages of intrabodies include very high specificity for the target, the possibility to knock down several protein isoforms by one intrabody and targeting of specific splice variants or even post-translational modifications. Different types of intrabodies must be designed to target proteins at different locations, typically either in the cytoplasm, in the nucleus or in the endoplasmic reticulum (ER). Most straightforward is the use of intrabodies retained in the ER (ER intrabodies) to knock down the function of proteins passing the ER, which disturbs the function of members of the membrane or plasma proteomes. More effort is needed to functionally knock down cytoplasmic or nuclear proteins because in this case antibodies need to provide an inhibitory effect and must be able to fold in the reducing milieu of the cytoplasm. In this review, we present a broad overview of intrabody technology, as well as applications both of ER and cytoplasmic intrabodies, which have yielded valuable insights in the biology of many targets relevant for drug development, including α-synuclein, TAU, BCR-ABL, ErbB-2, EGFR, HIV gp120, CCR5, IL-2, IL-6, β-amyloid protein and p75NTR. Strategies for the generation of intrabodies and various designs of their applications are also reviewed.


Racial and Ethnic Disparities in Renal Cell Carcinoma: An Analysis of Clinical Characteristics.
Racial/ethnic minority groups, including Hispanic Americans (HAs) and Native Americans (NAs), have a heavier burden of kidney cancer than European Americans (EAs). We investigated variations in clinical characteristics of HA and NA patients with renal cell carcinoma (RCC) who were previously underrepresented. Clinical records of 294 patients with RCC (151 EAs, 95 HAs, 22 NAs, and 26 others) without prior diagnosis of cancer were reviewed. Logistic regression analysis was performed to understand patients' clinical characteristics. HAs had about 5 years younger average age at diagnosis than EAs (55.8 vs. 60.5 years) and an almost 3-fold increased odds of diagnosis before age 50 years (odds ratio [OR], 2.77; 95% confidence interval [CI], 1.39-5.54). The mean age of diagnosis among NAs was 49.7 years, and NAs had an over 6-fold higher odds of diagnosis at a younger age (OR, 6.23; 95% CI, 2.00-19.46). Clear-cell RCC (ccRCC) was more common in HAs and NAs than EAs. Over 90% of HA patients had ccRCC, whereas only 78.8% of EA patients had ccRCC. HAs had increased odds of diagnosis with ccRCC compared with EAs (OR, 2.79; 95% CI, 1.15-6.80). Among HAs, older patients and patients who spoke Spanish as their primary language were more likely to have advanced stage RCC at diagnosis (OR, 10.48; 95% CI, 1.69-64.89 and OR, 4.61; 95% CI, 1.38-15.40). HA and NA patients with RCC had different clinical characteristics than EA patients. It is necessary to better understand the clinical characteristics of these underserved HA and NA populations with high kidney cancer burden.


Ciglitazone negatively regulates CXCL1 signaling through MITF to suppress melanoma growth.
We have previously demonstrated that the thiazolidinedione ciglitazone inhibited, independently of PPARγ activation, melanoma cell growth. Further investigations now show that ciglitazone effects are mediated through the regulation of secreted factors. Q-PCR screening of several genes involved in melanoma biology reveals that ciglitazone inhibits expression of the CXCL1 chemokine gene. CXCL1 is overexpressed in melanoma and contributes to tumorigenicity. We show that ciglitazone induces a diminution of CXCL1 level in different human melanoma cell lines. This effect is mediated by the downregulation of microphthalmia-associated transcription factor, MITF, the master gene in melanocyte differentiation and involved in melanoma development. Further, recombinant CXCL1 protein is sufficient to abrogate thiazolidinedione effects such as apoptosis induction, whereas extinction of the CXCL1 pathway mimics phenotypic changes observed in response to ciglitazone. Finally, inhibition of human melanoma tumor development in nude mice treated with ciglitazone is associated with a strong decrease in MITF and CXCL1 levels. Our results show that anti-melanoma effects of thiazolidinediones involve an inhibition of the MITF/CXCL1 axis and highlight the key role of this specific pathway in melanoma malignancy.


Trends in lung cancer among young European women: the rising epidemic in France and Spain.
Lung cancer mortality in young women in the European Union (EU) has steadily increased until the mid 1990 s and has levelled off thereafter, but trends have been heterogeneous in various countries. We analyzed therefore age-standardized trends in lung cancer mortality in young women (20-44) for the 6 major European countries, using joinpoint regression. In the early 1970s the highest lung cancer mortality in young women was in the UK (2.1/100,000). UK rates, however, steadily declined and in 2000-2004 they were the lowest of all 6 major EU countries (1.2/100,000). The second lowest rate in 2000-2002 was in Italy, whose rates remained around 1.1/100,000 between 1970 and 1994, and increased to 1.4 thereafter. In Germany and Poland, lung cancer rates in young women rose from 0.8-1.0/100,000 in the early 1970s to 1.7-1.9 in the mid 1990 s and levelled off during the last decade. Major rises over recent years were observed in France (from 0.8/100,000 in 1985-1989 to 2.2 in 2000-2003) and in Spain (from 0.8 in the 1985-1989 to 1.7 in 2000-2004). Thus, France showed both the highest rate observed over the last 3 decades and the largest rise over the last 2 decades. Since recent trends in the young give relevant information to the likely future trends in middle age, the female lung cancer epidemic is likely to expand in southern Europe from the current rates of 5.0/100,000 in Spain and 7.7 in France to approach 20/100,000 within the next 2-3 decades. Urgent interventions for smoking cessation in women are therefore required.


Cranial postnatal growth of the rat relative to environmental variance.
Neurocranial growth during the first 40 days of postnatal development was biometrically investigated relative to the specific parameters of calvarium length and width; basioccipital length and width; basisphenoid length; biparietal width; frontal bone length and cranial vault length. Specimens were obtained from rat litters subject to moderate nutritional suppression by raising the litter numbers above the norm via the cross-fostering technique and causing the overtaxing of the lactational capacity. Alterations in growth rate occurred throughout the pre- and postweaning periods with clearly demarcated phases of growth. Male and female growth in the preweaning period was uniform within each litter type but the phasic growth changes in the experimental litters differed from the control litters with regression line breakage emerging at different points and altering the phasic lengths. The preweaning phasic spectrum in both control and experimental litters was evidently linked to the maternal lactation capacity--relative to quantity and duration. Weaning was insidious in both litter types but occurred earlier in the experimental litters although the continuity of growth was maintained up to the end of the definitive preweaning period (day 20). The definitive postweaning period (day 21-40) showed considerable heterogeneity--unsatisfactory scatter--with differing regression line breakage points and phasic lengths. Analysis based on the total period (day 1-40) brought compensatory adjustments and indicated more acceptable phasic patterns in the postweaning period with confirmation of catch-up growth in the experimental litters. Allometric analysis of the parameters revealed varying rates of growth, line breakage points and differing phasic lengths indicating that each neurocranial parameter and the skeletal unit forming it had an individual characteristic response spectrum mostly attributable to the functional matrix with emphasis on the capsular rather than the periosteal.


