Strong inverse associations of Mediterranean diet, physical activity and their combination with cardiovascular disease: The Seguimiento Universidad de Navarra (SUN) cohort.
Background Inverse associations of the Mediterranean diet (MedDiet) and physical activity with cardiovascular disease have been previously reported. We investigated the individual and combined contributions of both to this inverse association in a Mediterranean cohort. Design We used data from 19,536 participants from a prospective cohort of Spanish university graduates, the 'Seguimiento Universidad de Navarra' (SUN) cohort, followed up between December 1999 and December 2016. Methods Adherence to the MedDiet was obtained from a 136-item validated food-frequency questionnaire and categorized in tertiles using four previously reported dietary scores. A validated questionnaire assessed the physical activity levels according to volume, intensity and frequency. Results Participants were followed up during a median time of 10.4 years. Compared with the lowest category of adherence to the MedDiet (≤3 in the Mediterranean Diet Score), higher adherence (6-9 points) was strongly inversely associated with cardiovascular disease (multivariable adjusted hazard ratio = 0.33; 95% confidence interval (CI) 0.20-0.55). Also, engaging in an active lifestyle (6-8 points in an eight-item score) compared with low activity (<2 points) was associated with a reduced risk of incident cardiovascular disease (hazard ratio = 0.43; 95% CI 0.20-0.90). Greater adherence to the MedDiet and engaging in high levels of active lifestyle showed a 75% relatively reduced risk of cardiovascular disease (hazard ratio = 0.25; 95% CI 0.13-0.48). Conclusions The combined effect of adherence to the MedDiet and adopting an active lifestyle showed a synergistic inverse association with cardiovascular disease risk.


Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer.
The immunosuppressive desmoplastic stroma of pancreatic cancer represents a major hurdle to developing an effective immune response. Preclinical studies in pancreatic cancer have demonstrated promising anti-tumor activity with Bruton tyrosine kinase (BTK) inhibition combined with programmed cell death receptor-1 (PD-1) blockade. This was a phase II, multicenter, open-label, randomized (1:1) clinical trial evaluating the BTK inhibitor acalabrutinib, alone (monotherapy) or in combination with the anti-PD-1 antibody pembrolizumab (combination therapy). Eligible patients were adults with histologically confirmed metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1 who had received at least one prior systemic therapy. Oral acalabrutinib 100 mg twice daily was administered with or without intravenous pembrolizumab 200 mg on day 1 of each 3-week cycle. Peripheral blood was analyzed for changes in immune markers, and tumors from exceptional responders were molecularly analyzed. A total of 77 patients were enrolled (37 monotherapy; 40 combination therapy) with a median age of 64 years; 77% had an ECOG PS of 1. The median number of prior therapies was 3 (range 1-6). Grade 3-4 treatment-related adverse events were seen in 14.3% of patients in the monotherapy arm and 15.8% of those in the combination therapy arm. The overall response rate and disease control rate were 0% and 14.3% with monotherapy and 7.9% and 21.1% with combination therapy, respectively. Median progression-free survival was 1.4 months in both arms. Peripheral blood flow analysis demonstrated consistent reductions in granulocytic (CD15+) myeloid-derived suppressor cells (MDSCs) over time. Two exceptional responders were found to be microsatellite stable with low tumor mutation burden, low neoantigen load and no defects in the homologous DNA repair pathway. The combination of acalabrutinib and pembrolizumab was well tolerated, but limited clinical activity was seen with either acalabrutinib monotherapy or combination therapy. Peripheral reductions in MDSCs were seen. Efforts to understand and target the pancreatic tumor microenvironment should continue. NCT02362048.


Water deprivation stimulates transforming growth factor-beta 2 accumulation in the juxtaglomerular apparatus of mouse kidney.
Transforming growth factor-beta (TGF-beta) modulates the growth and differentiation of many cells and often functions in an autocrine or paracrine fashion. The myoepithelial cells of the renal juxtaglomerular apparatus (JGA) synthesize and secrete renin. Under conditions which chronically stimulate renin production, the JGA undergoes hypertrophy and hyperplasia. The molecular factors responsible for these changes in the JGA have not been identified. In the present study, plasma renin activity was stimulated in the mouse by water deprivation. Using immunoperoxidase staining with specific antibodies against TGF-beta 1, beta 2, and beta 3, we found increased TGF-beta 2 accumulation in the JGA and interlobular arteries. Immunostaining with renin antiserum demonstrated colocalization of TGF-beta 2 and renin. TGF-beta 1 and beta 3 expression was not different between control and water-deprived mice. Our results suggest that in the setting of water deprivation, TGF-beta 2 is localized in a manner which would allow it to act either as a growth factor for or as a phenotypic modulator of the JGA and renal arterioles.


Patterns of adherence to antiretrovirals: why adherence has no simple measure.
The goal of this study was to explore patterns and explanations of adherence to antiretroviral therapies from the patient's perspective. It consisted of 78 in-depth interviews with patients attending an HIV clinic in New Orleans, Louisiana, to whom combination therapy had been prescribed. Interviews explored patient's definitions of adherence, beliefs about consequences of nonadherence, reasons for current and past adherence behavior, and contextual issues such as drug and alcohol use and social support. Respondents reported nine distinct patterns of adherence, which they perceived to have different consequences and causes. These patterns hid variations because respondents could have more than one pattern simultaneously and patterns were not stable over time. Although there are gold standards for adherence measurement, such as directly observed therapy, these measurements are most frequently used to classify respondents as adherers or nonadherers based on whether they take a certain percentage of their medication. Such a categorization is simplistic and does not reflect the complexity of adherence patterns.


Comparison of Efficacy and Safety of Recombinant Human Prourokinase and Alteplase in the Treatment of STEMI and Analysis of Influencing Factors of Efficacy.
To compare the efficacy and safety of recombinant human prourokinase (rhPro-UK) and alteplase for thrombolytic therapy in acute ST-segment elevation myocardial infarction (STEMI) and to analyze the related factors affecting efficacy. From January 2017 to December 2019, 100 patients diagnosed with STEMI were selected and randomly divided into the control group (n = 50) and the observation group (n = 50). Based on conventional treatments, the control group was treated with alteplase, and the observation group was treated with rhPro-UK, and both were treated for 7 days. After treatment, the vascular recanalization, left ventricular end-systolic diameter (LVESD), left ventricular end-diastolic diameter (LVEDD), and left ventricular ejection fraction (LVEF) were compared. The bleeding and major adverse cardiovascular events (MACE) were recorded in both groups. According to the patient's vascular recanalization, it was divided into two subgroups: recanalization group and occlusion group. Multiple logistic regression models were used to analyze the related factors that affect the efficacy. The recanalization rate of the observation group (96.00%) was higher than that of the control group (84.00%) (P < 0.05). After treatment, LVDs and LVEDD in both groups were lower than those before treatment, and LVEF was higher than that before treatment. The LVDs and LVEDD in the observation group were lower than those in the control group, and the LVEF was higher than that in the control group (P < 0.05). The incidence of bleeding in the observation group (2.00%) was lower than that in the control group (12.00%), and the incidence of MACE (4.00%) was lower than that in the control group (16.00%) (P < 0.05). Univariate analysis showed that age, smoking history, diabetes history, myocardial infarction history, infarct location, and intravenous thrombolysis time were related to the efficacy after treatment (P < 0.05). Multivariate logistic analysis showed that age, history of diabetes, vascular infarction site, and venous thrombolysis time were independent influencing factors after treatment (P < 0.05). Both rhPro-UK and alteplase thrombolytic therapy can effectively recanalize blood vessels and improve the cardiac function of patients with STEMI. However, rhPro-UK has better effect than alteplase and is safer and worth promoting. The curative effect is related to age, diabetes history, vascular infarction site, and venous thrombolysis time.


