Is the USA on track to end the HIV epidemic?
Despite progress in reducing new HIV infections in the USA, publicly available data suggest that new HIV infections continue to occur at an alarming rate. In this Viewpoint, we highlight the regularity with which the existing systems for HIV prevention and treatment delivery in the USA fail and the clearly inequitable effect of the systems' failure among several priority populations of the Ending the HIV Epidemic (EHE) initiative. Existing data cast doubt on whether the current EHE efforts will suffice to achieve its 2030 goal of reducing annual new HIV infections to fewer than 3000. We outline future directions in four priority areas to regain lost ground in pursuit of the 2030 EHE goals: reducing the stigma affecting people living with and most at risk of HIV; broadening the HIV workforce; mitigating harmful social determinants of health; and recommitting and reinvesting in health in the USA more broadly.


Intravesical chemotherapy of superficial bladder tumors in a controlled trial with cis-platinum versus cis-platinum plus hyaluronidase.
Twenty-three patients with superficial transitional cell carcinoma of the urinary bladder were randomized for intravesical chemotherapy with either cis-platinum or cis-platinum plus hyaluronidase, an enzyme promoting diffusion factor. Treatment was administered at 3-week intervals and checked for efficacy by repeated cystoscopies after every three instillations. Hematologic and biochemical tests were repeated prior to each treatment and, these, in additional to the cystoscopic findings, served for final evaluation of results and toxicity. The complete response rate was found to be superior with cis-platinum than with cis-platinum plus hyaluronidase. The complete plus partial response rates were equal in both groups. We conclude that the addition of hyaluronidase to cis-platinum revealed no superiority to cis-platinum alone, and both modes of treatment showed similar clinical efficacy as other drugs previously used for intravesical chemotherapy.


An expanded access program of erlotinib (Tarceva) in patients with advanced non-small cell lung cancer (NSCLC): data report from Italy.
Erlotinib demonstrated significantly prolonged survival versus placebo in patients with advanced NSCLC who had progressed after standard chemotherapy. TRUST is a phase IV trial initiated to provide erlotinib access to patients with advanced NSCLC. We report the interim analysis for patients enrolled in the TRUST trial in Italy. Eligible patients had stage IIIB/IV NSCLC and had failed or were unsuitable for chemotherapy. Erlotinib (150 mg/day orally) was given until disease progression or unacceptable toxicity. Patients were monitored monthly. At time of this analysis, data from 651 patients were available. Patient characteristics were: median age 66 years (range 30-87), male 69%, former or current smoker 71%, ECOG PS 0-1 81%, adenocarcinoma histology 52% and stage IV 82%. Erlotinib was administered as first-, second-, third- or other-line in 12, 45, 43 and <1% of patients, respectively. Response rate was 9%, with a disease-control rate of 63%. Median progression-free survival was 15 weeks and was longer in females (p<0.001), patients with adenocarcinoma (p=0.008), those with no smoking history (p<0.001) and patients who experienced skin toxicity (p<0.001). Safety data were available for 609 patients, 35% of whom had at least one adverse event (AE), but only 4% of patients discontinued treatment due to erlotinib-related AEs. This analysis of the Italian TRUST results confirms the activity and favourable safety profile of erlotinib in unselected patients with advanced NSCLC.


The Professional Future in Operated Carpal Tunnel Syndrome: A Cross-Sectional Study of Recognized Occupational Cases.
Carpal tunnel syndrome (CTS) is frequently present among workers. This syndrome's professional and economic impact makes it a priority in occupational health. We aimed to describe the professional future of workers suffering from occupational CTS after surgery and the factors that could influence their retention at the job. -Methods: A retrospective descriptive study of workers operated on occupational CTS was conducted from 2014 to 2019. The data was collected using pre-established and phone questionnaires to determine their professional future after surgery. We included 99 workers with operated CTS. They had a mean age of 45±6.5 years, were predominantly female (97%), and had two dependent children in 72.7% of cases. They worked as a seamstress in 44.4% of patients with a mean professional seniority of 18±7.2 years. The professional future was a return to work with a job transfer at 44.4% and job maintenance with ergonomic adjustments at 39.4%. A job loss was noticed in 12.2% of cases. Early retirement was noticed in 8.2%, dismissal in 3%, and resignation in 1% of cases. The factors influencing the professional future were age 50 to 59 years (p=0.01) and dependent children (p=0.02). In our survey, most operated-CTS workers benefited from a job transfer and kept their job with ergonomic adjustments to their work conditions. Therefore, interventions aiming to improve the professional future of workers operated on CTS by ensuring sufficient staff and adjusting workplaces are needed.


Associations Between Cancer Predisposition Mutations and Clonal Hematopoiesis in Patients With Solid Tumors.
Clonal hematopoiesis (CH), the expansion of clones in the hematopoietic system, has been linked to different internal and external features such as aging, genetic ancestry, smoking, and oncologic treatment. However, the interplay between mutations in known cancer predisposition genes and CH has not been thoroughly examined in patients with solid tumors. We used prospective tumor-blood paired sequencing data from 46,906 patients who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) testing to interrogate the associations between CH and rare pathogenic or likely pathogenic (P/LP) germline variants. We observed an enrichment of CH-positive patients among those carrying P/LP germline mutations and identified a significant association between P/LP germline variants in ATM and CH. Germline and CH comutation patterns in ATM, TP53, and CHEK2 suggested biallelic inactivation as a potential mediator of clonal expansion. Moreover, we observed that CH-PPM1D mutations, similar to somatic tumor-associated PPM1D mutations, were depleted in patients with P/LP germline mutations in the DNA damage response (DDR) genes ATM, CHEK2, and TP53. Patients with solid tumors and harboring P/LP germline mutations, CH mutations, and mosaicism chromosomal alterations might be at an increased risk of developing secondary leukemia while germline variants in TP53 were identified as an independent risk factor (hazard ratio, 36; P < .001) for secondary leukemias. Our results suggest a close relationship between inherited variants and CH mutations within the DDR genes in patients with solid tumors. Associations identified in this study might translate into enhanced clinical surveillance for CH and associated comorbidities in patients with cancer harboring these germline mutations.


A Diabetes Pay-for-Performance Program and Risks of Cancer Incidence and Death in Patients With Type 2 Diabetes in Taiwan.
We sought to evaluate the effects of diabetes disease management through a diabetes pay-for-performance (P4P) program in Taiwan on risks of incident cancer and mortality among patients with type 2 diabetes. We conducted a longitudinal observational cohort study using 3 population-based databases in Taiwan. Using propensity score matching, we compared patients with type 2 diabetes who enrolled in a P4P program with a similar group of patients who did not enroll in the in P4P program (non-P4P). Primary end points of interest were risks of incident cancer and all-cause, cancer-specific, and diabetes-related mortality. Total person-years and incidence and mortality rates per 1,000 person-years were calculated. Multivariable Cox proportional hazard models and competing risk regression were used in the analysis. Overall, our findings indicated that the diabetes P4P program was not significantly associated with lower risks of cancer incidence, but it was associated with lower risks of all-cause mortality (adjusted subdistribution hazard ratio [aSHR], 0.59; 95% confidence interval [CI], 0.55-0.63), cancer-specific mortality (aSHR, 0.85; 95% CI, 0.73-1.00), and diabetes-related mortality (aSHR, 0.54: 95% CI, 0.49-0.60). Metformin, thiazolidinediones, and α glucosidase inhibitors were associated with lower risks of cancer incidence and cancer-specific mortality. Our findings provide evidence of the potential benefit of diabetes P4P programs in reducing risks of all-cause mortality and competing causes of death attributable to cancer-specific and diabetes-related mortality among type 2 diabetes patients.


Ontogeny and characterization of [125I]Bolton Hunter-eledoisin binding sites in rat spinal cord by quantitative autoradiography.
The distribution and characteristics of [125I]Bolton Hunter-eledoisin binding sites in rat lumbar spinal cord were studied during postnatal development by in vitro receptor autoradiography. At three, six and 10 days of age, specific [125I]eledoisin binding was distributed throughout the dorsal and ventral horns of the spinal cord. In contrast, from day 24 onwards, specific binding of [125I]eledoisin was confined to superficial layers of the dorsal horn, with negligible amounts of specific binding in the ventral horn. [125I]Eledoisin binding to neonatal (three day) and adult (eight to 12 weeks) spinal cord sections was characterized using tachykinin agonists. In both dorsal and ventral horns of neonatal spinal cord, the rank order of potency of agonists indicated that the majority (64%) of specific [125I]eledoisin binding was to neurokinin-3 binding sites. The identity of the non-neurokinin-3 sites labelled by [125I]eledoisin remains to be determined. In adult rat spinal cord, [125I]eledoisin appeared to bind exclusively to neurokinin-3 binding sites. These results suggest that major changes take place in the localization of neurokinin-3 receptors during postnatal ontogeny of the rat spinal cord. These changes may reflect an important role for tachykinins in neuronal plasticity of the developing spinal cord.


[Intra-uterine pressure measurements during early pregnancy using endoradioprobes].
The intrauterine pressure was determined by means of endoradiosonde in 42 pregnant women before induced abortion. It was measured the tonus and after stimulation with oxytocin the liminal value the basic tonus and the highest increase of pressure. The values of pressure were higher after artificial rupture of the amnion than before. Telemetering of intrauterine pressure is an advantageous method.


An assessment of firework particle persistence on the hands and related police force practices in relation to GSR evidence.
In a previous study by Grima et al. Sci. Justice 52 (1) (2012) 49, it was shown that background particles can aid in the exclusion of firework particles which are indistinguishable from GSR. Issues relating to the persistence of such particle populations were presented. The scope of this project was to examine persistence on the hands in the context of possible post-display scene contamination and how this can affect GSR evidence, especially in light of possible GSR/firework mixtures. Persistence was investigated by recovering firework residues eight hours post-display following contact of the hands with bedding. In addition, particle profiling was carried out using SEM-EDX. Firework particle populations exhibited strong persistence in all displays, with not less than 667 particles persisting in each scenario. This factor challenges GSR evidence, especially if personnel stationed at display sites enter scenes of crime or come into contact with suspects after a display. A survey of UK police force practices following firework displays showed that authorities are not aware of the impact particle transfer may have on GSR evidence. Recommendations for the implementation of basic hygiene practices for particle transfer control have also been made.


