Provision of Paid Web-Based Medical Consultation in China: Cross-Sectional Analysis of Data From a Medical Consultation Website.
Web-based medical consultation, which has been adopted by patients in many countries, requires a large number of doctors to provide services. However, no study has provided an overall picture of the doctors who provide online services. This study sought to examine doctors' participation in medical consultation practice in an online consultation platform. This paper aimed to address the following questions: (1) which doctors provide Web-based consultation services, (2) how many patients do the doctors get online, and (3) what price do they charge. We further explored the development of market segments in various departments and various provinces. This study explored the dataset including all doctors providing consultation services in their spare time on a Chinese Web-based consultation platform. We also brought in statistics for doctors providing offline consultations in China. We made use of Bonferroni multiple comparison procedures and z test to compare doctors in each group. There are 88,308 doctors providing Web-based consultation in their spare time on Haodf, accounting for 5.25% (88,308/1,680,062) of all doctors in China as of September 23, 2017. Of these online doctors, 49.9% (44,066/88,308) are high-quality doctors having a title of chief physician or associate chief physician, and 84.8% (74,899/88,308) come from the top, level 3, hospitals. Online doctors had an average workload of 0.38 patients per doctor per day, with an online and offline ratio of 1:14. The average price of online consultation is ¥32.3. The online ratios for the cancer, internal medicine, ophthalmology-otorhinolaryngology, psychiatry, gynecology-obstetrics-pediatrics, dermatology, surgery, and traditional Chinese medicine departments are 16.1% (2,983/18,481), 4.4% (16,231/372,974), 6.3% (8,389/132,725), 9.5% (1,600/16,801), 5.8% (12,955/225,128), 18.0% (3,334/18,481), 10.8% (24,030/223,448), and 3.8% (8,393/22,3448), respectively. Most provinces located in eastern China have more than 4000 doctors online. The online workloads for doctors from most provinces range from 0.3 to 0.4 patients per doctor per day. In most provinces, doctors' charges range from ¥20 to ¥30. Quality doctors are more likely to provide Web-based consultation services, get more patients, and charge higher service fees in an online consultation platform. Policies and promotions could attract more doctors to provide Web-based consultation. The online submarket for the departments of dermatology, psychiatry, and gynecology-obstetrics-pediatrics developed better than other departments such as internal medicine and traditional Chinese medicine. The result could be a reference for policy making to improve the medical system both online and offline. As all the data used for analysis were from a single website, the data might be biased and might not be a representative national sample of China.


A case of left atrial myxoma: anaesthetic management.
Left Atrial Myxomas are notorious for their varied presentations. We describe one such case which initially presented with hemiparesis and seizures and was diagnosed as cerebral infarction and treated accordingly and decompression craniotomy with hinge flap was done for raised ICP and impending brain herniation. The main cause was a left atrial myxoma, which was diagnosed only in follow up. The myxoma has embolised to give rise to cerebral infarction. The LA myxoma was then successfully operated under general anaesthesia and Cardiopulmonary bypass (CPB).


QSAR Studies of Nitric Oxide Synthase Inhibitors.
Nitric oxide is a free radical bioregulator controlling homeostasis, vasodilation, and inhibition of platelet aggregation, significantly implicated in the nervous and immune system functionality. In vivo it is produced by nitric oxide synthases (NOSs). Overproduction of nitric oxide is linked to several inflammatory, immunological, and neurodegenerative diseases and for that, various compounds have been synthesized as inhibitors of NOSs. In this review, the QSAR analyses were summarized in a variety of compounds as potent inhibitors of NOSs, and the models derived through 1D, 2D and 3D QSAR analyses. Ten groups of various NOS inhibitors and 17 1D, 2D, and 3D QSAR models and analyses were presented and discussed. A lack of hydrophobic terms was noticed in most of the cases. Chemical substituents were selected considering the increase either of the hydrophilicity and/or of hydrophobicity, bulkiness supported steric interactions, and point to potent inhibitors. CMR (Calculated Molar Refractivity) a steric variable, with a negative sign, underlines the critical effects participating on (in) an active site on the enzymes. Indicator variables imply the influence of specific structural moieties. Electronic parameters were found to be significant.


Multiple-path dissociation mechanism for mono- and dinuclear tris(hydroxamato)iron(III) complexes with dihydroxamic acid ligands in aqueous solution.
Linear synthetic dihydroxamic acids ([CH3N(OH)C=O)]2(CH2)n; H2Ln) with short (n = 2) and long (n = 8) hydrocarbon-connecting chains form mono- and dinuclear complexes with Fe(III) in aqueous solution. At conditions where the formation of Fe2(Ln)3 is favored, complexes with each of the two ligand systems undergo [H+]-induced ligand dissociation processes via multiple sequential and parallel paths, some of which are common and some of which are different for the two ligands. The pH jump induced ligand dissociation proceeds in two major stages (I and II) where each stage is shown to be comprised of multiple components (Ix, where x = 1-3 for L2 and L8, and IIy, where y = 1-3 for L2 and y = 1-4 for L8). A reaction scheme consistent with kinetic and independent ESI-MS data is proposed that includes the tris-chelated complexes (coordinated H2O omitted for clarity) (Fe2(Ln)3, Fe2(L2)2(L2H)2, Fe(LnH)3, Fe(L8)(L8H)), bis-chelated complexes (Fe2(Ln)2(2+), Fe(LnH)2+, Fe(L8)+), and monochelated complexes (Fe(LnH)2+). Analysis of kinetic data for ligand dissociation from Fe2(Ln)(LnH)3+ (n = 2, 4, 6, 8) allows us to estimate the dielectric constant at the reactive dinuclear Fe(III) site. The existence of multiple ligand dissociation paths for the dihydroxamic acid complexes of Fe(III) is a feature that distinguishes these systems from their bidentate monohydroxamic acid and hexadentate trihydroxamic acid counterparts and may be a reason for the biosynthesis of dihydroxamic acid siderophores, despite higher environmental molar concentrations necessary to completely chelate Fe(III).


Reliance on prothrombin time ratios causes significant errors in anticoagulation therapy.
The intensity of warfarin anticoagulation in the United States may be inappropriate if the international normalized ratio (INR) is not used, or if the international sensitivity index (ISI) of the thromboplastin is outside the range of 2.2 to 2.6. Fifty-three hospital laboratories provided data on the sensitivity of their thromboplastin and whether they reported INR values. Additional data on thromboplastin sensitivity were obtained from 140 laboratories involved in the Stroke Prevention in Atrial Fibrillation study. The three major manufacturers of thromboplastin confirmed the range of thromboplastin sensitivity reported by the laboratories. Of 53 laboratories surveyed, 16 (30%) could not provide ISI data and only 11 (21%) reported INR results. Unlabeled thromboplastin was being used by 20% to 24% of laboratories, and only 8% to 20% were using thromboplastins with an ISI of 2.2 to 2.6. At the time the three manufacturers were contacted, they reported marketing thromboplastins with ISI values from 1.2 to 2.8, but none of the thromboplastins at that time had ISI values between 2.2 and 2.6. Warfarin therapy in the United States is managed inappropriately because most laboratories do not report INRs and the variability in thromboplastin sensitivity produces misleading prothrombin time ratio results. Additionally, recent research may require reexamination if INR or ISI data were not provided.


Macrophages and CD4+ T lymphocytes from two multiply exposed, uninfected individuals resist infection with primary non-syncytium-inducing isolates of human immunodeficiency virus type 1.
Despite multiple, high-risk sexual exposures, some individuals remain uninfected with human immunodeficiency virus type 1 (HIV-1). CD4+ lymphocytes from these individuals are less susceptible to infection in vitro with some strains of HIV-1, suggesting that the phenotype of the virus may influence its ability to interact with certain CD4+ cells. In the present study, we examined the susceptibility of CD4+ T lymphocytes and macrophages from two exposed uninfected individuals (EU2 and EU3) to infection with a panel of biologically cloned isolates of HIV-1 having either a non-syncytium-inducing (NSI) or a syncytium-inducing (SI) phenotype. Our results indicate that CD4+ T lymphocytes from EU2 and EU3 are resistant to infection with NSI isolates of HIV-1 but are susceptible to infection with primary SI isolates. In addition, we found that macrophages from EU2 and EU3 are resistant to infection with both NSI and SI isolates. The latter finding was confirmed by using several uncloned NSI and SI isolates obtained from patients during acute HIV-1 infection. In further experiments, env clones encoding glycoproteins characteristic of NSI or SI viruses were used in single-cycle infectivity assays to evaluate infection of CD4+ lymphocytes and macrophages from EU2 and EU3. Consistent with our previous results, we found that macrophages from these individuals are resistant to infection with NSI and SI env-pseudotyped viruses, while CD4+ T lymphocytes are resistant to NSI, but not SI, pseudotyped viruses. Overall, our results demonstrate that CD4+ cells from two exposed uninfected individuals resist infection in vitro with primary, macrophage-tropic, NSI isolates of HIV-1, which is the predominant viral phenotype found following HIV-1 transmission. Furthermore, infection with NSI isolates was blocked in both CD4+ T lymphocytes and macrophages from these individuals, suggesting that there may be a common mechanism for resistance in both cell types.


Rapid and well tolerated action of idarucizumab for antagonizing dabigatran in a patient needing urgent thrombolysis: a case report.
: Dabigatran is a direct oral anticoagulant drug exhibiting clinical benefits over vitamin K antagonists. A procedure for reversing the anticoagulant effect of direct oral anticoagulants may be needed in emergency clinical settings, and is traditionally accomplished by using plasma products or hemostatic physical interventions. Idarucizumab, a specific antidote for dabigatran, has recently become available. This compound can be rapidly administered by intravenous injection and is effective in reversing anticoagulation in few minutes. We describe here the case of a 78-year-old woman taking dabigatran for atrial fibrillation, who was admitted to the emergency department with a diagnosis of acute cerebral ischemia. Dabigatran plasma levels on admission (74 ng/ml) were measured with diluted thrombin time. Idarucizumab was immediately administered and dabigatran plasma concentration suddenly decreased to less than 2 ng/ml. Successful systemic thrombolysis could hence be performed with full recovery.