African Program for Onchocerciasis Control 1995-2010: Impact of Annual Ivermectin Mass Treatment on Off-Target Infectious Diseases.
Since its initiation in 1995, the African Program for Onchocerciasis Control (APOC) has had a substantial impact on the prevalence and burden of onchocerciasis through annual ivermectin mass treatment. Ivermectin is a broad-spectrum anti-parasitic agent that also has an impact on other co-endemic parasitic infections. In this study, we roughly assessed the additional impact of APOC activities on the burden of the most important off-target infections: soil-transmitted helminthiases (STH; ascariasis, trichuriasis, hookworm, and strongyloidiasis), lymphatic filariasis (LF), and scabies. Based on a literature review, we formulated assumptions about the impact of ivermectin treatment on the disease burden of these off-target infections. Using data on the number of ivermectin treatments in APOC regions and the latest estimates of the burden of disease, we then calculated the impact of APOC activities on off-target infections in terms of disability-adjusted life years (DALYs) averted. We conservatively estimated that between 1995 and 2010, annual ivermectin mass treatment has cumulatively averted about 500 thousand DALYs from co-endemic STH infections, LF, and scabies. This impact comprised approximately an additional 5.5% relative to the total burden averted from onchocerciasis (8.9 million DALYs) and indicates that the overall cost-effectiveness of APOC is even higher than previously reported.


Hospitalization Rates and Reasons Among HIV Elite Controllers and Persons With Medically Controlled HIV Infection.
Elite controllers spontaneously suppress human immunodeficiency virus (HIV) viremia but also demonstrate chronic inflammation that may increase risk of comorbid conditions. We compared hospitalization rates and causes among elite controllers to those of immunologically intact persons with medically controlled HIV. For adults in care at 11 sites from 2005 to 2011, person-years with CD4 T-cell counts ≥350 cells/mm(2) were categorized as medical control, elite control, low viremia, or high viremia. All-cause and diagnostic category-specific hospitalization rates were compared between groups using negative binomial regression. We identified 149 elite controllers (0.4%) among 34 354 persons in care. Unadjusted hospitalization rates among the medical control, elite control, low-viremia, and high-viremia groups were 10.5, 23.3, 12.6, and 16.9 per 100 person-years, respectively. After adjustment for demographic and clinical factors, elite control was associated with higher rates of all-cause (adjusted incidence rate ratio, 1.77 [95% confidence interval, 1.21-2.60]), cardiovascular (3.19 [1.50-6.79]) and psychiatric (3.98 [1.54-10.28]) hospitalization than was medical control. Non-AIDS-defining infections were the most common reason for admission overall (24.1% of hospitalizations) but were rare among elite controllers (2.7%), in whom cardiovascular hospitalizations were most common (31.1%). Elite controllers are hospitalized more frequently than persons with medically controlled HIV and cardiovascular hospitalizations are an important contributor.


Nose-to-brain transport of aerosolised quantum dots following acute exposure.
Nanoparticles are of wide interest due to their potential use for diverse commercial applications. Quantum dots (QDs) are semiconductor nanocrystals possessing unique optical and electrical properties. Although QDs are commonly made of cadmium, a metal known to have neurological effects, potential transport of QDs directly to the brain has not been assessed. This study evaluated whether QDs (CdSe/ZnS nanocrystals) could be transported from the olfactory tract to the brain via inhalation. Adult C57BL/6 mice were exposed to an aerosol of QDs for 1 h via nasal inhalation, and nanoparticles were detected 3 h post-exposure within the olfactory tract and olfactory bulb by a wide range of techniques, including visualisation via fluorescent and transmission electron microscopy. We conclude that, following short-term inhalation of solid QD nanoparticles, there is rapid olfactory uptake and axonal transport to the brain/olfactory bulb with observed activation of microglial cells, indicating a pro-inflammatory response. To our knowledge, this is the first study to clearly demonstrate that QDs can be rapidly transported from the nose to the brain by olfactory uptake via axonal transport following inhalation.


Age at diagnosis for lung, colon, breast and prostate cancers: An international comparative study.
Differences in the average age at cancer diagnosis are observed across countries. We therefore aimed to assess international variation in the median age at diagnosis of common cancers worldwide, after adjusting for differences in population age structure. We used IARC's Cancer Incidence in Five Continents (CI5) Volume XI database, comprising cancer diagnoses between 2008 and 2012 from population-based cancer registries in 65 countries. We calculated crude median ages at diagnosis for lung, colon, breast and prostate cancers in each country, then adjusted for population age differences using indirect standardization. We showed that median ages at diagnosis changed by up to 10 years after standardization, typically increasing in low- and middle-income countries (LMICs) and decreasing in high-income countries (HICs), given relatively younger and older populations, respectively. After standardization, the range of ages at diagnosis was 12 years for lung cancer (median age 61-Bulgaria vs 73-Bahrain), 12 years for colon cancer (60-the Islamic Republic of Iran vs 72-Peru), 10 years for female breast cancer (49-Algeria, the Islamic Republic of Iran, Republic of Korea vs 59-USA and others) and 10 years for prostate cancer (65-USA, Lithuania vs 75-Philippines). Compared to HICs, populations in LMICs were diagnosed with colon cancer at younger ages but with prostate cancer at older ages (both pLMICS-vs-HICs < 0.001). In countries with higher smoking prevalence, lung cancers were diagnosed at younger ages in both women and men (both pcorr < 0.001). Female breast cancer tended to be diagnosed at younger ages in East Asia, the Middle East and Africa. Our findings suggest that the differences in median ages at cancer diagnosis worldwide likely reflect population-level variation in risk factors and cancer control measures, including screening.


[Inferring Disease-miRNA Associations by Self-Weighting with Multiple Data Source].
Increasing evidence has suggested that microRNAs (miRNAs) may function as positive regulators at the post-transcriptional level. A search for associations between miRNAs and diseases is crucial for understanding the pathogenesis. Various publicly available databases have been constructed to store meaningful information on a large number of miRNA molecules. In this study, to resolve the limitation that individual sources of miRNA target data tend to be incomplete and noisy, we propose a network-based computational method called self-weighting for integrating multiple data sources. A bipartite phenotype-miRNA network (BPMN) incorporates known disease-miRNA interactions as well as the similarities between disease phenotypes and functional similarities of miRNAs. Random walk with restart algorithm was deployed on the bipartite network to predict novel disease-miRNA associations. In leave-one-out cross-validation experiments, our technique achieves an AUC of 0.801 when evaluating against known disease-related miRNAs from HMDD. Systematic prioritization of miRNAs for 11 common diseases obtained an average AUC of 0.765. Additionally, a case study on colon cancer uncovered a number of potential miRNA candidates as biomarkers of this disease.