[Prescription and consumption of antibiotics in ambulatory care].
This study was conducted to describe changes in prescription practices outside the hospital, to evaluate the adaptation of such prescriptions to current scientific knowledge, and to compare medical practices in France with those in other European countries. Data were collected from several sources: analysis of the literature, surveys conducted in the Loiret department and in the Rhone-Alpes region, ten-year health surveys (INSEE), data from the Sentinel network, sales statements from pharmaceutical firms, the Permanent Survey of Medical Prescription (EPPM) of the Medical Information and Statistics (IMS) firm. Comparisons between France, the United Kingdom and Germany were conducted by the French Medicine Agency's Pharmaco-economic Studies and Information Department using data furnished by the IMS firm and by pharmaceutical firms. In France, antibiotic sales increased by a mean annual rate of 2.1%, expressed in antibiotic units, and 2.6%, expressed in turnover (manufacturer price) between 1991 and 1996. The majority of these antibiotics were prescribed for respiratory and ENT infections with a presumed viral etiology such as rhinopharyngitis and acute bronchitis. The results of the different surveys were in agreement showing that antibiotic prescriptions are made in approximately 40% of all consultations for rhino-pharyngitis and in 80% of those for acute bronchitis. Antibiotics were prescribed in more than 90% of cases of pharyngitis whatever the age of the patient. The situation was different for acute middle ear infections as the number of consultations has remained relatively unchanged over the last 10 years while antibiotic prescriptions have strongly increased, reaching 80% of the consultations. The number of consultations for pharyngitis and acute rhino-pharyngitis appears to be greater in France than in the United Kingdom and in Germany. Likewise, the proportion of patients using antibiotics after consulting for presumed viral conditions would be higher in France with different antibiotic classes being used. There is a gap between official guidelines (product description documents, therapeutic information document good practice guidelines, consensus conferences) and the state of current practices. Excessive and poorly-adapted antibiotic prescription favors the disturbing phenomenon of resistance which is all the more alarming because the emergence of resistant strains is difficult to predict and concern bacteria causing the most common infections. To improve medical practices and achieve a persistent reduction in the use of antibiotics for viral infections, validated recommendations should be distributed to physicians. An effort should be made to prescribe the most appropriate active substance at optimal dose and treatment duration to limit the development of bacterial resistance. In addition, patients and the general public should be informed of the absence of any beneficial effect and the individual and collective risks involved in using antibiotic for viral infections in order to help them better understand and comply to their physician's prescription.


Prevalence, risk factors and health consequences of soil-transmitted helminth infection on the Bijagos Islands, Guinea Bissau: A community-wide cross-sectional study.
Soil-transmitted helminths (STH) are endemic and widespread across Sub-Saharan Africa. A community wide soil-transmitted helminth (STH) prevalence survey was performed on the island of Bubaque in Guinea-Bissau using both Kato-katz microscopy and qPCR methodology. Predictors of infection and morbidity indicators were identified using multivariable logistic regression, and diagnostic methods were compared using k statistics. Among 396 participants, prevalence of STH by microscopy was 23.2%, hookworm was the only species identified by this method and the mean infection intensity was 312 eggs per gram. qPCR analysis revealed an overall prevalence of any STH infection of 47.3%, with the majority A. duodenale (32.3%), followed by N. americanus (15.01%) and S. stercoralis (13.2%). A. lumbricoides, and T. trichiura infections were negligible, with a prevalence of 0.25% each. Agreement between diagnostic tests was k = 0.22, interpreted as fair agreement, and infection intensity measured by both methods was only minimally correlated (Rs = -0.03). STH infection overall was more common in females and adults aged 31-40. STH infection was associated with open defaecation, low socio-economic status and further distance to a water-source. The prevalence of anaemia (defined as a binary outcome by the WHO standards for age and sex) was 69.1%, and 44.2% of children were malnourished according to WHO child growth standards. Hookworm infection intensity by faecal egg count showed no statistically significant association with age (Rs 0.06) but S. Stercoralis infection intensity by qPCR cycle threshold was higher in pre-school aged children (Rs = 0.30, p-value 0.03) There was no statistically significant association between STH infection and anaemia (OR 1.0 p = 0.8), stunting (OR 1.9, p-value 0.5) and wasting (OR 2.0, p-value 0.2) in children. This study reveals a persistent reservoir of STH infection across the community, with high rates of anaemia and malnutrition, despite high-coverage of mebendazole mass-drug administration in pre-school children. This reflects the need for a new strategy to soil-transmitted helminth control, to reduce infections and ultimately eliminate transmission.


Estimation of gene expression in heterocysts of Anabaena variabilis by using DNA-RNA hybridization.
In the filamentous cyanobacterium Anabaena variabilis, specialized cells called heterocysts occur in a regular pattern along the filament and are the sites of nitrogen fixation. We used two different types of DNA-excess RNA hybridization techniques to estimate the number of genes expressed in recently differentiated, mature heterocysts. In the first, RNA and DNA were incubated in a phosphate buffer at 60 degrees C, and the hybrids were separated from the unhybridized material by hydroxylapatite chromatography. In the second, the nucleic acids were incubated at 50 degrees C in a buffer containing 50% formamide, and the fraction of DNA in duplexes was assayed by S1 nuclease digestion. Both techniques revealed that approximately 65% of the A. variabilis genome was expressed in vegetative cells and 45% of the genome was expressed in heterocysts. Two experiments were conducted to estimate the number of heterocyst-specific mRNA transcripts. In one, hybridization of heterocyst RNA to a null DNA probe (DNA not transcribed in vegetative cells) revealed that heterocyst-specific transcripts were encoded by 25% of the DNA sense strand, representing approximately 1,000 genes (assuming each to be 1,500 nucleotides in length). The second approach, in which total cell DNA was hybridized to a mixture of heterocyst and vegetative cell RNA, indicated that 14.7% of the DNA sense strand, or about 600 genes, was transcribed exclusively in the heterocyst. The remaining 900 to 1,300 transcripts present in the heterocyst appeared to be constitutively produced in both vegetative cells and heterocysts. The heterocyst-specific transcripts were present in abundant copies in the cell, while transcripts that occurred in both cell types were present at much lower frequency.


"Occult" ruptured cerebral aneurysms revealed by repeat angiography: result from a large retrospective study.
Not infrequently, cerebral angiography performed immediately after the onset of subarachnoid hemorrhage (SAH) fails to reveal any causative lesion. Although the cause of the SAH in most of these cases remains unknown, repeat angiography sometimes discloses a lesion not detected by the initial angiography. The frequency of finding a ruptured aneurysm by repeat angiography and the angiographic characteristics of such aneurysms have been investigated retrospectively. Nineteen among 316 non-traumatic SAH patients (6%) showed initially negative angiogram, and 7 of 19 patients (36%) were identified as harboring an "initially occult" aneurysm. It was possible to identify the expected cause of these initial false-negative angiograms in four of those seven patients. The aneurysm was located in the anterior communicating artery (ACoA) complex in four of the seven patients. When interpreting the angiograms of patients with SAH, neurologists and neurosurgeons should bear in mind the finding that the ACoA complex is the most frequent site of "initially occult" aneurysms. One patient had a dissecting aneurysm of the internal carotid artery, and although such lesions have been considered rare, they should be included in the differential diagnosis of SAH of unknown origin.