Prevalence and Factors Associated With Poor Sleep Quality Among Visitors of Primary Healthcare Centers in Al-Ahsa, Kingdom of Saudi Arabia: An Analytical Cross-Sectional Study.
Introduction Poor sleep quality can predict poor health and is associated with mortality risk. Many factors are associated with sleep quality such as gender, health, education, socioeconomic status, and stress. The objective of this study was to estimate the magnitude of poor sleep quality among visitors of Primary Healthcare Centers (PHCCs) in Al-Ahsa and to identify factors associated with poor sleep quality. Methods This is an analytical cross-sectional study. A multistage cluster sampling technique was used to recruit 461 visitors to PHCCs in Al-Ahsa Governorate in the Eastern Province of Saudi Arabia. A structured questionnaire was administered through face-to-face interviews. The questionnaire includes demographics, a validated Arabic version of the Pittsburgh Sleep Quality Index (PSQI), the Arabic version of the International Physical Activity Questionnaire (IPAQ), the Arabic version of the Patient Health Questionnaire-2 (PHQ-2), the Arabic version of the Generalized Anxiety Disorder-2 (GAD-2), the Arabic version of Perceived Stress Scale-10 (PSS-10), and a translated Mobile Related Sleep Risk Factors (MRSRF). Univariate analysis was performed using the Mann-Whitney U test for continuous data, the chi-square test (χ²) or Fishers's exact test (as appropriate) for categorical data, and logistic regression for multivariable analysis. A P-value of less than or equal to 0.05 was considered significant. Results The study included 433 participants, with 72.5% of them being poor sleepers (PSQI global score of over 5). The highest percentage of poor sleepers was found among those aged 18 - 28 years (81.7%), with no significant difference between genders (p = 0.676). The study's multivariable logistic regression analysis revealed that poor sleep is associated with smoking four hours before bedtime (OR = 2.9, CI = 1.2 - 6.7), consuming caffeine (drinks or pills) three hours before sleep (OR = 2.3, CI = 1.23 - 4.12) or immediately before bedtime (OR = 3.2, CI = 1.02 - 9.9), using mobile phones right before bedtime (OR = 2.6, CI = 1.5 - 4.5), having anxiety (OR = 5.8, CI = 1.3 - 26.2), and depression symptoms (OR = 6.5, CI = 2.9 - 14.5), among other risk factors. Conclusion The prevalence of poor sleep quality in our sample was notably high at 72.5%. Many factors are strongly associated with poor sleep quality including experiencing symptoms of anxiety and depression. Longitudinal studies are needed to explore this crucial health issue further. Healthcare providers in Al-Ahsa should pay particular attention while assessing patients who suffer from sleep disturbance by screening them for depression and anxiety and raising public awareness of the importance of good quality sleep and the factors that affect it.


Identification of the proteins interacting with tRNA in rat liver small ribosomal subunits.
Irradiation at 254 nm of the rat liver 40 S ribosomal subunit-poly(U)-Phe[32P]tRNA complex induced a covalent linkage of tRNA with a limited number of ribosomal proteins. After RNA hydrolysis, S10 was found to be the protein most highly labeled by radioactive nucleotides. Some radioactivity was also associated with protein S6-6a, S3a, S2 and S13-15.


Mesenchymal stromal cells promote the proliferation of basal stem cells and efficient epithelization in organotypic models of wound healing.
Adipose derived mesenchymal stromal cells (ADSCs) represent a fascinating tool in the scenario of wound healing and regenerative medicine. Recent data already demonstrated that ADSCs could exert a stimulatory action on epithelial cells through secretion of soluble factors. The aim of the present study was to assess how ADSCs guide wound re-epithelization in vitro in the presence of keratinocytes. We used an organotypic model of wound healing and we seeded keratinocytes on a ADSC-induced dermal matrix. Conventional hematoxylin-eosin stain and immunohistochemistry staining for Ki67, p63 and pan-keratins were performed at different timepoints. Histological sections of organotypic cultures showed complete coverage of the ADSC-induced matrix by keratinocytes. Proliferation of basal stem cells was found to be the main mechanism responsible for epithelization of the dermis. In conclusion, ADSC do not only stimulate dermal regeneration through collagen deposition but also promote epithelization. HIGHLIGHTS: Mesenchymal stromal cells (MSCs) are widely used in regenerative medicine and wound healing. MSCs do not only stimulate dermal regeneration through collagen deposition but also promote epithelization. MSCs directly target the basal stem cell niche and promote its proliferation, migration and subsequent differentiation.


NNK enhances cell migration through α7-nicotinic acetylcholine receptor accompanied by increased of fibronectin expression in gastric cancer.
In this study, we intended to dissect the mechanism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-enhanced migration of gastric cancer. Smoking has been defined as a risk factor for gastric cancer. Tobacco-specific carcinogen, NNK, was reported to enhance cancer progression in gastric cancer. Currently, metastasis is the major issue for clinical cancer therapy, but the influence of NNK on the migration of gastric cancer remains to be determined. The expression of nicotinic receptor in gastric cancer cells was identified by real-time polymerase chain reaction and Western blotting. The influence of NNK on migration of gastric cancer cells was evaluated by the transwell migration assay system. Receptor-mediated migration was studied by both inhibitor and small interfering RNA. Alpha7 nicotinic acetylcholine receptor, alpha7-nicotinic acetylcholine receptor (nAChR), was identified higher than alpha9-nAChR in gastric cancer cell lines, AGS cells. NNK enhanced significantly gastric cancer cell migration in transwell assay. We used inhibitor and siRNA to demonstrate that alpha7-nAChR mediated NNK-enhanced gastric cancer cell migration and upregulation of fibronectin were involved in NNK-enhanced migration of gastric cancer cells. Finally, we found that silenced fibronectin expression level inhibited the migratory ability in AGS cells. NNK enhanced gastric cancer metastasis through alpha7-nAChR and fibronectin-one of the hallmarks of epithelial mesenchymal transition.


Spatiotemporal insights of APP function.
The amyloid-β precursor protein (APP) is a ubiquitous protein with a strong genetic link to Alzheimer's disease. Although the protein was identified more than forty years ago, its physiological function is still unclear. In recent years, advances in technology have allowed researchers to tackle APP functions in greater depth. In this review, we discuss the latest research pertaining to APP functions from development to aging. We also address the different roles that APP could play in specific types of cells of the central and peripheral nervous system and in other organs of the body. We argue that, until we fully identify the functions of APP in space and time, we will be missing important pieces of the puzzle to solve its pathological implication in Alzheimer's disease and beyond.


Xp11.2 translocation renal cell carcinoma with NONO-TFE3 gene fusion: morphology, prognosis, and potential pitfall in detecting TFE3 gene rearrangement.
Xp11 translocation renal cell carcinomas are characterized by several different translocations involving the TFE3 gene. Tumors with different specific gene fusions may have different clinicopathological manifestations. Fewer than 10 renal cell carcinoma cases with NONO-TFE3 have been described. Here we examined eight additional cases of this rare tumor using clinicopathological, immunohistochemical, and molecular analyses. The male-to-female ratio of our study cohort was 1:1, and the median age was 30 years. The most distinctive feature of the tumors was that they exhibited glandular/tubular or papillary architecture that was lined with small-to-medium cuboidal to high columnar cells with indistinct cell borders and an abundantly clear or flocculent eosinophilic cytoplasm. The nuclei were oriented toward the luminal surface and were round and uniform in shape, which resulted in the appearance of secretory endometrioid subnuclear vacuolization. The distinct glandular/tubular or papillary architecture was often accompanied by sheets of epithelial cells that presented a biphasic pattern. Immunohistochemically, all eight cases demonstrated moderate (2+) or strong (3+) positive staining for TFE3, CD10, RCC marker, and PAX-8. None of the tumors were immunoreactive for CK7, Cathepsin K, Melan-A, HMB45, Ksp-cadherin, Vimentin, CA9, 34βE12 or CD117. NONO-TFE3 fusion transcripts were identified in six cases by RT-PCR. All eight cases showed equivocal split signals with a distance of nearly 2 signal diameters and sometimes had false-negative results. Furthermore, we developed a fluorescence in situ hybridization (FISH) assay to serve as an adjunct diagnostic tool for the detection of the NONO-TFE3 fusion gene and used this method to detect the fusion gene in all eight cases. Long-term follow-up (range, 10-102 months) was available for 7 patients. All 7 patients were alive with no evidence of recurrent disease or disease progression after their initial resection. This report adds to the known data regarding NONO-TFE3 renal cell carcinoma.


[Zonography in diagnosis of maxillary and frontal sinus pathology].
The results of a survey roentgenogram of the paranasal sinuses in the nasomental projection were compared to those of maxillary and frontal sinus zonography according to an original technique in 150 patients aged 15-67 years with acute and chronic lesions in the frontal or maxillary sinuses. Diagnostic efficacy of paranasal sinus zonography is shown.


Valorization of residual bacterial biomass waste after polyhydroxyalkanoate isolation by hydrothermal treatment.
Hydrothermal treatment (HTT) was used to convert residual bacterial biomass (RBB), recovered from poly(3-hydroxybutyrate-co-3-hydroxyvalerate) production, into valuable bioproducts. The effect of processing temperatures (150, 200, and 250°C) on the bioproducts (water-solubles (WSs), bio-oil, insoluble residue, and gas) was investigated. The yields of bio-oil and gas were higher at higher temperatures. The maximum WS content (28 wt%) was obtained at 200°C. GCMS analysis showed higher content of aromatics and N-containing compounds with increasing temperature. ESI-MS revealed chemical compounds (e.g. protein, carbohydrate, lipids, and lignin) associated with RBB are fragmented into smaller molecules (monomers) at higher HTT temperatures. The WS fraction contained totally 838, 889 and 886mg/g acids and 160, 31 and 21 mg/g carbohydrate for HTT at 150, 200, and 250°C, respectively. The solid residues contain unconverted compounds, especially after HTT at 150°C. The WS products (acids and carbohydrates) could be used directly for PHA biosynthesis.