Porcine circovirus type 2 (PCV2) induces cell proliferation, fusion, and chemokine expression in swine monocytic cells in vitro.
Granulomatous lymphadenitis is one of the pathognomonic lesions in post-weaning multisystemic wasting syndrome (PMWS)-affected pigs. This unique lesion has not been reported in direct association with viral infection in pigs. The objective of the present study was to evaluate whether porcine circovirus type 2 (PCV2) alone is able to induce functional modulation in porcine monocytic cells in vitro to elucidate its possible role in the development of granulomatous inflammation. It was found that the proliferation activity of blood monocytes (Mo) and monocyte-derived macrophages (MDM) was significantly enhanced by PCV2. During monocyte-macrophage differentiation, the PCV2 antigen-containing rate and formation of multinucleated giant cells (MGC) were significantly increased in MDM when compared to those in Mo. The MDM-derived MGC displayed a significantly higher PCV2 antigen-containing rate than did the mono-nucleated MDM. Supernatants from PCV2-inoculated MDM at 24 h post-inoculation induced an increased tendency of chemotactic activity for blood Mo. At the same inoculation time period, levels of mRNA expression of the monocytic chemokines, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1, also significantly increased in PCV2-inoculated MDM. The results suggest that PCV2 alone may induce cell proliferation, fusion, and chemokine expression in swine monocytic cells. Thus, PCV2 itself may play a significant role in the induction of granulomatous inflammation in PMWS-affected pigs.


A preliminary result of treatment of neuromyelitis optica with autologous peripheral hematopoietic stem cell transplantation.
Autologous peripheral hematopoietic stem cell transplantation (APHSCT) was performed to treat a patient with neuromyelitis optica. We observed that the patient achieved clinical remission after APHSCT during 12 months of follow-up. The patient improved on the expanded disability status scale neurologic assessment and the Scripps neurologic rating scale worksheet scores on follow-up examination compared with baseline. The MRI abnormalities on T1WI and T2WI improved. The postpartum maternal blood helper T (CD3+CD4+ T cell) and the CD4+/CD8+ ratio were decreased, and the cytotoxic T (CD3+CD8+ T) cell increased. This shows that APHSCT in this patient with neuromyelitis optica appears to reduce the frequency of attacks with improvement in disability. However, a larger study with more patients and a longer follow-up would be required to assess the encouraging preliminary results.


The DIEA branching pattern and its relationship to perforators: the importance of preoperative computed tomographic angiography for DIEA perforator flaps.
Abdominal donor-site flaps based on the deep inferior epigastric artery (DIEA) are the most common flaps used in autologous breast reconstruction. With significant variation in the vascular anatomy of the DIEA, preoperative imaging is desirable. Computed tomographic angiography, recently described for this purpose, uniquely demonstrates the branching pattern of the DIEA. The authors sought to correlate the DIEA branching pattern to the location and course of perforators as a preoperative planning tool for perforator flaps. Forty-five cadaveric hemi-abdominal walls were used for contrast injection of the DIEA with subsequent radiographic imaging. The branching pattern on radiography was thus correlated to the location and intramuscular course of perforators, from the main DIEA trunk to the point of the penetrating rectus sheath. The DIEA branching pattern correlated closely with the course of perforators. A bifurcating (type II) branching pattern demonstrated a reduced transverse distance traversed by each perforator, whereas a trifurcating (type III) branching pattern demonstrated significantly greater transverse distances (p = 0.0002). Type I vessels were intermediate. Vessel branching type, however, displayed no significant correlation with the number of perforators (p = 0.56). The distances traversed by perforators were significantly reduced with a bifurcating branching pattern of the DIEA, particularly those originating from the lateral branch, and were greatest with a trifurcating branching pattern. Increased transverse distances correlate with greater rectus muscle sacrificed during perforator flap surgery. As computed tomographic angiography is the optimal modality for demonstrating this pattern preoperatively, the authors suggest its use for preoperative assessment in transverse rectus abdominis musculocutaneous and DIEA perforator flaps.


Trial of Nemolizumab in Moderate-to-Severe Prurigo Nodularis.
Prurigo nodularis is a chronic pruritic skin disease with multiple nodular skin lesions. Nemolizumab is a monoclonal antibody targeting the interleukin-31 receptor, which is involved in the pathogenesis of prurigo nodularis. We conducted a 12-week, randomized, double-blind, phase 2 trial of nemolizumab (at a dose of 0.5 mg per kilogram of body weight) administered subcutaneously at baseline, week 4, and week 8, as compared with placebo, in patients with moderate-to-severe prurigo nodularis and severe pruritus. Moderate-to-severe prurigo nodularis was defined as 20 or more nodules, and severe pruritus was defined as a mean score of at least 7 for the worst daily intensity of pruritus on the numerical rating scale (scores range from 0 [no itch] to 10 [worst itch imaginable]). The primary outcome was the percent change from baseline in the mean peak score for pruritus on the numerical rating scale at week 4. Secondary outcomes included additional measures of itching and disease severity. Safety assessments were performed through week 18. A total of 70 patients were randomly assigned in a 1:1 ratio to receive nemolizumab (34 patients) or placebo (36). The initial pruritus score on the numerical rating scale was 8.4 in each group. At week 4, the peak pruritus score on the numerical rating scale was reduced from baseline by 4.5 points (change, -53.0%) in the nemolizumab group, as compared with a reduction of 1.7 points (change, -20.2%) in the placebo group (difference, -32.8 percentage points; 95% confidence interval, -46.8 to -18.8; P<0.001). Results for secondary outcomes were in the same direction as for the primary outcome. Nemolizumab was associated with gastrointestinal symptoms (abdominal pain and diarrhea) and musculoskeletal symptoms. Nemolizumab resulted in a greater reduction in pruritus and severity of skin lesions than placebo in patients with prurigo nodularis but was associated with adverse events. Larger and longer trials are needed to determine the durability and safety of nemolizumab for the treatment of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT03181503.).


Has GWAS lost its status as a paragon of open science?
Genomic research led the way in open science, a tradition continued by genome-wide association studies (GWAS)-through the sharing of materials, results, and data. Coordinated quality control procedures also contributed to robust findings. However, recent years have seen declines in GWAS transparency. Here, we assess some shifts away from open science practices with the aim of stimulating a discussion of these issues.


From Stigma to Validation: A Qualitative Assessment of a Novel National Program to Improve Retention of Physician-Scientists with Caregiving Responsibilities.
Background: Research is needed to improve understanding of work-life integration issues in academic medicine and to guide the implementation of the Doris Duke Charitable Foundation's Fund to Retain Clinical Scientists (FRCS), a national initiative offering financial support to physician-scientists facing caregiving challenges. Materials and Methods: In 2018, as part of a prospective program evaluation, the authors conducted a qualitative study to examine FRCS program participants' initial impressions, solicit descriptions of their career and caregiving experiences, and inquire how such factors might influence their professional advancement. The authors invited all 33 awardees who had been granted FRCS funding in the first year of the program to participate in the study, of whom 28 agreed to complete an interview. Analysts evaluated de-identified transcripts and explicated the data using a thematic analysis approach. Results: While participants described aspects of a culture that harbor stigma against caregivers and impede satisfactory work-life integration, they also perceived an optimistic cultural shift taking place as a result of programs like the FRCS. Their comments indicated that the FRCS has the potential to influence culture if institutional leadership simultaneously fosters a community that validates individuals both as caregivers and as scientists. Conclusions: Insights garnered from this qualitative study suggest that there is a pressing need for institutional leaders to implement programs that can foster awareness and normalization of caregiving challenges. In addition to providing funding and other tangible resources, interventions should strive to reinforce a broader culture that affirms the presence of work-life integration challenges and openly embraces solutions.


Pharmacological analgesia in neonates undergoing cardiac surgery.
The objectives of this study were to verify the frequency of pharmacological analgesia and the occurrence of postoperative pain in neonates undergoing cardiac surgery. This is a cross-sectional study and data were collected from 30 medical charts of neonates who underwent cardiac surgery in a private hospital in the city of São Paulo. The majority (96.6%) of neonates received analgesia: 18 (60.0%) received continuous analgesics, five (16.7%) received intermittent drugs, and six (20.0%) received a combination of continuous and intermittent analgesics. Fentanyl citrate was continuously administered to 24 (80.0%) neonates. Intermittent dipyrone and morphine was administered to ten (33.3%) and one (3.3%) neonates, respectively. Pain registers were observed in 17 (56.7%) medical charts and the occurrence of pain among neonates who received analgesics was 53.4%. There was no efficacy in pharmacological postoperative pain control in the neonates included in this study.


Predicting Individual Treatment Response to rTMS for Motor Recovery After Stroke: A Review and the CanStim Perspective.
Rehabilitation is critical for reducing stroke-related disability and improving quality-of-life post-stroke. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique used as stand-alone or adjunct treatment to physiotherapy, may be of benefit for motor recovery in subgroups of stroke patients. The Canadian Platform for Trials in Non-Invasive Brain Stimulation (CanStim) seeks to advance the use of these techniques to improve post-stroke recovery through clinical trials and pre-clinical studies using standardized research protocols. Here, we review existing clinical trials for demographic, clinical, and neurobiological factors which may predict treatment response to identify knowledge gaps which need to be addressed before implementing these parameters for patient stratification in clinical trial protocols. To provide a review of clinical rTMS trials of stroke recovery identifying factors associated with rTMS response in stroke patients with motor deficits and develop research perspectives for pre-clinical and clinical studies. A literature search was performed in PubMed, using the Boolean search terms stroke AND repetitive transcranial magnetic stimulation OR rTMS AND motor for studies investigating the use of rTMS for motor recovery in stroke patients at any recovery phase. A total of 1,676 articles were screened by two blinded raters, with 26 papers identified for inclusion in this review. Multiple possible factors associated with rTMS response were identified, including stroke location, cortical thickness, brain-derived neurotrophic factor (BDNF) genotype, initial stroke severity, and several imaging and clinical factors associated with a relatively preserved functional motor network of the ipsilesional hemisphere. Age, sex, and time post-stroke were generally not related to rTMS response. Factors associated with greater response were identified in studies of both excitatory ipsilesional and inhibitory contralesional rTMS. Heterogeneous study designs and contradictory data exemplify the need for greater protocol standardization and high-quality controlled trials. Clinical, brain structural and neurobiological factors have been identified as potential predictors for rTMS response in stroke patients with motor impairment. These factors can inform the design of future clinical trials, before being considered for optimization of individual rehabilitation therapy for stroke patients. Pre-clinical models for stroke recovery, specifically developed in a clinical context, may accelerate this process.


