More than 20 years after re-emerging in the 1990s, diphtheria remains a public health problem in Latvia.
In 1994, the World Health Organization (WHO) declared the goal of eliminating diphtheria within the WHO European Region by the year 2000. However, in 1990 an epidemic emerged within the Russian Federation and spread to other countries, including Latvia, by 1994. We describe national surveillance and immunisation coverage data in Latvia from 1994 to 2014 and present historical data from 1946. We defined a laboratory-confirmed case as a clinical case in which toxin-producing Corynebacterium diphtheriae, C. ulcerans or C. pseudotuberculosis was isolated. From 1994 to 2014, 1,515 cases were reported, giving an average annual incidence of 3.2 cases per 100,000 inhabitants (range 0.1-14.8), with the highest incidence in age groups 5-19 and 40-49 years (4.4 and 4.3/100,000, respectively); 111 deaths were reported, 83.8% cases were laboratory-confirmed. Most cases occurred in unvaccinated adults. To improve disease control a supplementary immunisation campaign for adults was initiated in 1995, and by the end of 1998 national coverage among adults reached 70%, and reached 77% in 2003, but declined to 59% by 2014. Diphtheria remains a problem in Latvia with continued circulation of toxin-producing strains of C. diphtheriae. We recommend to strengthen immunisation to cover adults, as well as the education of health professionals and a serological survey.


Increased age, bilirubin, international normalized ratio, and creatinine score to triglyceride ratio are associated with alcohol-associated primary liver carcinoma: a single-centered retrospective study.
This study analyzed the clinical features and biomarkers of alcohol-associated liver disease (ALD) to investigate the diagnostic value of age, bilirubin, international normalized ratio (INR), and creatinine (ABIC) score to triglyceride (TG) ratio (ABIC/TG) in ALD-associated primary liver carcinoma (PLC). Data were collected from 410 participants with ALD, and the epidemiological and clinical records of 266 participants were analyzed. Participants were divided into ALD-without-PLC and ALD-associated-PLC groups. Relationships between clinical characteristics, biomarkers and ALD-associated PLC were estimated. Serum lipid levels and liver function were compared between ALD patients without PLC and patients with ALD-associated PLC. Scoring systems were calculated to investigate ALD severity. The robustness of the relationship was analyzed by the receiver operating characteristic (ROC) curve. Age and dyslipidemia were more strongly associated with ALD-associated PLC than with ALD-without PLC, with AORs of 2.39 and 0.25, respectively, with P less than 0.05. Drinking time and average daily intake, ABIC score, and ABIC/TG ratio were significantly higher in the ALD-associated-PLC group than in the ALD-without-PLC group. The AUC for the ABIC/TG ratio predicting the incidence of PLC was 0.80 (P < 0.01), which was higher than that of the ABIC and TG scores alone; additionally, the specificity and Youden index for the ABIC/TG ratio were also higher, and the cutoff value was 6.99. In ALD patients, age, drinking time, and average daily intake were risk factors for PLC. Drinking time, average daily intake, TG and ABIC score have diagnostic value for ALD-associated PLC. The ABIC/TG ratio had a higher AUC value and Youden index than the ABIC score and TG level.


Effect of liming on sulfate transformation and sulfur gas emissions in degraded vegetable soil treated by reductive soil disinfestation.
Reductive soil disinfestation (RSD), namely amending organic materials and mulching or flooding to create strong reductive status, has been widely applied to improve degraded soils. However, there is little information available about sulfate (SO4(2-)) transformation and sulfur (S) gas emissions during RSD treatment to degraded vegetable soils, in which S is generally accumulated. To investigate the effects of liming on SO4(2-) transformation and S gas emissions, two SO4(2-)-accumulated vegetable soils (denoted as S1 and S2) were treated by RSD, and RSD plus lime, denoted as RSD0 and RSD1, respectively. The results showed that RSD0 treatment reduced soil SO4(2-) by 51% and 61% in S1 and S2, respectively. The disappeared SO4(2-) was mainly transformed into the undissolved form. During RSD treatment, hydrogen sulfide (H2S), carbonyl sulfide (COS), and dimethyl sulfide (DMS) were detected, but the total S gas emission accounted for <0.006% of total S in both soils. Compared to RSD0, lime addition stimulated the conversion of SO4(2-) into undissolved form, reduced soil SO4(2-) by 81% in S1 and 84% in S2 and reduced total S gas emissions by 32% in S1 and 57% in S2, respectively. In addition to H2S, COS and DMS, the emissions of carbon disulfide, methyl mercaptan, and dimethyl disulfide were also detected in RSD1 treatment. The results indicated that RSD was an effective method to remove SO4(2-), liming stimulates the conversion of dissolved SO4(2-) into undissolved form, probably due to the precipitation with calcium.


Percutaneous nephrolithotomy with ultrasonography-guided renal access: experience from over 300 cases.
To report our experience with over 300 patients treated with percutaneous nephrolithotomy (PNL), for although PNL was established as a treatment in the 1970s, its use diminished with the introduction of extracorporeal shockwave lithotripsy (ESWL); clinical experience with ESWL showed its limitations, and the role of PNL for treating urolithiasis was redefined, which with improvements in instruments and lithotripsy technology has expanded the capability of percutaneous stone disintegration. The study included 315 patients (156 males, 159 females, aged 13-85 years) treated with PNL in our department between 1987 and 2002. The mean (range) stone diameter was 27 (7-52) mm. The kidney was punctured under ultrasonography guidance via a lower-pole calyx whenever possible. The working channel was dilated using an Alken dilator under X-ray control. If necessary, a flexible renoscope was used. Ultrasonic, pneumatic and laser probes were used for lithotripsy. Four weeks after treatment the total stone-free rate was 96.5%; 45.7% of all patients were primarily stone-free, 21.3% had clinically insignificant residual stones that passed spontaneously within 4 weeks after PNL, and 33% of the patients needed auxiliary measures (a second PNL, ESWL, ureterorenoscopy). Overall, the early complication rate was 50.8%, the most common complications being transient fever (27.6%), clinically insignificant bleeding (7.6%) or both (3.2%); 3.5% of the patients developed urinary tract infections (with no signs of urosepsis), 3.2% had renal colic and 2.9% upper urinary tract obstruction. One patient (0.3%) developed acute pancreatitis after PNL; one died from urosepsis and one needed selective angiographic embolization of the punctured kidney due to bleeding. No patient required transfusions and there were no injuries to neighbouring organs. These results show that PNL causes no significant blood loss or major complications in almost all patients. Two aspects may especially reduce the potential complications: ultrasonography-guided renal puncture and using PNL in an experienced centre. PNL is a highly efficient procedure that provides fast and safe stone removal.


Differential use of antivirals for treatment of patients with influenza A(H1N1)pdm09 in Germany.
The World Health Organization recommends early antiviral treatment for patients with severe influenza illness or those at increased risk for severe illness. The aim of this study was to determine the proportion of cases with laboratory-confirmed A(H1N1)pdm09 infection that have been treated with antivirals in Germany during the pandemic (H1N1) 2009 and to investigate factors associated with the use of antivirals. We analyzed cases with laboratory-confirmed A(H1N1)pdm09 infection notified to national health authorities in Germany between week 29/2009 and week 17/2010 using multivariable logistic regression. Severity of disease was defined by pneumonia or death. Of 160,804 cases with laboratory-confirmed A(H1N1)pdm09 infection, 22% were treated with antivirals. Cases with severe disease were more likely to be treated with antivirals than cases without severe disease (odds ratio=1·66; 95% confidence interval: 1·46-1·89). In the group with at least one underlying medical condition, only children aged between 1 and 4 years had significant lower odds for receiving antiviral treatment compared with cases in the age group 15 to 49 years (odds ratio=0·75; 95% confidence interval: 0·6-0·94). In conclusion, the implementation of international recommendations on use of antivirals differed according to the age of patients in Germany during the pandemic (H1N1) 2009. This indicates that the potential of antivirals to prevent severe influenza might not have been fully exhausted. The reasons leading to the observed differences in patient management need to be investigated.


A systematic review and meta-analysis of the Ethiopian cohort of adult hypertensive people's adherence to healthy behaviors.
Adherence to healthy behavior has become increasingly important in recent years for better blood pressure management. For the management and prevention of hypertension, it is a strong recommendation. But there have been a number of observational studies conducted in Ethiopia on hypertensive people's healthy lifestyle choices. An extensive review, however, that would have provided even a sliver of supporting data for developing an intervention, is missing. The purpose of this review and meta-analysis was to fill in this gap. The meta-analysis of an observational study was followed by a systematic review. Searches and extracts from the databases CINAHL (EBSCO), MEDLINE (via Ovid), PubMed, EmCare, and Google Scholar have been conducted by three reviewers. Only studies with low and moderate risk were included in the analysis after the quality of the articles was evaluated by two independent reviewers using the Newcastle-Ottawa Scale. After accounting for heterogeneity and publication bias, this study presented the estimated overall and six major domains of adherence to healthy behaviors among hypertensive adult individuals. The PROSPERO database had this systematic review registered under protocol number CRD 42020206150. The overall estimated adherence to healthy lifestyle habits among Ethiopian hypertensive adult individuals was 42.45% (95% CI: 33.51-51.38, I2 = 95.2%). We also investigate the adherence of major domains of healthy behaviors, such as the estimated healthy dietary adherence: 50.86% (95% CI: 39.61-62.11%), the estimated adherence to physical activity: 48.74% (95% CI: 36.60-60.96), and the estimated adherence to sodium intake: 51.79% (95% CI: 36.77-66.8). The following variables were statistically significant predictors of adherence to the overall health behavior: education level (Pooled Odds Ratio (POR): 2.8; 95% CI: 1.98-3.63, I2 = 0.0%), duration of hypertension (POR: 3.1; 95% CI: 1.80-4.32, I2 = 0.0%), and hypertensive people who was knowledgeable of hypertension (POR: 6.8; 95% CI: 1.05-12.58, I2 = 89.3%). Less than half of the hypertension population in Ethiopia had healthy lifestyle behaviors. A low percentage of hypertensive adults also had adhered to salt (sodium) intake, physical activity, and weight management. So, intervention programs should focus on the health faithfulness of the specific section of adherence to healthy lifestyle practice according to recommended lifestyle practice guidelines.