Olfactory dysfunction and training in children with COVID-19 infection: A prospective study Post-COVID pediatric olfactory training.
Postviral olfactory dysfunction (OD) including corona 2019 viral disease (COVID-19) OD occurs in both adults and children. Despite limited reports of efficacy in treating adult postviral including COVID-19 OD with olfactory training (OT), its effects on children in general, and post-COVID-19 in specific, is unknown. The study aimed at evaluating the effects of OT in a COVID-19 OD pediatric cohort. A single-arm prospective study of pediatric COVID-19 OD subjects confirmed by the University of Pennsylvania Smell Identification Test (UPSIT), was conducted. All subjects underwent OT by sniffing 4 odorants (lavender, orange, peppermint, and eucalyptus) for 1 min twice a day for 3 months. Subjects underwent an odorant identification test (OIT) of the 4 odorants each visit. A repeat UPSIT was administered at the 4th visit. The study enrolled a total of 37 subjects [11 males/26 females with mean age/standard deviation (std) of 15.6(2.1) years]. The time interval between COVID-19 and entry was 5.3(2.4) months. The mean pre/post study UPSIT score improvement was 2.3(4.7), p = .09. OIT scores between entry and 3 subsequent visits showed a mean improvement of 1.8(1.5), 1.8(1.9) and 2.3(1.9) odorants, respectively, with P < .001 for all 3 comparisons. OT subjects were predominantly female teens with substantial OD lasting greater than 5 months. OT did not affect OD as measured by UPSIT but OIT scores improved during OT. We postulate that OT likely has a role in pediatric post-COVID OD recovery, but UPSIT likely is too rigid to detect disparate odorant improvement.


Independent and Combined Associations of Physical Activity and Sedentary Behavior with Depressive Symptoms Among Japanese Adults.
Associations between levels of sedentary behavior and depressive symptoms independently and in combination with different levels of physical activity remain unclear. This study aimed to examine independent and combined associations of physical activity (PA) and sedentary behavior (SB) with depressive symptoms among Japanese adults. An Internet-based survey collected data on depression levels (Center for Epidemiologic Studies Depression Scale), self-reported time spent in PA and SB (Japanese short version of the International Physical Activity Questionnaire), and sociodemographic variables from 2,914 adults in 2009. Binary logistic regression analyses were conducted to examine the odds ratios (ORs) for being depressed (depression scores ≥16) according to independent PA levels (none, insufficient, sufficient), SB levels (low, moderate, high), and nine combinations of PA and SB categories. After adjusting for potential confounders, sufficient PA level was found to be related to lower risk of depressive symptoms independently (OR = 0.61), whereas no significant associations were observed between SB levels and depression. In the combined associations, adults in the sufficient PA/high SB (OR = 0.44), sufficient PA/moderate SB (OR = 0.56), and sufficient PA/low SB (OR = 0.57) categories were significantly less likely to have depressive symptoms in comparison with the no PA/high SB category. Meeting physical activity recommendations is associated with a lower risk of depressive symptoms, regardless of time spent in total sedentary behavior. These results suggest that promoting physical activity may be an effective strategy against depressive symptoms among Japanese adults.


Democratizing the world health organization.
A progressive erosion of the democratic space appears as one of the emerging challenges in global health today. Such delimitation of the political interplay has a particularly evident impact on the unique public interest function of the World Health Organization (WHO). This paper aims to identify some obstacles for a truly democratic functioning of the UN specialized agency for health. The development of civil society's engagement with the WHO, including in the current reform proposals, is described. The paper also analyses how today's financing of the WHO--primarily through multi-bi financing mechanisms--risks to choke the agency's role in global health. Democratizing the public debate on global health, and therefore the role of the WHO, requires a debate on its future role and engagement at the country level. This desirable process can only be linked to national debates on public health, and the re-definition of health as a primary political and societal concern.


A new hereditary persistence of fetal hemoglobin deletion has the breakpoint within the 3' beta-globin gene enhancer.
A new deletion of the beta-globin gene cluster has been characterized in two Italian brothers who are heterozygous carriers of a G gamma A gamma hereditary persistence of fetal hemoglobin (HPFH). Restriction endonuclease mapping and DNA sequencing of the region encompassing the breakpoint show that the deletion starts 3.2 kilobases (kb) upstream from the delta gene and ends within the enhancer region 3' to the beta-globin gene. Here the deletion removes one of the four binding sites for an erythroid specific transcriptional factor (NF-E1). The molecular comparison of the new deletion with others of similar size and location but associated with a delta beta-thalassemia phenotype suggests that the residual enhancer element, relocated near gamma genes, may increase the fetal hemoglobin (HbF) expression above the level observed in delta beta-thalassemia.


Segmental Latissimus Dorsi Free Flap Attempting to Preserve Function at the Donor Site: Anatomical and Clinical Experiences.
Background The purpose of the present study was to evaluate arm and shoulder function prospectively after transfer of the lateral segment of the latissimus dorsi (LD) muscle. Methods In this study, 20 specimens of LD muscles from 10 cadavers were dissected to determine the relationship between the artery and the nerve. Twenty patients were recruited and functional disability was determined by the Disabilities of Arm, Shoulder, and Hand (DASH), and muscle strength by needle electromyography (EMG) before surgery and at five different time points postoperatively. Results Two specimens (10%) had no medial branch arising from the thoracodorsal artery. The pedicle length of the lateral branch was longer than that of the medial branch (mean 10.41 vs. 9.27 cm, p = 0.03). All DASH scores and EMG amplitudes at half a month postoperative decreased compared with those preoperatively, with no significant difference at 3 months postoperative. Conclusion Lateral segmental LD muscle transfer, leaving the residual segment motor function intact, can be recommended as an alternative for moderate and small-size bone exposure wounds, especially in the lower extremities, that minimizes loss of donor-site function.


Capturing structural changes of the S1 to S2 transition of photosystem II using time-resolved serial femtosecond crystallography.
Photosystem II (PSII) catalyzes light-induced water oxidation through an S i -state cycle, leading to the generation of di-oxygen, protons and electrons. Pump-probe time-resolved serial femtosecond crystallography (TR-SFX) has been used to capture structural dynamics of light-sensitive proteins. In this approach, it is crucial to avoid light contamination in the samples when analyzing a particular reaction intermediate. Here, a method for determining a condition that avoids light contamination of the PSII microcrystals while minimizing sample consumption in TR-SFX is described. By swapping the pump and probe pulses with a very short delay between them, the structural changes that occur during the S1-to-S2 transition were examined and a boundary of the excitation region was accurately determined. With the sample flow rate and concomitant illumination conditions determined, the S2-state structure of PSII could be analyzed at room temperature, revealing the structural changes that occur during the S1-to-S2 transition at ambient temperature. Though the structure of the manganese cluster was similar to previous studies, the behaviors of the water molecules in the two channels (O1 and O4 channels) were found to be different. By comparing with the previous studies performed at low temperature or with a different delay time, the possible channels for water inlet and structural changes important for the water-splitting reaction were revealed.


The role of latent internalizing and externalizing predispositions in accounting for the development of comorbidity among common mental disorders.
Although numerous studies have examined the latent structure of internalizing and externalizing mental disorders, the effects of this structure in predicting the development of comorbidity have remained unexamined until recently. A novel approach to study the effects of latent internalizing and externalizing predispositions to the development of comorbidity was used to analyze data from 14 countries in the WHO World Mental Health Survey Initiative. Pervasive significant positive associations were found between temporally primary and secondary internalizing and externalizing disorders in survival analyses, with time-lagged associations consistently stronger within domains than between domains. The vast majority of these associations were explained by latent internalizing and externalizing variables. Specific phobia and obsessive compulsive disorder were the most important internalizing components and hyperactivity disorder and oppositional-defiant disorder the most important externalizing components. Several intriguing residual time-lagged associations remained significant, though, even after controlling latent predispositions. The latent variable model suggests that common causal pathways account for most comorbidity among internalizing-externalizing disorders. These pathways should be the focus of future research on the development of comorbidity, although isolation of consistent residual time-lagged associations between certain pairs of primary-secondary disorders is also important in pointing the way to subsequent focused study.