HTLV-1 Tax Functions as a Ubiquitin E3 Ligase for Direct IKK Activation via Synthesis of Mixed-Linkage Polyubiquitin Chains.
The HTLV-1 oncoprotein Tax plays a key role in CD4+ T cell transformation by promoting cell proliferation and survival, mainly through permanent activation of the NK-κB pathway and induction of many NF-κB target genes. Elucidating the underlying molecular mechanism is therefore critical in understanding HTLV-1-mediated transformation. Current studies have suggested multiple but controversial mechanisms regarding Tax-induced IKK activation mainly due to blending of primary Tax-induced IKK activation events and secondary IKK activation events induced by cytokines secreted by the primary Tax-induced IKK-NF-κB activation events. We reconstituted Tax-stimulated IKK activation in a cell-free system to dissect the essential cellular components for primary IKK activation by Tax and studied the underlying biochemical mechanism. We found that Tax is a putative E3 ubiquitin ligase, which, together with UbcH2, UhcH5c, or UbcH7, catalyzes the assembly of free mixed-linkage polyubiquitin chains. These free mixed-linkage polyubiquitin chains are then responsible for direct IKK activation by binding to the NEMO subunit of IKK. Our studies revealed the biochemical function of Tax in the process of IKK activation, which utilizes the minimal cellular ubiquitination components for NF-κB activation.


A Systematic Review and Metaanalysis of Predictors of Mortality in Idiopathic Inflammatory Myopathy-Associated Interstitial Lung Disease.
Idiopathic inflammatory myopathy (IIM)-associated interstitial lung disease (ILD) can range from rapidly progressive disease with high mortality to indolent disease with minimal morbidity. This systematic review and metaanalysis describe immunological, clinical, and radiographical predictors of mortality in IIM-ILD. MEDLINE and Embase database searches were completed on October 18, 2021, to identify articles providing survival data according to baseline characteristics in patients with concurrent IIM and ILD. Prognostic factors common to more than 5 papers were included in the metaanalysis using a random-effects model to report odds ratios (ORs) for binary variables and Hedges g for continuous variables. Risk of bias was assessed using the Newcastle-Ottawa Scale score and the Egger test for publication bias. From 4433 articles, 62 papers were suitable for inclusion; among these studies, 38 different variables were considered. The OR for risk of death regarding the presence of anti-melanoma differentiation-associated protein 5 (MDA5) antibodies was 6.20 (95% CI 3.58-10.71), and anti-tRNA synthetase antibodies were found to be protective (OR 0.24, 95% CI 0.14-0.41). Neither antinuclear antibodies, anti-52-kDa Ro antigen antibodies, nor SSA significantly altered mortality, nor was MDA5 titer predictive. Examples of prognostic factors that are significantly associated with mortality in this study include the following: age; male sex; acute/subacute onset; clinically amyopathic dermatomyositis; dyspnea; ulceration; fever; raised C-reactive protein, ferritin, lactate dehydrogenase, alveolar to arterial O2 (A-aO2) gradient, ground-glass opacity on high-resolution computed tomography (HRCT), and overall HRCT score; and reduced albumin, lymphocytes, ratio of partial pressure of oxygen in the arterial blood to fraction of inspired oxygen (PF ratio), percentage predicted transfer factor for carbon monoxide, and percentage predicted forced vital capacity. Baseline surfactant protein-D and Krebs von den Lungen-6 levels were not predictors of mortality. Many mortality risk factors were identified, though heterogeneity was high, with a low quality of evidence and a risk of publication bias. Studies regarding anti-MDA5 antibody-positive disease and and those from East Asia predominate, which could mask risk factors relevant to other IIM subgroups or populations.


[Alpha lipoic acid and its antioxidant against cancer and diseases of central sensitization].
The alpha lipoic acid (ALA) may control and limit the production of free radicals, influencing the development of pathologies such cancer or central sensitization diseases. However, the molecular mechanisms are still not elucidated. The objective of the present review is to contrast the antioxidant properties of ALA in the prevention and development of pathologies related to the oxidative stress. In this work, more than 100 articles published during the last 20 years that relate ALA consumption and pathologies related to the oxidative stress have been analysed. The articles have been obtained from different specialized databases (PubMed central, Web of science, Elsevier Journal, Science Direct) and included experiments in animals, cells, and humans. Domains evaluated included ALA, central sensitization diseases, free radicals, and ALA. Results from in vitro and laboratory animals experiments demonstrate that ALA controls the cell apoptosis of different type of cancers through out the increase of reactive oxygen species, and decrease of cell growth. Moreover, results demonstrated that ALA presents an antioxidant capacity and the ability to regenerate other antioxidants, which is essential to treat the central sensitization diseases. The ALA plays a significant role as antioxidant and prooxidant in cancer and central sensitization diseases, although more extensive studies are required to determine the clinical significance in humans.


Use of the Center for Epidemiologic Studies Depression (CES-D) Scale in Korea.
We translated the Center for Epidemiologic Studies Depression (CES-D) Scale into Korean, paying careful attention to culturally different modes of expression of depressive feelings and thoughts. The final translated version (CES-D-K) was administered to 164 psychiatric patients and 464 normal subjects residing in the community. Reliability, validity, and the optimal cutoff point of this scale were estimated, including ROC analysis. The CES-D-K was reliable and valid for the Korean population. Two optimal cutoff points were suggested: 24/25, the point which best corresponded to the clinical diagnosis of depression, and 20/21, which most effectively detects and covers depressive symptoms during screening. The higher cutoff points than those in Western countries may be due to different ways of expression affect, especially the suppression of positive affect, in cultures based on Confucian ethics.


Comparison of Symptoms From C6 and C7 Radiculopathy.
Case series. This study compared the locations of arm pain, sensory symptoms, and subjective complaints of arm weakness in patients with cervical radiculopathy from MRI confirmed C6 and C7 nerve root compression. Cervical radiculopathy is defined as arm pain, sensory and motor symptoms caused by irritation of a cervical nerve root. The C6 and C7 roots are most commonly involved, and differentiating symptoms associated with each root has proven difficult. Cervical MRI allows accurate identification of nerve root compression and therefore makes it possible to explore symptom patterns that may differentiate C6 from C7 radiculopathy. A total of 122 patients with symptoms suggestive of cervical radiculopathy were recruited. Of these, 30 patients had MRI confirmed C6 and 39 patients C7 nerve root compression. By completing a study questionnaire, patients reported specific arm weakness, and marked the location of arm pain and tingling/numbness on graphic representations of the arm. Marked areas were interpreted by superimposing a grid that divided the arm into 54 distinct areas. The frequencies of reported symptoms with C6 and C7 were totaled and then compared with likelihood rations. Power analysis calculated that 27 patients would be needed in each group based on the assumption that a 30 percentage point difference in frequency of specific symptom would be clinically useful for differentiating C6 from C7 radiculopathy. Arm pain and sensory symptoms were diffuse, and were not distinctly different for C6 or C7 radiculopathy. Some weakness was reported by 41 percent of patients, with specific descriptions of weakness having limited value for differentiating between radiculopathies. The location of pain and sensory symptoms, and specific weakness complaints associated with symptomatic C6 and C7 nerve root compression overlap to the extent that caution should be exercised when predicting root involvement based on symptoms. 3.


Advances in understanding pathogenic mechanisms of thrombophilic disorders.
Venous thromboembolism is a major medical problem, annually affecting 1 in 1000 individuals. It is a typical multifactorial disease, involving both genetic and circumstantial risk factors that affect a delicate balance between procoagulant and anticoagulant forces. In the last 50 years, the molecular basis of blood coagulation and the anticoagulant systems that control it have been elucidated. This has laid the foundation for discoveries of both common and rare genetic traits that tip the natural balance in favor of coagulation, with a resulting lifelong increased risk of venous thrombosis. Multiple mutations in the genes for anticoagulant proteins such as antithrombin, protein C, and protein S have been identified and constitute important risk factors. Two single mutations in the genes for coagulation factor V (FV Leiden) and prothrombin (20210G>A), resulting from approximately 20,000-year-old mutations with subsequent founder effects, are common in the general population and constitute major genetic risk factors for thrombosis. In celebration of the 50-year anniversary of the American Society of Hematology, this invited review highlights discoveries that have contributed to our present understanding of the systems that control blood coagulation and the genetic factors that are involved in the pathogenesis of venous thrombosis.


[The observation of experimental respiratory distress syndrome and effects of anisodamine].
The respiratory distress syndrome (RDS) model induced by oleic acid injection in dogs and treated by anisodamine were observed. The clinical picture, blood gas parameters, Pap, Pwp, blood cells count, hemocoagulogram, CH50, and surface tension of BALF were studied in order to determine the pathophysiological mechanism and effects of anisodamine. According to the studies in our laboratory, it was suggested that the complement activation and neutrophil aggregation induced by C5a and mediators released by it and other way are likely to be the initiation factors. The lung injuries complicated diffuse intravascular coagulation with fibrinolysis occurred for whole 72 hours period. The anisodamine seems to exert certain therapeutic effects on RDS through preventing the complement activation and enable the lysosomal elimination decrease and stimulate the II-type epithelia to be repaired.