False-negative malaria rapid diagnostic tests in Rwanda: impact of Plasmodium falciparum isolates lacking hrp2 and declining malaria transmission.
Rapid diagnostic tests (RDTs) for histidine rich protein 2 (HRP2) are often used to determine whether persons with fever should be treated with anti-malarials. However, Plasmodium falciparum parasites with a deletion of the hrp2 gene yield false-negative RDTs and there are concerns the sensitivity of HRP2-based RDTs may fall when the intensity of transmission decreases. This observational study enrolled 9226 patients at three health centres in Rwanda from April 2014 to April 2015. It then compared the sensitivity of RDTs based on HRP2 and the Plasmodium lactate dehydrogenase (pLDH) to microscopy (thick smears) for the diagnosis of malaria. PCR was used to determine whether deletions of the histidine-rich central repeat region of the hrp2 gene (exon 2) were associated with false-negative HRP2-based RDTs. In comparison to microscopy, the sensitivity and specificity of HRP2- and pLDH-based RDTs were 89.5 and 86.2% and 80.2 and 94.3%, respectively. When the results for both RDTs were combined, sensitivity rose to 91.8% and specificity was 85.7%. Additionally, when smear positivity fell from 46 to 3%, the sensitivity of the HRP2-based RDT fell from 88 to 67%. Of 370 samples with false-negative HRP2 RDT results for which PCR was performed, 140 (38%) were identified as P. falciparum by PCR. Of the isolates identified as P. falciparum by PCR, 32 (23%) were negative for the hrp2 gene based on PCR. Of the 32 P. falciparum isolates negative for hrp2 by PCR, 17 (53%) were positive based on the pLDH RDT. This prospective study of RDT performance coincided with a decline in the intensity of malaria transmission in Kibirizi (fall in slide positivity from 46 to 3%). This decline was associated with a decrease in HRP2 RDT sensitivity (from 88 to 67%). While P. falciparum isolates without the hrp2 gene were an important cause of false-negative HRP2-based RDTs, most were identified by the pLDH-based RDT. Although WHO does not recommend the use of combined HRP2/pLDH testing in sub-Saharan Africa, these results suggest that combination HRP2/pLDH-based RDTs could reduce the impact of false-negative HRP2-based RDTs for detection of symptomatic P. falciparum malaria.


Fabrication of bacterial cellulose with TiO2-ZnO nanocomposites as a multifunctional membrane for water remediation.
Superhydrophilic/underwater superoleophobic (SUS) membrane technology has attracted extensive attention for water purification. However, the fabrication of multifunctional membranes to satisfy the complex wastewater treatment is still a big challenge. In this work, bacterial cellulose (BC) based multifunctional SUS membranes were designed for water purification. Membranes were prepared by blending BC nanofibers with TiO2 nanoparticles (NPs), and further modified by the in situ growth of ZnO-NPs. The composite membranes showed oil/water (o/w) separation under a small driving pressure (0.2-0.3 bar) with a flux rate of 8232.81 ± 212 L m-2h-1 and with a high separation efficiency (>99.9%). Membranes could also separate oil-in-water emulsion with a separation flux of 1498 ± 74 L m-2h-1 and with high efficiency (99.25%). Moreover, the composite membrane exhibited photocatalytic activity under visible light with a high efficiency (>92%). The composite membranes were also investigated for antibacterial activity against Gram-positive and Gram-negative bacterial strains. This work may inspire the fabrication of next-generation multifunctional membranes for wastewater treatment, particularly oily wastewater, dyes and microbial contaminated water.


The quality of life for black Americans twenty years after the civil rights revolution.
The United States has an extensive statistical system that generates hundreds of indicators of the health and economic status of its population components. Yet, there is no consensus about how different indicators should be weighted and interpreted to judge the absolute and relative progress of black Americans. Neither a "melting pot" nor a "polarization" model adequately describes the conflicting areas of gain, pervasive stagnation, and substantial loss in racial equality of life.


[Cytomegalovirus sensitivity to anti-retroviral agents in patients infected with the human immunodeficiency virus with chorioretinitis in Spain].
To determine the prevalence of the in vitro resistance rate of cytomegalovirus (CMV) to gancyclovir (GCV) and foscarnet (FOS) among patients with AIDS and chorioretinitis. Furthermore, in vitro sensitivity results were compared with the clinical response to therapy. Thirty-six patients with the diagnosis of CMV retinitis and AIDS were included in the study. Antiviral sensitivity testing was performed to 51 clinical CMV strains from these patients. The in vitro sensitivity was compared with the clinical response to therapy. The resistance criteria were the inhibitory dose50 (ID50) GCV > 5 M and ID50 FOS > 400 M. None of the CMV tested strains was resistant to GCV or FOS; however, six patients who had relapses of chorioretinitis while on maintenance therapy and isolation during the condition had mean ID50 of strains (n=8) of 1,95 M for GCV (standard deviation [SD] of 0.71) and 115.2 for FOS (SD, 34.7). These patients responded well when drugs were used at induction doses. The in vitro sensitivity testing is not a good predictor of infection control when the drug is used at maintenance doses. This suggests that these strains should be classified in the intermediate resistant category.


System for accepting server predictions in CASP6.
We describe the new CASP system for collecting and verifying predictions generated by servers. The system was developed to ensure reliable execution of the server assessment part of CASP, with particular emphasis on data consistency. Following the principle that predictions should not be modified by anyone but their authors and to allow a later meaningful assessment, submissions are now verified for correctness of format and contents within the strict 48 hour CASP deadlines for this type of submission. This article also provides an overview of the rules governing server participation in CASP6 and some statistics pertaining to servers in CASP6.


Absence of potentiation of bromoform hepatotoxicity and lethality by chlordecone.
Our previous studies indicated that the toxicity of chloro- or bromo-methanes is potentiated by chlordecone (CD). The present work was conducted to study the effect of prior dietary exposure to CD on toxicity of bromoform. Male S-D rats (175-200 g) were fed 0 or 10 ppm CD in the powdered ration for 15 days. Bromoform (25 to 300 microliters/kg) was given i.p. on day 15. 24 h later, hepatotoxicity was assessed by functional, biochemical and histopathological parameters. Excretion of phenolphthalein glucuronide in bile and the rate of bile flow were unaltered by either bromoform or CD-bromoform combination. Serum enzymes (GPT, GOT and isocitric dehydrogenase (ICD) were also not significantly elevated by any treatment. The results suggest that, unlike chloroform, CHBr3 does not act as a potent hepatotoxin and that its effects are not potentiated by CD to any significant extent.


Dynamic 3D Chromatin Reorganization during Establishment and Maintenance of Pluripotency.
Higher-order chromatin structure is tightly linked to gene expression and therefore cell identity. In recent years, the chromatin landscape of pluripotent stem cells has become better characterized, and unique features at various architectural levels have been revealed. However, the mechanisms that govern establishment and maintenance of these topological characteristics and the temporal and functional relationships with transcriptional or epigenetic features are still areas of intense study. Here, we will discuss progress and limitations of our current understanding regarding how the 3D chromatin topology of pluripotent stem cells is established during somatic cell reprogramming and maintained during cell division. We will also discuss evidence and theories about the driving forces of topological reorganization and the functional links with key features and properties of pluripotent stem cell identity.


Repeated treatment with levoprotiline, a novel antidepressant, up-regulates histamine H1 receptors and phosphoinositide hydrolysis response in vivo.
The effects of repeated administration of levoprotiline, a novel type of tetracyclic antidepressant on histamine H1, muscarinic acetylcholine and alpha 1-adrenergic receptors and the response of phosphoinositide hydrolysis (PI) stimulated by histamine in the cortex of the rat brain were investigated. Histamine H1 receptors were up-regulated to 120% and PI response stimulated by histamine was enhanced to 160%-200% after repeated treatment with levoprotiline (20 mg/kg, i.p., once a day for 28 days) when compared to that of the saline-treated group. No significant alterations of muscarinic acetylcholine and alpha 1-adrenergic receptors were observed. This demonstrates that the repeated treatment with levoprotiline has prominent action on the regulation of histamine H1 receptors and PI response coupling to histamine H1 receptors in vivo.


Cancer trajectories at the end of life: is there an effect of age and gender?
Few empirical data show the pattern of functional decline at the end of life for cancer patients, especially among older patients. In a mortality follow-back survey (the Italian Survey of the Dying of Cancer - ISDOC) a random sample of 1,271 lay caregivers were interviewed, at a mean of 234 days after bereavement. The main outcome was number of days before death when the patient experienced a permanent functional decline. 1,249 (98%) caregivers answered the question about patient's function. The probability to be free from a functional disability was high (94%) 52 weeks before death, but was lower for older age groups (15% for those aged 85 or more) and women (8%). It remained stable until 18 weeks before death, then fell to 63% at 12 weeks and 49% at 6 weeks before death (among those aged 85 or more the figures were 50% and 41%). The pattern was consistent across sub-groups, except for patients affected by Central Nervous System tumors who experienced a longer, slower functional decline. This study provides empirical support for the declining trajectory in cancer, and suggests that the decline commences at around 12 weeks in all age groups, even among patients over 85 years.


Does insulin-like growth factor moderate the association between height and risk of cancer at 24 sites?
Whether the association of height with cancers differs by insulin-like growth factors has not been fully elucidated. Therefore, this study aimed to investigate the sex-specific associations between height and 24 site-specific cancers and to assess whether the association differed by IGF-1. In total, 414,923 participants from the UK Biobank prospective cohort study were included. The association of height (per 5-cm increment) with incidence and mortality from 24 cancer sites was investigated by using Cox proportional hazard models. The median follow-up was 6.0 years. In men, height was positively associated with incidence risk of all-cause cancer and at five sites (lung, lymphatic, leukaemia, non-Hodgkin lymphoma and melanoma). In women, it was associated with breast, melanoma, lymphatic, non-Hodgkin lymphoma and all-cause cancer. The association was stronger in women than men for all-cause cancer incidence. The strength of the association did not differ by IGF-1 concentration. Adult height was associated with risk of several cancer sites. However, some of these associations were sex-specific. There was no strong evidence to support IGF-1 moderating the association between height and cancer.


Morphological relationships between external auditory canal and vital structures of tympanic cavity.
We aimed to evaluate the morphology of the external auditory canal (EAC) using a three-dimensional (3D) reconstruction of computed tomography (CT) scans of the temporal bone to corroborate and predict important anatomical structures involved in middle ear surgery based on the EAC morphology. Temporal bone CT from 62 patients (120 ears) was used to perform 3D reconstruction (maximum intensity projection), of which 32 patients (60 ears) had chronic otitis media and 30 patients (60 ears) had normal temporal bones. The anatomical morphology of the EAC, tympanic sinus, vertical portion of the facial nerve, and jugular bulb were measured, and the anatomical relationship between the EAC morphology and important structures of the middle ear was analyzed. In ears with chronic otitis media, the overhang of the inferior wall of the EAC was significantly more than that in normal ears, and the antero-posterior length of the bony tympanic ring was short. Furthermore, the tympanic sinus was shallow, and vertical portion of the facial nerve tended to run outward. The EAC morphology correlated with the tympanic sinus depth and outward orientation of the vertical portion of the facial nerve. A severe overhang of the inferior wall of the EAC and short antero-posterior length of the bony tympanic ring indicates a higher possibility of a shallow tympanic sinus and an outward orientation of the vertical portion of the facial nerve. These findings aid in predicting the difficulty of tympanic sinus operation and reducing facial nerve damage risk during EAC excision.