[Significance of material factors in the assessment of cognitive functional disorders in patients with a dementia syndrome].
In 1973 a psychodiagnostic instrument was developed that used slides as stimulus material. This instrument proved to be reliable in measuring functional disabilities in psychogeriatric patients. However, use of slides meant a serious drawback for those working in ambulatory practice. As an alternative, photographs were printed from the original slides. To evaluate their usefulness, 29 patients selected from two psychogeriatric hospitals were examined with both versions, slides and photographic prints, with an interval of 2-3 weeks between sessions. The average performance on one subtest (the perception of overlapping figures) improved on successive trials. A high degree of association (greater than or equal to .80), measured by Pearson's product moment correlation coefficient, was found for three subtests: object naming, reading aloud and the perception of line drawings. Performance on these subtests did not differ significantly between the two test versions. Two subtests yielded significantly better results when they were slide projected: the recall of five simple objects and the perception of ordinary situations. It is assumed that the results may be due to differences in experimental circumstances, which seemed beneficial to aspects of concentration in the slide condition. On average, the performance on the remaining subtests (clock reading, category fluency, text comprehension and recall, the perception of overlapping figures and recognition memory) does not differ for the slide presentation and for photographic print presentation. However, the moderately low correlations between the two versions of these subtests do not justify the conclusion that presentation by slides is equivalent to presentation by photographic prints.


[New approaches to treatment of various cancers based on cytotoxic analogs of LHRH, somatostatin and bombesin].
The development of targeted cytotoxic analogs of hypothalamic peptides for the therapy of various cancers is reviewed and various oncological studies on experimental tumors are summarized. Novel therapeutic modalities for breast, prostate and ovarian cancer consist of the use of targeted cytotoxic analogs of LH-RH containing doxorubicin (DOX) or 2-pyrrolino-DOX. The same radicals have been incorporated finto cytotoxic analogs of somatostatin which can be also targeted to receptors for this peptide in prostatic, mammary, ovarian, renal cancers, brain tumors and their metastases, A targeted cytotoxic analog of bombesin containing 2-pyrrolino-DOX has been also synthesized and successfully tried in experimental models of prostate cancer, small cell lung carcinoma and brain tumors. The development of these new classes of peptide analogs should lead to a more effective treatment for various cancers.


Preoperative sleep complaints are associated with poor physical recovery in the months following cardiac surgery.
Sleep disturbance is associated with poorer outcomes in cardiac patients, but little is known about the independent role of sleep quality in coronary artery bypass graft (CABG) patients. This study aims to examine the relationship between preoperative sleep complaints and post-operative emotional and physical recovery in CABG surgery patients, independently of demographic, clinical and mood factors. Two hundred thirty CABG patients (aged 67.81 ± 9.07 years) completed measures of self-reported sleep complaints before surgery and health-related quality of life (HRQoL), physical symptoms and pain 2 months after surgery. Greater sleep complaints prior to surgery were associated with greater physical symptoms, poorer physical HRQoL and greater sensory pain after surgery (p < 0.05), but not with affective pain or mental HRQoL. Preoperative mood was not able to explain these associations. Sleep complaints may be implicated in physical recovery from CABG surgery but further work is needed to understand the role of causal pathways.


[Color vision impairment in workers exposed to mercury vapor].
Acquired reversible dyschromatopsia has been associated with occupational exposure to mercury vapor. Early-detected impairments in color discrimination precede adverse permanent effects of mercury, so they may help to monitor the health of the exposed workers. The aim of this study was to evaluate the color discrimination ability in this group of workers, using Lanthony D-15d test. Employed in a chloralkali plant, 27 male workers exposed to mercury vapor and 27 healthy white-collar workers (control group) were qualified for the study. To assess color discrimination, the Lanthony 15-Hue desaturated test (Lanthony D-15) was used. In order to investigate quantitative and qualitative results, the Lanthony D-15d scoring software was performed. Urinary mercury was determined using flameless atomic absorption spectrometry. In the workers exposed to mercury vapor, urine mercury concentration was 117.4 +/- 62.6 microg/g creatinine on average compared with 0.279 +/- 0.224 mg/g creatinine in the control group (p < 0.0001). In 18 exposed persons (66.7%), the results of the Lanthony D-15d test showed qualitative changes, which are borderline corresponding to the early stage of developing dyschromatopsia type III. The quantitative analysis of the test findings indicated a significantly higher value of the Color Confusion Index (CCI) in the right eye in the exposed group compared to the control group (p = 0.01), with no significant difference in the CCI in the left eye. In the exposed group, the CCI in the right eye was significantly higher than the CCI in the left eye (p = 0.0005). There was neither correlation between CCI and the level of urinary mercury, nor between CCI and duration of exposure. The results showed that the Lanthony D-15d test is useful in the detection of early toxic effects in the eyesight of the workers exposed to mercury vapor. The observed color vision impairments are borderline corresponding to the early stage of developing dyschromatopsia type III.


Occult HBV infection in continuous ambulatory peritoneal dialysis and hemodialysis patients.
Occult hepatitis B virus (HBV) infection can be defined as the presence of HBV DNA in the liver and/or blood in the absence of detectable serum hepatitis B surface antigen (HBs Ag). There is a high prevalence of occult HBV infection in dialysis patients. This study investigated the prevalence of occult HBV infection in continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) patients and compared the prevalence of occult HBV infection in dialysis patients either with or without hepatitis C virus (HCV) infection. In this cross-sectional study, 71 CAPD patients and 71 HD patients were evaluated. HBV DNA testing was performed by polymerase chain reaction (PCR). We recorded general characteristics of the patients, duration of dialysis, HBs Ag, antibody to hepatitis B surface antigen (anti-HBs), antibody to hepatitis B core antigen (anti-HBc), anti-HCV antibody (anti-HCV), HCV RNA, serum alanine aminotransferase (ALT), and aspartate aminotransferase levels (AST). Twelve (16.9%) of the 71 HD patients and seven (9.8%) of the 71 CAPD patients were HBV DNA-positive. A statistically significant difference was not observed in the groups. Anti-HCV was negative and AST and ALT levels were normal in all of the HBV-DNA positive patients. Viral loads were low in both groups. This is the first study that analyzes occult HBV prevalence in CAPD patients. We conclude that the prevalence of the occult HBV may be common in CAPD patients as in HD patients, and HCV positivity is not a contributing factor to occult HBV infection in dialysis patients.


Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity.
Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A;I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.


Time-consuming and expensive data quality monitoring procedures persist in clinical trials: A national survey.
The Good Clinical Practice guideline identifies that data monitoring is an essential research activity. However, limited evidence exists on how to perform monitoring including the amount or frequency that is needed to ensure data quality. This study aims to explore the monitoring procedures that are implemented to ensure data quality in Australian clinical research studies. Clinical studies listed on the Australian and New Zealand Clinical Trials Registry were invited to participate in a national cross-sectional, mixed-mode, multi-contact (postal letter and e-mail) web-based survey. Information was gathered about the types of data quality monitoring procedures being implemented. Of the 3689 clinical studies contacted, 589 (16.0%) responded, of which 441 (77.4%) completed the survey. Over half (55%) of the studies applied source data verification (SDV) compared to risk-based targeted and triggered monitoring (10-11%). Conducting 100% on-site monitoring was most common for those who implemented the traditional approach. Respondents who did not conduct 100% monitoring, included 1-25% of data points for SDV, centralized or on-site monitoring. The incidence of adverse events and protocol deviations were the most likely factors to trigger a site visit for risk-based triggered (63% and 44%) and centralized monitoring (48% and 44%), respectively. Instead of using more optimal risk-based approaches, small single-site clinical studies are conducting traditional monitoring procedures which are time consuming and expensive. Formal guidelines need to be improved and provided to all researchers for 'new' risk-based monitoring approaches.