[Histomorphometric differences between the left and right internal thoracic arteries in humans].
The use of the left internal thoracic artery in coronary artery bypass surgery is currently recognized as the best option, providing lesser incidence of cardiovascular events and superior long-term survival. As a result, great expansion of bilateral internal thoracic artery (ITAs) grafts has been observed, with additional demonstration of improved long-term survival. Therefore the aim of this study was to examine and compare the histomorphometric structure among different segments of the left and right ITA. Specimens of ITAs harvested from 18 cadavers were divided in nine proportional segments. Cuts of each segment had been stained with hematoxylin-eosin and Verhoeff-Van Gieson technique. The following parameters had been analyzed: perimeter of the arterial lumen, thickness of the intima, thickness of the media layer and amount of elastic fiber in the media layer. The perimeter of both ATIs decreases downstream its course, the proximal segments of the right ITA exhibit perimeter significantly greater than left ITA The analysis of the intima thickness revealed no significant difference between left and right ITA, except in the segment 9. The thickness of media layer showed no statistical difference between them, except in the segment 1. The number of elastic layers in the distal left ITA segments is significantly higher than right ITA. Data analyses from this study suggest structural differences between the left and right internal thoracic arteries.


Variation in stress and innate immunity in the tree lizard (Urosaurus ornatus) across an urban-rural gradient.
The urban environment presents new and different challenges to wildlife, but also potential opportunities depending on the species. As urban encroachment onto native habitats continues, understanding the impact of this expansion on native species is vital to conservation. A key physiological indicator of environmental disturbance is the vertebrate stress response, involving increases in circulating glucocorticoids (i.e. corticosterone), which exert influence on numerous physiological parameters including energy storage, reproduction, and immunity. We examined how urbanization in Phoenix, Arizona influences corticosterone levels, blood parasitism, and innate immunity in populations of tree lizards (Urosaurus ornatus) to determine whether urbanization may be detrimental or beneficial to this species. Both baseline and stress-induced corticosterone concentrations were significantly lower in urban lizards relative to the rural ones, however, the magnitude of the increase in corticosterone with stress did not differ across populations. Urban lizards also had a lower ratio of heterophils to lymphocytes, but elevated overall leukocyte count, as compared to lizards from the natural site. Urban and rural lizards did not differ in their prevalence of the blood parasite, Plasmodium mexicanum. Taken together, these results suggest that urban tree lizards may have suppressed overall corticosterone concentrations possibly from down-regulation as a result of frequent exposure to stressors, or increased access to urban resources. Also, urban lizards may have bolstered immunocompetence possibly from increased immune challenges, such as wounding, in the urban environment, or from greater energetic reserves being available as a result of access to urban resources.


Potential energy surfaces of quintet and singlet O4.
We present global ground-state potential energy surfaces for the quintet and singlet spin states of the O4 system that are suitable for treating high-energy vibrational-rotational energy transfer and collision-induced dissociation in electronically adiabatic, spin-conserving O2-O2 collisions. The surfaces are based on MS-CASPT2/maug-cc-pVTZ electronic structure calculations with scaled external correlation. The active space has 16 electrons in 12 orbitals. The calculations cover nine kinds of geometrical arrangements corresponding to dissociative diatom-diatom collisions of O2, geometries corresponding to O3-O, geometries identified by running trajectories, and geometries along linear synchronous transit paths. The global ground-state potential energy surfaces were obtained by a many-body approach with an accurate O-O pairwise interaction and a fit of the many-body interaction to 12 684 electronic structure data points for the singlet and 10 543 electronic structure data points for the quintet. The many-body fit is based on permutationally invariant polynomials in terms of bond-order functions of the six interatomic distances; the bond-order functions are mixed exponential-Gaussian functions.


The use of resin composite pins to improve retention of Class IV resin composite restorations.
This study evaluated the effect of an intracoronal resin composite pin on Class IV resin composite restorations. A control group of 16 bovine teeth was prepared with standardized conventional Class IV preparations. For an experimental group, 16 similar Class IV preparations were made, with the addition of an intracoronal pin channel prepared with a #330 bur into the dentin. All specimens were restored with Herculite XRV and OptiBond according to the manufacturer's recommendations. After one week, specimens were placed in an Instron Universal Testing Machine and loaded at 90 degrees to the long axis until the restorations failed. Results indicated that the mean fracture load of the Class IV restoration group, with the resin composite pin, was 36% higher than the conventional Class IV group (p = 0.02). An intracoronal resin composite pin may aid the retention and resistance form of complex resin composite restorations.


Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice.
Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study, we explore the effects of one such transcript-Z+Agrin-known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice increases muscle fiber size, enhances the post-synaptic NMJ area, reduces the abnormal accumulation of intermediate filaments in nerve terminals of the neuromuscular synapse and improves the innervation of muscles. While these effects are independent of changes in SMN levels or increases in motor neuron numbers they nevertheless have a significant effect on the overall disease phenotype, enhancing mean survival in severely affected SMA model mice by ∼40%. We conclude that Agrin is an important target of the SMN protein and that mitigating NMJ defects may be one strategy in treating human spinal muscular atrophy.


Growth factor signal transduction immediately after two-thirds partial hepatectomy in the rat.
Liver regeneration after partial hepatectomy (PHx) of the liver serves as a model for studying normal growth factor signals that become aberrant in cancer. Growth factor signals that may play a role in initiating the proliferation of hepatocytes after 70% PHx in the rat were investigated immediately after surgical resection of the liver. Presumptive activity was evaluated by determining the tyrosine phosphorylation state of receptors for epidermal growth factor (EGF) and hepatocyte growth factor (HGF) in the liver after PHx and after sham operation as a control. Under these conditions, it was determined that the EGF receptor was constitutively phosphorylated. EGF receptor tyrosine phosphorylation, however, was increased over basal levels by 60 min after resection. The HGF receptor, c-Met, was minimally phosphorylated in control livers, but a biphasic increase in phosphorylation was observed at 1-5 min after PHx and 60 min postsurgery. A slight increase in c-Met phosphorylation was observed in the sham-operated livers, but the signal was significantly less when compared with that in resected livers. Furthermore, 1 min after PHx, but not sham operation, urokinase-type plasminogen activator (u-PA) and u-PA receptor were observed in the immunoprecipitates of c-Met. Signaling downstream of growth factor receptor activation was also examined. There were no discernible phosphorylation changes in focal adhesion kinase during the early events after surgery in PHx; however, a rapid and sustained increase in the tyrosine phosphorylation of paxillin beginning 1 min after PHx, and a gradual increase in the phosphorylation beginning 5 min postsham operation, were observed. Changes in the activated state of the small GTP-binding protein Rho A and its associated proteins were seen but only after 3 h after PHx. The results indicate that HGF-related signal transduction cascades, which contribute to hepatocyte proliferation, are initiated within one min after PHx.


Bayesian hierarchical modelling of continuous non-negative longitudinal data with a spike at zero: An application to a study of birds visiting gardens in winter.
The development of methods for dealing with continuous data with a spike at zero has lagged behind those for overdispersed or zero-inflated count data. We consider longitudinal ecological data corresponding to an annual average of 26 weekly maximum counts of birds, and are hence effectively continuous, bounded below by zero but also with a discrete mass at zero. We develop a Bayesian hierarchical Tweedie regression model that can directly accommodate the excess number of zeros common to this type of data, whilst accounting for both spatial and temporal correlation. Implementation of the model is conducted in a Markov chain Monte Carlo (MCMC) framework, using reversible jump MCMC to explore uncertainty across both parameter and model spaces. This regression modelling framework is very flexible and removes the need to make strong assumptions about mean-variance relationships a priori. It can also directly account for the spike at zero, whilst being easily applicable to other types of data and other model formulations. Whilst a correlative study such as this cannot prove causation, our results suggest that an increase in an avian predator may have led to an overall decrease in the number of one of its prey species visiting garden feeding stations in the United Kingdom. This may reflect a change in behaviour of house sparrows to avoid feeding stations frequented by sparrowhawks, or a reduction in house sparrow population size as a result of sparrowhawk increase.


Device-Measured Desk-Based Occupational Sitting Patterns and Stress (Hair Cortisol and Perceived Stress).
Background: Stress and poor mental health are significant issues in the workplace and are a major cause of absenteeism and reduced productivity. Understanding what might contribute towards employee stress is important for managing mental health in this setting. Physical activity has been shown to be beneficial to stress but less research has addressed the potential negative impact of sedentary behaviour such as sitting. Therefore, the aim of this study was to assess the relationship between device-measured occupational desk-based sitting patterns and stress (hair cortisol levels (HCL), as a marker of chronic stress and self-reported perceived stress (PS)). Methods: Employees were recruited from four workplaces located in Central Scotland with large numbers of desk-based occupations. Seventy-seven participants provided desk-based sitting pattern data (desk-based sitting time/day and desk-based sit-to-stand transitions/day), a hair sample and self-reported perceived stress. HCL were measured using enzyme-linked immunosorbent assay and PS using the Cohen Self-Perceived Stress Scale. Linear regression models were used to test associations between desk-based sitting time/day, desk-based sit-to-stand transitions/day, HCL and PS. Results: There were no associations between any of the desk-based sitting measures and either HCL or PS. Conclusions: Desk-based sitting patterns in the workplace may not be related to stress when using HCL as a biomarker of chronic stress or PS. The relationship between sitting patterns and stress therefore requires further investigation.


Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation.
In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p < 0.001; ANCOVA). There were no differences in graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All but two episodes of BPAR in each group were mild. Adverse events occurred in 95.1% of everolimus patients and 90.0% controls (p = 0.19), with serious adverse events in 53.9% and 38.0%, respectively (p = 0.025). Discontinuation because of adverse events was more frequent with everolimus (25.5%) than controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent.


Halfway there: the struggle to manage conflicts of interest.
Conflicts of interest are known to create problems for the integrity of biomedical research. The editors of the JCI have set out a rigorous policy to help manage conflicts. But they focus only on financially generated conflicts. Here I identify other sources of conflict and offer some suggestions for their management.


Metabolism of sanguinarine: the facts and the myths.
Sanguinarine, a quaternary benzo[c]phenanthridine alkaloid, exhibits antimicrobial and anti-inflammatory activities and for this reason it is used in dental hygiene products and feed additives. Its metabolism and disposition is the subject of constant scientific discourse. In this paper we summarize current knowledge on sanguinarine metabolism. We show in particular that: (i) Sanguinarine is not transformed to 3,4-benzacridine and that the literature reporting this compound as a metabolite of sanguinarine is based on artifacts and misinterpretations that in course of time have created a dogma; (ii) Sanguinarine is converted to dihydrosanguinarine in vivo, the conversion being tentatively a detoxication pathway; (iii) Aryl hydrocarbon receptor metabolic signaling pathways modulate sanguinarine biological activity.