A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection.
Hypoxia inducible factor-1 (HIF-1) is a transcription factor that is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress. HIF-1 is also activated in response to bacterial pathogens and supports the innate immune response of both phagocytes and keratinocytes. In this work, we show that a new pharmacological compound AKB-4924 increases HIF-1 levels and enhances the antibacterial activity of phagocytes and keratinocytes against both methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus in vitro. AKB-4924 is also effective in stimulating the killing capacity of keratinocytes against the important opportunistic skin pathogens Pseudomonas aeruginosa and Acinetobacter baumanii. The effect of AKB-4924 is mediated through the activity of host cells, as the compound exerts no direct antimicrobial activity. Administered locally as a single agent, AKB-4924 limits S. aureus proliferation and lesion formation in a mouse skin abscess model. This approach to pharmacologically boost the innate immune response via HIF-1 stabilization may serve as a useful adjunctive treatment for antibiotic-resistant bacterial infections.


Volcanic ash melting under conditions relevant to ash turbine interactions.
The ingestion of volcanic ash by jet engines is widely recognized as a potentially fatal hazard for aircraft operation. The high temperatures (1,200-2,000 °C) typical of jet engines exacerbate the impact of ash by provoking its melting and sticking to turbine parts. Estimation of this potential hazard is complicated by the fact that chemical composition, which affects the temperature at which volcanic ash becomes liquid, can vary widely amongst volcanoes. Here, based on experiments, we parameterize ash behaviour and develop a model to predict melting and sticking conditions for its global compositional range. The results of our experiments confirm that the common use of sand or dust proxy is wholly inadequate for the prediction of the behaviour of volcanic ash, leading to overestimates of sticking temperature and thus severe underestimates of the thermal hazard. Our model can be used to assess the deposition probability of volcanic ash in jet engines.


Lung abscess: an unusual presentation of congenital tracheoesophageal fistula without atresia.
Tracheoesophageal fistula (TEF) without atresia is rare and usually presents with symptoms from birth. In this report, a 9-year-old boy presented with productive cough of 4 month's duration and was shown to have a right lung abscess seen on chest radiograph. His parents denied earlier respiratory symptoms or illnesses. Rigid bronchoscopy showed a fistulous opening of about 1 mm in diameter in the posterior wall of the trachea about 16 cm from the upper incisor teeth. Cannulation with a ureteral catheter demonstrated that the fistulous opening communicated with the esophageal lumen. The tracheoesophageal fistula was 1 cm long and was divided through a right supraclavicular incision. The postoperative period was uneventful, and the patient was discharged on the third postoperative day. This case demonstrated that TEF should be considered in any patient presenting with chronic respiratory problems even after a prolonged symptom-free period.


Comparison of pressure measurement, dobutamine contrast stress echocardiography and SPECT for the evaluation of intermediate coronary stenoses. The COMPRESS trial.
DSE and SPECT are two well-established methods to non-invasively investigate the functional significance of coronary artery stenoses in patients with coronary artery disease. The measurement of Fractional Flow Reserve has emerged a new invasive reference standard for lesion specific quantification of coronary artery stenoses. The objective of our prospective study was to compare sensitivity and specificity of Dobutamine Stress Echocardiography (DSE) and Single Photon Emission Computer tomography (SPECT) with the pressure derived Fractional Flow Reserve (FFR) for the identification of hemodynamic relevant coronary lesions in patients with predominately coronary multivessel disease and angiographically intermediate stenoses. Inclusion criteria were a coronary lesion of 50-75% diameter stenosis by visual assessment in patients with known or suspected CAD. SPECT, DSE and FFR testing was performed within one week of coronary angiography. The study comprised 48 consecutive symptomatic patients. In 41 cases, a coronary multivessel disease was present. Mean FFR was 0.80 +/- 0.13 (0.41-1.0). Overall sensitivity of DSE and SPECT was 67% and 69% whereas specificity reached 77% and 87%. However, sensitivity was significantly reduced if the target lesion was located distally. DSE showed poor results if the lesions were located in the circumflex artery or if a history of prior myocardial infarctions was present. DSE and SPECT are both useful methods for the non-invasive assessment of coronary artery disease. DSE showed reasonable combination of sensitivity and specificity even in patients with multivessel disease. Although use of noninvasive stress tests is only limited in patients with prior myocardial infarctions and invasive stress testing should be preferred in these patients.


CL316,243, a selective β3-adrenoceptor agonist, activates protein translation through mTOR/p70S6K signaling pathway in rat skeletal muscle cells.
Functional β3-adrenoceptors have been found in skeletal muscle where they mediate metabolic oxidation and glucose utilization. Whether β3-adrenoceptors (ARs) also play any role in muscle protein metabolism still remains uncertain. By using rat L6 myocyte cultures, we found that CL316,243, a β3-AR selective agonist, at the concentration of 10(-6) M for 24 h, induced a significant increase of skeletal muscle constitutive proteins such as H- and L-myosin and β-actin. Such effect was correlated to an increased expression of phosphorylated p70(S6K) that was significantly inhibited by β3-AR antagonist, SR 59230A, but not by β2-AR antagonist, ICI-118,551. The CL316,243-induced activation of p70(S6K) was markedly inhibited by wortmannin, a PI3K inhibitor, and rapamycin, a specific inhibitor of mTOR, suggesting a critical involvement of the PI3K-mTOR-p70(S6K) signaling cascade in the anabolic response of L6 cells to β3-AR agonist. Taken together, these results suggest that stimulation of β3-AR in skeletal muscle cells activates a specific signaling pathway leading to protein synthesis and, eventually, muscle growth.


Further insight into the mode of action of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
Chemical reactions of MPDP+, a recognized intermediate in the metabolic conversion of the neurotoxin MPTP by monoamine oxidase B into its major metabolite MPP+, were studied. Addition of cyanide to MPDP+ bromide in aqueous solutions afforded cyano-compound 5 which isomerized in the presence of silica gel into compound 6. Both 5 and 6 when heated yielded a third isomer 7. MPDP+ bromide disproportionated into MPTP and MPP+ in aqueous solution near neutral or slightly alkaline pH, a reaction which also occurred when MPDP+ bromide was treated with an amine in dichloromethane solution. Disproportionation of MPDP+ at physiological pH may be of biochemical significance, since formation of MPP+ from MPDP+ can occur non-enzymatically. MPTP, MPDP+, and MPP+ inhibited dopamine uptake in rat synaptosomal preparations with I50 values of 30, 37, and 3.4 microM, respectively. The competition of these compounds with dopamine for uptake sites in the membrane may contribute in part to the reduced levels of dopamine observed in animals treated with MPTP.


Difficulty of diagnosing Wegener's granulomatosis in the head and neck region.
The objective of this study was to review the various clinical features associated with Wegener's granulomatosis (WG) in the head and neck region and to discuss the difficulty of diagnosing patients with early stage WG. Between January 1998 and August 2007, WG was diagnosed and treated in 16 patients at the Department of Otolaryngology, Hyogo College of Medicine. Clinical and operating records of these patients were analyzed retrospectively. Diagnosis was based on the Japanese criteria proposed by the Japanese Ministry of Health and Welfare in 1998. Ten patients (62.5%) had a definite diagnosis of WG, and the other six patients (37.5%) had a probable diagnosis of WG. The period from the onset to diagnosis was between 1 month and 30 years. The generalized form of WG was observed in three patients (18.8%), and the limited form of WG was observed in the other 13 patients (81.2%). Nasal, aural, and ophthalmic symptoms were initially presented in 10, 3, and 3 patients, respectively. Cytoplasmic pattern antineutrophil cytoplasmic antibodies (cANCAs) and perinuclear pattern ANCA (pANCA) were positively detected in 68.8% (11/16) and 27.2% (3/11) of the patients, respectively. Five of 14 patients (35.7%) had pathologic features of WG in biopsy samples from the head and neck region. Three patients in whom a diagnosis of WG was difficult are presented, and immediate lessons of our experience were discussed. This study emphasized the difficulty of diagnosing WG, particularly at an early stage and when limited to the head and neck region. The biggest challenge faced in diagnosing WG is that it requires a high index of suspicion. When WG was suspected, we should obtain an accurate medical history from patients and repeat serologic and histopathologic examinations.


A rapid HPLC technique for determining levels of histamine in tears from normal and inflamed human eyes.
Because of the important role of histamine in the inflammatory process, the measurement of histamine levels in tears has been considered as a possible index of eye irritancy. Histamine levels have been measured using an HPLC procedure involving fluorimetric detection after fluorescamine derivatization. Analyses, at picomole levels, were carried out in less than 5 minutes using 10 microliter of tear samples collected from either normal or inflamed human eyes.


Comparison of capillary electrophoretic techniques for analysis and characterization of metallothioneins.
To explore and understand the significance of individual metallothionein isoforms, the methods of their identification are needed. Separation of these isoforms requires a high resolution technique which can exploit very small differences in mass, charge, and hydrophobicity. In this report, three different techniques of CE were analyzed and used for metallothionein separation: detection using capillary gel electrophoresis, capillary zone electrophoresis, and capillary isoelectric focusing. Also, three different metallothionein samples were used from horse kidney, rabbit liver, and human liver. We identified metallothionein isoforms based on the determination of their relative molecular masses, on the charge differences in different pH buffers, and based on the pI value. Methods used in this report allow metallothionein identification, permit to quantify the purity and content of its isoforms, and allow studying its polymerization. This report supports and endorses the increased application of CE methodology in proteomics.