Saphenous vein graft failure after coronary artery bypass surgery: insights from PREVENT IV.
Coronary artery bypass grafting success is limited by vein graft failure (VGF). Understanding the factors associated with VGF may improve patient outcomes. We examined 1828 participants in the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial undergoing protocol-mandated follow-up angiography 12 to 18 months post-coronary artery bypass grafting or earlier clinically driven angiography. Outcomes included patient- and graft-level angiographic VGF (≥75% stenosis or occlusion). Variables were selected by using Fast False Selection Rate methodology. We examined relationships between variables and VGF in patient- and graft-level models by using logistic regression without and with generalized estimating equations. At 12 to 18 months post-coronary artery bypass grafting, 782 of 1828 (42.8%) patients had VGF, and 1096 of 4343 (25.2%) vein grafts had failed. Demographic and clinical characteristics were similar between patients with and without VGF, although VGF patients had longer surgical times, worse target artery quality, longer graft length, and they more frequently underwent endoscopic vein harvesting. After multivariable adjustment, longer surgical duration (odds ratio per 10-minute increase, 1.05; 95% confidence interval, 1.03-1.07), endoscopic vein harvesting (odds ratio, 1.41; 95% confidence interval, 1.16-1.71), poor target artery quality (odds ratio, 1.43; 95% confidence interval, 1.11-1.84), and postoperative use of clopidogrel or ticlopidine (odds ratio, 1.35; 95% confidence interval, 1.07-1.69) were associated with patient-level VGF. The predicted likelihood of VGF in the graft-level model ranged from 12.1% to 63.6%. VGF is common and associated with patient and surgical factors. These findings may help identify patients with risk factors for VGF and inform the development of interventions to reduce VGF. http://www.clinicaltrials.gov. Unique identifier: NCT00042081.


Effect of team sport participation on genetic predisposition to adolescent smoking progression.
There is much to be learned about why some adolescents progress to a regular smoking habit and others do not. To evaluate whether (1) team sport participation buffers the effect of having 2 smoking risk genotypes (the dopamine reuptake transporter [SLC6A3] and the dopamine D(2) receptor [DRD2]) or 1 of these risk genotypes vs having none on adolescent smoking progression and (2) the buffering effects of team sports were due to physical activity associated with team sport participation. Longitudinal cohort study. Survey data were collected annually from grade 9 to the end of grade 12. Self-report measures included smoking, team sport participation, physical activity, depression, smoking exposure, and alcohol and marijuana use. DNA was collected via buccal swabs. Data were analyzed using latent growth modeling. Five public high schools in Virginia. A total of 361 students of European ancestry. Main Outcome Measure Smoking progression. For adolescents participating in at least 1 team sport, but not for adolescents with no team sport participation, physical activity had a significant negative effect on smoking progression (z = -3.85, P<.001; chi(2)(1,N = 361) = 6.73, P = .009). In addition, having 1 (z = 2.69; P = .007) and 2 (z = 2.22; P = .03) smoking risk genotypes had a positive effect on physical activity. These represented significant between-group effects (chi(2)(1,N = 361) = 6.29, P = .01; chi(2)(1,N = 361) = 3.81, P = .05, respectively). Thus, having 1 or more smoking risk genotypes was related to higher levels of physical activity, which, in turn, was related to lower levels of smoking progression for adolescents participating in at least 1 team sport but not for adolescents with no team sport participation. This study provides the first evidence of an interaction between environmental influences and specific genes on adolescent smoking and may promote an understanding of important protective relationships in the environment.


Surgical Site Infections after Inguinal Hernia Repairs Performed in Low and Middle Human Development Index Countries: A Systematic Review.
Inguinal hernias are a common disorder in low- and middle-human development index countries (LMHDICs). Poor access to surgical care and lack of patient awareness often lead to delayed presentations of incarcerated or strangulated hernias and their associated morbidities. There is a scarcity of data on the baseline incidence of surgical site infections (SSIs) after hernia repair procedures in LMHDICs. We performed a systematic review of the literature describing the incidence and management of SSIs after inguinal hernia repair in LMHDICs. We conducted qualitative and quantitative analyses of manuscripts describing patients undergoing hernia repair to establish a baseline SSI rate for this procedure in these settings. Three hundred twenty-three abstracts were identified after applying search criteria, and 31 were suitable for the quantitative analysis. The overall pooled SSI rate was 4.1 infections/100 open hernia repairs (95% confidence interval [CI] 3.0-5.3 infections/100 open repairs), which is consistent with infection rates from high-human development index countries. A separate subgroup analysis of laparoscopic hernia repairs found a weighted pooled SSI rate of 0.4 infections/100 laparoscopic repairs (95% CI 0-2.4 infections/100 laparoscopic repairs). As surgical access continues to expand in LMHDIC settings, it is imperative to monitor surgical outcomes and ensure that care is provided safely. Establishing a baseline SSI rate for inguinal hernia repairs offers a useful benchmark for future studies and surgical programs in these countries.


Overexpression of transferrin receptor and ferritin related to clinical symptoms and destabilization of human carotid plaques.
Accumulation of tissue iron has been implicated in development of atherosclerotic lesions mainly because of increased iron-catalyzed oxidative injury. However, it remains unknown whether cellular iron import and storage in human atheroma are related to human atheroma development. We found that transferrin receptor 1 (TfR1), a major iron importer, is highly expressed in foamy macrophages and some smooth muscle cells in intimal lesions of human carotid atheroma, mainly in cytoplasmic accumulation patterns. In 52 human carotid atherosclerotic lesions, TfR1 expression was positively correlated with macrophage infiltration, ectopic lysosomal cathepsin L, and ferritin expression. Highly expressed TfR1 and ferritin in CD68-positive macrophages were significantly associated with development and severity of human carotid plaques, smoking, and patient's symptoms. The findings suggest that pathologic macrophage iron metabolism may contribute to vulnerability of human atheroma, established risk factors, and their clinical symptoms. The cytoplasmic overexpression of TfR1 may be the result of lysosomal dysfunction and ectopic accumulation of lysosomal cathepsin L caused by atheroma-relevant lipids in atherogenesis.


Population-based study of dying in hospital in six European countries.
This study examined the proportion of deaths taking place in hospitals in six European countries in relation to demographic, epidemiologic and healthcare factors. Retrospective analyses were performed on a database integrating death certificate data of all deaths in 2002 in Sweden and 2003 in Belgium, England, Scotland, the Netherlands and Wales (N = 891,780). Data were linked with regional healthcare statistics. Of all deaths, from 33.9% (the Netherlands) to 62.8% (Wales) occurred in hospital. Large country differences in hospital deaths were partly explained by the availability of care home and hospital beds. Differences between countries were strikingly large in older patients and cancer patients. Older patients had a higher probability of dying in hospital in Sweden, Scotland, England and Wales than in Flanders and, in particular, in the Netherlands. Cancer patients often died in hospitals in Sweden but less frequently so in the Netherlands and England. Country differences in the proportion of patients dying in hospital are only partly the result of differences in health care provision, and are in particular larger for certain patient categories, suggesting country-specific end-of-life practices in these categories. These findings can contribute to rational public health policies aimed at reducing hospital deaths.