Overweight is associated with lower resting state functional connectivity in females after eliminating genetic effects: A twin study.
Obesity is related to altered functional connectivity of resting state brain networks that are involved in reward and motivation. It is unknown to what extent these associations reflect genetic confounding and whether the obesity-related connectivity changes are associated with differences in dietary intake. In this study, resting state functional MRI was performed after an overnight fast in 16 female monozygotic twin pairs (aged 48.8 ± 9.8 years) with a mean BMI discordance of 3.96 ± 2.1 kg/m2 (range 0.7-8.2). Functional connectivity of the salience, basal ganglia, default mode and anterior cingulate-orbitofrontal cortex networks was examined by independent component analysis. Dietary intake was assessed using 3-day 24-hour recalls. Results revealed that within the basal ganglia network, heavier versus leaner co-twins have decreased functional connectivity strength in bilateral putamen (P < 0.05, FWE-corrected). There were no differences in connectivity in the other networks examined. In the overall group, lower functional connectivity strength in the left putamen was correlated with higher intake of total fat (P < 0.01). It was concluded that, after eliminating genetic effects, overweight is associated with lower resting state functional connectivity in bilateral putamen in the basal ganglia network. The association between lower putamen connectivity and higher fat intake suggests an important role of the putamen in appetitive mechanisms. The cross-sectional nature of our study cannot discriminate cause and consequence, but the findings are compatible with an effect of lower putamen connectivity on increased BMI and associated higher fat intake. Hum Brain Mapp 38:5069-5081, 2017. © 2017 Wiley Periodicals, Inc.


Genetic insights into the evolution of genera with the eastern Asia-eastern North America floristic disjunction: a transcriptomics analysis.
Large disjunctions in species distributions provide excellent opportunities to study processes that shape biogeographic patterns. One such disjunction is the eastern Asia-eastern North America (EA-ENA) floristic disjunction. For many genera with this disjunction, species richness is greater in EA than in ENA; this pattern has been attributed, in part, to higher rates of molecular evolution and speciation in EA. Longer branch lengths have been found in some EA clades, relative to their ENA sister clades, suggesting that the EA lineages have evolved at a higher rate, possibly due to environmental heterogeneity, potentially contributing to the species richness anomaly. To evaluate whether rates of molecular evolution are elevated in EA relative to ENA, we used transcriptomes from species in 11 genera displaying this disjunction. Rates of molecular evolution were estimated for up to 385 orthologous nuclear loci per genus. No statistically significant differences were identified in pairwise comparisons between EA and ENA sister species, suggesting equal rates of molecular evolution for both species; the data also suggest similar selection pressures in both regions. For larger genera, evidence likewise argues against more species-rich clades having higher molecular evolutionary rates, regardless of region. Our results suggest that genes across multiple gene ontology categories are evolving at similar rates under purifying selection in species in both regions. Our data support the hypothesis that greater species richness in EA than ENA is due to factors other than an overall increase in rates of molecular evolution in EA.


Environmental influences on serotonin and cyclic nucleotides in rat cerebral cortex.
The response to different environmental conditions and negative air ions was investigated on cerebral cortical serotonin and cyclic nucleotides. The results indicated that negative air ions alter the weight of the cerebral cortex and that concentrations of serotonin and cyclic nucleotides can be altered both by different environments and by negative air ions. The data stress the importance of the role of the environment when studying the structure and chemistry of the cerebral cortex.


The Scientific Misconduct Questionnaire--Revised (SMQ-R): validation and psychometric testing.
The overall purposes of this article are to report the development of a survey instrument, Scientific Misconduct Questionnaire-Revised (SMQ-R) that elicits the perceptions of research coordinators managing clinical trials about the various aspects of scientific misconduct and to present psychometric analyses for the SMQ-R. A panel of five researchers and research coordinators reviewed the original SMQ (Rankin and Esteeves, 1997) and suggested an additional 42 items based on the review of the literature and their own experiences in research. The SMQ-Revised (SMQ-R) consists of 68 closed-choice items in six sections and one section with 12 open-ended questions. The SMQ-R was sent to 5302 persons who were members of the Association for Clinical Research Professionals (ACRP) or subscribers to Research Practitioner, published by the Center for Clinical Research Practice (CCRP). Internal consistency of subscales was assessed with Cronbach's alpha and ranged from .83 to .84. Confirmatory factor analysis was used to test construct validity of the instrument subscales. The factor structure was assessed with the principal factors method, using the squared multiple correlations as initial communality estimates followed by varimax (orthogonal) or biquartimax (oblique) rotations. Analyses revealed five distinct factors among three subscales. Construct validity for the SMQ-R was also assessed by testing hypothesized relationships using the known groups approach. The current effort demonstrated the usefulness of the SMQ-R in obtaining information from a national sample of experienced research coordinators about their perceptions of the prevalence of different types of scientific misconduct and of factors that influence the occurrence of misconduct. The psychometric evaluation of the SMQ-R suggests good internal consistency for most subscales and suggests adequate construct validity of the instrument as a whole. The analyses also suggest that further refinement of the instrument for future studies is warranted.


A general and maladaptive personality perspective on youth obsessive-compulsive symptoms.
Based on Krueger's (2005) conceptual model of the personality-psychopathology relationship, this study examines how personality predicts different youth obsessive-compulsive symptoms, comparing the relative contribution of general and maladaptive personality traits. Three-hundred forty-four adolescents provided self-reports on an obsessive-compulsive scale, and their mothers rated their child's general and maladaptive personality. Hierarchical regression analyses revealed that personality differentially predicts obsessive-compulsive symptomatology, and that the relative significance of general versus maladaptive personality predictors differs across various forms of obsessive-compulsive pathology. The results are discussed in terms of the value of including both general and maladaptive personality measures in the assessment of early obsessive-compulsive difficulties.


Transgenerational effects on the liver and pancreas resulting from maternal vitamin D restriction in mice.
This study aimed to investigate the effects of maternal vitamin D restriction on carbohydrate metabolism and alterations in the pancreas and liver in the F1 and F2 generations. Therefore, we studied the first two generations of offspring (F1 and F2) of Swiss mice from mothers fed one of two diets: SC (standard chow) or VitD⁻ (vitamin D-deficient). Biometric, biochemical and molecular analyses were performed. The VitD-F1 mice had greater body mass (BM) than the SC-F1 mice. The BM changes were accompanied by increased insulin secretion. The VitD-F1 mice had a higher area under the curve in the oral glucose tolerance test and exhibited larger islet diameters than the SC-F1 mice. In addition, the VitD-F1 mice showed marked diffuse hepatic steatosis and higher expression of fatty acid synthase (FAS) protein than the SC animals in either generation or the ViD-F2 mice. Diet accounted for a greater fraction of the total variation for BM, fat pad mass and insulin secretion than generation. Both diet and generation contributed to the variation in steatosis in the liver, islet diameter and expression of FAS. However, interactions between diet and generation were observed only for insulin secretion, steatosis in the liver and FAS expression. In conclusion, these results provide compelling evidence that maternal vitamin D restriction affects the development of the offspring and leads to metabolic alterations accompanied by structural alterations in the liver and pancreas, especially in the F1 generation.


Regulatory circular RNAs in viral diseases: applications in diagnosis and therapy.
Circular RNA (circRNA) forms closed loops via back-splicing in precursor mRNA, resisting exonuclease degradation. In higher eukaryotes, protein-coding genes create circRNAs through exon back-splicing. Unlike mRNAs, circRNAs possess unique production and structural traits, bestowing distinct cellular functions and biomedical potential. In this review, we explore the pivotal roles of viral circRNAs and associated RNA in various biological processes. Analysing the interactions between viral circRNA and host cellular machinery yields fresh insights into antiviral immunity, catalysing the development of potential therapeutics. Furthermore, circRNAs serve as enduring biomarkers in viral diseases due to their stable translation within specific tissues. Additionally, a deeper understanding of translational circRNA could expedite the establishment of circRNA-based expression platforms, meeting the rising demand for broad-spectrum viral vaccines. We also highlight the applications of circular RNA in biomarker studies as well as circRNA-based therapeutics. Prospectively, we expect a technological revolution in combating viral infections using circRNA.


Drug-Free Macromolecular Therapeutics--A New Paradigm in Polymeric Nanomedicines.
This review highlights a unique research area in polymer-based nanomedicine designs. Drug-free macromolecular therapeutics induce apoptosis of malignant cells by the crosslinking of surface non-internalizing receptors. The receptor crosslinking is mediated by the biorecognition of high-fidelity natural binding motifs (such as antiparallel coiled-coil peptides or complementary oligonucleotides) that are grafted to the side chains of polymers or attached to targeting moieties against cell receptors. This approach features the absence of low-molecular-weight cytotoxic compounds. Here, we summarize the rationales, different designs, and advantages of drug-free macromolecular therapeutics. Recent developments of novel therapeutic systems for B-cell lymphomas are discussed, as well as relevant approaches for other diseases. We conclude by pointing out various potential future directions in this exciting new field.


Methuselah-like genes affect development, stress resistance, lifespan and reproduction in Tribolium castaneum.
Methuselah (Mth) is associated with lifespan, stress resistance and reproduction in Drosophila melanogaster, but Mth is not present in nondrosophiline insects. A number of methuselah-likes (mthls) have been identified in nondrosophiline insects, but it is unknown whether the functions of mth are shared by mthls or are divergent from them. Five mthls have been identified in Tribolium castaneum. Although they have different developmental expression patterns, they all enhance resistance to starvation. Only mthl1 and mthl2 enhance resistance to high temperature, whereas mthl4 and mthl5 negatively regulate oxidative stress in T. castaneum. Unlike in the fly with mth mutation, knockdown of mthls, except mthl3, shortens the lifespan of T. castaneum. Moreover, mthl1 and mthl2 are critical for Tribolium development. mthl1 plays important roles in larval and pupal development and adult eclosion, while mthl2 is required for eclosion. Moreover, mthl1 and mthl2 silencing reduces the fertility of T. castaneum, and mthl1 and mthl4 are also essential for embryo development. In conclusion, mthls have a significant effect on insect development, lifespan, stress resistance and reproduction. These results provide experimental evidence for functional divergence among mthls/mth and clues for the signal transduction of Mthls.