Hypertension and insulin resistance: role of sympathetic nervous system activity.
The purpose of this study was to test the hypothesis that heightened sympathetic nervous system (SNS) activity contributes to the mechanism by which hypertension is associated with insulin resistance in humans. We performed frequently sampled intravenous glucose tolerance tests to determine tissue sensitivity to metabolic effects of insulin (SI) and measured plasma norepinephrine (NE) levels in 21 normotensive and 14 hypertensive Caucasian subjects. Compared with the normotensive subjects, hypertensive subjects had decreased SI (5.4 +/- 0.5 vs. 4.0 +/- 0.7 x 10(-5) x min-1 x pM-1; P = 0.03) but similar plasma NE levels (normotensive: 1.82 +/- 0.12 vs. hypertensive: 1.73 +/- 0.16 nM; P = 0.23). In a multiple regression model, only body mass index (BMI) and mean arterial blood pressure (MABP) were significant independent predictors of SI [SI = (-0.513)(BMI) + (-0.058)(MABP) + 23.6; r = 0.748; P = 0.0001]; age, plasma glucose, epinephrine, and NE level did not enter this model. As an additional test of this hypothesis, seven hypertensive subjects were restudied after 10 days of guanadrel therapy to determine whether SI would increase during suppression of SNS activity by guanadrel. Despite a significant reduction in plasma NE levels with guanadrel (baseline: 1.63 +/- 0.18 vs. guanadrel: 0.99 +/- 0.14 nM; P = 0.01), there was no significant change in SI (baseline: 2.97 +/- 0.78 vs. guanadrel: 2.41 +/- 0.54 x 10(-5).min-1 x pM-1; analysis of variance P = 0.57). We conclude that, in the Caucasian population we studied, heightened SNS activity is not essential for the insulin resistance observed in hypertensive humans.


Eccentric Exercise Reduces Upper Trapezius Muscle Stiffness Assessed by Shear Wave Elastography and Myotonometry.
In this study, we tested the hypotheses that unaccustomed eccentric exercise (ECC) would reduce the elastic modulus and dynamic stiffness of the upper trapezius muscle and that these changes would correlate with increases in muscle thickness, reflecting muscle edema. Shear wave elastography was used to measure elastic modulus, dynamic stiffness was assessed using myotonometry, and muscle thickness was measured using ultrasonography. All measurements were performed at four locations over the upper trapezius before and 24 h after a single bout of ECC. Fourteen healthy participants (11 males and 3 females; 23.2 ± 3.0 years; height 175.1 ± 10.4 cm; body mass 73.8 ± 11.3 kg) took part in the study. Overall, ECC resulted in decreased elastic modulus (from 45.8 ± 1.6 to 39.4 ± 1.2 kPa, p < 0.01) and dynamic muscle stiffness (from 369.0 ± 7.3 to 302.6 ± 6.0 N/m, p < 0.01). Additionally, ECC resulted in increased muscle thickness (from 6.9 ± 0.4 to 7.3 ± 0.4 mm, p < 0.01). Spatial changes (across the four locations) were found for elastic modulus, stiffness and thickness. No significant correlations were found between changes in measures of muscle stiffness, or between changes in stiffness and changes in thickness. In conclusion, the present pilot study showed that ECC altered biomechanical muscle properties, reflected by decreased elastic modulus and dynamic muscle stiffness 24 h after ECC.


[TNF-α Decreased Corticosteroid Responsiveness in Mice Models of Airway Inflammation Induced by Double Strand RNA and/or Tobacco Smoke Exposure].
Reduction of corticosteroid responsiveness is one of the important clinical problems in chronic obstructive pulmonary disease (COPD). In this study, we determined the effects of neutralization of tumor necrosis factor-α (TNF-α) on corticosteroid insensitivity in mice models of airway inflammation induced by poly(I:C) and tobacco smoke (TS) exposure. Mice (male A/J strain, 5 weeks old) were exposed to TS for 10 d, or TS for 11 d and poly(I:C) for 3 d. Anti-TNF-α antibody was intranasally treated once every other day 2 h before the TS exposure, and dexamethasone 21-phosphate (DEX) was treated 30 min before the TS or poly(I:C) exposure. On the next day of the last stimulation, mice were sacrificed. The combination treatment of DEX and TNF-α neutralization was significantly attenuated the increase of the numbers of inflammatory cells in BALF and the TNF-α mRNA expression levels induced by TS and poly(I:C) exposure, even though TNF-α neutralization alone had little effect. These data indicated that neutralization of TNF-α restores corticosteroid responsiveness. Therefore, our study suggests that targeting TNF-α signaling pathway provides a new therapeutic approach to corticosteroid refractory airway diseases.


Neuropsychologic effects of long-term exposure to pesticides: results from the French Phytoner study.
The Phytoner study investigated a possible association between neuropsychologic performances and long-term exposure to pesticides in Bordeaux vineyard workers, most of whom use fungicides. Among the 917 subjects interviewed from February 1997 to August 1998, 528 were directly exposed to pesticides through mixing and/or spraying (mean exposure duration: 22 years), 173 were indirectly exposed through contact with treated plants, and 216 were never exposed. All subjects performed neuropsychologic tests administered at home by trained psychologists. The risk of scoring a low performance on the tests was constantly higher in exposed subjects. When taking into account educational level, age, sex, alcohol consumption, smoking, environmental exposures, and depressive symptoms and when restricting analysis to subgroups, results remained significant for most tests, with odds ratios (OR) exceeding 2. These results point to long-term cognitive effects of low-level exposure to pesticides in occupational conditions. Given the frequency of pesticide use and the potential disabilities resulting from cognitive impairments, further toxicologic and epidemiologic research is needed to confirm these results and assess the impact on public health.


Clinical epidemiology of cardiovascular disease in chronic kidney disease.
The public health importance of chronic kidney disease (CKD) has only come to be appreciated in the last decade. While glomerular filtration rate (GFR) and urinary albumin creatinine levels are highly predictive of mortality, thresholds that may be useful for screening may be much closer to 'normal' than generally recognised. When optimising the balance between true negative and true positive mortality prediction, GFR from creatinine and GFR from cystatin C and albumin creatinine ratios all seem to perform similarly. Among the older population, mortality rates with creatinine-based GFR are lowest for those with levels between 60 and 90 ml/min/1.73 m(2), unlike with GFR from cystatin C, where mortality rates climb monotonically with declining GFR. Thus, the validity of creatinine-based GFR in older community-dwelling individuals is questionable. Nationally, representative data suggest management of modifiable cardiovascular risk factors in adults with CKD is far from optimal. This paper explores the possibility that robust associations between declining kidney function and cardiovascular outcomes could be caused by an unknown, confounding, shared-risk factors and extrapolates findings from renal transplant donor populations to support this hypothesis.


The emergence and perils of polarization.
We provide commentaries on the papers included in the Dynamics of Political Polarization Special Feature. Baldassarri reads the contribution of the papers in light of the theoretical distinction between ideological partisanship, which is generally rooted in sociodemographic and political cleavages, and affective partisanship, which is, instead, mostly fueled by emotional attachment and repulsion, rather than ideology and material interests. The latter, she argues, is likely to lead to a runaway process and threaten the pluralistic bases of contemporary democracy. Page sees the contribution of the many distinct models in the ensemble as potentially contributing more than the parts. Individual papers identify distinct causes of polarization as well as potential solutions. Viewed collectively, the papers suggest that the multiple causes of polarization may self-reinforce, which suggests that successful interventions would require a variety of efforts. Understanding how to construct such interventions may require larger models with greater realism.