COPD exacerbations . 3: Pathophysiology.
Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with increased morbidity and mortality. The effective management of COPD exacerbations awaits a better understanding of the underlying pathophysiological mechanisms that shape its clinical expression. The clinical presentation of exacerbations of COPD is highly variable and ranges from episodic symptomatic deterioration that is poorly responsive to usual treatment, to devastating life threatening events. This underscores the heterogeneous physiological mechanisms of this complex disease, as well as the variation in response to the provoking stimulus. The derangements in ventilatory mechanics, muscle function, and gas exchange that characterise severe COPD exacerbations with respiratory failure are now well understood. Critical expiratory flow limitation and the consequent dynamic lung hyperinflation appear to be the proximate deleterious events. Similar basic mechanisms probably explain the clinical manifestations of less severe exacerbations of COPD, but this needs further scientific validation. In this review we summarise what we have learned about the natural history of COPD exacerbations from clinical studies that have incorporated physiological measurements. We discuss the pathophysiology of clinically stable COPD and examine the impact of acutely increased expiratory flow limitation on the compromised respiratory system. Finally, we review the chain of physiological events that leads to acute ventilatory insufficiency in severe exacerbations.


Synthesis, cytotoxic assessment, and molecular docking studies of 2,6-diaryl-substituted pyridine and 3,4- dihydropyrimidine-2(1H)-one scaffolds.
Cancer is one of the main global health problems. In order to develop novel antitumor agents, we synthesized 3,4-dihydropyrimidine-2(1H)-one (DHPM) and 2,6-diaryl-substituted pyridine derivatives as potential antitumor structures and evaluated their cytotoxic effects against several cancer cell lines. An easy and convenient method is reported for the synthesis of these derivatives, employing cobalt ferrite (CoFe 2 O 4 @SiO 2 -SO 3 H) magnetic nanoparticles under microwave irradiation and solvent-free conditions. The structural characteristics of the prepared nanocatalyst were investigated by FTIR, XRD, SEM, and TGA techniques. In vitro cytotoxic effects of the synthesized products were assessed against the human breast adenocarcinoma cell line (MCF-7), gastric adenocarcinoma (AGS), and human embryonic kidney (HEK293) cells via MTT assay. The results indicated that compound 4r (DHPM derivative) was the most toxic molecule against the MCF-7 cell line (IC 50 of 0.17 μg/mL). Moreover, compounds 4j and 4r (DHPM derivatives) showed excellent cytotoxic activities against the AGS cell line, with an IC 50 of 4.90 and 4.97 μg/mL, respectively. Although they are pyridine derivatives, compounds 5g and 5m were more active against the MCF-7 cell line. Results showed that the candidate compounds exhibited low cytotoxicity against HEK293 cells. The kinesin Eg5 inhibitory potential of the candidate compounds was evaluated by molecular docking. The docking results showed that, among the pyridine derivatives, compound 5m had the most free energy of binding (-9.52 kcal/mol) and lowest Ki (0.105 μM), and among the pyrimidine derivatives, compound 4r had the most free energy of binding (-7.67 kcal/mol) and lowest Ki (2.39 μM). Ligand-enzyme affinity maps showed that compounds 4r and 5m had the potential to interact with the Eg5 binding site via H-bond interactions to GLU116 and GLY117 residues. The results of our study strongly suggest that DHPM and pyridine derivatives inhibit important tumorigenic features of breast and gastric cancer cells. Our results may be helpful in the further design of DHPMs and pyridine derivatives as potential anticancer agents.


Fibrous hamartoma of infancy of the spinal cord resembling conus and filum, with a coexisting sacral dimple.
Fibrous hamartoma of infancy (FHI) is a rare benign soft tissue lesion of infants and young children. It usually occurs within the first 2 years of life at the superficial layer of the axilla, trunk, upper arm, and external genitalia. FHI in the central nervous system (CNS) is extremely rare. So far, only two spinal cord FHI cases have been reported. We present a case of a 1-month-old girl who presented with a skin dimple in the coccygeal area. Her MRI showed a substantial intramedullary mass in the thoracolumbar area with a sacral soft tissue mass and a track between the skin lesion to the coccygeal tip. Her normal neurological status halted immediate surgical resection. A skin lesion biopsy was first performed, revealing limited information with no malignant cells. A short-term follow-up was performed until the intramedullary mass had enlarged on the 5-month follow-up MRI. Based on the frozen biopsy result of benign to low-grade spindle cell mesenchymal tumor, subtotal resection of the mass was done, minimizing damage to the functioning neural tissue. Both the skin lesion and the intramedullary mass were diagnosed as FHI. Postoperative 5.5-year follow-up MRI revealed minimal size change of the residual mass. Despite being diagnosed with a neurogenic bladder, the patient maintained her ability to void spontaneously, managed infrequent UTIs, and continued toilet training, all while demonstrating good mobility and no motor weakness. This case is unique because the lesion resembled the secondary neurulation structures, such as the conus and the filum, along with a related congenital anomaly of the dimple.


Efficacy of 2 Trabecular Micro-Bypass Stents During Phacoemulsification for Mild to Advanced Primary Open-angle Glaucoma Controlled With Topical Hypotensive Medications.
The purpose of the current study was to evaluate the efficacy and adverse event profile of 2 trabecular micro-bypass stents implanted during standard phacoemulsification cataract surgery in patients with mild to advanced open-angle glaucoma whose intraocular pressure (IOP) was well controlled by topical medications. This study was a retrospective analysis of patients with mild to advanced chronic open-angle glaucoma who underwent phacoemulsification and implantation of 2 stents. For all patients, preoperative and postoperative characteristics were evaluated, including number of medications and IOP. Postoperative visits were scheduled at 7 days and at months 1, 6, 12, and 24 after surgery. At each visit, IOP and the number of medications were noted. In total, 63 eyes of 41 patients were included in the study. The vast majority of eyes (85.7%) were diagnosed with primary open-angle glaucoma. Preoperative mean IOP at baseline was 16.8±3.0 mm Hg (range, 10 to 24 mm Hg) with a mean of 2.3±0.9 medications. The mean IOP reduction represented a 13% decrease at 1 month (P<0.001), 13% at 6 months (P<0.001), 12% at 1 year (P<0.001), and 10% at 2 years (P<0.001), concomitant with a 23% reduction in the mean number of medications (P<0.001), 35% (P<0.001), 40% (P<0.001), and 40% (P<0.001), respectively, at each scheduled follow-up visit. At 24 months postoperatively, 19 of 23 (83%) patients experienced an IOP decrease compared with the preoperative visit. No severe device-related adverse events were observed. Patients with mild to advanced glaucoma can benefit from micro-bypass implantation even if their IOP is well controlled with topical hypotensive medications. Expectations for these reductions should be moderate.


The crystal structure of a five-stranded coiled coil in COMP: a prototype ion channel?
Oligomerization by the formation of alpha-helical bundles is common in many proteins. The crystal structure of a parallel pentameric coiled coil, constituting the oligomerization domain in the cartilage oligomeric matrix protein (COMP), was determined at 2.05 angstroms resolution. The same structure probably occurs in two other extracellular matrix proteins, thrombospondins 3 and 4. Complementary hydrophobic interactions and conserved disulfide bridges between the alpha helices result in a thermostable structure with unusual properties. The long hydrophobic axial pore is filled with water molecules but can also accommodate small apolar groups. An "ion trap" is formed inside the pore by a ring of conserved glutamines, which binds chloride and probably other monatomic anions. The oligomerization domain of COMP has marked similarities with proposed models of the pentameric transmembrane ion channels in phospholamban and the acetylcholine receptor.