A systematic review and meta-analysis on the accuracy of rapid immunochromatographic tests for dengue diagnosis.
Rapid immunochromatographic tests are frequently used to diagnose dengue due to their easy use, low cost, and fast response. A high level of accuracy is essential for rapid diagnostic tests to support their large-scale use. Thus, this systematic review aims to evaluate the accuracy of rapid dengue diagnostic tests. The investigation was run through the following databases: LILACS, Medline (Pubmed), CRD, The Cochrane Library, Trip Medical Database, and Google Scholar. To solve difficulties, two independent reviewers performed document screening and selection. ELISA assay was adopted as a reference test because of several methodologic advantages. Seventeen articles were included accordingly, reckoning 6837 participating individuals. The receiver operating characteristic (ROC) and Forest Plot were conducted to evaluate the sensitivity and specificity for each analyzed parameter (anti-dengue IgM, IgG, and NS1 antigen). The risk of bias and quality of evidence were assessed as moderate using QUADAS-2 and Grading of Recommendations Assessment, Development, and Evaluation (GRADE), respectively. The sensitivity of IgM concerning the studied tests ranged from 13.8 to 90%, while that of NS1 ranged from 14.7 to 100% (95% CI). The antibodies with NS1 presented increased sensitivity; pooled data show that the association of the three analytes bestows the best result, with a combined sensitivity of 90% (CI 95%: 87-92%) and a pooled specificity of 89% (CI 95%: 87-92%). Thus, the present review provides relevant knowledge for decision-making between available rapid diagnostic tests.


Prevention of rheumatic fever and heart disease.
This brief overview of current information on rheumatic fever and rheumatic heart disease focuses on the problems of diagnosis, prevention, and treatment in relatively undeveloped countries.


Examining the influence of information overload on consumers' purchase in live streaming: A heuristic-systematic model perspective.
In recent years, the number of live streaming platforms and the number of viewers have exploded. For example, in China, there are already more than 100 live streaming platforms as well as more than 300 million consumers. In live commerce, streamers use 'information overload' to affect purchase decisions, by making it difficult for consumers to think systematically; however, the mechanism of impact in this way has not been confirmed. In order to clarify how information overload affects users' purchasing decisions in live commerce, this study introduces information overload from the perspective of "Heuristic-systematic model" to develop a research model. And 400 respondents were randomly recruited through various SNS platforms in Guangdong Province, China from July 1 to July 20, 2022 using a random survey method, and finally 297 valid sample data were obtained. To verify the validity of the model and to illustrate the impact of information overload marketing on consumer purchase decisions in live commerce this study conducted an empirical analysis using Smart PLS 3.0. The findings show that perceived product quality and fit, and streamer influence and expertise, positively affect consumers' purchase intentions. The information overload strategy can significantly reduce consumers' perceptions of merchandise fit and enhance their perceptions of streamer influence and expertise. The results of this study provide a theoretical basis for marketing strategies in live commerce, and enrich literature in the field of marketing.


Differentiating, evaluating, and classifying three quinoa ecotypes by washing, cooking and germination treatments, using 1H NMR-based metabolomic approach.
We processed three quinoa ecotypes as they are commonly consumed in a daily diet. For the treatments, quinoa seeds were washed, cooked, and/or germinated. Following treated, we used 1H NMR-based metabolomic profiling to explore differences between the ecotypes. Then, for a non-targeted and targeted food fingerprint analysis of samples, we performed multivariable data analyses, including principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA), and hierarchical cluster analysis. From our study, we were able to discriminate each quinoa ecotype regardless of treatment based on its metabolomic profiling. Additionally, we were able to identify 30 metabolites that were useful to determine the effect of each treatment on nutritional composition. Germination increased the content of most metabolites irrespective of ecotype. In general, ecotype CQE_03 was different from ecotypes CQE_01 and CQE_02. Our phytochemical analysis revealed the effects of washing, cooking, and/or germination, particularly on saponins content.


A facial swelling with multiple discharging sinuses: a diagnostic conundrum.
Many disease processes can present with facial swelling and multiple discharging sinuses. A differential diagnosis would include actinomycosis, tuberculosis and osteomyelitis, but tinea barbae is a relatively uncommon presentation. The following case report describes a 48-year-old jockey who was diagnosed with tinea barbae. It chronicles the investigations that were performed to determine the offending pathogen and the difficulty in achieving a diagnosis. The investigations and the pathophysiology of dermatophytic infections and their management in a maxillofacial/oral medicine environment are discussed.


Modulation of anxiety in rats evaluated in the elevated T-maze: evidence of the relationship between substance P and diazepam.
This study aimed to investigate the relationship between substance P (SP) and diazepam (DZP) in the modulation of anxiety and memory in rats as evaluated in the elevated T-maze (ETM). For this purpose, in the first experiment, rats were intraperitoneally (i.p.) pretreated with saline or DZP (1mg/kg) and 25min later they were intracerebroventricularly (i.c.v.) injected with PBS or SP (10 pmol). In the second experiment, rats were i.p. pretreated with saline or DZP (1mg/kg) and 25 min later were i.c.v. injected with FK888 (100 pmol, a NK1 antagonist). After 1 min, animals were i.c.v. injected with vehicle (PBS+ethanol 10%) or SP (10 pmol). Our results show that DZP significantly decreased the latency to leave the enclosed arm of the ETM in the test and re-test session, indicating an anxiolytic and an amnesic effect, respectively. Although the central administration of SP did not significantly alter 'per se' the latency to leave the enclosed arm of the ETM in the test and re-test sessions, there was a trend to increase this parameter in the test session (indicating an anxiogenic-like effect). Furthermore, SP was able to reverse, via NK1 receptors, the effect produced by DZP during the test session. Moreover, none of the treatments interfered in the one-way escape behavior recorded in the test or re-test session in the ETM. In conclusion, our results strengthen and extend previous experimental data showing an interaction between the tachykinergic and benzodiazepine-GABA systems in the modulation of anxiety.


Histological examinations of chief and parietal cells of the rat gastric glands after experimental administration of cephalexin and ethanol.
The experiment was carried out on Wistar rat males weighting about 200 g. Animals from experimental group I received 20% ethanol for drinking (ad libitum), animals from experimental group II--cephalexin in the dose of 42 mg/24 h, animals from experimental group III--cephalexin and ethanol in mentioned doses. After 10 days animals were decapitated and specimens of the stomach were taken from the greater curvature. It was stated that 10-day administration of 20% ethanol causes hyperemia of the gastric mucous membrane and the decrease of secretory activity of the glands. On the contrary, cephalexin causes the increase of secretory activity of chief and parietal cells. Concomitant administration of ethanol and cephalexin damages the gastric mucous membrane causing its narrowing, flattening of gastric pits and atrophy of secretory cells in the glands.


Electrochemical non-enzymatic glucose sensors.
The electrochemical determination of glucose concentration without using enzyme is one of the dreams that many researchers have been trying to make come true. As new materials have been reported and more knowledge on detailed mechanism of glucose oxidation has been unveiled, the non-enzymatic glucose sensor keeps coming closer to practical applications. Recent reports strongly imply that this progress will be accelerated in 'nanoera'. This article reviews the history of unraveling the mechanism of direct electrochemical oxidation of glucose and making attempts to develop successful electrochemical glucose sensors. The electrochemical oxidation of glucose molecules involves complex processes of adsorption, electron transfer, and subsequent chemical rearrangement, which are combined with the surface reactions on the metal surfaces. The information about the direct oxidation of glucose on solid-state surfaces as well as new electrode materials will lead us to possible breakthroughs in designing the enzymeless glucose sensing devices that realize innovative and powerful detection. An example of those is to introduce nanoporous platinum as an electrode, on which glucose is oxidized electrochemically with remarkable sensitivity and selectivity. Better model of such glucose sensors is sought by summarizing and revisiting the previous reports on the electrochemistry of glucose itself and new electrode materials.


Carboxymethyl chitosan-quercetin conjugate: A sustainable one-step synthesis and use for food preservation.
Bioactive polysaccharide, carboxymethyl chitosan-quercetin (CMCS-q) was prepared by a one-step reaction utilizing Schiff base chemistry. Notably, the presented conjugation method involves neither radical reactions nor auxiliary coupling agents. Physicochemical properties and bioactivity of the modified polymer were studied and compared to those of the pristine carboxymethyl chitosan, CMCS. The modified CMCS-q demonstrated antioxidant activity by TEAC assay and antifungal activity by inhibiting spore germination of plant pathogen Botrytis cynerea. Then, CMCS-q was applied as an active coating on fresh-cut apples. The treatment resulted in enhanced firmness, inhibited browning and improved microbiological quality of the food product. The presented conjugation method allows retaining antimicrobial and antioxidant activity of quercetin moiety in the modified biopolymer. This method can be further used as a platform for binding ketone/aldehyde-containing polyphenols and other natural compounds to form various bioactive polymers.


Role of serotonin 5-HT1B receptors in psychostimulant addiction.
Psychostimulant (cocaine, amphetamine and its derivatives) addiction is an important health problem with implications in social and economic life. Although mesocorticolimbic dopamine system plays a crucial role in the mechanism responsible for the rewarding effects of these drugs, recent data also show involvement of the brain serotonin (5-HT) system. In the present review we discuss the role of 5-HT(1B) receptors in the psychostimulant addiction on the base of the effects of 5-HT(1B) receptor ligands on the behavioral effects of the psychostimulants in experimental models (sensitization, intracranial self-stimulation, conditioned place preference, self-administration and extinction/reinstatement model) used to assess their addictive properties. Moreover, the effect of long-term treatment with psychostimulants on 5-HT(1B) receptors is also discussed.


3D Printing of Collagen Scaffold with Enhanced Resolution in a Citrate-Modulated Gellan Gum Microgel Bath.
3D printing in a microgel-based supporting bath enables the construction of complex structures with soft and watery biomaterials but the low print resolution is usually an obstacle to its practical application in tissue engineering. Herein, high-resolution printing of a 3D collagen organ scaffold is realized by using an engineered Gellan gum (GG) microgel bath containing trisodium citrate (TSC). The introduction of TSC into the bath system not only mitigates the aggregation of GG microgels, leading to a more homogeneous bath morphology but also suppresses the diffusion of the collagen ink in the bath due to the dehydration effect of TSC, both of which contribute to the improvement of print resolution. 3D collagen organ structures such as hand, ear, and heart are successfully constructed with high shape fidelity in the developed bath. After printing, the GG and TSC can be easily removed by washing with water, and the obtained collagen product exhibits good cell affinity in a tissue scaffold application. This work offers an easy-to-operate strategy for developing a microgel bath for high-resolution printing of collagen, providing an alternative path to in vitro 3D organ construction.