Cloning of a full-length cDNA encoding bovine thymus poly(ADP-ribose) synthetase: evolutionarily conserved segments and their potential functions.
The primary structure of bovine thymus poly(ADP-ribose) synthetase, as deduced from the nucleotide sequence of a cloned cDNA, indicated that this enzyme is composed of 1016 amino acids (aa) with an Mr of 113,481. An abundance of Lys and Arg residues was in accord with the known basic nature of this protein. A comparison with reported sequences of human counterparts revealed: (1) three functional domains separated by partial proteolysis, i.e., DNA-binding (N-terminal), automodification (central), and NAD-binding (C-terminal) domains, have, in this order, increasing degrees of homology; (2) the DNA-binding domain is composed of two distinct regions: one, less conserved, containing zinc-binding fingers and the other, more conserved, containing helix-turn-helix motifs; (3) all Glu and Asp residues in the automodification domain are conserved; and (4) a 78-aa stretch encompassing the nucleotide-binding fold in the NAD-binding domain is completely conserved. These results are compatible with specific features of each domain, i.e., complex DNA-enzyme interactions, multiple automodification at acidic aa residues, and a stringent specificity for the substrate, NAD.


Effects of in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on serum androgens and steroidogenic enzyme activities in the male rat reproductive tract.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to impair reproductive function of males in animal models, possibly due to a reduction in serum androgen levels. Thus, TCDD may alter the testosterone biosynthetic pathway in the testis or the conversion of testosterone to 5alpha-dihydrotestosterone (DHT) in androgen target tissues. Pregnant Sprague Dawley rats were gavaged with TCDD (0, 0.2 or 1.0 microg/kg) on day 15 of gestation only. TCDD caused a reduction in the body weight gain of the dams in both dose groups and a significant reduction in litter size in the higher dose group. Litters delivered normally and TCDD exposed male offspring grew at the same rate as controls. Males were sacrificed at 15, 30, 45, 60, 90 and 120 d of age. Steroidogenic enzyme activities were determined in testicular microsomes and androgen target tissue nuclear fractions. Serum androgens were measured by radioimmunoassay (RIA). At 30 d of age, rats exposed to 1.0 microg/kg TCDD exhibited lower 17-hydroxylase activity (P < 0.05) and lower caput-corpus epididymal weights (P < 0.05). At 45 d of age, the same treatment resulted in testicular 3beta-HSD, 17beta-HSD and 5alpha-reductase activities that were significantly greater (P < 0.05) but, conversely, serum androgens were one quarter the values evident in controls (P < 0.05). At the other ages, no differences were observed in serum androgens and, with the exception of lower 17beta-HSD activity at 90 d of age (P < 0.05), no other differences in testicular steroidogenic enzyme activities were found. 5Alpha-reductase activities in the androgen target tissues were also unchanged. Histological examination of testes showed that the spermatogenic profile was identical to controls at all ages.


Conservative management after prenatal ultrasound diagnosis of meconium periorchitis.
Meconium periorchitis is caused by the leakage of meconium from a bowel perforation into the peritoneal cavity via a patent processus vaginalis into the scrotal sac during fetal life or in the early postnatal period. Intrauterine meconium peritonitis causes sterile inflammatory response and calcification. Here, we describe a prenatally diagnosed case of meconium periorchitis. During the ultrasound scan at 29 weeks' gestation, enlargement of the scrotum with many small hyperechogenic masses and normal anatomy of testis was observed. Our case is the 11th prenatally diagnosed case presented in the worldwide literature and the first one described in Poland. This case confirms the latest tendency for the conservative management of meconium periorchitis and an asymptomatic postnatal course.


A history of oculogyric crises during the encephalitis lethargica pandemic.
A pandemic of what came to be known as encephalitis lethargica spread starting in the winter of 1916-1917 and continued into the 1930s. Neurological after-effects, namely permanent parkinsonian syndromes and various abnormal movements, permanently disabled the survivors of the one or two million victims, often children or young adults. Among them, a small proportion developed a symptom that was little known up to that point and that is currently exceptional: oculogyric crises; that is, a lateralised, dystonic upward movement of the eyes known as a tonic eye fit. This paper proposes a history of the recognition of this symptom, its inclusion in the neurological nosography, and the pathophysiological hypotheses postulated a century ago.


Preeclampsia-Associated lncRNA INHBA-AS1 Regulates the Proliferation, Invasion, and Migration of Placental Trophoblast Cells.
Preeclampsia is believed to be caused by impaired placentation with insufficient trophoblast invasion, leading to impaired uterine spiral artery remodeling and angiogenesis. However, the underlying molecular mechanism remains unknown. We recently carried out transcriptome profiling of placental long noncoding RNAs (lncRNAs) and identified 383 differentially expressed lncRNAs in early-onset severe preeclampsia. Here, we are reporting our identification of lncRNA INHBA-AS1 as a potential causal factor of preeclampsia and its downstream pathways that may be involved in placentation. We found that INHBA-AS1 was upregulated in patients and positively correlated with clinical severity. We systematically searched for potential INHBA-AS1-binding transcription factors and their targets in databases and found that the targets were enriched with differentially expressed genes in the placentae of patients. We further demonstrated that the lncRNA INHBA-AS1 inhibited the invasion and migration of trophoblast cells through restraining the transcription factor CENPB from binding to the promoter of TNF receptor-associated factor 1 (TRAF1). Therefore, we have identified the dysregulated pathway "INHBA-AS1-CENPB-TRAF1" as a contributor to the pathogenesis of preeclampsia through prohibiting the proliferation, invasion, and migration of trophoblasts during placentation.


Autoradiographic study on some proliferative properties of human buccal mucosa.
This study was designed to investigate the proliferative activity of the buccal mucosa in healthy adult persons with regard to individual age. Punch biopsy specimens were taken from the buccal mucosa of 19 individuals (10 females, 9 males) ranging in age from 24 to 80 years, and were then examined autoradiographically, applying nuclear 3H-thymidine labelling in vitro under oxygen pressure of 2.2 atm. The mean total labelling index in the progenitor compartment amounted to 26.0 +/- 2.6% including 6.2 +/- 2.0% labelled basal nuclei and 19.8 +/- 2.6% labelled suprabasal nuclei. Related to 1,000 mu surface length, the mean number of basal cells runs up to 270.7 +/- 38.6 and the total nuclear labelling index to 70.9 +/- 10.4. This high rate of S phase nuclei, exceeding that of the epidermis several times, depends on the ample progenitor compartment as well as on the basal epithelium length which, as compared to the epithelium surface length, was shown to be extended by a mean proportion of 1.75. None of the autoradiographic results obtained in the present study revealed an age dependency of the buccal mucosa proliferative activity. The magnitude of the proliferative pool constitutes the matrix of the high renewal rate of the healthy buccal mucosa and provides a steady state of superficial cell loss and basal cell regeneration, that was proved, at least in the normal mucosa, to continue until senile age.


Time-lapse image analysis for whole colony growth curves and daily distribution of the cell number per colony during the expansion of mesenchymal stem cells.
Mesenchymal stem cells from the synovium (synovial MSCs) are attractive for cartilage and meniscus regeneration therapy. We developed a software program that can distinguish individual colonies and automatically count the cell number per colony using time-lapse images. In this study, we investigated the usefulness of the software and analyzed colony formation in cultured synovial MSCs. Time-lapse image data were obtained for 14-day-expanded human synovial MSCs. The cell number per colony (for 145 colonies) was automatically counted from phase-contrast and nuclear-stained images. Colony growth curves from day 1 to day 14 (for 140 colonies) were classified using cluster analysis. Correlation analysis of the distribution of the cell number per colony at 14 days versus that number at 1-14 days revealed a correlation at 7 and 14 days. We obtained accurate cell number counts from phase-contrast images. Individual colony growth curves were classified into three main groups and subgroups. Our image analysis software has the potential to improve the evaluation of cell proliferation and to facilitate successful clinical applications using MSCs.


The immunoelectron-microscopical demonstration of antibodies against endoplasmic reticulum (microsomes) in chronic aggressive hepatitis and liver cirrhosis.
Electron microscopic findings made on microsomal fractions of rat liver after treatment with microsomal antibodies obtained from the blood of patients diagnosed as having chronic aggressive hepatitis and liver cirrhosis and after incubation with peroxidase-labelled antihuman IgG are described and presented in this paper. Interpretation of these findings as the substrate of an antibody reaction directed against membranes of the endoplasmic reticulum of hepatocytes is discussed.


Effects of placental infarctions on the fetal outcome in pregnancies complicated by hypertension.
To determine the frequency of placental infarcts and its effects on the fetal outcome in pregnancies complicated by hypertension. Case control. Obstetrics Unit of North Colombo Teaching Hospital, Ragama, Sri Lanka, from January 2003 to January 2004. Placentae of 150 normotensive women and 200 hypertensive women were studied to detect the number of placentae with infarctions. Apgar score, birth weight and the head circumference of the newborns were measured and analyzed. The frequency of placental infarcts was significantly higher in hypertensive group (30%) compared to normotensive group (18.7%). An association between placental infarction and low Apgar score of the newborn was seen in the hypertensive group (p<0.001). The difference in the birth weight of the newborns in hypertensive and normotensive groups in relation to placental infarction was statistically significant (2.2 vs. 3.1 kg, p<0.001). A highly significant difference was observed in the head circumference of the newborns of hypertensive group compared to normotensive group in relation to placental infarctions (30.7 cm vs. 32.3 cm, p<0.001). The frequency of placental infarcts was higher in hypertensive women when compared to normotensives. Placental infarctions had an adverse effect on growth and development of the newborns. This information can be useful in planning and management of future pregnancies.


Magnetically driven preparation of 1-D nano-necklaces capable of MRI relaxation enhancement.
We report a novel magnetically-facilitated approach to produce 1-D 'nano-necklace' arrays composed of 0-D magnetic nanoparticles, which are assembled and coated with an oxide layer to produce semi-flexible core@shell type structures. These 'nano-necklaces' demonstrate good MRI relaxation properties despite their coating and permanent alignment, with low field enhancement due to structural and magnetocrystalline anisotropy.


In vitro culture of epicardial cells from adult zebrafish heart on a fibrin matrix.
We describe here a protocol for culturing epicardial cells from adult zebrafish hearts, which have a unique regenerative capacity after injury. Briefly, zebrafish hearts first undergo ventricular amputation or sham operation. Next, the hearts are excised and explanted onto fibrin gels prepared in advance in a multiwell tissue culture plate. The procedure allows the epicardial cells to outgrow from the ventricle onto a fibrin matrix in vitro. This protocol differs from those used in other organisms by using a fibrin gel to mimic blood clots that normally form after injury and that are essential for proper cell migration. The culture procedure can be accomplished within 5 h; epicardial cells can be obtained within 24-48 h and can be maintained in culture for 5-6 d. This protocol can be used to investigate the mechanisms underlying epicardial cell migration, proliferation and epithelial-to-mesenchymal transition during heart regeneration, homeostatic cardiac growth or other physiological processes.