Experience of racism and tooth brushing among pregnant Aboriginal Australians: exploring psychosocial mediators.
Despite burgeoning evidence regarding the pathways by which experiences of racism influence health outcomes, little attention has been paid to the relationship between racism and oral health-related behaviours in particular. We hypothesised that self-reported racism was associated with tooth brushing, and that this association was mediated by perceived stress and sense of control and moderated by social support. Data from 365 pregnant Aboriginal Australian women were used to evaluate tooth brushing behaviour, sociodemographic factors, psychosocial factors, general health, risk behaviours and racism exposure. Bivariate associations were explored and hierarchical logistic regression models estimated odds ratios (OR) and 95% confidence intervals (CI) for tooth brushing. Perceived stress and sense of control were examined as mediators of the association between self-reported racism and tooth brushing using binary mediation with bootstrapping. High levels of self-reported racism persisted as a risk indicator for tooth brushing (OR 0.51, 95%CI 0.27,0.98) after controlling for significant covariates. Perceived stress mediated the relationship between self-reported racism and tooth brushing: the direct effect of racism on tooth brushing was attenuated, and the indirect effect on tooth brushing was significant (beta coefficient -0.09; bias-corrected 95%CI -0.166,-0.028; 48.1% of effect mediated). Sense of control was insignificant as a mediator of the relationship between racism and tooth brushing. High levels of self-reported racism were associated with non-optimal tooth brushing behaviours, and perceived stress mediated this association among this sample of pregnant Aboriginal women.. Limitations and implications are discussed.


PET-guided repeat transsphenoidal surgery for previously deemed unresectable lateral disease in acromegaly.
The object of this study was to determine if revision transsphenoidal surgery (TSS), guided by 11C-methionine PET/CT coregistered with volumetric MRI (Met-PET/MRCR), can lead to remission in patients with persistent acromegaly due to a postoperative lateral disease remnant. The authors identified 9 patients with persistent acromegaly following primary intervention (TSS ± medical therapy ± radiotherapy) in whom further surgery had initially been discounted because of equivocal MRI findings with suspected lateral sellar and/or parasellar disease (cases with clear Knosp grade 4 disease were excluded). All patients underwent Met-PET/MRCR. Scan findings were used by the pituitary multidisciplinary team to inform decision-making regarding repeat surgery. Revision TSS was performed with wide lateral exploration as guided by the PET findings. Endocrine reassessment was performed at 6-10 weeks after surgery, with longitudinal follow-up thereafter. Met-PET/MRCR revealed focal tracer uptake in the lateral sellar and/or parasellar region(s) in all 9 patients, which correlated with sites of suspected residual tumor on volumetric MRI. At surgery, tumor was identified and resected in 5 patients, although histological analysis confirmed somatotroph tumor in only 4 cases. In the other 4 patients, no definite tumor was seen, but equivocal tissue was removed. Despite the uncertainty at surgery, all patients showed immediate significant improvements in clinical and biochemical parameters. In the 8 patients for whom long-term follow-up data were available, insulin-like growth factor 1 (IGF-1) was ≤ 1.2 times the upper limit of normal (ULN) in all subjects and ≤ 1 times the ULN in 6 subjects, and these findings have been maintained for up to 28 months (median 8 months, mean 13 months) with no requirement for adjunctive medical therapy or radiotherapy. No patient suffered any additional pituitary deficit or other complication of surgery. This study provides proof of concept that Met-PET/MRCR can be helpful in the evaluation of residual lateral sellar/parasellar disease in persistent acromegaly and facilitate targeted revision TSS in a subgroup of patients.


Characteristics of two different cryoballoon systems for treatment of paroxysmal atrial fibrillation: study protocol for a multicenter randomized controlled trial (CONTRAST-CRYO Trial).
Single-shot pulmonary vein isolation (PVI) utilizing cryothermal energy is an effective and safe treatment for atrial fibrillation (AF) patients. A novel cryoballoon system, POLARx™, has been recently introduced. The aim of this study was to compare the efficacy, safety, and biophysical parameters of PVI between the novel cryoballoon system, POLARx™, and the standard cryoballoon system, Arctic Front Advance Pro™ (AFA-Pro), in patients with paroxysmal AF. The CONTRAST-CRYO trial is a prospective, multicenter, open-label, randomized controlled study performed at seven large cardiac centers. This study was approved by the central ethics committee or the local ethics committee of each participating hospital and has been registered at UMIN Clinical Trials Registry (UMIN000049948). The trial will assign 200 patients with paroxysmal AF undergoing PVI to POLARx™ and AFA-Pro in a 1:1 randomization. The primary endpoint is the one-shot acute success rate of the right inferior pulmonary vein. Second endpoints include freedom from documented atrial fibrillation, atrial flutter, or atrial tachycardia without antiarrhythmic drugs at 12 months after the procedure, freedom from re-do procedures, the incidence of procedure-related adverse events, freezing duration, and the biophysical parameters during applications for each PV, total procedure and fluoroscopy time, and PVI durability during re-do procedures. The CONTRAST-CRYO trial is a prospective, multicenter, randomized study designed to elucidate the difference in the efficacy, safety, and biophysical parameters between POLARx™ and AFA-Pro in paroxysmal AF patients undergoing PVI. The findings from this trial may provide a valuable indication for selecting the optimal cryoballoon system. UMIN000049948.


Cutaneous immunopathology of androgenetic alopecia.
Male pattern baldness is assumed to result from a combination of normal serum concentrations of androgen and an appropriate genetic background. To study whether inflammation contributes to the development of androgenetic alopecia, direct immunofluorescence and dermatopathologic studies were performed on biopsy specimens from bald scalp of patients, with specimens from uninvolved scalp of these patients or from scalp of volunteers who were not bald serving as controls. Granular deposits of Immunoglobulin M or C3 (or both) were found at the basement membrane in 25 (96%) of 26 study patients and 1 (12%) of 8 control subjects. Granular C3 was also deposited on eccrine myoepithelial cells in 8 (31%) of 26 study patients, but no control subjects. Porphyrins were found in the pilosebaceous canal in 15 (58%) of 26 study subjects and in 1 (12%) of 8 control subjects. These results support an inflammatory pathogenesis of androgenetic alopecia. Propionibacterium acnes is known to produce porphyrins. Ultraviolet radiation may excite microbiologic porphyrins that could activate C3 and, subsequently, the complement cascade producing inflammatory mediators.


[Ultrastructural changes in the arterioles of rats with experimental salt hypertension].
The ultrastructure of arterioles in experimental salt loading in rats was studied. It was established that prolonged feeding with salt-rich diet led to stable hypertension in some experimental animals, and ultrastructural changes in arterioles were noted only in rats which had developed stable hypertension. The changes in arterioles in experimental salt hypertension in principle were similar to those observed in other chronic forms of hypertensive states, but they developed slower and were less pronounced. The present study does not confirm the views advocated by some authors about a direct effect of salt on the ultrastructure of the arteriolar wall. The mechanism responsible for the changes in the arterial wall occurring in experimental salt hypertension remains unclear.


A simple, selective method for freeze-fracturing spherical cells.
A simple and selective method for freeze-fracturing spherical cells is described. The cells are loaded into the holes of a thin nickel screen. A metal hat is applied to the cell monolayer and the whole assembly, hat-cells-screen, is frozen and then fractured by ripping the hat off. The fractured face on the screen is replicated. By varying the size of the screen holes and by applying the hat to either side of the screen, this method can selectively expose the E face (or the outer half of plasma membrane), the P face (or the inner half of the plasma membrane), or the cytoplasm of the cells. It also provides a means to produce fractures at a preselected area on the cell, if the cells can be loaded onto the screen in an oriented fashion.