Phoneme awareness is a key component of alphabetic literacy skills in consistent and inconsistent orthographies: evidence from Czech and English children.
Two studies investigated the importance of phoneme awareness relative to other predictors in the development of reading and spelling among children learning a consistent orthography (Czech) and an inconsistent orthography (English). In Study 1, structural equation models revealed that Czech (n=107) and English (n=71) data were fitted well by the same predictors of reading and spelling. Phoneme awareness was a unique predictor in all models. In Study 2, Czech (n=40) and English (n=27) children with dyslexia showed similar deficits on phoneme awareness relative to their age- and spelling-matched control peers. Phoneme awareness appears to be a core component skill of alphabetic literacy, which is equally important for learners of consistent and inconsistent orthographies.


Molecular structure and vibrational spectral investigation of charge transfer NLO crystal naphthalene picrate for THz application.
Molecular structure and the vibrational spectra of Naphthalene Picrate have been calculated using density functional theoretical computation and compared with the experimental. The dipole moments (μ), polarizability (α), first hyperpolarizabilities (β) second hyperpolarizability (γ) and frontier molecular orbital energies are computed at the DFT level. The frontier molecular orbital calculation shows the inverse relationship of HOMO-LUMO gap with the total static hyperpolarizability. The hyperpolarizability value reveals that these classes of organic compounds show very large non-linear optical properties. Natural Bond Orbital analysis confirms the presence of intramolecular charge transfer and the hydrogen bonding interaction. Terahertz time-domain spectroscopy has been used to detect the absorption spectra in the frequency range from 0.2 to 1.5 THz.


Outcome of hypocalcaemia after thyroidectomy treated only in symptomatic patients.
Calcium supplementation has been proposed after bilateral thyroid surgery, either to all patients or to those with biochemical hypocalcaemia. It has also been suggested that supplementation aids parathyroid recovery and prevents permanent hypoparathyroidism. This single-centre study investigated the feasibility of a restrictive management of post-thyroidectomy hypocalcaemia. Serum calcium was checked before surgery, on postoperative day 1 (POD) 1, at a follow-up visit 6-8 weeks after surgery and after a minimum of 12 months in all patients. Regardless of serum calcium levels, patients with symptoms of hypocalcaemia were prescribed oral calcium supplementation (0·5-1·0 g twice daily) and asymptomatic patients were not. Asymptomatic patients were informed about hypocalcaemic symptoms and instructed to contact the surgical ward should symptoms appear. Some 640 patients underwent bilateral thyroid surgery without previous or intentional simultaneous parathyroidectomy. A subnormal serum calcium level (below 2·15 mmol/l) was observed in 412 patients (64·4 per cent) on POD 1. By comparison, only 63 patients (9·8 per cent) experienced symptoms of hypocalcaemia in the postoperative period, all but one with a corresponding biochemical hypocalcaemia on POD 1. Calcium levels in all patients with asymptomatic postoperative hypocalcaemia recovered to normal without supplementation. Serum calcium was also normalized during follow-up in all symptomatic patients, except 22 (3·4 per cent) who became permanently hypoparathyroid. No patient without early hypocalcaemic symptoms developed permanent hypoparathyroidism. The proposed restrictive management of postoperative hypocalcaemia after bilateral thyroid surgery avoids unnecessary supplementation for most patients.


Regional studies of myelin proteins in human brain and spinal cord.
The myelin specific proteins, myelin basic protein (MBP) and myelin proteolipid protein (PLP) were quantitated by radioimmunoassay (RIA) and the activity of the enzyme 2',3'-cyclic 3' phosphohydrolase (CNP) measured, in 27 regions of normal brain and spinal cord. Varying regional concentrations for each protein and regional variations for protein ratios were noted, supporting the concept of a varying chemical composition for myelin throughout the central nervous system (CNS). Variation was also noted among myelin subfractions from a single region. Regions with special sensitivity to the multiple sclerosis process had relatively lower proportions of CNP in several, but not all cases.


N-Aralkyl substitution increases the affinity of adrenergic drugs for the alpha-adrenoceptor in rat liver.
1 The alpha-adrenoceptor of rat liver plasma membranes was studied by use of the specific alpha-antagonist [3H]-dihydroergocryptine ([3H]-DHEC). Catecholamines and adrenergic compounds displayed an order of affinity that is typical of an alpha-receptor. Nevertheless, protokylol, a potent beta-adrenoceptor agonist, exhibited a higher affinity than that of adrenaline for alpha-sites. This result might be due to its bulky substituent on the amino group. 2 Further displacement experiments between [3H]-DHEC and four pairs of drugs differently substituted on the amino group (isoprenaline vs Cc-25, orciprenaline vs fenoterol, AH 3474 vs labetalol, pindolol vs hydroxybenzylpindolol) provided evidence that N-alkyl substitution decreased the affinity for alpha-sites (20 micromolar less than KD less than 200 micromolar), whereas an N-aralkyl one increased the affinity (0.17 micromloar less than KD less than 4.6 micromolar). 3 It is concluded that a substitution on the amino group by a bulky, hydrophobic moiety enhances the affinity of drugs for the alpha-adrenoceptors.


Modulation of interfacial interactions toward strong and tough cellulose nanofiber-based transparent thin films with antifogging feature.
Cross-linking is often performed to overcome the weak mechanical properties of native polymer films in order to expand their functional properties and applications. While this approach offers enhanced strength to the film, the film also suffers from low flexibility, low toughness and high brittleness. However, in view of the growing demand for strong and tough transparent thin films, this article reported our study to develop films made from cellulose nanofiber (CNF) via tailoring the interfacial bonding interactions through the application of glycerol (Gly) and glutaraldehyde (GA), which functioned as a plasticizer and cross-linking agent, respectively. Among the prepared films, the 10GA-8Gly-CNF film exhibited the best results with regard to the enhancement in the tensile strength (21.1%), Young's modulus (10.6%), elongation at break (100%) and toughness (32.7%), as compared to the native CNF film. Importantly, treating the surface of the film to radiofrequency oxygen plasma endowed the film with antifogging property, without compromising the optical clarity.


[Neurodystrophic lesions of the osteoarticular apparatus and their importance in assessing the trophic function of the spinal cord].
An analysis of neurodystrophical lesions of the bone-joint apparatus of spinal etiology permitted to establish some general regularities and their expression and to detect their interrelation between disturbances of the spinal trophical functions as well. Neurodystrophical lesions should be considered as indices of disturbed spinal trophical functions and secondary inadequacy of the locomotor system.


Targeting the Microbiome in Heart Failure.
Heart failure is the leading cause of mortality and morbidity in the world today. While there have been major advances in our understanding of the pathophysiology of heart failure over the past decades, disease progression remains inevitable in the majority of patients and effective therapies to prevent heart failure are still lacking. Research has turned to better understand the gut microbiome because alterations in their ecosystems have been associated with various downstream chronic conditions including cardiovascular diseases. The gut microbiome is complex and diverse in nature, making it difficult to generalize to specific populations or individual patients. Nevertheless, current evidence has found links between heart failure and alterations in microbial composition and function, since heart failure has long been associated with impaired intestinal barrier function and bacterial translocation leading to inflammatory and immune responses. Recent studies have also shed light on the contributions of gut microbiota-derived metabolites from dietary nutrients that can promote adverse effects in the setting of cardiorenal diseases. In this review, we will discuss the role of gut microbiome in the setting of heart failure and potential interventional approaches that may potentially lower the risk of disease progression in heart failure.


Calculating equivalent dose received from a patient undergoing nuclear medicine procedure by merge phantoms tool and GAMOS/Geant4 6.0.0 software.
This report introduces a tool for merging two voxel phantoms to calculate the deposited dose that a person receives from a patient undergoing Nuclear medicine procedures. The phantoms must be converted to the text format used by GEANT4 to treat DICOM images via the GAMOS utilities. The Merge Phantoms Tool can merge two phantoms in two different cases: standing either side by side or opposite. The merged phantom is also in text format and is subsequently input back into GAMOS to calculate the equivalent dose that a person receives from a patient. The equivalent doses to the eyes of people in contact are calculated in a case where a patient was administered 185 MBq of 18F-FDG during a PET examination. The corresponding doses when the two phantoms are standing opposite are greater than those when they are standing side by side and smaller than those from point and tube source calculated by Sumi Yokoyama at any distance. The Merge phantoms tool and GAMOS software can be used to calculate the deposited dose that a person receives from a patient. An accurate dose calculation can be used for radiation protection, or deciding whether a patient can be released from isolation if the dose is small even in a close contact.


Blood flow in the resting forearm during prolonged contralateral isometric handgrip at maximal effort.
1. In earlier studies we have shown that muscle contraction performed as handgrip at constant force, one third of maximal voluntary contraction (MVC), induces a rapid vasodilation in the resting contralateral forearm which in all probability is neurogenically mediated, followed by a relative increase in resistance.2. The maintenance of contraction at one third MVC for 2 min requires continuously increasing effort because of fatigue, as also evidence by the e.m.g. The biphasic response of the vascular bed may then be related to the increasing intensity of somatomotor activation which is needed to maintain contraction force, or, alternatively, to differences in vasomotor activity on initiation of and continued muscle activity.3. To elucidate these two possibilities blood flow in the resting forearm was measured during contralateral handgrips at constant maximal effort for 6 min (in which case force will drop) and compared to handgrip at constant force, one third MVC, for 2 min.4. The flow reaction during prolonged contraction at maximal effort was similar to that induced by contraction at constant force with a marked transient lowering of vascular resistance, although maximal vasodilation tended to be more pronounced and occur earlier.5. The results indicate that the rapid decrease in vascular resistance is related primarily to the initiation of somatomotor activity, whereas continued muscle contraction produces a relative increase in vasoconstrictor activity irrespective of changes in contraction effort.


Intraperitoneal cytokine response after major surgery: higher postoperative intraperitoneal versus systemic cytokine levels suggest the gastrointestinal tract as the major source of the postoperative inflammatory reaction.
Cytokine response is an important factor in the development of shock and organ failure. The aim of this study was to investigate intraperitoneal (peritoneal) and venous (systemic) postoperative cytokine release after major surgery. Major abdominal surgery was performed in 19 patients. Preoperative systemic measurements and postoperative systemic and peritoneal measurements of C-reactive protein (CRP) and the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL-6), and IL-10 were performed. Significantly higher TNF-alpha, IL-6, and IL-10 peritoneal values were recorded compared with systemic values, whereas peritoneal CRP was significantly decreased. CRP increased significantly over time, whereas postoperative values of IL-6, IL-10, and peritoneal TNF-alpha decreased. Systemic TNF-alpha was constant over time, but values after emergent abdominal surgery showed a more extensive response. An additional effect of surgery and emergent abdominal disease was seen in increased TNF-alpha and IL-10 levels. Compared with systemic cytokines, peritoneal cytokines respond extensively after major surgery, indicating that measurement of peritoneal cytokines is a more sensible method to determine postoperative inflammatory reaction. A normal postoperative course is characterized by decreasing levels of peritoneal cytokines.