Development of Urdu version of Chronic Respiratory Disease Questionnaire Self-Administered Standardized (CRQ-SAS); validity and reliability analysis in COPD patients.
Chronic Respiratory Disease Questionnaire Self-Administered Standardized (CRQ-SAS) is a valid and reliable tool that evaluates the health-related quality of life among the adult population affected with chronic respiratory disorders (CRDs) and has been translated into many languages as per need. The main objective of this study was to translate the CRQ-SAS into the Urdu language and evaluate its psychometric properties. It was a two-staged study that consisted of translating the original version into Urdu language and then psychometric testing of the translated version. The reliability of the translated questionnaire was assessed by measuring its internal consistency, test-retest reliability, standard error of mean (SEM) & minimal detectable change (MDC). Validity was determined by evaluating its content for content validity, construct (convergent and discriminative) validity, and exploratory factor analysis. Data was analyzed using SPSS v 28 with an alpha level < 0.05 considered to be significant. CRQ-SAS U had an excellent internal consistency (Cronbach's Alpha α = 0.89), test-retest reliability (ICC2,1) = 0.91 of all items, and low SEM = 0.11 and MDC = 0.65. S-CVI was 0.9, with statistically significant difference across the response of COPD patients and healthy subjects, and a high degree of correlation with St Georges Respiratory Questionnaire (r = 0.7-0.9) proving CRQ-SAS U content, discriminant and convergent valid respectively. Exploratory factor analysis identified two factors responsible for 80% of the variance. CRQ-SAS U demonstrated optimal psychometric properties which renders it to be used in Urdu speaking populations with COPD.


Multidisciplinary approach to osteosarcoma.
Osteosarcoma is a malignant bone tumor composed of mesenchymal cells producing osteoid and immature bone. Osteosarcoma is the most frequent primary malignant bone tumor, if we excluded myeloma, a haematologic disease. The incidence of osteosarcoma is 2-3/million/year, but is higher in adolescence, in which the annual incidence peaks at 8-11/million/year at 15-19 years of age. Local pain, followed by localized swelling and limitation of joint movement, are the typical signs and symptoms. Correct diagnosis can be achieved through a correct approach to the disease and the combination of clinical and radiographic aspects. The final step to confirm the diagnosis is the biopsy. Computer Tomography of the chest and Positron-Emission Tomography are mandatory to complete the staging, which is performed according the Musculoskeletal Tumor Society staging system. A multidisciplinary approach is needed both to get to a correct diagnosis (orthopaedic surgeon, radiologist and histopathologist) and to perform definitive treatment. Multidisciplinary approach should be performed in reference centers able to provide access to the full spectrum of care and where orthopaedic surgeon, oncologist, histopathologist, radiologist and radiotherapist can cooperate. The management of osteosarcoma is based primarily on neo-adjuvant and adjuvant chemotherapy and surgical resection; radiotherapy is not effective as osteosarcomas are relatively radioresistant. Prognostic factors include metastases at presentation, histologic response to induction chemotherapy, the site of the primary tumor (with axial lesions having an inferior outcome), serum lactate dehydrogenase and alkaline phosphatase levels.


Recognition, investigation and management of mitochondrial disease.
Mitochondria are dynamic organelles present in virtually all human cells that are needed for a multitude of cellular functions, including energy production, control of cell apoptosis and numerous biochemical catabolic and synthetic pathways that are critical for cellular health. Primary mitochondrial disorders are a group of greater than 200 single gene defects arising from two genomes (nuclear and mitochondrial) leading to mitochondrial dysfunction, and are associated with extremely heterogeneous phenotypes. Neuromuscular features predominate, but often with multisystem involvement. Clinical suspicion of a mitochondrial disorder should prompt multipronged investigation with biochemical and molecular genetic studies. Recent wide-scale adoption of next-generation sequencing approaches has led to a rapid increase in the number of disease genes. The advances in unravelling the genetic landscape of mitochondrial diseases have not yet been matched by progress in developing effective therapies, and the mainstay of care remains supportive therapies in a multidisciplinary team setting.


Identification of nasal morphologic features that indicate susceptibility to nasal tip deflection with the LeFort I osteotomy.
The goal of this investigation was to identify and quantify nasal morphologic features which predispose to the nasal tip deflection associated with the LeFort I osteotomy. Fifty patients who had undergone LeFort I osteotomies were studied retrospectively from presurgical and postsurgical cephalograms and facial photographs. The magnitude of hard tissue change was measured in the vertical and horizontal planes, and soft tissue nasal change was measured in the vertical plane at two points on the outline of the soft tissue nose. Additional parameters were tested as potential predictors of nasal tip deflection, including the Deflection Resistance Index (DRI), which is a quantitative measure of nasal morphologic features. Data were subjected to a hierarchical multiple regression analysis allowing for multivariate prediction capability. At the supra nasal tip (SNt), magnitude of advancement, magnitude of impaction, and the DRI were all significant predictors (multiple R = 0.86). At the anterior nasal tip (ANt), magnitude of advancement, preoperative columellar angle, magnitude of impaction, the DRI, the interactions of advancement and DRI, and columellar angle and DRI were the significant predictors (multiple R = 0.89). It is concluded that the vertical deflection of the nasal tip resulting from the LeFort I osteotomy is influenced not only by the hard tissue movements but also by nasal structure. The DRI is a quantitative measure that can be used clinically to improve the predictability of vertical nasal tip deflection.


Novel spinal pathways identified by neuronal c-Fos expression after urethrogenital reflex activation in female guinea pigs.
Pudendal nerve-spinal pathways are involved in urethrogenital sensation, pain and sexual activity. However, details of these pathways and their modulation are unclear. We examined spinal pathways activated by the urethrogenital reflex (UGR) and visualized by c-Fos immunoreactivity in reflexly activated neurons within spinal cord. In anesthetized female guinea pigs, a balloon was inserted into the urethra and inflated with short-repeat or long-continuous distension to activate the UGR. A second balloon recorded reflex contractions of the vagina and uterus. Two control groups had either no balloon or a vaginal balloon (VB) only. Ninety minutes after UGR activation, c-Fos immunoreactivity in L3 and S2 spinal segments was examined. Reflex activated c-Fos immunoreactivity also was investigated in some animals with acute spinal transections at either L4 or T12 levels. There was no significant difference in spinal c-Fos expression between the control groups. Short-repeat distension reliably induced a UGR and a two- to threefold increase in c-Fos-expressing neurons throughout dorsal, intermediate and lateral spinal gray matter at S2 and about twofold increase in superficial dorsal horn at L3. T12 transection had little effect on c-Fos expression at either spinal level. However, after L4 transection, UGR generation was associated with a four- to sixfold increase in c-Fos-expressing neurons in lateral horn (LH) and central canal areas at S2, and but only 20-30% increase at L3. Thus, UGR activates preganglionic neurons projecting to pelvic viscera in both sacral and lumbar spinal cord. The reflex also must activate ascending and descending spinal inhibitory circuits that suppress c-Fos-expression in neurons at both sacral and lumbar spinal levels.