Diastolic asynchrony and myocardial dysfunction in patients with univentricular heart after Fontan operation.
We aimed to assess the existence of myocardial dysfunction and intra-univentricular diastolic asynchrony in patients after Fontan operation. Twenty patients after Fontan procedure and 30 age-matched controls were included in the study. The global function of the univentricular heart was analyzed by the Tei index. Regional myocardial velocities and strain of the univentricular heart including the rudimentary right ventricle (RV) were quantified by tissue Doppler imaging. Intra-univentricular or intra left ventricular (LV) diastolic delay was measured from the difference of diastolic intervals (time to peak early diastolic velocity), measured at LV lateral wall and the rudimental RV wall in patients, or LV lateral wall and the ventricular septum in controls. Compared to the control group, patients after Fontan operation had significantly elevated Tei index (0.24 ± 0.02 vs. 0.41 ± 0.1, p < 0.001). On the other hand, the regional myocardial velocities and strains of the univentricular heart including the rudimentary RV were significantly reduced (p < 0.001). Among patients, there was a significant correlation between the Tei index of the univentricular ventricle and rudimentary RV strain (r = -0.66, p = 0.01). The heart rate-corrected intra-univentricular diastolic delay was significantly prolonged among patients when compared to the intra-LV diastolic delay in controls (0.01 ± 0.9 vs. 1 ± 1.1, p = 0.005). Myocardial dysfunctions and intra-univentricular diastolic asynchrony of the univentricular heart in patients after Fontan procedure are evident. The rudimentary RV in patients after Fontan procedure plays an important role in the determination of the global function of the univentricular heart.


Thermal Behavior of Sweet Potato Starch by Non-Isothermal Thermogravimetric Analysis.
In this study, X-ray diffraction (XRD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) methods were used to study the structure, the thermal degradation kinetics, and the thermogram of sweet potato starch, respectively. The thermal decomposition kinetics of sweet potato starch was examined within different heating rates in a nitrogen atmosphere. Different models of kinetic analysis were used to calculate the activation energies using the thermogravimetric data of the thermal degradation process. The activation energies got from Kissinger, Flynn⁻Wall⁻Ozawa, and Šatava⁻Šesták models were 173.85, 174.87, and 174.34 kJ·mol-1, respectively. Thermogravimetry⁻Fourier transform infrared spectroscopy (TG-FTIR) analysis showed that the main pyrolysis products included water, carbon dioxide, and methane.


Cisplatin neuropathy in brain tumor chemotherapy.
38 patients with glial brain tumors received 135 mg/m2 cisplatin intravenously every month for 5 courses. Signs and symptoms of peripheral neuropathy were evaluated clinically and electrophysiologically. This approach differs from methods previously reported in that it offers two major advantages: primary brain tumors do not cause paraneoplastic neuropathy; no neurotoxic drugs other than cisplatin were employed. Our study confirmed in this highly specific clinical model the existence of cisplatin peripheral neuropathy: we observed definite clinical signs or symptoms of neuropathy in 80% of patients receiving a cumulative cisplatin dosage of 675 mg/m2; there was a progressive dose-related decrease in SAP amplitudes, expression of a sensory axonopathy or neuronopathy.


Actual over 3-year survival after stereotactic body radiation therapy in patients with unresectable intrahepatic cholangiocarcinoma.
As a non-invasive treatment, stereotactic body radiation therapy (SBRT) has been an emerging and effective option for patients with unresectable intrahepatic cholangiocarcinoma (ICC). The Cyber Knife has an SBRT system, which can realize real-time tracking of tumors during treatment. It can protect the surrounding normal liver tissue while the tumor gets the therapeutic dose. The purpose of this study was to evaluate the factors affecting the local control rate for patients after SBRT treatment, and to predict the factors affecting survival rates, then to report the 3-year actual survival rates after treatment and identify the influencing factors of 3-year survival rate. We conducted a long-term follow-up of 43 patients with unresectable intrahepatic cholangiocarcinoma who underwent Cyber Knife in our hospital from January 2016 to December 2018. Regular medical check-ups were performed every 2-3 months after SBRT to evaluated the effect of treatment. The median follow-up time was 15 months (4-78 months), and the median progression-free survival (PFS) was 6 months (95% CI, 2.788-9.212) and the median overall survival (OS) was 12 months (95% CI, 3.434-20.566), respectively. Based on modified Response Evaluation and Criteria in Solid Tumor (mRECIST), response rate (RR) and disease control rate (DCR) of SBRT in unresectable ICC were 55.2% and 86%. The 1-, 2- and 3-years OS rate were 51.2%, 32.6% and 23.3%. Multivariate analysis based on competing risk survival analysis identified that patients with multiple nodules, large diameter, high level of CA199 and CEA, poor ECOG performance status had worse overall survival (p < 0.05). Patients who survived ≥3 years had significantly lower levels of CEA, CA199, smaller tumor diameters and lower number of lesions (p < 0.05). The SBRT might be a candidate option for patients who unable to perform surgery. The rate of 3-year survival after SBRT for unresectable ICC can be expected with 23.3%.


Salinicola peritrichatus sp. nov., isolated from deep-sea sediment.
A Gram stain-negative, aerobic and rod-shaped bacterium, strain DY22(T), was isolated from a deep-sea sediment collected from the east Pacific Ocean. The isolate was found to grow in the presence of 0-20.0 % (w/v) NaCl and at pH 4.5-8.5; optimum growth was observed with 0.5-2.0 % (w/v) NaCl and at pH 5.0-7.0. Chemotaxonomic analysis showed the presence of ubiquinone-9 as predominant respiratory quinone and C16:0, C19:0 ω8c cyclo and C12:0 3-OH as major cellular fatty acids. The genomic DNA G+C content was determined to be 59.6 mol%. Comparative 16S rRNA gene sequence analysis revealed that the novel isolate belongs to the genus Salinicola. Strain DY22(T) exhibited the closest phylogenetic affinity to the type strain of Salinicola salarius with 97.2 % sequence similarity and less than 97 % sequence similarity with respect to other Salinicola species with validly published names. The DNA-DNA reassociation values between strain DY22(T) and S. salarius DSM 18044(T) was 52 ± 4 %. On the basis of phenotypic, chemotaxonomic and genotypic data, strain DY22(T) represents a novel species of the genus Salinicola, for which the name Salinicola peritrichatus sp. nov. (type strain DY22(T) = CGMCC 1.12381(T) = JCM 18795(T)) is proposed.


Psychosocial aspects of patient-activated atrial defibrillation.
Atrial Defibrillator. The atrial defibrillator empowers patients to cardiovert themselves from atrial arrhythmias at a time that is socially and physically acceptable, thereby preventing hospitalization. The long-term psychosocial effects of repeated use of the patient-activated atrial defibrillator at home are unknown. Eighteen patients underwent placement of the Jewel AF atrial defibrillator for persistent atrial fibrillation only. All patients performed manually activated cardioversions at home under self-administered sedation. Automatic shock therapies were disabled. Hospital Anxiety and Depression Scale and Multidimensional Health Locus of Control questionnaires were obtained before implant. All patients completed questionnaires 1 year after device implant and at long-term follow-up. The spouse or partner of each patient was interviewed to identify positive and negative aspects of manual cardioversion at home. The baseline patient scores for both anxiety (5.7 +/- 2.7) and depression (3.4 +/- 2.3) fell within the predefined range of normality. At 1 year, there was no significant change in anxiety (4.9 +/- 3.7, P = 0.39) or depression (2.4 +/- 1.8, P = 0.06). At long-term follow-up (mean 28 months), a total of 377 patient-activated cardioversions were performed out of hospital (median 15 per patient). Scores for anxiety (6.0 +/- 4.0, P = 0.70) and depression (3.2 +/- 2.5, P = 0.68) remained unchanged. During long-term follow-up, patient-activated cardioversion using the atrial defibrillator was not associated with increased anxiety or depression. The procedure was well tolerated by patients and their partners, offering an acceptable treatment option for patients with recurrent persistent atrial fibrillation.


Evaluation of cell viability and T2 relaxivity of fluorescein conjugated SPION-PAMAM third generation nanodendrimers for bioimaging.
This study has investigated the possibility of using fluorescent dendronized magnetic nanoparticles (FDMNPs) for potential applications in drug delivery and imaging. FDMNPs were first synthesized, characterized and then the effect of Polyamidoamine (PAMAM) dendrimer functionalization and fluorescein isothiocyanate (FITC) conjugation on biocompatibility of superparamagnetic iron oxide nanoparticles (SPIONs) was evaluated. The nanostructures' cytotoxicity tests were performed at different concentrations from 10 to 500 μg/mL using MCF-7 and L929 cell lines. IC50 in MTT assay were 139.22 and 201.88 μg/mL for DMNP incubated L929 and MCF-7 cell lines respectively, whereas the cell viability for FDMNPs did not decrease to 50%. The results showed that FITC conjugation diminishes the toxicity of dendronized magnetic nanoparticles (DMNPs) mainly due to the reduction of surface charge. DMNP appears to be cytotoxic at the concentration levels being used for both cell lines. On the contrary, FDMNPs showed more biocompatibility and cell viability of MCF-7 and L929 cell lines at all concentrations. The fluorescence microscopy of FDMNPs incubated with MCF-7 cells showed a successful localization of cells indicating their ability for applications such as a magnetic fluorescent probe in cell studies and imaging purposes. T2 relaxivity measurements demonstrated the applicability of the synthesized nanostructures as the contrast agents in tissue differential assessment by altering their relaxation times. In our case, the r2 relaxivity of FDMNPs was measured as 103.67 mM(-1)S(-1).


MCP-1 expression in CNS-1 astrocytoma cells: implications for macrophage infiltration into tumors in vivo.
Gliomas are among the most resistant tumors to conventional anti-tumor therapy, and are typified by their highly infiltrative nature and ill-defined borders. Macrophages constitute a major proportion of the tumor cell mass in both primary human gliomas and as shown here, a CNS-1 glioma model. The objective of this study was to identify tumor-cell-derived chemotactic factor(s) which participate in macrophage recruitment into tumors in vivo. This study demonstrates the constitutive expression of monocyte chemoattractant protein-1 (MCP-1), a potent monocyte chemoattractant, by the rat astrocytoma cell line CNS-1. Characterization of cytokine expression by CNS-1 cells in vitro revealed the constitutive expression of TGF-beta but not other proinflammatory cytokines. However, numerous cytokines were detected in CNS-I tumors in vivo including Ltbeta, IL-1alpha, IL-1beta, TNF-alpha, TNF-beta, IL-10, and IFN-gamma. Attenuation of MCP- I release from CNS-1 cells using an anti-sense approach revealed no significant alterations in macrophage infiltration into tumors in vivo, suggesting redundancy in the signal(s) involved in macrophage recruitment. Depletion of peripheral macrophages using liposome-encapsulated clodronate revealed no significant differences in tumor growth or in the degree of macrophage infiltration into CNS-1 tumors in vivo. These results indicate that CNS-1 cells produce chemotactic factors which likely participate in macrophage recruitment into tumors in vivo. Whether or not macrophage recruitment confers a growth advantage for the tumor remains to be determined.