Mass spectrometric fragmentation analysis of oligosialic and polysialic acids.
Oligosialic and polysialic acids (oligo/polySia) are characterized by high structural diversity, because of different types of sialic acids and glycosidic linkages. Although several methods have been described for the analysis of oligo/polySia, only high-performance liquid chromatography (HPLC) analysis in conjunction with 1,2-diamino-4,5-methylenedioxybenzene labeling, fluorometric C7/C9 detection, Western blotting, and matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy (MALDI-TOF-MS) of lactonized oligo/polySia species, require submicrogram amounts of analyte. Since these methods do not provide detailed structural information, this study is focused on the characterization of oligo/polySia by tandem mass spectrometry (MS/MS). MALDI-TOF-MS/MS and electrospray ionization tandem mass spectrometry (ESI-MS/MS), employing up to three cycles of ion isolation and fragmentation in an ion trap, have been used for the characterization of nonderivatized glycans, oligoSia species modified at their reducing or nonreducing ends, as well as partially O-acetylated oligoSia derivatives. The obtained spectra were dominated by simultaneous cleavage of glycosidic linkages and the corresponding lactone ring, whereas classical cross-ring fragments were of minor abundance. However, the combined use of the two different types of fragmentation analysis allowed a sensitive and detailed characterization of both short-chained oligoSia and long polySia species. Furthermore, oxidation of the nonreducing end sugar moiety enabled sequence determination and localization of acetylated and nonacetylated sialic acid residues.


CKAMP44: a brain-specific protein attenuating short-term synaptic plasticity in the dentate gyrus.
CKAMP44, identified here by a proteomic approach, is a brain-specific type I transmembrane protein that associates with AMPA receptors in synaptic spines. CKAMP44 expressed in Xenopus oocytes reduced GluA1- and A2-mediated steady-state currents, but did not affect kainate- or N-methyl-D-aspartate (NMDA) receptor-mediated currents. Mouse hippocampal CA1 pyramidal neurons expressed CKAMP44 at low abundance, and overexpression of CKAMP44 led to stronger and faster AMPA receptor desensitization, slower recovery from desensitization, and a reduction in the paired-pulse ratio of AMPA currents. By contrast, dentate gyrus granule cells exhibited strong CKAMP44 expression, and CKAMP44 knockout increased the paired-pulse ratio of AMPA currents in lateral and medial perforant path-granule cell synapses. CKAMP44 thus modulates short-term plasticity at specific excitatory synapses.


Temporal deletion of Aqp11 in mice is linked to the severity of cyst-like disease.
Aquaporin 11 (AQP11) is a channel protein with unknown biological function that is expressed in multiple tissues, including the kidney proximal tubule (PT) epithelium. Constitutive deletion of Aqp11 in mice (Aqp11-/-) results in early postnatal vacuolization in the PT and development of apparent cysts at 2 wk of age. Electron microscopy of adult Aqp11-/- mouse PT cells revealed a dilated rough endoplasmic reticulum. These changes may cause renal failure and premature death. This study examined 1) whether postnatal deletion of Aqp11 affects PT injury and cyst formation, 2) the temporal role of Aqp11 deletion on cyst development, and 3) the nature of apparent cysts. Tamoxifen-inducible Aqp11-/- mice were generated (Ti-Aqp11-/-). Deletion of Aqp11 at postnatal days (P) P2, P4, P6, P8, and P12 was investigated. Deranged renal development, especially in kidney cortex, PT cell vacuolization, and apparent tubular cysts developed only in mice where Aqp11 gene disruption was induced until P8. Aqp11 gene deletion from P12 onward did not result in a clear deficiency in renal development, PT injury, or cyst formation. Intraperitoneal injection of biotinylated-dextran (10 kDa) into adult mice resulted in extensive endocytic dextran uptake in both cystic Aqp11-/- and control PT epithelium, respectively. This suggests that apparent cysts are not membrane-enclosed structures but represent PT dilations. We conclude that Aqp11-/- mice develop cyst-like dilated proximal tubules without documented cysts at time of death.


Effects of a fluoride-releasing fissure sealant on artificial enamel caries.
This study examined the effect of a fluoride-releasing fissure sealant upon enamel demineralization in an artificial-caries system. Twenty extracted human molars were randomly assigned to two treatment groups consisting of (1) conventional fissure sealant and (2) fluoride-releasing sealant. Specimens were acid-etched, rinsed, dried, sealant applied, and photocured for 20 seconds. Teeth were thermocycled 500x between 5 degrees C and 55 degrees C using 1 minute dwell times. Acid-resistant varnish was placed on the specimens to within 1 mm of the sealant and the teeth were subjected to an artificial-caries challenge at pH 4.2 for 62 hours. Teeth were then sectioned and the thin-sections photographed using a polarizing-light microscope. Areas of the artificial-caries lesions and their depths were measured using a sonic-digitizing pad. Mean lesion depths (in arbitrary units from the digitizing pads) were 4.17 +/- 0.95 for Group 1 and 1.22 +/- 0.61 for Group 2. Mean areas were 17.26 +/- 7.32 for Group 1 and 3.12 +/- 2.59 for Group 2. Students' t-tests indicated statistically significant differences (P less than 0.001) between groups for both measures. This artificial-caries study indicates that a fluoride-releasing fissure sealant substantially reduces the amount of enamel demineralization adjacent to the material.


[Effect of the amount of protein and calcium in the diet on cadmium chloride absorption from the gastrointestinal tract].
Experiments on rats kept on the diets with different content of protein (18, 30 and 5%) and calcium (0,6, 2.4, 0.1%) for a month were made to study the absorption coefficient of labeled cadmium from the gastrointestinal tract. It was established that the quota of calcium and protein in the diet exerts an appreciable effect on cadmium chloride absorption via the gastrointestinal tract. The highest coefficient of cadmium absorption was recorded on excess protein (30%) and calcium deficiency (0,1%) in the diet, whereas the least one in the group of animals fed the diet with a low protein quota (5%).


[Sexually transmitted infection as a cause of anal cancer].
Interviews were carried out with 423 women and 93 men with invasive or in situ anal cancer in Denmark and Sweden in a search for clues to the aetiology of this neoplasm. Patients with rectal adenocarcinoma (n = 534) and persons drawn from the background population (n = 554) served as controls. Multivariate logistic regression analyses confirmed previous observations of a strong association between either male homosexual experience or a history of anogenital warts and the risk for anal cancer. Moreover, hitherto unknown, but strong and consistent associations were observed between measures of high heterosexual activity and the risk for anal cancer among both sexes. Polymerase chain reaction analysis revealed human papilloma-virus DNA in the majority (88%) of anal cancer specimens but in none of 20 examined rectal adenocarcinomas. It is concluded that most anal cancers appear to be caused by sexually transmitted types of human papillomaviruses and, consequently, that anal cancer is a potentially preventable neoplasm.


Exposure to Vitamin D Fortification Policy in Prenatal Life and the Risk of Childhood Asthma: Results From the D-Tect Study.
Prenatal vitamin D insufficiency may be associated with an increased risk of developing childhood asthma. Results from epidemiological studies are conflicting and limited by short follow-up and small sample sizes. The objective of this study was to examine if children born to women exposed to the margarine fortification policy with a small dose of extra vitamin D during pregnancy had a reduced risk of developing asthma until age 9 years, compared to children born to unexposed women. The termination of a Danish mandatory vitamin D fortification policy constituted the basis for the study design. We compared the risk of inpatient asthma diagnoses in all Danish children born two years before (n = 106,347, exposed) and two years after (n = 115,900, unexposed) the termination of the policy. The children were followed in the register from 0-9 years of age. Data were analyzed using Cox proportional hazards regression. The Hazard Ratio for the first inpatient asthma admission among exposed versus unexposed children was 0.96 (95%CI: 0.90-1.04). When stratifying by sex and age, 0-3 years old boys exposed to vitamin D fortification showed a lower asthma risk compared to unexposed boys (HR 0.78, 95%CI: 0.67-0.92). Prenatal exposure to margarine fortification policy with extra vitamin D did not affect the overall risk of developing asthma among children aged 0-9 years but seemed to reduce the risk among 0-3 years old boys. Taking aside study design limitations, this could be explained by different sensitivity to vitamin D from different sex-related asthma phenotypes in children with early onset, and sex differences in lung development or immune responses.


Hormonal responses to high- and moderate-intensity strength exercise.
The hormonal responses of nine male, strength athletes to strength exercise were examined. The athletes performed one moderate- and one high-intensity strength exercise workout. In the high-intensity workout, the load was 100% of each subject's three-repetition maximum (3-RM) for squats and front squats, and 100% of each subject's six-repetition maximum (6-RM) for leg extensions. In the moderate-intensity workout, the load was 70% of the high-intensity protocol. Rest periods between sets were 4-6 min for both workouts. Blood samples were taken before, 30 min into, and every 15 min for the 1st h after exercise, and then 3, 7, 11, 22 and 33 h after exercise, thus allowing examination of both the acute and prolonged hormonal responses. Blood samples were analyzed for testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), cortisol, adrenocorticotrophic hormone (ACTH), growth hormone (GH), insulin-like growth factor (IGF-1), insulin, sex hormone binding globulin, creatine kinase, total protein, glucose and lactate. The acute responses of testosterone and cortisol were greater during the high-intensity protocol as compared to the moderate-intensity protocol. The cortisol response was associated with an increase in ACTH concentration. LH and FSH showed no response to either protocol. Acute GH responses were not different between protocols. There were great inter-individual differences in acute GH responses to both protocols. There were no significant differences between protocols with regard to prolonged responses for any hormone. In both trials, IGF-1 concentrations were significantly lower at 0800 hours the morning after exercise as compared to concentrations found at 0800 hours the morning before exercise. The mechanisms responsible for reducing IGF-1 concentration in these trials are unclear, and it is not known if this reduction observed 22 hours after exercise is of physiological significance.