Molding the sensory cortex: spatial acuity improves after botulinum toxin treatment for cervical dystonia.
Disorganization of sensory cortical somatotopy has been described in adult onset primary torsion dystonia (AOPTD). Although botulinum toxin type A (BTX-A) acts peripherally, some studies have suggested a central effect. Our primary hypothesis was that sensory cortical reorganization occurs after BTX-A treatment of AOPTD. Twenty patients with cervical dystonia and 18 healthy age-matched control patients had spatial discrimination thresholds (SDTs) measured at baseline and monthly for 3 months. Mean baseline SDT (+/-SD) was 1.75 +/-0.76 mm in the dystonia group, greater than the control group mean of 1.323 +/- 0.45 mm (P = 0.05). Mean control group SDT did not vary significantly over time. A transient improvement of 23% from baseline (P = 0.005) occurred in the dystonia group 1 month after injection, which did not positively correlate with changes in physician and patient ratings of torticollis severity. The presumed mechanism of SDT improvement is a modulation of afferent cortical inputs from muscle spindles. Society.


MRI of the cranial nerves--more than meets the eye: technical considerations and advanced anatomy.
Magnetic resonance (MR) imaging is the method of choice to evaluate the cranial nerves. Although the skull base foramina can be seen on CT, the nerves themselves can only be visualized in detail on MR. To see the different segments of nerves I to XII, the right sequences must be used. Detailed clinical information is needed by the radiologist so that a tailored MR study can be performed. In this article, MR principles for imaging of the cranial nerves are discussed. The basic anatomy of the cranial nerves and the cranial nerve nuclei as well as their central connections are discussed and illustrated briefly. The emphasis is on less known or more advanced extra-axial anatomy, illustrated with high-resolution MR images.


Orienting reaction may help recognition of patients with psychogenic nonepileptic seizures.
Psychogenic nonepileptic seizures (PNES) are abrupt, paroxysmal changes in behavior or consciousness that may phenomenologically resemble epileptic seizures. Given the known association between anxiety and PNES, we hypothesized that in these subjects there may be evidence that the nervous system is hypersensitive to external stimuli. We aimed to test our hypothesis by means of the auditory startle reaction (ASR). By investigating ASR, we also had the opportunity to test presence of orienting reaction, which is generally defined as the second phase of response after the auditory stimulus, with longer latency. We included 22 patients diagnosed as PNES and 25 age- and gender-matched healthy subjects. Clinical assessments and ASR recordings were performed. Electrophysiological findings were compared between patients with PNES and healthy subjects, including the presence of an orienting reaction. Orienting reaction was defined as a late response with latency between 100-1000ms. The mean ages of patients with PNES and healthy subjects were 34.9±12.3 years and 33.3±10.9 years, respectively (P=0.709). All patients were diagnosed as having conversion disorder. Additionally, 19 patients had depressive disorder and four had anxiety. The recruitment pattern of muscles and probability were similar between patients with PNES and healthy subjects. Orienting reaction was solely observed in patients with PNES (n=13, 59.1% of the patients vs. no healthy subject). The sequence and contribution of muscles in the orienting reaction changed almost in all patients. The duration of these responses was long, sometimes more than 200ms. PNES is associated with orienting reaction. This provides a possible electrophysiological marker of altered nervous system function in patients with PNES and may also reflect the distorted emotional processing in these patients.


Safety of two common laparoscopic inguinal herniorrhaphy approaches: an updated systematic review with meta-analysis of randomized clinical trials.
Previous evidence indicated that total extraperitoneal (TEP) and transabdominal preperitoneal (TAPP) are advantageous in efficacy of inguinal herniorrhaphy. Therefore, our aim in this study was to evaluate the association of the two laparoscopic approaches on safety of inguinal herniorrhaphy. In this update study, we searched the Cochrane Library, EMBASE, PubMed, Scopus, and Web of Science and identified randomized clinical trials comparing complications in TEP and TAPP herniorrhaphy. We mainly used Peto odds ratio with 95% confidence interval (CI) for meta-analysis because of zero-cell. Fourteen eligible trials recruited 659 and 682 patients in TEP and TAPP respectively. In overall pooling, although TEP had a higher seroma rate than TAPP (Peto odds ratio =2.01; 95% CI, 1.39 to 2.91), it had a lower scrotal/cord edema rates at immediate postoperative (Peto odds ratio =0.22; 95% CI, 0.09 to 0.57) and 1 week after inguinal hernia repair (Peto odds ratio =0.58; 95% CI, 0.37 to 0.91) than TAPP. TEP and TAPP have their own advantages in inguinal herniorrhaphy. TAPP was associated with a lower seroma rate, and TEP was associated with a lower edema rate. Therefore, shared decision-making on laparoscopic inguinal herniorrhaphy with TEP and TAPP is still needed.


Galectin-3 as TREM2 upstream factor contributes to lung ischemia-reperfusion injury by regulating macrophage polarization.
Lung ischemia-reperfusion injury (LIRI) is a complex "aseptic" inflammatory response, macrophage play a pivotal role in the pathogenesis of LIRI. Galectin-3 (Gal3), a lectin implicated inflammation, has received limited attention in LIRI. Studies have reported Gal3 as a ligand for triggering receptor expressed on myeloid cell 2 (TREM2) in macrophages in Alzheimer's disease. Hence, we established LIRI C57BL/6 mice model and hypoxia/glucose deprivation and reoxygenation (OGD/R) model to investigate the relationship among Gal3, TREM2, and macrophage polarization. Our result demonstrated inhibition of Gal3 significantly reduced M1-type macrophage polarization while markedly increased M2-type in LIRI. In addition, we observed colocalization of Gal3 and TREM2 in macrophages, inhibition of Gal3 could recover the downregulation of TREM2 induced by LIRI while promoting TREM2 expression could attenuate lung injury in LIRI. In summary, our findings suggest Gal3 as an upstream factor of TREM2, play a crucial role in LIRI by regulating macrophage polarization.


Declining Long-term Risk of Adverse Events after First-time Community-presenting Venous Thromboembolism: The Population-based Worcester VTE Study (1999 to 2009).
Contemporary trends in health-care delivery are shifting the management of venous thromboembolism (VTE) events (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) from the hospital to the community, which may have implications for its prevention, treatment, and outcomes. Population-based surveillance study monitoring trends in clinical epidemiology among residents of the Worcester, Massachusetts, metropolitan statistical area (WMSA) diagnosed with an acute VTE in all 12 WMSA hospitals. Patients were followed for up to 3 years after their index event. Total of 2334 WMSA residents diagnosed with first-time community-presenting VTE (occurring in an ambulatory setting or diagnosed within 24 hours of hospitalization) from 1999 through 2009. While PE patients were consistently admitted to the hospital for treatment over time, the proportion diagnosed with DVT-alone admitted to the hospital decreased from 67% in 1999 to 37% in 2009 (p value for trend <0.001). Among hospitalized patients, the mean length of stay decreased from 5.6 to 4.8 days (p value for trend <0.001). Between 1999 and 2009, treatment of VTE shifted from warfarin and unfractionated heparin towards use of low-molecular-weight heparins and newer anticoagulants; also, 3-year cumulative event rates decreased for all-cause mortality (41-26%), major bleeding (12-6%), and recurrent VTE (17-9%). A decade of change in VTE management was accompanied by improved long-term outcomes. However, rates of adverse events remained fairly high in our population-based surveillance study, implying that new risk-assessment tools to identify individuals at increased risk for developing major adverse outcomes over the long term are needed.


Fractionation, biochemical characterization and lysosomal phospholipases of human liver.
Human liver was homogenised and fractionated by differential centrifugation, and the subcellular fractions were characterised biochemically. Absolute values and distribution patterns of protein and marker enzyme activities obtained from human liver have also been compared with those from rat liver. In addition, acid phospholipase activities have been studied in human liver. On the basis of product formation from stereo-specifically radiolabeled phosphatidylethanolamine substrates, lysosomal phospholipases A1 and A2 with optimal activities at pH 4.7 have been identified in human liver. Acid phospholipase C and lysophospholipase activities, however, were not found in human liver. Cationic amphiphilic drugs inhibited the activities of the acid phospholipases A in human and rat liver lysosomes to about the same extent.


Effects of feeding Saccharomyces cerevisiae fermentation products on the health and growth performance of Holstein dairy calves.
It is essential to reduce antibiotic use in the livestock industry, which leads to a need for alternatives to antibiotics that reduce illness and promote growth in dairy calves. The objective of this study was to evaluate the effect of feeding dairy calves Saccharomyces cerevisiae fermentation products (SCFP) on average daily gain (ADG) and antibiotic use in dairy calves through 4 mo of age. Holstein bull calves (n = 60; 5 ± 3 d old) were blocked by body weight (BW) and serum total protein (STP) and assigned to 1 of 2 treatments. The control treatment (CON) fed a 24% crude protein (CP):17% fat milk replacer (MR), calf starter, grower #1, and grower #2 with no SCFP added. The SCFP treatment fed the same MR with 1 g/d of SCFP, calf starter with 0.8% (dry matter; DM) SCFP, grower #1 with 0.44% (DM) SCFP, and grower #2 with 0.275% (DM) SCFP. Calves were offered 2.84 L (12.5% solids) of MR twice daily (0630 and 1630 h) through d 51 and MR once daily (0630 h) from d 52 to 56, and were weaned on d 57. From d 1 to 56, calves also received ad libitum access to calf starter and water. On d 57, calves were switched to grower #1 and on d 84, calves were switched to grower #2, which contained a lower level of CP and a higher level of neutral detergent fiber (NDF). Individual calf BW, body condition score (BCS), hip height (HH), and hip width (HW) were measured biweekly from d 0 to 112. Feed intake was recorded daily, and feed efficiency (gain:feed) and ADG were calculated. Daily fecal and respiratory scores were recorded for each calf through d 56, and all medical interventions were recorded for the duration of the study and grouped based on illness. We found no effect of treatment on STP, BW, BCS, HH, or HW at d 0 or 56, nor effects on preweaning ADG and feed efficiency. No treatment effect was observed for BCS or HH at d 112; however, BW and HW were increased in SCFP calves at d 112. A treatment tendency was observed for postweaning ADG, with SCFP calves being larger than CON calves and SCFP calves having improved feed efficiency compared with CON calves after weaning. A treatment effect was observed for respiratory treatments postweaning, with SCFP calves being treated less frequently than CON calves. Our results suggest that feeding SCFP to calves improves postweaning growth and feed efficiency, and reduces postweaning respiratory disease interventions.