Elucidating the substrate specificities of acyl-lipid thioesterases from diverse plant taxa.
Acyl-ACP thioesterase enzymes, which cleave fatty acyl thioester bonds to release free fatty acids, contribute to much of the fatty acid diversity in plants. In Arabidopsis thaliana, a family of four single hot-dog fold domain, plastid-localized acyl-lipid thioesterases (AtALT1-4) generate medium-chain (C6-C14) fatty and β-keto fatty acids as secondary metabolites. These volatile products may serve to attract insect pollinators or deter predatory insects. Homologs of AtALT1-4 are present in all plant taxa, but are nearly all uncharacterized. Despite high sequence identity, AtALT1-4 generate different lipid products, suggesting that ALT homologs in other plants also have highly varied activities. We investigated the catalytic diversity of ALT-like thioesterases by screening the substrate specificities of 15 ALT homologs from monocots, eudicots, a lycophyte, a green microalga, and the ancient gymnosperm Gingko biloba, via expression in Escherichia coli. Overall, these enzymes had highly varied substrate preferences compared to one another and to AtALT1-4, and could be classified into four catalytic groups comprising members from diverse taxa. Group 1 ALTs primarily generated 14:1 β-keto fatty acids, Group 2 ALTs produced 6-10 carbon fatty/β-keto fatty acids, Group 3 ALTs predominantly produced 12-14 carbon fatty acids, and Group 4 ALTs mainly generated 16 carbon fatty acids. Enzymes in each group differed significantly in the quantities of lipids and types of minor products they generated in E. coli. Medium-chain fatty acids are used to manufacture insecticides, pharmaceuticals, and biofuels, and ALT-like proteins are ideal candidates for metabolic engineering to produce specific fatty acids in significant quantities.


High-throughput sorting of drops in microfluidic chips using electric capacitance.
We analyze a recently introduced approach for the sorting of aqueous drops with biological content immersed in oil, using a microfluidic chip that combines the functionality of electrowetting with the high throughput of two-phase flow microfluidics. In this electrostatic sorter, three co-planar electrodes covered by a thin dielectric layer are placed directly below the fluidic channel. Switching the potential of the central electrode creates an electrical guide that leads the drop to the desired outlet. The generated force, which deflects the drop, can be tuned via the voltage. The working principle is based on a contrast in conductivity between the drop and the continuous phase, which ensures successful operation even for drops of highly conductive biological media like phosphate buffered saline. Moreover, since the electric field does not penetrate the drop, its content is protected from electrical currents and Joule heating. A simple capacitive model allows quantitative prediction of the electrostatic forces exerted on drops. The maximum achievable sorting rate is determined by a competition between electrostatic and hydrodynamic forces. Sorting speeds up to 1200 per second are demonstrated for conductive drops of 160 pl in low viscosity oil.


Improved sensitivity of T-cell clonality detection in mycosis fungoides by hand microdissection and heteroduplex analysis.
The presence of a dominant T-cell clone is an important diagnostic criterion in cutaneous T-cell lymphomas (CTCLs) and in atypical T-cell cutaneous infiltrates. Procedures based on polymerase chain reaction (PCR) are the most sensitive to detect clonality, but heteroduplex analysis is less sensitive than other methods such as denaturing gradient gel electrophoresis. To assess whether a gross hand microdissection of the superficial (papillary) portion of the dermal infiltrate may improve the sensitivity of T-cell clonality detection by PCR-heteroduplex analysis in CTCL. Regional university hospital (secondary or tertiary referral center). Patients A total of 29 patients with a definite diagnosis of mycosis fungoides based on typical histologic and immunophenotypic features were selected with patch (16) or plaque (13) stages. Assessment of T-cell clonality by PCR amplification of the T-cell receptor gamma chain followed by heteroduplex analysis using DNA extracted from the entire biopsy specimen and after gross microdissection of the subepidermal bandlike dermal infiltrate. T-cell clonality was demonstrated in 24 of 29 cases when hand microdissection was used compared with 16 of 29 cases with DNA analysis from entire biopsy specimens; thus, hand microdissection resulted in a sensitivity improvement of approximatively 50%. Hand microdissection substantially improves the detection of a T-cell clone in CTCL when using a PCR-heteroduplex analysis and could be used routinely in the clinical evaluation of T-cell infiltrates. Importantly, the microdissection method was found to be more useful for the detection of T-cell clones in early patch stages of CTCL than in plaque-stage disease.


Effects of L-thyroxine in rats with chronic heart failure after myocardial infarction.
The effects of thyroid hormone on left ventricular (LV) function and myosin isoenzyme distribution were evaluated in rats 3 wk after myocardial infarction. When compared with normal rats, animals selected for study had moderately severe LV dysfunction as judged by decreased aortic and LV systolic pressures and a 34% decrease in LV maximum rate of pressure development (dP/dt). Average LV end-diastolic pressure was increased to 26 +/- 1 mmHg from 5 +/- 1 mmHg. The infarcted rats were divided into saline-treated control (n = 10) and treatment (n = 13) groups. The latter group received thyroxine (T4, 1.5 micrograms/100 g body wt) immediately after the first determination of pressures and at 24 and 48 h. At 72 h, aortic and LV pressures and myosin isoenzyme composition were measured. In the thyroxine-treated group LV end-diastolic pressure decreased from 27 +/- 2 to 18 +/- 2 mmHg, and LV dP/dt increased from 5,627 +/- 249 to 6,064 +/- 355 mmHg/s. Heart rate and aortic pressure did not change. After saline injections, LV end-diastolic pressure remained elevated, and the other hemodynamic parameters were unchanged. Determination of ventricular myosin isoenzyme composition in the saline-treated group revealed an increase in the V3 myosin isoform and a decrease in the V1 isoform as compared with the normal values. This pattern was not altered by T4 treatment. A separate group (n = 7) of rats was treated with a 10 times larger dose of thyroxine (15 micrograms/100 g body wt) for the same period of time. In this group, there was neither hemodynamic improvement nor changes in myosin isoenzyme distribution.(ABSTRACT TRUNCATED AT 250 WORDS)


Development of telemetric techniques for use in studies of the electrical activity of the brain.
A telemetry system has been designed to transmit two channels of wideband activity (0.2 Hz-2.5 KHz) recorded from high-impedance microelectrodes in the brains of free-moving cats. Thus, both unit activity and slow-wave field activity are accessible without disruption of the animals' behavior. In addition, circuitry is described that conditions the receiver signals, that dicriminates valid subcarrier signals from receiver noise and that automatically aborts data output in the absence of discriminable subcarrier. This receiver signal processing circuitry thus assures the fidelity of the decoded subcarrier, greatly facilitates further machine processing of the data and frees the experimenter from having to continuously monitor the receiver signals to subjectively edit out noisy data.