Polyclonal gammopathy with marked increase in serum viscosity.
A 45-year-old man with polyclonal hypergammaglobulinemia (gamma globulins, 102 g/L) had a serum relative viscosity of 13 nu but did not manifest clinical signs of hyperviscosity syndrome (e.g., retinopathy, bleeding diathesis, and neurological alterations), except for fatigue and anorexia. In contrast with other patients with polyclonal hyperviscosity reported so far, this patient did not have detectable rheumatoid factor in serum. Analytical ultracentrifugation of his serum showed aggregates of polyclonal IgG3 of various sizes (between 10 and 36 S). The serum also contained immune complex-like material, as demonstrated by the Raji cell immunoradiometric assay and the C1q solid-phase enzyme immunoassay.


Ossification of the vascular pedicle in microsurgical fibular free flap reconstruction of the head and neck.
The fibular free flap, often used for osseous reconstruction following extirpation of head and neck malignancies, has been associated with heterotopic periosteal ossification. We aimed to determine the frequency and radiologic characteristics of this process and describe its clinical correlates. Surgical records for 2 years and neck imaging reports for 10 years were evaluated to identify patients with fibular free flap reconstruction and CT and/or PET/CT imaging available for review. The images were evaluated for the quality, type, and contour of ossification, and the reports were reviewed for associated clinical findings and radiologic impressions. Of 32 patients with posttreatment CT or PET/CT imaging, ossification was evident in 16 patients (50%) as early as 1 month following fibular free flap reconstruction. In 8 patients, it mimicked a new bone; in 5, it appeared as linear attenuation; in 2, as multiple short segments; and in 1 patient, a mixed appearance was found. No associated FDG uptake was seen on PET/CT. On MR imaging, these findings were extremely subtle or not appreciable. In only 1 patient was new bone associated with symptoms. Periosteal ossification of the vascular pedicle is commonly evident on CT following fibular free flap, even as early as 1 month after reconstruction, though the finding is not typically noted on imaging. While symptoms related to new bone are uncommon, they may mimic recurrent tumor. The location and pattern of ossification and the absence of a soft-tissue mass or FDG uptake are useful distinguishing imaging features.


Severe SOPH syndrome due to a novel NBAS mutation in a 27-year-old woman-Review of this pleiotropic, autosomal recessive disorder: Mystery solved after two decades.
Autosomal recessive SOPH syndrome was first described in the Yakuts population of Asia by Maksimova et al. in 2010. It arises from biallelic pathogenic variants in the NBAS gene and is characterized by severe postnatal growth retardation, senile facial appearance, small hands and feet, optic atrophy with loss of visual acuity and color vision, and normal intelligence (OMIM #614800). The presence of Pelger-Hüet anomaly in this disorder led to its name as an acronym for Short stature, Optic nerve atrophy, and Pelger-Hüet anomaly. Recent publications have further contributed to the characterization of this syndrome through additional phenotype-genotype correlations. We review the clinical features described in these publications and report on a 27-year-old woman with dwarfism with osteolysis and multiple skeletal problems, minor anomalies, immunodeficiency, diabetes mellitus, and multiple secondary medical problems. Her condition was considered an unknown autosomal recessive disorder for many years until exome sequencing provided the diagnosis by revealing a founder disease-causing variant that was compound heterozygous with a novel pathogenic variant in NBAS. Based on the major clinical features of this individual and others reported earlier, a revision of the acronym is warranted to facilitate clinical recognition.


[Regulation of voice quality parameters at the beginning of phonation].
In 8 healthy probands, 6 patients with functional voice disorders, 3 singers and 3 deaf patients we studied the regulation of the voice parameters amplitude and fundamental frequency at the beginning of phonation. Analyses were performed under the following conditions: (1) normal conditions; (2) after troubling pharyngeal and/or glottic mucosal receptors by topical anaesthesia; (3) in the case of normal hearing during disturbance of the audiophonatory feedback mechanism by binaural masking, and (4) with a combination of the latter two situations. The results are discussed.


DVT Management and Outcome Trends, 2001 to 2014.
A comprehensive evaluation of temporal trends in the treatment of patients who have DVT may assist with identification of modifiable factors that contribute to short-term outcomes. We assessed temporal trends in length of hospital stay and use of pharmacological and interventional therapies among 26,695 adults with DVT enrolled in the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001 and 2014. We also examined temporal trends in risk-adjusted rates of all-cause, pulmonary embolism-related, and bleeding-related death to 30 days after diagnosis. The mean length of hospital stay decreased from 9.0 days in 2001 to 2005 to 7.6 days in 2010 to 2014 (P < .01). For initial DVT treatment, the use of low-molecular-weight heparin decreased from 98% to 90% (P < .01). Direct oral anticoagulants use increased from 0.5% in 2010 to 13.4% in 2014 (P < .001). Risk-adjusted rates of 30-day all-cause mortality decreased from 3.9% in 2001 to 2005 to 2.7% in 2010 to 2014 (adjusted rate ratio per year, 0.84; 95% CI, 0.74-0.96; P < .01). VTE-related mortality showed a nonstatistically significant downward trend (adjusted rate ratio per year, 0.70; 95% CI, 0.44-1.10; P = .13), whereas 30-day bleeding-related mortality significantly decreased from 0.5% in 2001 to 2005 to 0.1% in 2010-2014 (adjusted rate ratio per year, 0.55; 95% CI, 0.40-0.77; P < .01). This international registry-based temporal analysis identified reductions in length of stay for adults hospitalized for DVT. The study also found a decreasing trend in adjusted rates of all-cause and bleeding-related mortality.


Black carbon emissions and reduction potential in China: 2015-2050.
Black carbon is a product of the incomplete combustion of carbonaceous fuels and has significant adverse effects on climate change, air quality, and human health. China has been a major contributor to global anthropogenic black carbon emissions. This study develops a black carbon inventory in China, using 2015 as the base year, and projects annual black carbon emissions in China for the period 2016-2050, under two scenarios: a Reference scenario and an Accelerated Reduction scenario. The study estimates that the total black carbon emissions in China in 2015 were 1100 thousand tons (kt), with residential use being the biggest contributor, accounting for more than half of the total black carbon emissions, followed by coke production, industry, agricultural waste burning, and transportation. This study then projects the total black carbon emissions in China in 2050 to be 278 kt in the Reference scenario and 86 kt in the Accelerated Reduction Scenario. Compared to the Reference scenario, the Accelerated Reduction scenario will achieve much faster and deeper black carbon reductions in all the sectors. The dramatic reductions can be attributed to the fuel switching in the residential sector, faster implementation of high-efficiency emission control measures in the industry, transportation, and coke production sectors, and faster phase-out of agricultural waste open burning. This analysis reveals the high potential of black carbon emission reductions across multiple sectors in China through the next thirty years.


Separation of gravitational-wave and cosmic-shear contributions to cosmic microwave background polarization.
Inflationary gravitational waves (GW) contribute to the curl component in the polarization of the cosmic microwave background (CMB). Cosmic shear--gravitational lensing of the CMB--converts a fraction of the dominant gradient polarization to the curl component. Higher-order correlations can be used to map the cosmic shear and subtract this contribution to the curl. Arcminute resolution will be required to pursue GW amplitudes smaller than those accessible by the Planck surveyor mission. The blurring by lensing of small-scale CMB power leads with this reconstruction technique to a minimum detectable GW amplitude corresponding to an inflation energy near 10(15) GeV.


Extracorporeal shock wave therapy induces alveolar bone regeneration.
Periodontal inflammation with alveolar bone resorption is a hallmark of periodontitis. We hypothesized that extracorporeal shock wave therapy (ESWT) could promote the regeneration of alveolar bone following Porphyromonas gingivalis-induced periodontitis in rats. Rats were infected with P. gingivalis for 10 wks, which caused alveolar bone resorption. The rats were then treated with a single episode of 100, 300, or 1000 impulses of shock wave on both cheeks at energy levels 0.1 mJ/mm(2). Alveolar bone levels were determined at 0, 3, 6, and 12 wks following ESWT and compared with those in untreated controls. Infected rats treated with 300 and 1000 impulses demonstrated significantly improved alveolar bone levels at 3 wks compared with untreated controls, and the improved levels remained for at least 6 wks in most rats. The results demonstrated effective regeneration of alveolar bone by ESWT and suggested that ESWT should be evaluated as an adjunct in the regeneration of periodontal tissues following periodontal disease. ESWT, extracorporeal shock wave therapy; PCR, polymerase chain-reaction.


Minimally invasive intramedullary nailing of midshaft clavicular fractures using titanium elastic nails.
In up to 31% of cases, nonsurgical treatment of midshaft clavicular fractures leads to unsatisfactory results such as nonunion, brachial plexus irritation, shortening and limited function of the shoulder. To date, various implants have been developed for open reduction including intramedullary wires, screws, and plates. This study discusses elastic stable intramedullary nailing of midshaft clavicular fractures. Between 2000 and 2005, 31 midshaft clavicular fractures were treated by intramedullary nailing with a titanium elastic nail (TEN). Subjective and clinical outcome were evaluated after an average follow-up of 26 (6-46) months. Patients were divided into three groups: patients with isolated clavicular fractures (group 1, n = 9); patients with additional injuries (group 2, n = 15), and patients with multiple injuries (group 3, n = 7). Nonunion was not observed. No patient sustained a refracture after TEN removal. Medial migration of the TEN in seven patients and iatrogenic perforation of the lateral cortex in one patient required secondary shortening on five occasions. Nail breakage after fracture healing was observed twice. Subjective outcome did not differ significantly between the three groups. Constant and Murley Score and the Disability of the Arm, Shoulder, and Hand Questionnaire Score showed no significant difference in the clinical outcome of the three groups. Intramedullary fixation of midshaft clavicular fractures with a TEN is a safe minimally invasive surgical technique achieving primary stability for practice. It can be seen as an alternative to plate or screw fixation or nonsurgical treatment, as it produces excellent cosmetic and functional results regardless whether patients suffered from isolated clavicular fractures, additional injuries, or multiple traumas.