Xylitol pentanitrate - Its characterization and analysis.
Xylitol is a polyhydric alcohol that may be nitrated to form an explosive (xylitol pentanitrate or XPN). Consequently, forensic and first response personnel may encounter XPN in post-blast residues or as a bulk material. Despite this, key analytical data for XPN that may be used in first response or forensic operations to aid its detection are not yet available in the literature. The present article provides infrared spectrometry, Raman spectrometry, nuclear magnetic resonance spectrometry, chromatography and mass spectrometry data in order to address this knowledge gap.


[Immunopathology of cutaneous drug eruptions].
Adverse drug reactions (ADR) are common and may present clinically and histologically in a very heterogeneous manner. The pathophysiological understanding about causal immunological and non-immunological events has developed significantly over the past years. Skin and mucosa are commonly affected and are prone for histopathological examination. Certain groups of drugs such as immune checkpoint inhibitors may cause specific adverse reactions. To provide a comprehensive overview of the complex immunological events and the most common dermatohistopathological findings of cutaneous adverse drug reactions. Review of the literature (PubMed), own study data and pictures obtained via routine diagnostics at the University of Bonn. Drugs may induce a wide range of skin reactions displaying a diversity of cutaneous inflammatory patterns. Histopathological clues for drug eruptions may be: eosinophils, lichenoid infiltrate and isolated keratinocytic apoptosis; a thorough medical history and correlation of clinical findings and dermatohistopathology are most important. Knowledge of typical adverse reactions to checkpoint inhibitors and their management is of great clinical interest as their use is rising steadily.


Hydroxypropyl-β-cyclodextrin impacts renal and systemic hemodynamics in the anesthetized dog.
Hydroxypropyl-β-cyclodextrin (HPβCD) is a complexation agent used to enhance drug solubilization and formulation stability. Although its toxicity is well characterized, its cardiovascular effects are less known. To investigate them, HPβCD was infused intravenously over 10 min in anesthetized dogs (10-40% (w/v, i.e. 200-800 mg/kg) in non-denervated animals and at 40% in denervated animals). HPβCD increased renal arteriolar resistance and decreased renal blood flow at all doses, almost immediately after infusion start, more drastically in females. A less pronounced increase in total peripheral resistance occurred in females only due to sex difference in sympathetic tone. Pulmonary hemodynamic parameters remained unaffected, suggesting that the renal effect was rather selective. As a consequence of the increased systemic blood pressure, heart rate decreased in normal animals without direct effect on cardiac conductance. This effect was abolished in denervated animals. This suggests that autonomous nervous feedback loops are functional in normal animals and that HPβCD has no direct chronotropic effect. In conclusion, systemic and renal hemodynamic changes should be considered as potential background effects at 200-400 mg/kg. At higher doses (800 mg/kg), changes are more pronounced and could mask/exacerbate hemodynamic response of drug candidate; such doses should be avoided in nonclinical safety studies.


Myophosphorylase deficiency associated with a defect in complex I of the mitochondrial respiratory chain.
We studied a 21-year-old patient with clinical, biochemical and histochemical evidence of myophosphorylase deficiency and unusual repetitive episodes of pigmenturia. His muscle biopsy also revealed morphological signs of mitochondrial proliferation and a defect of complex I of the respiratory chain. His mother had exercise intolerance without myoglobinuria and no histochemical evidence of myophosphorylase deficiency. In muscle, the mother showed some ragged-red fibers, normal respiratory chain levels and a significant residual phosphorylase activity. Molecular genetic analysis revealed that the proband was homozygous for the mutation commonly found in McArdle's disease. The mother, father, and the five siblings were all heterozygous for the same mutation. Mitochondrial DNA analysis of the proband's muscle failed to demonstrate known mutations associated with his clinical pattern. Moreover, we sequenced his tRNA(Leu(UUR)) gene, a hot spot for mutations, showing no abnormality.


The effect of constraining mediolateral ankle moments and foot placement on the use of the counter-rotation mechanism during walking.
During walking, the center of mass (CoM) position can be controlled relative to the base of support by shifts of the center of pressure through modulation of foot placement and ankle moments (CoP-mechanism). An additional mechanism is the counter-rotation mechanism, i.e. changing the angular momentum of segments around the CoM to change the direction of the ground reaction force. It is unknown if, and how, humans use the counter-rotation mechanism to accelerate the CoM during walking and how this interacts with the CoP-mechanism. Thirteen healthy adults walked on a treadmill, while full-body kinematic and force plate data were obtained. The contributions of the CoP and the counter-rotation mechanisms to CoM-acceleration during steady-state walking, walking on LesSchuh (i.e. constraining mediolateral CoP shifts underneath the stance foot) and walking on LesSchuh at 50% of normal step width, constraining both foot placement and ankle mechanisms (LesSchuh50%) were calculated. The within-stride variance in CoM-acceleration due to the CoP-mechanism was smaller and the within-stride variance in CoM-acceleration due to the counter-rotation mechanism was larger during LesSchuh50% compared to steady-state walking. This suggests that the counter-rotation mechanism is used to stabilize gait when needed, but the CoP-mechanism was the main contributor to the total CoM-acceleration. The use of the counter-rotation mechanism may be limited, because angular accelerations ultimately need to be reversed and because of interference with other task constraints, such as head stabilization and preventing interference with the gait pattern.


Complete Genome Sequence of Lactococcus cremoris Strain 7-1, a Lactic Acid Bacterium Isolated from a Traditional Mongolian Milk Product Possessing Mucin-Adhesive Ability.
We report the complete genome sequence of Lactococcus cremoris strain 7-1, which was isolated from urum, a traditional Mongolian milk product. Strain 7-1 adhered to porcine gastric mucin in a carbon source-dependent manner. The genome consists of a circular chromosome (2,557,589 bp; GC content, 35.7%) and two circular plasmids.


Calcium-phosphate and polymethylmethacrylate cement in long-term outcome after kyphoplasty of painful osteoporotic vertebral fractures.
A comparative prospective trial evaluating 3-year outcome. To compare clinical and morphologic outcomes as well as follow-up fractures after kyphoplasty of painful osteoporotic vertebral fractures with calcium-phosphate (CaP) cement (group 1) and with polymethylmethacrylate (PMMA)-cement (group 2). CaP cements seem to be an alternative material for usage in kyphoplasty of vertebral fractures. CaP cements are biodegradable and replaceable by newly formed bone after implantation. Concerns have been raised with regard to the stability of resorbable CaP-cements after implantation into vertebrae post kyphoplasty. Calcibon is a possible CaP cement, which exhibited adequate stability in short-term observations. Kyphoplasty was performed in 40 consecutive patients with primary osteoporosis and painful vertebral fractures, 20 received CaP-cement, 20 were treated with PMMA-cement. All patients received a pharmacological antiosteoporosis treatment (1000 mg calcium, 1000 IU vitamin D3, and oral aminobisphosphonate), pain medication, and physiotherapy. Pain (visual analog scale [VAS]; range, 0-100), mobility (EVOS-score; range, 0-100) and radiomorphologic measurements were assessed at baseline and after 6, 12, and 36 months. There were no statistically significant differences between the CaP and PMMA-cement group regarding VAS-scores, EVOS-scores, or height-restoration at any time point. Furthermore, there was no significant difference in the occurrence of vertebral follow-up fractures between both groups during the 3-year follow-up period. CaP cement, e.g., Calcibon, is as effective and safe as conventional PMMA-cement with regard to immediate and sustained pain reduction and improvement of mobility after kyphoplasty of patients with painful osteoporotic vertebral fractures. CaP cement has the potential of being resorbed and replaced by newly formed bone tissue; thus, it seems to be a promising alternative for PMMA also in younger patients with painful vertebral fractures.


Paradoxical embolism associated with oral contraceptives: an underdiagnosed lesion?
A case of cerebral embolism is described in which paradoxical features have been proved clinically, and which may explain some hitherto unaccountable reported cases, and suggests the value of prospective studies. A successful outcome of such a proved case, associated with oral contraceptives, does not appear to have been reported previously.


Sediment transport in two mediterranean regulated rivers.
Mediterranean climate is characterized by highly irregular rainfall patterns with marked differences between wet and dry seasons which lead to highly variable hydrological fluvial regimes. As a result, and in order to ensure water availability and reduce its temporal variability, a high number of large dams were built during the 20th century (more than 3500 located in Mediterranean rivers). Dams modify the flow regime but also interrupt the continuity of sediment transfer along the river network, thereby changing its functioning as an ecosystem. Within this context, the present paper aims to assess the suspended sediment loads and dynamics of two climatically contrasting Mediterranean regulated rivers (i.e. the Ésera and Siurana) during a 2-yr period. Key findings indicate that floods were responsible for 92% of the total suspended sediment load in the River Siurana, while this percentage falls to 70% for the Ésera, indicating the importance of baseflows on sediment transport in this river. This fact is related to the high sediment availability, with the Ésera acting as a non-supply-limited catchment due to the high productivity of the sources (i.e. badlands). In contrast, the Siurana can be considered a supply-limited system due to its low geomorphic activity and reduced sediment availability, with suspended sediment concentration remaining low even for high magnitude flood events. Reservoirs in both rivers reduce sediment load up to 90%, although total runoff is only reduced in the case of the River Ésera. A remarkable fact is the change of the hydrological character of the River Ésera downstream for the dam, shifting from a humid mountainous river regime to a quasi-invariable pattern, whereas the Siurana experiences the opposite effect, changing from a flashy Mediterranean river to a more constant flow regime below the dam.


Induction of arousal in hibernating European hamsters (Cricetus cricetus L.) by vasopressin infusion in the lateral septum.
Vasopressin immunostaining in the lateral septum of the European hamster (Cricetus cricetus L.) disappears in autumn, at the time of the first appearance of hypothermic periods characteristic to hibernation. Previous results have shown that chronic administration of vasopressin in the lateral septum during winter prevents the expression of hypothermic periods, suggesting a role for this peptide in hibernation. It is now observed that acute infusion of vasopressin, and in 50% of the cases, of a specific vasopressin V1 receptor agonist, during a hypothermic period results in an immediate termination of hypothermia. Infusion of oxytocin or a vasopressin V2 receptor agonist were without effect. The results indicate that the seasonal variation in central vasopressin activity, possibly through an interaction with V1 receptors, may play an important role in the expression of hibernation in the European hamster.