Isolation and characterization of the tricarboxylate transporter from pea mitochondria.
The tricarboxylate transporter was solubilized from pea (Pisum sativum) mitochondria with Triton X-114, partially purified over a hydroxylapatite column, and reconstituted in phospholipid vesicles. The proteoliposomes exchanged external [(14)C]citrate for internal citrate or malate but not for preloaded d,l-isocitrate. Similarly, although external malate, succinate, and citrate competed with [(14)C]citrate in the exchange reaction, d,l-isocitrate and phosphoenolpyruvate did not. This tricarboxylate transporter differed from the equivalent activity from animal tissues in that it did not transport isocitrate and phosphoenolpyruvate. In addition, tricarboxylate transport in isolated plant mitochondria, as well as that measured with the partially purified and reconstituted transporter, was less active than the transporter isolated from animal tissues.


Inverse Design of Ultralow Lattice Thermal Conductivity Materials via Materials Database Screening of Lone Pair Cation Coordination Environment.
The presence of lone pair (LP) electrons is strongly associated with the disruption of lattice heat transport, which is a critical component of strategies to achieve efficient thermoelectric energy conversion. By exploiting an empirical relationship between lattice thermal conductivity, κL, and the bond angles of pnictogen group LP cation coordination environments, we develop an inverse design strategy based on a materials database screening to identify chalcogenide materials with ultralow κL for thermoelectrics. Screening the ∼635 000 real and hypothetical inorganic crystals of the Open Quantum Materials Database based on the constituent elements, nominal electron counting, LP cation coordination environment, and synthesizability, we identify 189 compounds expected to exhibit ultralow κL. As a validation, we explicitly compute the lattice dynamical properties of two of the compounds (Cu2AgBiPbS4 and MnTl2As2S5) using first-principles calculations and successfully find both achieve ultralow κL values at room temperature of ∼0.3-0.4 W/(m·K) corresponding to the amorphous limit. Our data-driven approach provides promising candidates for thermoelectric materials and opens new avenues for the design of phononic properties of materials.


Transitioning to Remote Clinic Visits in a Smoking Cessation Trial During the COVID-19 Pandemic: Mixed Methods Evaluation.
The pandemic of SARS-CoV-2, which causes COVID-19, has caused disruptions in ongoing clinical trials and is expected to accelerate interest in conducting research studies remotely. A quasi-experimental, mixed methods approach was used to examine the rates of visit completion as well as the opinions and experiences of participants enrolled in an ongoing clinical trial of smoking cessation who were required to change from in-person clinic visits to remote visits using video or telephone conferencing due to the COVID-19 pandemic. For quantitative comparisons, we used a quasi-experimental design, comparing a cohort of participants followed during the pandemic (n=23, COVID-19 cohort) to a comparable cohort of participants followed over a similar time period in the calendar years 2018 and 2019 (n=51, pre-COVID-19 cohort) to examine the rates of completion of scheduled visits and biospecimen collection. For the qualitative component, interviews were conducted with participants who experienced the transition from in-person to remote visits. Participants in the COVID-19 cohort completed an average of 83.6% of remote clinic visits (95% CI 73.1%-91.2%), which was not significantly different than the in-person completion rate of 89.8% in the pre-COVID-19 cohort. Participants in the COVID-19 cohort returned an average of 93.2% (95% CI 83.5%-98.1%) of saliva specimens for remote clinic visits completed, which was not significantly different than the in-person saliva specimen completion rate of 100% in the pre-COVID-19 cohort. Two broad themes emerged from the qualitative data: (1) the benefits of remote visits and (2) the challenges of remote counseling compared to in-person counseling. Despite limited experience with telehealth prior to this transition, most participants expressed a willingness to engage in remote visits in the future. Even in the context of a rapid transition from in-person to remote visits necessitated by the COVID-19 pandemic, rates of visit completion and return of biospecimens remained high. Participants were generally accepting of the transition. Further research is needed to identify the optimal mix of in-person and remote visits beyond the pandemic context and to better understand how these changes may impact study outcomes. ClinicalTrials.gov NCT03262662; https://clinicaltrials.gov/ct2/show/study/NCT03262662.


NHL in adolescents and young adults: A unique population.
Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies with high incidence in adolescents and young adults (AYAs). The most common diseases include diffuse large B-cell lymphoma, anaplastic large cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, and primary mediastinal large B-cell lymphoma. In comparison to younger children and adults, AYAs (15-39 years) with NHL present a specific set of challenges including variations in tumor biology, inconsistent treatment, pharmacodynamics, and psychosocial barriers. While survival of AYAs with NHL has improved, cure rates remain suboptimal. Incorporation of novel agents into pediatric-inspired treatment regimens specifically designed for NHL in AYAs has led to improved outcomes. Consideration of AYAs as a distinct population in the diagnosis and treatment of NHL is encouraged.


Clinical Performance and Concurrent Validity of the Adult Spinal Deformity Surgical Decision-making Score.
Multicenter, retrospective study. The aim of this study was to examine the performance and concurrent validity of the adult spinal deformity surgical decision-making (ASD-SDM) score compared to decision-making factors in the ASD population. The ASD-SDM score, which has been recently proposed, is a scoring system to guide the selection of treatment modality for the ASD population. To secure the justification for its clinical use, it is necessary to verify its clinical performance and concurrent validity. A multicenter prospective ASD database was retrospectively reviewed. The data were analyzed separately in younger (≤40 years) and older (≥41 years) age groups. The discriminating capacity of the ASD-SDM score in cases who selected surgical and nonsurgical management was compared using area under the receiver operator characteristic curves (AUROC). Concurrent validity was examined using Spearman correlation coefficients, comparing factors that are reported to be associated with the decision-making process for ASD, including baseline symptomatology, health-related quality of life measures, and the severity of radiographic spinal deformity. There were 338 patients (mean age: 26.6 years; 80.8% female; 129 surgical and 209 nonsurgical) in the younger age group and 750 patients (mean age: 63.5 years; 84.3% female; 410 surgical and 340 nonsurgical) in the older age group. In both younger and older patients, the ASD-SDM score showed a significantly higher performance for discriminating the surgical and nonsurgical cases (AUROC: 0.767, standard error [SE]: 0.026, P < 0.001, 95% confidence interval [CI]: 0.712-0.813; AUROC: 0.781, SE: 0.017, P < 0.001, 95% CI: 0.747-0.812, respectively) compared to the decision-making factors analyzed. In addition, the ASD-SDM showed significant correlations with multiple decision-making factors. The ASD-SDM score alone can effectively grade the indication for surgical management whilst considering multiple decision-making factors. 3.