The dlx5a/dlx6a genes play essential roles in the early development of zebrafish median fin and pectoral structures.
The Dlx5 and Dlx6 genes encode homeodomain transcription factors essential for the proper development of limbs in mammalian species. However, the role of their teleost counterparts in fin development has received little attention. Here, we show that dlx5a is an early marker of apical ectodermal cells of the pectoral fin buds and of the median fin fold, but also of cleithrum precursor cells during pectoral girdle development. We propose that early median fin fold establishment results from the medial convergence of dlx5a-expressing cells at the lateral edges of the neural keel. Expression analysis also shows involvement of dlx5a during appendage skeletogenesis. Using morpholino-mediated knock down, we demonstrate that disrupted dlx5a/6a function results in pectoral fin agenesis associated with misexpression of bmp4, fgf8a, and1 and msx genes. In contrast, the median fin fold presents defects in mesenchymal cell migration and actinotrichia formation, whereas the initial specification seems to occur normally. Our results demonstrate that the dlx5a/6a genes are essential for the induction of pectoral fin outgrowth, but are not required during median fin fold specification. The dlx5a/6a knock down also causes a failure of cleithrum formation associated with a drastic loss of runx2b and col10a1 expression. The data indicate distinct requirements for dlx5a/6a during median and pectoral fin development suggesting that initiation of unpaired and paired fin formation are not directed through the same molecular mechanisms. Our results refocus arguments on the mechanistic basis of paired appendage genesis during vertebrate evolution.


Comparative Contents of Polyphenolic Compounds in Aerial Parts of Cirsium esculentum, C. serratuloides, and Ancathia igniaria (Asteraceae).
Because Ancathia igniaria (Spreng.) DC. (Cirsium igniarium Spreng.) has been segregated as a monotypic genus from the genus Cirsium on the basis of phylogenetic data, chemotaxonomic differences are of interest to detect in the composition of polyphenolic components of aerial plant parts. Phenolic compounds are of chemotaxonomic significance in a number of genera and families. The polyphenolic profile of aerial parts was therefore compared for Cirsium esculentum (Siev.) C.A. Mey., Cirsium serratuloides (L.) Hill, and A. igniaria. The last two species were for the first time examined in this context. The compounds were identified against known standard via high-performance liquid chromatography (HPLC). The species of the genus Cirsium were found to have similar compositions of simple phenols, but differ in the set of flavonoids. Six to eight phenolic compounds were detected in the species, and three simple polyphenols (syringin, chlorogenic acid, and ethyl gallate) proved to be common. The flavonoid profiles of aerial parts included rutin in both Cirsium species. Cymaroside and quercetin-3-O-β-D-diglucoside-O-α-L-rhamnoside were species specific for C. serratuloides; salipurposide and hyperoside, for C. esculentum. An extract of A. igniaria aerial parts contained cinaroside (like in C. serratuloides), chrysin 7-O-glucoside, and eriodictyol. A greater difference in flavonoid composition was observed between the genera Cirsium and Ancathia. Data on phenolic compound composition are of importance for chemosystematics and use of plants as medicinal raw materials. The total content of coumarins, aglycones, and flavonoid glycosides in the species was determined by a spectrophotometric method. The contents of flavonoids and coumarins in C. esculentum and C. serratuloides were comparable and exceeded their contents in A. igniaria. Thus, A. igniaria proved to differ from the genus Cirsium in the quantitative and qualitative composition of phenolic compounds.


The carcinogenicity of metals in humans.
Epidemiologic evidence on the relation between exposure to metals and cancer is reviewed. Human exposure to metals is common, with wide use in industry and long-term environmental persistence. Historically, the heaviest metal exposures occurred in the workplace or in environmental settings in close proximity to industrial sources. Among the general population, exposure to a number of metals is widespread but generally at substantially lower levels than have been found in industry. The carcinogenicity of arsenic, chromium, and nickel has been established. Occupational and environmental arsenic exposure is linked to increased lung cancer risk in humans, although experimental studies remain inconclusive. Experimental studies clearly demonstrate the malignant potential of hexavalent(VI) chromium compounds, with solubility being an important determining factor. Epidemiologic studies of workers in chromium chemical production and use link exposure to lung and nasal cancer. Experimental and epidemiologic data show that sparingly-soluble nickel compounds and possibly also the soluble compounds are carcinogens linked to lung and nasal cancer in humans. Some experimental and epidemiologic studies suggest that lead may be a human carcinogen, but the evidence is inconclusive. Although epidemiologic data are less extensive for beryllium and cadmium, the findings in humans of excess cancer risk are supported by the clear demonstration of carcinogenicity in experimental studies. Other metals, including antimony and cobalt, may be human carcinogens, but the experimental and epidemiologic data are limited.


Steroid-binding G-protein-coupled receptors: new drug discovery targets for old ligands.
Steroid-binding receptors have long been a successful target class for the pharmaceutical industry. Clinical applications for steroids range from contraception and hormone replacement therapy to immune regulation and cancer therapy. With the recent demonstration that the orphan GPCR, GPR30 binds and is activated by estrogen, as well as the identification of a GPR30-selective agonist, it is likely that GPR30 represents a novel drug target with many potential clinical applications. This review discusses the role of GPR30 in mediating the effects of estrogen, as well as recent efforts to isolate GPR30-specific ligands using a combination of virtual and biomolecular screening. Finally, comments are made on the future directions regarding GPCRs, steroids and drug discovery.


Where does serum amylase come from and where does it go?
The serum amylase concentration reflects the balance between the rates of amylase entry into and removal from the blood. Hyperamylasemia can result either from an increased rate of entry of amylase into the circulation and/or a decreased metabolic clearance of this enzyme. The pancreas and salivary glands have amylase concentrations that are several orders of magnitude greater than that of any other normal tissue, and these two organs probably account for almost all of the serum amylase activity in normal persons. A variety of techniques are now available to distinguish pancreatic from salivary-type isoamylase. Pancreatic hyperamylasemia results from an insult to the pancreas, ranging from trivial (cannulation of the pancreatic duct) to severe (pancreatitis). In addition, loss of bowel integrity (infarction or perforation) causes pancreatic hyperamylasemia due to absorption of amylase from the intestinal lumen. Hyperamylasemia due to salivary-type isoamylase is observed in conditions involving the salivary glands. In addition, this type of hyperamylasemia occurs in conditions in which there is no clinical evidence of salivary gland disease, such as chronic alcoholism, postoperative states (particularly postcoronary bypass), lactic acidosis, anorexia nervosa or bulimia, and malignant neoplasms that secrete amylase. Hyperamylasemia can also result from decreased metabolic clearance of amylase due to renal failure or macroamylasemia (a condition in which an abnormally high-molecular-weight amylase is present in the serum). Patients with abdominal pain and a markedly elevated serum amylase (more than three times the upper limit of normal) usually have acute pancreatitis, and additional serum enzyme testing is not helpful. Patients with smaller elevations of serum amylase often have conditions other than pancreatitis, and measurement of a serum enzyme more specific for the pancreas (pancreatitic isoamylase, lipase or trypsin) is frequently of diagnostic value in such patients.


Examination of data from programs of in vitro fertilization in relation to sperm integrity and reproductive success.
This paper reviews the work of 11 different in vitro fertilization (IVF) groups from around the world in an effort to determine the effectiveness of IVF as a therapy for male factor infertility as well as threshold values for semen parameters that are synonymous with success. Two key questions that are asked are: 1) What fertilization rate is expected for male factor patients and 2) Can we predict which patients will fertilize. The immediate problem which arises in attempting to compare results from various groups is that there is no standardization in male factor criteria. This lack of agreement in what constitutes an abnormal semen sample is also reflected in the fertilization rates and threshold values. The first group reviewed (Mahadevan, 1983) suggest greater than 20% motile in the initial semen sample as a threshold value required for success while the second group (Cohen, 1985) presents 6 couples with less than 20% motility achieving pregnancy. Such inconsistencies in results are typical of this confusing and controversial area. Fertilization in IVF has been achieved with as few as 2 x 10(6) sperm/ml or as low as only 2% motility in the initial semen sample. It appears that most workers would agree that the lower limits of traditional semen parameters that are compatible with success are not well defined. Consensus might also be reached on the fact that fertilization rates are usually significantly lower in male factor cases than in normal semen parameters coupled with tubal infertility. Beyond those two factors, little agreement is found in the literature. The spectrum of methodology for semen processing is very broad and often not clearly detailed. In addition to the additional semen parameters of count, motility, and morphology, attempts have been made to establish other prognostic tests such as the sperm penetration assay (SPA), acrosome reaction determinations, and motility parameters such as velocity, linearity and lateral head displacement. Controversy abounds concerning the value of these newer tests. Threshold values for acrosome reaction and motility parameters have not been established. The SPA is believed to be highly predictive by some and unreliable by others. The one redeeming feature of this IVF male factor area is that it seems to be one of the most effect treatments for male factor infertility.


Arthritis-specific health beliefs related to aging among older male patients with knee and/or hip osteoarthritis.
Disease-specific beliefs may impact patients' perceptions of the efficacy of various treatment options, thus, it is important to understand these beliefs. We examined the relationship between patients' demographic characteristics and arthritis-specific beliefs related to aging. We performed a cross-sectional survey of 591 elderly primary care patients, who had symptomatic osteoarthritis (OA) of the knee and/or hip, at the Louis Stokes VA Medical Center in Cleveland, Ohio. Data were collected on age, race, educational level, income, and whether patients agreed or disagreed with four statements regarding aging and arthritis. We also assessed OA symptom severity using the Western Ontario McMaster Universities Index (WOMAC) and depressive symptoms using the Geriatric Depression Scale. We used logistic regression analyses to examine relationships between patients' age, race, and educational level and arthritis-specific health beliefs, while adjusting for OA symptom severity, radiographic confirmation of OA, OA joint burden, depressive symptoms, and income. Patients 70 years old or older, as compared to patients 50-59 years old, were more likely to believe that: arthritis is a natural part of growing old; people should expect that when they get older, they won't be able to walk as well, and people should expect to live with pain as they grow older. Among older, male veterans, health beliefs regarding the relationship between aging and arthritis vary by age. Clinicians should consider these differences when discussing treatment strategies with their patients with knee and/or hip OA.