Sleep states and learning: a review of the animal literature.
Animal studies are examined in relation to the sleep-learning hypothesis. It is concluded that the data best support the idea of special periods of paradoxical sleep (PS) within the 24 hour period which are specifically involved with the learning process. The onset and duration of these PS "windows" varies with strain of animal, type of task and number of training trials per session. Alternative explanations and theories are considered.


Ethnic variation in the prevalence of echogenic intracardiac foci and the association with Down syndrome.
To determine whether the prevalence of fetal echogenic intracardiac foci (EIF) differs according to maternal ethnicity. We performed a retrospective cohort study of all women undergoing second-trimester diagnostic ultrasound examination and amniocentesis at a prenatal diagnosis referral center from January 1 2000 to July 1 2003. Data were collected on the presence of EIF, gestational age at time of ultrasound scan, karyotype results, maternal age and ethnicity. Univariate and multivariate analyses of EIF, ethnicity and presence of aneuploidy were conducted. Among the 7480 women qualifying for the study, EIF were found in 309 (4.1%). When maternal ethnicity was subdivided into Caucasian, African-American, Hispanic, Asian-American, Native American, Asian Indian, and Middle Eastern, the highest rates of EIF were found in fetuses of African-American (6.7%), Asian-American (6.9%), and Middle Eastern (8.1%) mothers compared to a rate of 3.3% in Caucasians (P < 0.001). In all ethnic groups except Hispanics, EIF was associated with an increased risk for Down syndrome (odds ratio range from 1.8 to 15.7). African-American, Asian-American, and Middle Eastern patients are more likely than patients of other ethnicities to have a fetus with an EIF. Even controlling for ethnicity, fetuses with an EIF still have an increased risk for Down syndrome. As more data accumulate, the prevalence of EIF and its association with Down syndrome among different ethnic groups can be incorporated into patient counseling.


The Application of HEXS and HERFD XANES for Accurate Structural Characterisation of Actinide Nanomaterials: The Case of ThO2.
Invited for the cover of this issue is Lucia Amidani and co-workers from the The European Synchrotron, Helmholtz Zentrum Dresden-Rossendorf, Lomonosov Moscow State University, Kurchatov Institute, and the Université Grenoble Alpes. The image depicts the atomic structure of the sample being viewed through "atomic googles", which represent the X-ray techniques used in this work. Read the full text of the article at 10.1002/chem.202003360.


Functions and expression of liver N-CAM.
In conclusion we have shown that: (a) liver N-CAM is a functionally active adhesion molecule, (b) its expression during the morphogenetic processes occurring during Xenopus laevis metamorphosis correlates with morphological changes in the cell-to-cell interaction; (c) Thyroxine is not directely involved in the activation of the expression of liver N-CAM.


Repressible Promoter System to Study Essential Genes in Mycobacteria.
Inducible gene expression systems represent powerful tools for studying essential gene function and for validation of drug targets in bacteria. Even if several regulated promoters have been characterized, only a few of them have been successfully used in Mycobacteria. Here we describe a successful mycobacterial gene regulation system based on the presence of two chromosomally encoded repressors: Pip and TetR, and a tunable promoter (Pptr) that allows a tight regulation of gene expression.


Retroperitoneal urothelial carcinoma arising after bladder diverticulectomy: a case report.
Urothelial carcinoma arises from the inner urothelial membrane of the renal pelvis, ureter, and bladder and often causes macrohematuria. Here, we report a rare case in which the patient developed non-symptomatic urothelial carcinoma anatomically outside the bladder wall 17 years after bladder diverticulectomy. An 82-year-old male patient previously underwent gastrectomy for stomach cancer and partial hepatectomy for intrahepatic cholangiocarcinoma. Follow-up computed tomography revealed a tumor in the retroperitoneal space, where a bladder diverticulum was removed 17 years earlier. Multiparametric magnetic resonance imaging suggested that the tumor was malignant with rectal invasion. Subsequent computed tomography-guided percutaneous biopsy revealed that the tumor was urothelial carcinoma. The patient underwent two courses of neoadjuvant chemotherapy followed by pelvic exenteration with pelvic lymph node dissection. He is currently receiving adjuvant therapy with an immune checkpoint inhibitor and has had no recurrence for 3 months. Multiparametric magnetic resonance imaging is a helpful tool for predicting both tumor malignancy and invasion before a pathologically confirmed diagnosis. Although this case is rare, urologists should be aware of the occurrence of urothelial carcinoma after bladder diverticulectomy in cases of incomplete resection of the diverticulum.


The structure of a new phospholipid from the koilin-glandular layer of chicken gizzard.
A new phospholipid (Mr = 653; C32H64NO10P; [alpha]22D: - 24) was isolated from the keratinoidal layer of chicken gizzard. After acid hydrolysis the following products were identified: a C22-saturated aldehyde, sn-glycerol 3-phosphate, ethanolamine and D(-)-ribose. The substance is stable to alkali, it has saturated character, and after hydrolysis with CH3OH/HCI, yields only C22-dimethyl acetal. It contains a free NH2 group, and methylation produces 2,3,4-tri-O-methyl-D-ribose. The probable structure of the isolated phospholipid is proposed as 1,2-O-do-cosylidene-sn-glycero-3-phospho-(1 inch-ribosyl)-ethanolamine.


Vaginal misoprostol aids in difficult intrauterine contraceptive removal: a report of three cases.
Intrauterine devices are the most used long-acting reversible contraceptive method worldwide. Under normal circumstances, removal of an intrauterine contraceptive (IUC) is an uncomplicated procedure requiring gentle traction on the string. We report three cases of nonvisible IUC strings where, following use of vaginal misoprostol, the IUC strings were visualized and the IUCs were removed intact with gentle traction. The uterotonic and uterocontractile effects following vaginal misoprostol facilitated removal in three cases of nonvisible IUC strings. We suggest that clinicians consider including vaginal misoprostol alone or prior to planned repeat office or procedure-clinic interventions for nonvisible IUC strings.


Column liquid chromatography determination of vitamins A and E in powdered milk and local flour: a validation procedure.
A high-performance liquid chromatography method was developed for the simultaneous routine determination of vitamins A and E in powdered milk and flour made from local plants and purchased from open markets in the Ivory Coast. The method involves saponification followed by extraction with a mixture of organic solvents. The vitamins were resolved by reversed-phase HPLC and detection at a single wavelength. The main tests of method validation were applied to the procedure. The results show the reliability of the analytical method for the intended application.


Identification of novel targets for cancer therapy using expression proteomics.
Although most drugs target proteins, the proteome has remained largely untapped for the discovery of drug targets. The sequencing of the human genome has had a tremendous impact on proteomics and has provided a framework for protein identification. There is currently substantial interest in implementing proteomics platforms for drug target discovery. Although the field is still in the early stages, current proteomic tools include a variety of technologies that could be implemented for large-scale protein expression analysis of cells and tissues, leading to discovery of novel drug targets. Proteomics uniquely allows delineation of global changes in protein expression patterns resulting from transcriptional and post-transcriptional control, post-translational modifications and shifts in proteins between different cellular compartments. Some of the current technologies for proteome profiling and the application of proteomics to the analysis of leukemias by our group are reviewed.


Graphic and tabular expressions of Bayes' theorem.
Bayes' theorem, as applied to the interpretation of diagnostic tests, is reexpressed as a two-step transformation. This allows for the construction of graphic and tabular expressions of this important principle.


Behaviour of recombinant plasmids in Aspergillus nidulans: structure and stability.
A pyrG- Aspergillus strain was transformed with plasmid pDJB-1, derived from pBR325 by insertion of the Neurospora crassa pyr4 gene (orotidine 5'-phosphate carboxylase), giving mitotically unstable transformants. Aspergillus DNA which acted as an "autonomously replicating sequence" (ARS) in yeast was inserted into pDJB-1 and the resulting construct, pDJB12.1, gave mitotically stable transformants when introduced into Aspergillus. Transformants obtained with pDJB-1 and pDJB12.1 gave few pyr- progeny in crosses to a pyrG+ strain. Southern hybridisation analysis of pyr+ transformants obtained with pDJB-1 revealed restriction fragments expected for integrated plasmid but transformants obtained with pDJB12-1 showed only bands derived from free plasmid. pDJB-1 and derivatives of pDJB12.1 could be recovered from transformants. These derivatives could not be explained by straightforward excision of integrated pDJB12.1 sequences but could result from recombination between plasmid molecules. Hybridisation of undigested transformant DNAs showed that the transforming DNA was present in a high molecular weight form. These results suggest: (1) pDJB12.1 derivatives and possibly pDJB-1 can replicate autonomously in Aspergillus; (2) A. nidulans DNA acting as an ARS in yeast enhances replication and/or segregation of transforming plasmids in Aspergillus; and (3) recombinant plasmids may undergo rearrangements when introduced into Aspergillus.


Medical School Experiences Associated with Change in Implicit Racial Bias Among 3547 Students: A Medical Student CHANGES Study Report.
Physician implicit (unconscious, automatic) bias has been shown to contribute to racial disparities in medical care. The impact of medical education on implicit racial bias is unknown. To examine the association between change in student implicit racial bias towards African Americans and student reports on their experiences with 1) formal curricula related to disparities in health and health care, cultural competence, and/or minority health; 2) informal curricula including racial climate and role model behavior; and 3) the amount and favorability of interracial contact during school. Prospective observational study involving Web-based questionnaires administered during first (2010) and last (2014) semesters of medical school. A total of 3547 students from a stratified random sample of 49 U.S. medical schools. Change in implicit racial attitudes as assessed by the Black-White Implicit Association Test administered during the first semester and again during the last semester of medical school. In multivariable modeling, having completed the Black-White Implicit Association Test during medical school remained a statistically significant predictor of decreased implicit racial bias (-5.34, p ≤ 0.001: mixed effects regression with random intercept across schools). Students' self-assessed skills regarding providing care to African American patients had a borderline association with decreased implicit racial bias (-2.18, p = 0.056). Having heard negative comments from attending physicians or residents about African American patients (3.17, p = 0.026) and having had unfavorable vs. very favorable contact with African American physicians (18.79, p = 0.003) were statistically significant predictors of increased implicit racial bias. Medical school experiences in all three domains were independently associated with change in student implicit racial attitudes. These findings are notable given that even small differences in implicit racial attitudes have been shown to affect behavior and that implicit attitudes are developed over a long period of repeated exposure and are difficult to change.