Canine ganglioneuroblastoma in the oral mucosa.
A ganglioneuroblastoma of the oral cavity in a dog was examined histologically and immunohistochemically. This rare neoplasm was considered to be derived from ectopic neural crest cells. This is the first report of a canine ectopic ganglioneuroblastoma located in the oral mucosa.


Virus protein assembly in microgravity.
The coat of polyomavirus is composed of three proteins that can self-assemble to form an icosahedral capsid. VP1 represents 75% of the virus capsid protein and the VP1 capsomere subunits are capable of self assembly to form a capsid-like structure. Ground-based and orbiter studies were conducted with VP1 protein cloned in an expression vector and purified to provide ample quantities for capsomere-capsid assembly. Flight studies were conducted on STS-37 on April 5-9, 1991. Assembly initiated when a VP1 protein solution was interfaced with a Ca+2 buffer solution (pH 5.0). After four days a second alignment terminated the assembly process and allowed for glutaraldehyde fixation. Flight and ground-based samples were analyzed by electron microscopy. Ground-based experiments revealed the assembly of VP1 into capsid-like structures and a heterogenous size array of capsomere subunits. Samples reacted in microgravity, however, showed capsomeres of a homogenous size, but lack of capsid-like assembly.


HSP70i accelerates depigmentation in a mouse model of autoimmune vitiligo.
Vitiligo is a T-cell-mediated autoimmune disease of the skin. Progressive depigmentation accelerates in response to stress. Personal trauma, contact with bleaching phenols, overexposure to UV, and mechanical injury can lead to progressive loss of melanocytes. This study was focused on the role of stress protein heat shock protein (HSP)70 for translating stress into an autoimmune disease to melanocytes. Intracellular HSP70 can act as a cytoprotectant, preventing apoptosis in cells under stress. Isoform HSP70i can be secreted by live cells, and in prior in vitro studies, HSP70 has been shown to activate dendritic cells and elicit an immune response to chaperoned proteins and peptides. Here, the role of HSP70 in precipitating and perpetuating vitiligo was assessed in vivo in a mouse model of autoimmune vitiligo. In this model, depigmentation was introduced by gene gun vaccination with eukaryotic expression plasmids encoding melanocyte differentiation antigens. Inclusion of human and mouse-derived inducible HSP70 in the vaccination protocol significantly increased and accelerated depigmentation in this model, accompanied by the induction of prolonged humoral responses to HSP70. Cytotoxicity toward targets loaded with a K(b)-restricted tyrosinase-related protein 2-derived peptide correlated with depigmentation. The data presented strongly support a role for HSP70i in progressive depigmentation in vivo.


The effect of mouth breathing on exercise induced fall in lung function in children with allergic asthma and rhinitis.
Exercise induced bronchospasm (EIB) represents a common feature of childhood asthma which is most commonly revealed during free running. On the other hand aerobic exercise shows significant beneficial effects in asthmatics especially on the reduction of the level of systemic inflammation and is recommended as part of its treatment. The aim of this study was to test how mandatory mouth breathing influences the exercise induced level of decrease in lung function according to the level of severity of allergic rhinitis (AR). Free 6-minute running test preceded and followed by spirometry done with and without a nose clip a day apart was conducted in 55 children with moderate persistent asthma and AR. Children were divided into two groups according to the severity of nasal symptoms. There was a greater fall in forced expiratory volume in one second after exercise with a nose clip in children with less nasal symptoms than in children with more nasal symptoms (mean ± SD; -5.28 (7.91) vs. -0.08 (4.58), p = 0.0228) compared to testing without the nose clip (mean ± SD; LNS, -1.31 ± 3.89%, p = 0.2408; MNS, -1.47 ± 3.68%, p = 0.2883). Our results show that regular mouth breathing due to nasal congestion may lessen the degree of EIB in patients with persistent AR and allergic asthma.


The reaction of Rhodospirillum rubrum cytochrome c2 with iron hexacyanides.
The reaction of Rhodospirillum rubrum cytochrome c2 with the nonphysiological reactants, ferrocyanide and ferricyanide has been investigated as a function of ionic strength, temperature and pH, using both stopped-flow and temperature-jump kinetic methods. The results are consistent with a complex reaction mechanism involving the formation of two intermediate complexes. The site of electron transfer appears to be at the front of the cytochrome c2 molecule near the hem e crevice with interacton of both ferri and ferrocyanide with a positively charged region of the molecule. Comparison of the proposed electron transfer mechanism of cytochrome c2 with ferro-ferricyanide is made with the mechanism proposed based upon structural considerations.


A method for displaying two images on a screen in distance medical education.
This article describes a method for simultaneously displaying several images on a screen during an online multimedia presentation. Users with 'REALPLAYER' software and Web browsers can view images with synchronous audio on their personal computers via the Internet. Medical researchers and physicians often find it useful to compare images after treatment with those before treatment, by displaying several arranged images simultaneously. Medical care providers can browse this type of multimedia content in their offices and universities at their convenience. There presently exist two methods for creating multimedia content with voice and images using RealSystem technology. Electronic lectures of otorhinolaryngology explaining new surgical procedures for patients with chronic otitis media were created with this method and made available to otorhinolaryngologists through the Internet.


[Law of emergency representation by spouses in matters of healthcare-Practical implementation of a controversial norm].
The scope of the German law of emergency representation by spouses ("Ehegattenvertretungsrecht"), which has been in effect since 1 January 2023, is currently being described as uncertain, fuzzy and insufficiently defined in many aspects. Treating physicians are confronted with a long legal text characterized by references to other norms and in need of interpretation. The law itself is not limited to representation in emergency measures sensu stricto, although the right of representation should only be based on treatment that is "necessary from a medical point of view and cannot be postponed". Pending established case law, this article attempts to present guidelines for the practical application of the law of emergency representation by spouses. Special aspects such as medical liability, the central register of lasting powers of attorney and the inclusion of the represented spouse in studies are discussed.


"A proof of life" through transition from hospital to home after a stroke in a Portuguese setting - a multi-perspective, longitudinal qualitative study.
The impact of a stroke is particularly evident during the transition home, with reported unmet needs. However, little is known about post-stroke adaptation in Portugal. This study aimed to understand how Portuguese people with stroke and their informal carers/family adapt over time, and how health professionals support their adaptation. A multi-perspective, longitudinal qualitative study was conducted using in-depth semi-structured interviews one and six months after inpatient discharge. A purposive sample of 24 participants (8 triads) participated. Thematic and narrative analysis strategies were used. Three themes were identified: Managing change over time; Balancing support over time; Changing priorities. These suggest the importance of time and gradual adjustment of health professionals' approach throughout the rehabilitation process tailored to people with stroke' and carers' needs. Both valued positive thoughts and support from others to adjust life goals and find a balance between a mutual/bidirectional support and time for themselves. Findings show that the manner in which changes after a stroke are approached may be positively transformed to provide strength. As a result of the deeper understanding gained from this study, health professionals may be better placed to acknowledge the needs of people with stroke and carers and find effective ways of supporting them.


Nasal airway microRNA profiling of infants with severe bronchiolitis and risk of childhood asthma: a multicentre prospective study.
Severe bronchiolitis (i.e. bronchiolitis requiring hospitalisation) during infancy is a major risk factor for childhood asthma. However, the exact mechanism linking these common conditions remains unclear. We examined the longitudinal relationship between nasal airway miRNAs during severe bronchiolitis and the risk of developing asthma. In a 17-centre prospective cohort study of infants with severe bronchiolitis, we sequenced their nasal microRNA at hospitalisation. First, we identified differentially expressed microRNAs (DEmiRNAs) associated with the risk of developing asthma by age 6 years. Second, we characterised the DEmiRNAs based on their association with asthma-related clinical features, and expression level by tissue and cell types. Third, we conducted pathway and network analyses by integrating DEmiRNAs and their mRNA targets. Finally, we investigated the association of DEmiRNAs and nasal cytokines. In 575 infants (median age 3 months), we identified 23 DEmiRNAs associated with asthma development (e.g. hsa-miR-29a-3p; false discovery rate (FDR) <0.10), particularly in infants with respiratory syncytial virus infection (FDR for the interaction <0.05). These DEmiRNAs were associated with 16 asthma-related clinical features (FDR <0.05), e.g. infant eczema and corticosteroid use during hospitalisation. In addition, these DEmiRNAs were highly expressed in lung tissue and immune cells (e.g. T-helper cells, neutrophils). Third, DEmiRNAs were negatively correlated with their mRNA targets (e.g. hsa-miR-324-3p/IL13), which were enriched in asthma-related pathways (FDR <0.05), e.g. toll-like receptor, PI3K-Akt and FcɛR signalling pathways, and validated by cytokine data. In a multicentre cohort of infants with severe bronchiolitis, we identified nasal miRNAs during illness that were associated with major asthma-related clinical features, immune response, and risk of asthma development.


Evaluation of Inhaled Tobramycin in Early Eradication of Pseudomonas aeruginosa in Infants With Cystic Fibrosis.
Early antibiotic therapy has the potential to eradicate initial Pseudomonas aeruginosa infection and postpone chronic infection. There are limited data evaluating the efficacy and safety of inhaled tobramycin in patients with cystic fibrosis (CF) who are younger than 1 year. The objective of this study was to evaluate the effectiveness of inhaled tobramycin in early eradication of P aeruginosa in infants with CF. This retrospective study evaluated patients with CF younger than 1 year with first time infection with P aeruginosa. The primary outcome was the frequency of P aeruginosa eradication. Secondary outcomes were sustained culture negativity at 12 and 18 months and safety assessments. Of 18 patients included in the study, 9 received inhaled tobramycin and an enteral fluoroquinolone and 9 received inhaled tobramycin alone. Microbiologic clearance of respiratory cultures was observed in 83% patients at end of therapy and 78% of patients at 1 month posttherapy. Eradication of P aeruginosa was observed in 56% of patients at 6 months posttreatment with sustained culture negativity observed in 39% of patients up to 18 months. Inhaled-tobramycin therapy is effective in early eradication of P aeruginosa infection and is well tolerated in infants younger than 1 year.