[Investigation on strains of Legionella pneumophila, isolated from a hospital of Milano, with three genotyping methods].
Various techniques have been developed in recent years for the molecular typing of microorganisms. Remains particularly difficult to isolate clinical strains for the low availability of cases and even more problematic matching clinical / environmental strains. We investigated 13 strains of Legionella pneumophila of clinical and environmental origin, isolated in 3 Health Facilities in Milan (2003-2006), using three molecular typing methods: Pulse-Field Gel Electrophoresis, Amplified Fragment Length Polymorphism and Sequence-Based Typing. PFGE and AFLP showed the correlation between a clinical case with only one of the environmental isolates taken from the places frequented by the patient, demonstrating with certainty the nosocomial origin of the case and identifying the source of infection in the shower water (Clin. 1 and Env. 1N). Two clinical samples from patients admitted to different wards presented an identical profile, which suggests that the nosocomial origin assumed an epidemic form, even without having isolated the environmental strain due to the absence of samples drawn during the period under consideration (Clin. 2 and 3). Finally, the comparison between the isolated environmental strains demonstrated a heterogeneous presence of strains, not correlated to each other although they belong to the same serum-group, having profiles that are clearly different regarding number and position of bands (Env. 2 and 4). The profile 2,10,18,10,1,1 had never been isolated and typed previously in Europe. The SBT has proved a better technique for reproducibility and interpretation of results than PFGE and AFLP To complete studies on SBT method, now considered gold standard, is currently being the EWGLI 5th Proficiency Panel, in which we are actively involved with the genotyping of five strains according to the latest version of the protocol (4.1).


Colour helps to solve the binocular matching problem.
The spatial differences between the two retinal images, called binocular disparities, can be used to recover the three-dimensional (3D) aspects of a scene. The computation of disparity depends upon the correct identification of corresponding features in the two images. Understanding what image features are used by the brain to solve this binocular matching problem is an important issue in research on stereoscopic vision. The role of colour in binocular vision is controversial and it has been argued that colour is ineffective in achieving binocular vision. In the current experiment subjects were required to indicate the amount of perceived depth. The stimulus consisted of an array of fronto-parallel bars uniformly distributed in a constant sized volume. We studied the perceived depth in those 3D stimuli by manipulating both colour (monochrome, trichrome) and luminance (congruent, incongruent). Our results demonstrate that the amount of perceived depth was influenced by colour, indicating that the visual system uses colour to achieve binocular matching. Physiological data have revealed cortical cells in macaque V2 that are tuned both to binocular disparity and to colour. We suggest that one of the functional roles of these cells may be to help solve the binocular matching problem.


AARON: An Automated Reaction Optimizer for New Catalysts.
We describe an open-source computational toolkit (AARON: An Automated Reaction Optimizer for New catalysts) that automates the quantum mechanical geometry optimization and characterization of the transition state and intermediate structures required to predict the activities and selectivities of asymmetric catalytic reactions. Modern computational quantum chemistry has emerged as a powerful tool for explaining the selectivity and activity of asymmetric catalysts. However, reliably predicting the stereochemical outcome of realistic reactions often requires the geometry optimization of hundreds of transition state and intermediate structures, which is a tedious process. AARON automates these optimizations through an interface with a popular electronic structure package, accelerating quantum chemical workflows to enable the computational screening of potential catalysts. AARON is built using a collection of object-oriented Perl modules (AaronTools) that provide functionality to build and modify molecular and supramolecular structures. The main functionalities of AaronTools are also available as stand-alone command-line scripts. The core features of AaronTools and AARON are explained, and representative applications of AARON to both organocatalyzed and transition-metal-catalyzed reactions are presented.


Posterior single-stepping thresholds are prospectively related to falls in older women.
Falls are a leading cause of injury in older women. Stepping thresholds quantify balance-reaction capabilities. It is unclear how such evaluations predict falls in comparison to, or as a complement to, other objective measures of gait, standing postural control, strength, and balance confidence. The objective of this study was to determine if stepping thresholds are prospectively related to falls in older women. For this prospective cohort study, 125 ambulatory, community-dwelling women, age ≥ 65 years were recruited. Using a treadmill to deliver perturbations to standing participants, we determined anteroposterior single- and multiple-stepping thresholds. Here, thresholds represent the minimum perturbation magnitudes that consistently evoke one step or multiple steps. In addition, gait kinematics, obstacle-crossing kinematics, standing sway measures, unipedal stance time, the functional reach, lower extremity isometric strength, grip strength, balance confidence, and fall history were evaluated. Falls were prospectively recorded for one year. Seventy-four participants (59%) fell at least once. Posterior single-stepping thresholds were the only outcome that predicted future fall status (OR = 1.50, 95% CI 1.01-2.28; AUC = .62). A multivariate approach added postural sway with eyes closed as a second predictive variable, although predictive abilities were not meaningfully improved. These results align with the previous evidence that reactive balance is a prospective indicator of fall risk. Unlike previous studies, strength scaled to body size did not contribute to fall prediction. Posterior single-stepping thresholds held a significant relationship with future fall status. This relationship was independent of, and superior to that of, other measures of standing balance, gait, strength, and balance confidence.


Effects of Deficits in the Neuromuscular and Mechanical Properties of the Quadriceps and Hamstrings on Single-Leg Hop Performance and Dynamic Knee Stability in Patients After Anterior Cruciate Ligament Reconstruction.
Understanding the role of neuromuscular and mechanical muscle properties in knee functional performance and dynamic knee stability after anterior cruciate ligament reconstruction (ACLR) may help in the development of more focused rehabilitation programs. To compare the involved and uninvolved limbs of patients after ACLR in terms of muscle strength, passive muscle stiffness, muscle activation of the quadriceps and hamstrings, hop performance, and dynamic knee stability and to investigate the association of neuromuscular and mechanical muscle properties with hop performance and dynamic knee stability. Cross-sectional study; Level of evidence, 3. The authors studied the quadriceps and hamstring muscles in 30 male patients (mean ± SD age, 25.4 ± 4.1 years) who had undergone unilateral ACLR. Muscle strength was measured using isokinetic testing at 60 and 180 deg/s. Passive muscle stiffness was quantified using ultrasound shear wave elastography. Muscle activation was evaluated via electromyographic (EMG) activity. Hop performance was evaluated via a single-leg hop test, and dynamic knee stability was evaluated via 3-dimensional knee movements during the landing phase of the hop test. Compared with the uninvolved limb, the involved limb exhibited decreased peak torque and shear modulus in both the quadriceps and hamstrings as well as delayed activity onset in the quadriceps (P < .05 for all). The involved limb also exhibited a shorter hop distance and decreased peak knee flexion angle during landing (P < .05 for both). Decreased peak quadriceps torque at 180 deg/s, the shear modulus of the semitendinosus, and the reactive EMG activity amplitude of the semimembranosus were all associated with shorter hop distance (R 2 = 0.565; P < .001). Decreased quadriceps peak torque at 60 deg/s and shear modulus of the vastus medialis were both associated with smaller peak knee flexion angle (R 2 = 0.319; P < .001). In addition to muscle strength deficits, deficits in passive muscle stiffness and muscle activation of the quadriceps and hamstrings were important contributors to poor single-leg hop performance and dynamic knee stability during landing. Further investigations should include a rehabilitation program that normalizes muscle stiffness and activation patterns during landing, thus improving knee functional performance and dynamic knee stability.