Unlocking the monolithic integration scenario: optical coupling between GaSb diode lasers epitaxially grown on patterned Si substrates and passive SiN waveguides.
Silicon (Si) photonics has recently emerged as a key enabling technology in many application fields thanks to the mature Si process technology, the large silicon wafer size, and promising Si optical properties. The monolithic integration by direct epitaxy of III-V lasers and Si photonic devices on the same Si substrate has been considered for decades as the main obstacle to the realization of dense photonics chips. Despite considerable progress in the last decade, only discrete III-V lasers grown on bare Si wafers have been reported, whatever the wavelength and laser technology. Here we demonstrate the first semiconductor laser grown on a patterned Si photonics platform with light coupled into a waveguide. A mid-IR GaSb-based diode laser was directly grown on a pre-patterned Si photonics wafer equipped with SiN waveguides clad by SiO2. Growth and device fabrication challenges, arising from the template architecture, were overcome to demonstrate more than 10 mW outpower of emitted light in continuous wave operation at room temperature. In addition, around 10% of the light was coupled into the SiN waveguides, in good agreement with theoretical calculations for this butt-coupling configuration. This work lift an important building block and it paves the way for future low-cost, large-scale, fully integrated photonic chips.


R-LOOPs on Short Tandem Repeat Expansion Disorders in Neurodegenerative Diseases.
Expansions of short tandem repeats (STRs) have been found to be present in more than 50 diseases and have a close connection with neurodegenerative diseases. Transcriptional silencing and R-LOOP formation, RNA-mediated sequestration of RNA-binding proteins (RBPs), gain-of-function (GOF) proteins containing expanded repeats, and repeat-associated non-AUG (RAN) translation of toxic repeat peptides are some potential molecular mechanisms underlying STR expansion disorders. R-LOOP, a byproduct of transcription, is a three-stranded nucleic acid structure with abnormal accumulation that participates in the pathogenesis of STR expansion disorders by inducing DNA damage and genome instability. R-LOOPs can engender a series of DNA damage, such as DNA double-strand breaks (DSBs), single-strand breaks (SSBs), DNA recombination, or mutations in the DNA replication, transcription, or repair processes. In this review, we provide an in-depth discussion of recent advancements in R-LOOP and systematically elaborate on its genetic destabilizing effects in several neurodegenerative diseases. These molecular mechanisms will provide novel targets for drug design and therapeutic upgrading of these devastating diseases.


A pathological fracture of the femur through a histiocytic granuloma.
We present the first reported case of a fracture through a granuloma in the shaft of the femur of a child with histiocytosis X. This fracture united with conservative management but without resolution of the granuloma.


Rapid diversification of wild social groups driven by toxin-immunity loci on mobile genetic elements.
Many species form distinct social groups that provide fitness advantages to individuals. However, the evolutionary processes that generate new social groups are not well understood. Here we examined recently diverged natural isolates of the model social bacterium, Myxococcus xanthus, to probe the genetic mechanisms and evolutionary processes of kin discrimination that occurred naturally in soil. We show that social incompatibilities were formed from horizontal gene transfer of effectors belonging to three distinct polymorphic toxin systems; outer membrane exchange, type VI secretion and rearrangement hotspot systems. Strikingly, the unique toxin effectors and their respective immunity genes that are responsible for social incompatibilities reside on mobile genetic elements, which make up nearly all of the genotypic variation between isolates within clades. By disrupting these three toxin systems, we engineered social harmony between strains that were originally incompatible. In addition, a horizontal allele swap of a single kin recognition receptor changed social interactions and competition outcomes. Our results provide a case study for how horizontal gene transfer led to social diversification in a natural context. Finally, we show how genomic information of kin discriminatory loci can be used to predict social interactions.


Compartmentalized DNA repair: Rif1 S-acylation links DNA double-strand break repair to the nuclear membrane.
DNA double-strand breaks (DSBs) disrupt the structural integrity of chromosomes. Proper DSB repair pathway choice is critical to avoid the type of gross chromosomal rearrangements that characterize cancer cells. Recent findings reveal S-fatty acylation and membrane anchorage of Rap1-interacting factor 1 (Rif1) as a mechanism providing spatial control over DSB repair pathway choice.


Two-stage posterior decompression and fusion for tuberculous spondylitis after intravesical bacillus Calmette-Guerin instillation.
Intravesical bacillus Calmette-Guerin (BCG) instillation is an effective treatment for nonmuscle invasive superficial bladder cancer. BCG induces a massive influx of inflammatory cells and production of cytokines in the bladder mucosa and lumen that leads to an immune response against tumor cells, acting as an immunotherapy. Cystitis, bladder ulceration, and bladder contracture are known local genitourinary complications, whereas systemic complications such as miliary pulmonary tuberculosis, mycotic aneurysms, tuberculous spondylodiscitis, and granulomatous hepatitis are very rare. A case of tuberculous spondylodiscitis at the T8 and T9 levels following intravesical BCG instillation for bladder carcinoma is reported. The patient initially underwent decompressive laminectomy for spastic paraparesis. After reporting improvement for few weeks, the patient again presented with similar complaints and was found to have an increased kyphotic deformity, for which he underwent fixation surgery.


Associations Between Serum Magnesium Concentrations and Polycystic Ovary Syndrome Status: a Systematic Review and Meta-analysis.
Magnesium (Mg) is the second most frequent intracellular cation in humans with a critical role in insulin metabolism and glucoregulation. Women with polycystic ovary syndrome (PCOS) often present with insulin resistance and impaired glucoregulatory status; however, their Mg status remains unclear. Therefore, we aimed to conduct a systematic review and meta-analysis to evaluate serum Mg concentration in women with PCOS and compare it with that of controls without PCOS. Online databases of PubMed, Scopus, Cochrane Library, and ISI Web of Science were searched for studies evaluating the relationship between Mg concentrations and PCOS status until October 2019. Pooled weighted mean differences (WMDs) of serum Mg levels were calculated using random effects models. A total of eight studies (10 arms; n = 2026 women) were included. Pooled effect sizes, expressed as WMD and 95% CI, revealed decreased serum Mg concentrations in women with PCOS compared with controls (- 0.09 (- 0.17, - 0.02) mmol/L; P = 0.01). However, significant heterogeneity was detected across the studies (I 2 = 98.0%, P < 0.001). Despite the classification of studies based on baseline BMI classes, we did not detect the potential source of the observed heterogeneity. Subgroup analysis showed that overweight and obese women (BMI ≥ 25 kg/m2, 0.07 mmol/L (- 0.14, - 0.01); P = 0.02) with PCOS had lower magnesium concentrations than normal women (BMI < 25 kg/m2, - 0.11 (- 0.25, 0.04) mmol/L; P = 0.14) compared with the control group. Serum Mg concentrations appear to be declined in overweight or obese women with PCOS, which may warrant screening and management of Mg status in this clinical population. High-quality studies are needed to elucidate the relationship between Mg concentrations and the development of PCOS.


Electrophysiologic effects of intravenous verapamil in children after operations for congenital heart disease.
To assess the effect of verapamil in children with congenital heart disease after surgical correction, an electrophysiologic study was undertaken in 19 patients, 0.8 to 15 years old. Atrial pacing and programmed atrial extrastimulation were performed before and 5 mn after intravenous administration of verapamil. A significant increase in conduction time and refractory periods was observed at the atrioventricular node level. Dual or accessory atrioventricular pathways, present in 14 cases, appear to have been suppressed in 9. The effect on the sinus node was of particular interest: The corrected sinus node recovery time was strongly prolonged by verapamil in 6 patients, 5 of whom had undergone surgery with extensive atrial reconstruction (Senning 2, anomalous pulmonary venous return 3) and 1 of whom had undergone correction of tetralogy of Fallot. Additional effects of verapamil were the disappearance of a sinus node entrance block in 8 patients and emergence of an ectopic pacemaker in 6. Although verapamil has electrophysiologic properties that should make it a useful drug in the treatment of reentry tachycardia, caution is indicated after extensive atrial surgery because sinus node depression may occur.


Composition of proteoglycans synthesized by rabbit aortic explants in culture and the effect of experimental atherosclerosis.
The synthesis of proteoglycans by aorta explants from rabbits with diet-induced atherosclerosis and controls was studied by 35S-incorporation. Proteoglycans were isolated under dissociative conditions from incubation medium and from arterial explants. Additionally, the tissue proteoglycans that were not extracted by 4 M guanidine-HCl were solubilized by digestion of the tissue by elastase in the presence of proteinase inhibitors. The residual tissue was hydrolyzed by papain and glycosaminoglycans were isolated. The atherosclerotic aorta tissue incorporated twice the amount of 35S into proteoglycans than observed for controls; in both groups about 70% of the label incorporated into the tissue was noted in the proteoglycans extracted by guanidine-HC;, while about 30% of the total 35S-labeled proteoglycans synthesized by the explants were found in the media. Atherosclerotic tissue incorporated 35S predominantly into chondroitin sulfate proteoglycans when compared to control tissue. The chondroitinase ABC-digestable proteoglycans that were extracted by guanidine-HCl from atherosclerotic tissues were of larger molecular size than those from control tissue, but the core proteins from these preparations were similar. The heparan sulfate proteoglycan that was obtained by dissociative extraction from atherosclerotic tissue had greater amounts of N-acetyl and lesser amounts of N-sulfate ester groups than the preparation from control tissue. Digestion of the tissue by elastase yielded heparan sulfate proteoglycan as the major constituent in both groups, although atherosclerotic tissue contained relatively small amounts of this proteoglycan. The residual tissue from both groups contained chondroitin sulfate and heparan sulfate as the major glycosaminoglycans with the latter showing a decrease with atherosclerosis. Atherosclerotic tissue secreted into the medium about two-fold more 35S-labeled proteoglycans with larger molecular size than control tissue; proteoglycans of the heparan sulfate and chondroitin sulfate types were the major constituents in the culture medium of both tissues. Thus, proteoglycans undergo both quantitative and qualitative changes in atherosclerosis, reflecting the enhanced smooth muscle cell activity. These changes are potentially important in modulating lipoprotein binding and hemostatic properties, as well as fibrillogenesis of the arterial wall.