Cancer of the urinary bladder in highly exposed workers in the production of dinitrotoluenes: a case report.
Technical dinitrotoluene (consisting of 2,4- and 2,6-dinitrotoluene isomers) has been widely used as explosives. Both technical isomers are mutagenic in Salmonella typhimurium TA98 strains and carcinogenic in rodents. 2,4-dinitrotoluene shows a dose-dependency of malignant tumors of the kidneys, liver, and mammary glands in rats and mice. In this case report, we discuss a cluster of three cases of urothelial cancer amongst a group of about 60 workers exposed to dinitrotoluenes. The workers were employed in the manufacturing of nitrotoluene explosives in the former German Democratic Republic. The cases occurred within a period of 12 years (1990-2002) leading to a 15.9 fold higher incidence of cancer of the urinary bladder than of the federal state where the chemical factory was located. The observation of the cluster of urothelial cancer in persons highly exposed to nitrotoluenes underlines the putative human carcinogenicity of dinitrotoluenes with the human urothelium as a relevant target tissue.


Stress, sensitive periods and maturational events in adolescent depression.
In this paper, we provide an overview of how the maturation of specific brain regions and stress exposure during windows of vulnerability initiate a series of events that render adolescents exceptionally susceptible to the development of depression. This stress-incubation/corticolimbic development cascade provides a means of understanding why depression emerges with such force and frequency in adolescence. The development of the prefrontal cortex, hippocampus, amygdala and ventral striatum is described from a translational perspective as they relate to stress exposure, onset, pathogenesis and gender differences in depression. Adolescent depression is a serious recurrent brain-based disorder. Understanding the genesis and neurobiological basis is important in the development of more effective intervention strategies to treat or prevent the disorder.


An oblique muscle hematoma as a rare cause of severe abdominal pain: a case report.
Abdominal wall hematomas are an uncommon cause of acute abdominal pain and are often misdiagnosed. They are more common in elderly individuals, particularly in those under anticoagulant therapy. Most abdominal wall hematomas occur in the rectus sheath, and hematomas within the oblique muscle are very rare and are poorly described in the literature. Here we report the case of an oblique muscle hematoma in a middle-aged patient who was not under anticoagulant therapy. A 42-year-old Japanese man presented with a painful, enlarging, lateral abdominal wall mass, which appeared after playing baseball. Abdominal computed tomography and ultrasonography showed a large soft tissue mass located in the patient's left internal oblique muscle. A diagnosis of a lateral oblique muscle hematoma was made and the patient was treated conservatively. Physicians should consider an oblique muscle hematoma during the initial differential diagnosis of pain in the lateral abdominal wall even in the absence of anticoagulant therapy or trauma.


Ultrastructural pattern of acetylcholinesterase distribution in the cerebellar cortex of the quail.
The ultrastructural localization of acetylcholinesterase (AChE) was studied in the cerebellar cortex of the quail by means of histochemical method. The greater amount of AChE was detected at leve of the molecular layer in the intracellular spaces between parallel fibers and between parallel fibers and dendritic terminals. Many neurons showed intracellular localization of enzyme activity: the AChE positive neurons were all Golgi cells, most stellate the basket cells and different aliquots of Purkinje and granule cells. The enzymatic activity was usually localized in the cisternae of endoplasmic reticulum, in the nuclear envelope (but this last localization was not present in Purkinje cells- and sometimes in the Golgi apparatus; reaction granules were usually scarce in the different dendritic branches ramifying in the molecular layer. On the basis of the ultrastructural pattern of AChE distribution, some considerations are developed on the methodological aspects concerning the reliability of histochemical methods, the differences recorded at light and electron microscope level, the problems related to extracellular localization of enzyme, the difficulty of establishing a precise correlation between AChE localization in a cerebellar neuron and its possible cholinergic and/or cholinoceptive nature.


A review of approaches to optimise chest compressions in the resuscitation of asphyxiated newborns.
Provision of chest compressions (CCs) and/or medications in the delivery room is associated with poor outcomes. Based on the physiology of perinatal asphyxia, we aimed to provide an overview of current recommendations and explore potential determinants of effective neonatal cardiopulmonary resuscitation (CPR): balancing ventilations and CC, CC rate, depth, full chest recoil, CC technique and adrenaline. A search in the databases MEDLINE (Ovid) and EMBASE until 10 April 2015. Delivery room. Asphyxiated newborn infants. CCs. Haemodynamics, recovery and survival. Current evidence is derived from mathematical models, manikin and animal studies, and small case series. No randomised clinical trials examining neonatal CC have been performed. There is no evidence to refute a CC to ventilation (C:V) ratio of 3:1. Raising the intrathoracic pressure, for example, by superimposing a sustained inflation on uninterrupted CC, and a CC rate >120/min may be beneficial. The optimal neonatal CC depth is unknown, but factors influencing depth and consistency include the C:V ratio. Incomplete chest wall recoil can cause less negative intrathoracic pressure between CC and reduced CPR effectiveness. CC should be performed with the two-thumb method over the lower third of the sternum. The optimal dose, route and timing of adrenaline administration remain to be determined. Successful CPR requires the delivery of high-quality CC, encompassing optimal (A) C:V ratio (B) rate, (C) depth, (D) chest recoil between CC, (E) technique and (F) adrenaline dosage. More animal studies with high translational value and randomised clinical trials are needed.


Beyond the gastric epithelium - the paradox of Helicobacter pylori-induced immune responses.
Chronic infections are typically characterized by an ineffective immune response to the inducing pathogen. While failing to clear the infectious microbe, the provoked inflammatory processes may cause severe tissue damage culminating in functional impairment of the affected organ. The human pathogen Helicobacter pylori is a uniquely successful Gram-negative microorganism inhabiting the gastric mucosa in approximately 50% of the world's population. This bacterial species has evolved spectacular means of evading immune surveillance and influencing host immunity, leading to a fragile equilibrium between proinflammatory and anti-inflammatory signals, the breakdown of which can have serious consequences for the host, including gastric ulceration and cancer. This review highlights novel insights into this delicate interaction between host and pathogen from an immunological perspective.


Chemometric-assisted surface-enhanced Raman spectroscopy for metformin determination using gold nanoparticles as substrate.
A fast, simple, and reliable method for determination of metformin was developed by coupling surface-enhanced Raman spectroscopy (SERS) with chemometric methods. This relayed on the utilization of a portable Raman spectrometer and of citrate stabilized gold nanoparticles (AuNPs) as substrate, to carry out the measurement of SERS scattering signals, thus assuring improved sensitivity. The obtained datasets were analysed using principal component analysis (PCA) and partial least squares (PLS) regression. Upon optimization of the PLS model, in terms of latent variables, spectral region and pre-processing techniques, RMSECV and R2CV values of 0.42 mg/L and 0.94, respectively, were obtained. The optimized PLS regression model was further validated with the projection of commercial pharmaceutical samples, providing good results in terms of R2P (0.97), RE (4.54 %) and analytical sensitivity (2.13 mg/L).


Transformation of functional groups and environmentally persistent free radicals in hydrothermal carbonisation of lignin.
In this study, lignin was selected as the main component of waste biomass to synthesise carbonaceous adsorbents with environmentally persistent free radicals (EPFRs) through hydrothermal carbonisation (HTC) under different conditions. The HTC method with Fe(III) doping was superior for promoting dehydration and decarboxylation of lignin hydrochar than that with HTC Cu(II) doping. The deconstruction of oxygen-containing groups of lignin was reduced while esterification was enhanced by Fe(III). The Fe(III) addition was conducive to the formation of EPFRs as carbon-centred radicals with an adjacent oxygen atom and oxygen-centred radicals. A comparison of lignin with cellulose and d-xylose suggests that the formed EPFRs on lignin hydrochar were derived from their phenolic hydroxyl groups. A high removal efficiency of bisphenol A by lignin hydrochar was observed owing to oxygen-centred radicals, which activated H2O2 to produce OH. These results will facilitate the design and application of novel hydrochar materials with EPFRs.


Evidence-based recommendations on upper gastrointestinal tract stenting: a report from the stent study group of the korean society of gastrointestinal endoscopy.
Endoscopic stents have evolved dramatically over the past 20 years. With the introduction of uncovered self-expanding metal stents in the early 1990s, they are primarily used to palliate symptoms of malignant obstruction in patients with inoperable gastrointestinal (GI) cancer. At present, stents have emerged as an effective, safe, and less invasive alternative for the treatment of malignant GI obstruction. Clinical decisions about stent placement should be made based on the exact understanding of the patient's condition. These recommendations based on a critical review of the available data and expert consensus are made for the purpose of providing endoscopists with information about stent placement. These can be helpful for management of patients with inoperable cancer or various nonmalignant conditions in the upper GI tract.


Invasive carcinomas of the urinary bladder. Evaluation of tunica muscularis mucosae involvement.
Awareness of the existence of a tunica muscularis mucosae in the urinary bladder complicates the assessment of muscle invasive carcinomas on bladder biopsy. Sixty cystectomy specimens and select bladder biopsies were reviewed to analyze this problem. The patterns of development of the tunica muscularis mucosae were categorized as continuous, interrupted, scattered, or absent. Most bladders demonstrated several patterns of development rather than a uniform appearance. The most frequently observed pattern was that of scattered smooth muscle fibers seen in 33 of 40 (82.5%) cases. The rarity of carcinomatous invasion limited to the tunica muscularis mucosae is emphasized. The authors conclude that the potential for overstaging bladder carcinomas because of misinterpretation of this structure is small.


Molecular cloning and functional analysis of Drosophila TAF110 reveal properties expected of coactivators.
The general transcription factor TFIID is a multiprotein complex containing the TATA-binding protein and several associated factors (TAFs), some of which may function as coactivators that are essential for activated, but not basal, transcription. Here we describe the isolation and characterization of the first gene encoding a TAF protein. The deduced amino acid sequence of TAF110 revealed the presence of several glutamine- and serine/threonine-rich regions reminiscent of the protein-protein interaction domains of the regulatory transcription factor Sp1 that are involved in transcription activation and multimerization. In both Drosophila cells and yeast, TAF110 specifically interacts with the glutamine-rich activation domains of Sp1. Moreover, purified Sp1 selectively binds recombinant TAF110 in vitro. These findings taken together suggest that TAF110 may function as a coactivator by serving as a site of protein-protein contact between activators like Sp1 and the TFIID complex.