Role of CMV in transplant coronary artery disease and survival after heart transplantation.
The development of arteriosclerosis after heart transplantation plays a major role in decreased graft and patient survival. Although several pathogenic mechanisms have been proposed for the development of posttransplant coronary artery disease (CAD), a significant amount of accumulating evidence suggests that cytomegalovirus is a critical factor in this disease. Because post-transplant CAD is often a silent disease and early detection escapes conventional angiography, physicians must maintain close surveillance of heart transplant patients and institute prophylaxis in high-risk groups. In addition to targeting conventional risk factors, prophylaxis against CMV disease should decrease the incidence of the disease.


Fear of Recurrence as a Predictor of Care Needs for Long-Term Breast Cancer Survivors.
The improved survival rate for breast cancer has increased the number of women living with the diagnosis for more than 5 years. Limited studies have focused on the care needs for long-term healthy survivors of breast cancer. The aims of this study were to understand the care needs of long-term breast cancer survivors and identify related factors that influence these needs. A convenience sampling with a correlational study design was used. Women at least 20 years old, who were given a diagnosis of breast cancer at least 5 years, were recruited from 2 hospital clinics in southern Taiwan. A self-administered questionnaire measuring cancer survivors' unmet needs was administered after obtaining informed consent. Binary logistic regression was used to examine variables associated with unmet care needs. Of the 192 women participating, the highest unmet needs related to existential survivorship. The most frequently endorsed unmet need was for an ongoing case manager. Fear of recurrence was associated with 3 aspects including existential survivorship, comprehensive cancer, and quality-of-life unmet needs (odds ratio, 1.14-1.21). Even 5 years after the diagnosis and completion of therapy, women continue to report unmet needs. Evaluating women's fear of recurrence to identify high-risk women with unmet needs is critical to providing quality care. Developing appropriate survivorship care programs combined with managing concerns regarding recurrence by a nursing case manager is needed.


Immunoelectron microscopy study of superficial skin nerves in drug-induced acute urticaria.
Few studies have evaluated the ultrastructure of the superficial skin nerves in urticaria. The objective of this study was to describe findings in superficial skin nerves in cases of drug-induced acute urticaria. Seven patients with drug-induced acute urticaria were included in the study. Skin biopsies were obtained from the urticarial lesion and from the apparently normal skin. The 14 fragments collected were processed for immunogold electron microscopy using single stains for antitryptase and anti-FXIIIa antibodies, as well as double immunogold labeling for both. Some sections showed mast cells in the process of degranulation. Following double immunogold staining, 10 nm (FXIIIa) and 15 nm (Tryptase) gold particles were found together throughout the granules in mast cells, indicating that tryptase and FXIIIa are located inside each one of the granules of these cells. Interestingly, we found strong evidence of the presence of tryptase and factor XIIIa in the superficial skin nerves of these patients, both in cases of urticarial lesions (wheals) and in the apparently normal skin. Tryptase and FXIIIa are present in the superficial nerves of the skin in drug-induced acute urticaria. This is the first report of tryptase and FXIIIa expression in the superficial skin nerves of patients with urticaria. Tryptase may be participating in neural activation in these patients, while FXIIIa may be present in the nerves to guarantee the functional integrity of structures.


Multi-solvent large stopband monitoring based on the insolubility/superoleophilicity of PEDOT inverse opals.
Monitoring and post-processing of organic solvents are important for environmental protection. Challenges remain in the development of a universal material which can detect any solvent with a large stopband shift and show excellent stability. Herein, we demonstrate a poly 3,4-ethylenedioxythiophene inverse opal (PEDOT-IO) with a large stopband shift toward various solvents based on the insolubility/superoleophilicity properties. The PEDOT-IO film was fabricated by the potentiostatic polymerization of 3,4-ethylene dioxythiophene using a three-electrode system, infiltrating the interstices of the photonic crystal template with PEDOT and subsequently removing the template. The surface of the PEDOT-IO film presented a composite structure: interconnected pores and hollow shells. When the solvent was introduced into the voids of PEDOT-IO film, the effective refractive index (n) of the whole sample increased due to the replacement of air with the solvent, and the pores and hollow shells showed different degrees of swelling. The synergistic effect of increased n and volume expansion contributed to a large redshift of the stopband of the PEDOT-IO film. PEDOT-IO film exhibited excellent resistance to various solvents and high/low temperature. This work further enriches the application of conductive polymers in solvent-responsive PC sensors and provides a novel means of creating PC-based optical materials and devices.


Genetics and physiology of proline utilization in Saccharomyces cerevisiae: mutation causing constitutive enzyme expression.
A mutation resulting in inducer-independent expression of the proline-degradative enzymes was isolated in the yeast Saccharomyces cerevisiae. Strains carrying the mutation, put3, are partially constitutive for proline oxidase and delta 1-pyrroline-5-carboxylate dehydrogenase when grown on a medium lacking proline and are hyperinducible for both enzyme activities when grown on a proline-containing medium. put3 segregates as a single nuclear gene, is not linked to either of the presumed structural genes for proline oxidase and delta 1-pyrroline-5-carboxylate dehydrogenase, and does not affect proline transport. When heterozygous in diploid strains, put3 behaves neither fully dominant nor fully recessive. Endogenous induction by proline has been eliminated as a cause of the inducer-independent enzyme expression in the put3 mutant and the mutation is believed to be in a regulatory component of the proline-degradative pathway.


Apigenin enhances apoptosis induction by 5-fluorouracil through regulation of thymidylate synthase in colorectal cancer cells.
Although effective drugs have been developed, including 5-fluorouracil (5-FU), advanced colorectal cancer (CRC) shows low therapeutic sensitivity resulting from the development of 5-FU resistance. Thymidylate synthase (TS) is a target protein of 5-FU, and elevated TS lowers the 5-FU sensitivity of CRC cells. Here, we tested the efficacy of several candidate phytochemicals against human CRC-derived HCT116 cells expressing wild-type tumor suppressor protein P53 and HT29 cells expressing mutant P53. Among them, we found that apigenin enhanced the inhibitory effect of 5-FU on cell viability. In addition, apigenin inhibited the upregulation of TS induced by 5-FU. Apigenin also potentiated 5-FU-induced apoptosis of HCT116 cells and enhanced cell cycle disruption. Furthermore, apigenin increased reactive oxygen species production, intracellular and intramitochondrial Ca2+ concentrations, and mitochondrial membrane potential upon cotreatment with 5-FU. Knockdown of forkhead box protein M, a transcription factor modulating 5-FU sensitivity, enhanced the potentiation of apoptosis by apigenin in HCT116 cells. Moreover, apigenin suppressed TS expression and inhibited the viability of 5-FU-resistant HCT116 cells. Therefore, apigenin may improve the therapeutic efficacy of 5-FU against CRC by suppressing TS, but apoptosis induction is mainly dependent on functional P53.