Spanish Society of Primary Care Physicians (SEMERGEN) and Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) survey on the management of patients with inflammatory bowel disease.
Collaboration between Primary Care (PC) and Gastroenterology in inflammatory bowel disease (IBD) is crucial to provide high-quality healthcare. The aim of this study is to analyse the relationship between PC and gastroenterologists at a national level in order to identify areas for improvement in the management of patients with inflammatory bowel disease (IBD) and how to address them, with the aim of subsequently developing concrete proposals and projects between SEMERGEN and GETECCU. Descriptive, observational, cross-sectional study, was carried out using an anonymous online questionnaire between October 2021 and March 2022. A total of 157 surveys from Gastroenterology and 222 from PC were collected. 43.8% and 34.3% of gastroenterologists and family practitioners, respectively, considered that there was a good relationship between the units. The level of knowledge from family practitioners regarding different aspects of IBD out of 10 was: clinical 6.67±1.48, diagnosis 6.47±1.46, treatment 5.63±1.51, follow-up 5.53±1.68 and complications 6.05±1.54. The perception of support between both units did not exceed 4.5 on a scale from 0 to 10 in either of the surveys. The most highly voted improvement proposals were better coordination between the units, implementation of IBD units, and nursing collaboration. There are deficiencies in the relationship between PC and Gastroenterology with special dedication to IBD that require the efforts of the scientific societies that represent them for greater coordination with the development of joint protocols and agile, fast, and effective communication channels.


Routine Evaluation of Minimal Residual Disease in Myeloma Using Next-Generation Sequencing Clonality Testing: Feasibility, Challenges, and Direct Comparison with High-Sensitivity Flow Cytometry.
The 2016 International Myeloma Working Group consensus recommendations emphasize high-sensitivity methods for minimal residual disease (MRD) detection, treatment response assessment, and prognostication. Next-generation sequencing (NGS) of IGH gene rearrangements is highly specific and sensitive, but its description in routine clinical practice and performance comparison with high-sensitivity flow cytometry (hsFC) remain limited. In this large, single-institution study including 438 samples from 251 patients, the use of NGS targeting the IGH and IGK genes for clonal characterization and monitoring, with comparison to hsFC, is described. The index clone characterization success rate was 93.6% (235/251), which depended on plasma cell (PC) cellularity, reaching 98% when PC ≥10% and below 80% when PC <5%. A total of 85% of cases were successfully characterized using leader and FR1 primer sets, and most clones showed high somatic hypermutation rates (median, 8.1%). Among monitoring samples from 124 patients, 78.6% (147/187) had detectable disease by NGS. Concordance with hsFC was 92.9% (170/183). Discordant cases encompassed 8 of 124 hsFC MRD+/NGS MRD- patients (6.5%) and 4 of 124 hsFC MRD-/NGS MRD+ patients (3.2%), all with low-level disease near detection limits for both assays. Among concordant hsFC MRD-/NGS MRD- cases, only 5 of 24 patients (20.8%) showed subsequent overt relapse at 3-year follow-up. HsFC and NGS showed similar operational sensitivity, and the choice of test may depend on practical, rather than test performance, considerations.


Protocol for a double-blind randomised controlled trial of low dose intradermal grass pollen immunotherapy versus a histamine control on symptoms and medication use in adults with seasonal allergic rhinitis (PollenLITE).
Subcutaneous immunotherapy with high dose grass pollen (typically microgram quantities) was first described over 100 years ago. This treatment suppresses allergen-induced cutaneous late responses, with lesser effects on early responses. We previously reported that repeated 2-weekly intradermal injections of grass pollen - containing approximately 7 ng of major allergen Phl p 5 - led to a progressive suppression of the allergen-induced cutaneous response, and that by the sixth injection, this was inhibited by over 90%. The purpose of this trial is to investigate the clinical efficacy of intradermal desensitisation with low doses (i.e. nanogram quantities) of grass pollen allergen for seasonal allergic rhinitis. The Pollen Low dose Intradermal therapy Evaluation (PollenLITE) is a single centre double-blind randomised parallel group controlled trial of the efficacy and safety of intradermal grass pollen injections plus standard treatment, versus histamine injections plus standard treatment, in adults with moderate-severe grass pollen-induced allergic rhinitis ('summer hay fever'). A minimum of ninety adults with a history of moderate-severe persistent allergic rhinitis during the UK grass pollen season will be randomised into two equal groups to receive 7 or 8 intradermal injections of grass pollen extract (containing approximately 7 ng of major allergen Phl p 5) or histamine, before the grass pollen season. In the summer, participants will score their symptoms, medication requirements, visual analogue scores, and complete EuroQOL (EQ-5D-5 L) and mini Rhinoconjunctivitis Quality of Life Questionnaires. Global assessments will also be recorded at the end of the pollen season. Blood samples will be collected from all participants for mechanistic immune assays. Skin punch biopsies will also be collected in 40 participants selected at random from intradermal injection sites after the grass pollen season for mechanistic assays. Finally, to investigate if the desensitising effect of intradermal immunotherapy on cutaneous responses is long-lasting, all participants will be randomised to receive a follow up intradermal injection after 3, 6 or 12 months with measurement of early and late response sizes. Randomisation began in February 2013 and the final participant will complete the trial protocol in August 2014. ISRCTN 78413121EudraCT number 2012-002193-31.


Transient effects of smoking on the eye.
To investigate the immediate short-term effects of smoking in habitual smokers, on the tear film, pupil size and accommodative ability of the human eye. Habitual smokers were tested within 5 min of smoking a cigarette. The tear film analysis was undertaken using tear break-up time (TBUT), tear lipid layer thickness and tears meniscus height (TMH) measurements. Three different ways of tear break-up time (TBUT) were used; using fluorescein; a non-invasive TBUT using tearscope; and a video captured method with a corneal topographer. Pupil size was measured objectively using the video capture on the corneal topographer. Accommodative ability was checked by performing a 'push up test' to measure amplitudes of accommodation (AoA) and by measuring defocus curves. Forty-five participants were enrolled (mean age 22.0 ± 4.4 years). TBUT was reduced after smoking a cigarette with all three assessment methods and this reduction was statistically significant (p < 0.001). A reduction in lipid layer thickness was seen after smoking a cigarette with both methods used and was statistically significant (p < 0.01). A significant reduction in pupil size (p < 0.01) and in AoA (p < 0.001) was observed after smoking a cigarette. The difference in TMH and defocus curves, before and after smoking, were not statistically significant (p > 0.05). The study shows that there is an immediate adverse effect of smoking on TBUT and AoA which seems to be very transient.


Wavelet analysis demonstrates no abnormality in contralateral suppression of otoacoustic emissions in tinnitus patients.
The efferent auditory system is thought to play a role in the origin of tinnitus. Part of this system can be tested in humans with contralateral suppression of otoacoustic emissions. Stimulation of the medial olivocochlear efferent system is responsible for this reduction of otoacoustic emissions after contralateral acoustic stimulation. Previous research on patients with tinnitus showed inconclusive results. With wavelet analysis both time and frequency information of the emission can be analysed and compared. Contralateral suppression of otoacoustic emissions was therefore measured in tinnitus patients (n = 26) and normal subjects (n = 37) and analysed using wavelets. No significant difference in suppression was found between the tinnitus patients and the control group.


Nonpharmacological techniques to support patients with intellectual developmental disorders to receive dental treatment: A systematic review of behavior change techniques.
To identify the nonpharmacological patient-support techniques (nPSTs) reported, used or recommended for people with intellectual-developmental-disorders (IDD) to receive dental treatment; to identify their active ingredients and evaluate their effectiveness by adopting an existing taxonomy of behavior-change techniques (BCTs). Following a protocol, a search strategy was undertaken using Medline, Embase, Cochrane Library, Scopus, Cinahl, and Psychinfo (EBSCO). Selection criteria were applied, with review and extraction in duplicate. A comprehensive list of nPSTs were identified and coded by their constituent behavior-change techniques (BCTs), where BCT-taxonomy-Version-1 criteria were satisfied. Quality assessment was undertaken and effectiveness of BCTs reported. From 915 screened articles, 23 were included. In 207 instances nPSTs were identified, representing 46 distinct nPST techniques, such as positive-reinforcement (n = 18) and tell-show-do (n = 9). Of the 207 nPST codes, 135 were coded as BCTs (65.2%). The most commonly coded BCT was demonstration of the behavior (BCT6.1; n = 25). Considering studies of interventions (n = 11), all were at moderate to critical risk of bias. No interventions or outcome measures were comparable across studies. This is the first review to bring together techniques dentists use in practice and theory-driven BCTs. A significant overlap between nPSTs and BCTs was evident supporting the use of BCT taxonomy to code dental interventions. No strong evidence supporting any intervention was identified.


A case series and literature review of blastomycosis during pregnancy amidst the COVID-19 crisis.
Blastomycosis dermatitidis is a rare fungus known for is classic mimicry of pneumonia, lung cancer, and mycobacterial infections. Whilst it is known best for affecting those in the Ohio and Mississippi River basins, several cases have erupted in the Midwest region. Few case reports have focused on blastomycosis and its sequalae in pregnancy. We present a case series of blastomycosis diagnosed during the second and third trimesters in two women amidst the COVID-19 pandemic. Given immunosuppression, complications and treatment can be challenging for clinicians. This case series and discussion hopes to provide future clinicians with the presentation, diagnosis, management, and treatment of this uncommon infection.


Detection of chloramphenicol with an aptamer-based colorimetric assay: critical evaluation of specific and unspecific binding of analyte molecules.
A chloramphenicol (CAP)-binding aptamer of 80 nucleotides (nt) was reported in 2011. In 2014, it was truncated to 40 nt and has since been used by most researchers, although a careful binding study is still lacking. In this work, binding assays using isothermal titration calorimetry and various DNA-staining dyes were performed. By comparing the truncated aptamer with three control sequences, no specific binding of CAP was observed in each case. The secondary structures of the original and truncated aptamers were analyzed, and it was shown that the likelihood of the truncated aptamer to retain the same binding mechanism as the original sequence is low. We further examined gold nanoparticle (AuNP)-based label-free colorimetric assays. By quantifying the extinction ratio at 620 nm over that at 520 nm, a similar color response was observed regardless of the sequence of DNA, suggesting the color change mainly reflected other events such as the adsorption of CAP by the AuNPs, instead of aptamer binding to CAP. Salt-induced aggregation experiments suggested direct adsorption of CAP on AuNPs. CAP only weakly inhibited DNA adsorption by AuNPs but did not displace pre-adsorbed DNA. Therefore, CAP adsorption by AuNPs needs to be considered when designing related sensors, for example, by using non-aptamer sequences as controls. This work calls for careful confirmation of aptamer binding and control experiments for designing aptamer and AuNP-based biosensors.