Risk factors for bloodborne viral hepatitis in healthcare workers of Pakistan: a population based case-control study.
A high prevalence of viral hepatitis B and C was found among healthcare workers during a province-wide screening in Sindh Province, Pakistan. A follow-up study was undertaken to identify risk factors for this high prevalence in healthcare workers. Population based case-control design. Public sector healthcare facilities in a rural district of Pakistan. Healthcare workers who were screened for hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) antibodies. 178 healthcare workers employed at the public sector clinics and hospitals of the district were approached, of which 14 refused to participate. Cases had detectable serum antibodies against HCV and the presence of HBsAg. Healthcare workers non-reactive to HCV antibodies and with no HBsAg were controls. These were matched in a ratio of 1:1. Detectable serum HBsAg and HCV antibody titer were taken as outcome. OR for various exposures was calculated; those with p<0.25 were entered in a multivariate logistic regression model to find out significant predictors. Needle stick injury (OR=6; CI95 1.4 to 23), recapping the needle (OR=5.7; CI95 1.1 to 28), wound care at accident and emergency of a hospital (OR=5.5; CI95 1 to 28), female gender (OR=3.4; CI95 1 to 12) and more than 10 years of formal education (OR=0.25; CI95 0.07 to 0.8) were associated with hepatitis C. Hepatitis B was found to be associated with trying to bend or break a needle after use (OR=4.9; CI95 1 to 24). Healthcare workers in Pakistan are at additional risk of exposure to bloodborne pathogens. Bi-dimensional risk factors present at individual and broader health systems levels are responsible. Occupational safety, health trainings and redesigning of the curriculum for allied health professionals are required.


Chemopreventive efficacy of suberoylanilide hydroxamic acid (SAHA) against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in female A/J mice.
Histone deacetylase (HDAC) inhibitors, such as suberoylanilide hydroxamic acid (SAHA), represent a promising new class of chemopreventive agents. We have synthesized SAHA by an improved method and examined its efficacy as a dietary supplement at 450 ppm against lung tumor development in female A/J mice induced by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). We observed significant inhibition (80%, p < 0.0001) of lung tumor multiplicity in mice treated with NNK plus SAHA compared to NNK-treated controls. SAHA inhibited the carbonyl reductive pathways of NNK in a dose-dependent manner in liver, but not lung microsomes, obtained from A/J mice. However, a significant inhibition of the a-hydroxylation pathway of NNK was observed in both lung and liver microsomes, suggesting that SAHA may act to inhibit the activation pathways of NNK metabolism. The results of this model study indicate that SAHA holds promise as a potential chemopreventive agent against lung cancer.


Genetic covariation in low alcohol-sensitive and high alcohol-sensitive selected lines of rats: behavioral and electrophysiological sensitivities to the depressant effects of ethanol and the development of acute neuronal tolerance to ethanol in situ at generation eight.
Phenotypic differences in behavioral and initial neuronal sensitivities to acute ethanol (EtOH) administration were examined and compared among replicate lines of rats, which were selectively bred for low and high EtOH sensitivity. The eighth generation of HAS (EtOH-sensitive) and LAS (EtOH-insensitive) rats were significantly different in terms of sensitivity both to EtOH-induced loss of righting response (sleep time) and to EtOH-induced depressions of cerebellar Purkinje neuron firing rates. This study provides the first evidence for a significant correlation between behavioral and electrophysiological EtOH sensitivities among individual animals and between replicate selected rodent lines. These data support the hypothesis that a genetic correlation exists between these two phenotypes. In addition, the LAS rats expressed a significantly higher incidence of acute cellular tolerance to the depressant neuronal effects of repeated local applications of EtOH over a period of a few minutes. We have characterized this response and concluded that it may contribute to EtOH sensitivity. However, our data also suggest that the EtOH insensitivity of cerebellar Purkinje neurons in LAS rats is not only a consequence of acute neuronal tolerance to EtOH, but also due to low initial EtOH sensitivity of these neurons. Both behavioral and electrophysiological EtOH phenotypes of LAS and HAS rats have diverged with the application of selection pressure for behavioral EtOH sensitivity; these data suggest that the mechanisms underlying neuronal sensitivity and acute neuronal tolerance to EtOH are important in determining the behavioral EtOH sensitivities of these animals.


Risk of Giardia infection for drinking water and bathing in a peri-urban area in Sao Paulo, Brazil.
A high incidence of waterborne diseases is observed worldwide and in order to address contamination problems prior to an outbreak, quantitative microbial risk assessment is a useful tool for estimating the risk of infection. The objective of this paper was to assess the probability of Giardia infection from consuming water from shallow wells in a peri-urban area. Giardia has been described as an important waterborne pathogen and reported in several water sources, including ground waters. Sixteen water samples were collected and examined according to the US EPA (1623, 2005). A Monte Carlo method was used to address the potential risk as described by the exponential dose response model. Giardia cysts occurred in 62.5% of the samples (<0.1-36.1 cysts/l). A median risk of 10⁻¹ for the population was estimated and the adult ingestion was the highest risk driver. This study illustrates the vulnerability of shallow well water supply systems in peri-urban areas.


A critical appraisal of guidelines for electronic communication between patients and clinicians: the need to modernize current recommendations.
Patient-provider electronic communication has proliferated in recent years, yet there is a dearth of published research either leading to, or including, recommendations that improve clinical care and prevent unintended negative consequences. We critically appraise published guidelines and suggest an agenda for future work in this area. To understand how existing guidelines align with current practice, evidence, and technology. We performed a narrative review of provider-targeted guidelines for electronic communication between patients and providers, searching Ovid MEDLINE, Embase, and PubMed databases using relevant terms. We limited the search to articles published in English, and manually searched the citations of relevant articles. For each article, we identified and evaluated the suggested practices. Across 11 identified guidelines, the primary focus was on technical and administrative concerns, rather than on relational communication. Some of the security practices recommended by the guidelines are no longer needed because of shifts in technology. It is unclear the extent to which the recommendations that are still relevant are being followed. Moreover, there is no guideline-cited evidence of the effectiveness of the practices that have been proposed. Our analysis revealed major weaknesses in current guidelines for electronic communication between patients and providers: the guidelines appear to be based on minimal evidence and offer little guidance on how best to use electronic tools to communicate effectively. Further work is needed to systematically evaluate and identify effective practices, create a framework to evaluate quality of communication, and assess the relationship between electronic communication and quality of care.


Deep sleep maintains learning efficiency of the human brain.
It is hypothesized that deep sleep is essential for restoring the brain's capacity to learn efficiently, especially in regions heavily activated during the day. However, causal evidence in humans has been lacking due to the inability to sleep deprive one target area while keeping the natural sleep pattern intact. Here we introduce a novel approach to focally perturb deep sleep in motor cortex, and investigate the consequences on behavioural and neurophysiological markers of neuroplasticity arising from dedicated motor practice. We show that the capacity to undergo neuroplastic changes is reduced by wakefulness but restored during unperturbed sleep. This restorative process is markedly attenuated when slow waves are selectively perturbed in motor cortex, demonstrating that deep sleep is a requirement for maintaining sustainable learning efficiency.


The first International Standard anti-Brucella melitensis Serum.
The World Organisation for Animal Health (OIE) requested an International Standard anti-Brucella melitensis Serum (ISaBmS) to standardise diagnostic tests and reagents for sheep and goats. The agreed criteria were the highest dilution (in negative serum) of the standard which must give a positive result and the lowest dilution (in negative serum) which must simultaneously give a negative result. The two dilutions for each assay were, respectively: indirect enzyme-linked immunosorbent assay (iELISA) 1/64 and 1/750, competitive ELISA (cELISA) 1/8 and 1/300, fluorescent polarisation assay (FPA) 1/16 and 1/200, Rose Bengal test (RBT) 1/16 and 1/200. The OIE International Standard Serum (OIEISS) will remain the primary standard for the RBT; the ISaBmS is an additional standard. It was impossible to set criteria for the complement fixation test, therefore the OIEISS will remain the primary standard. The ISaBmS can be used to standardise iELISA, cELISA and FPA to diagnose sheep and goat brucellosis. This standard should facilitate harmonisation of tests used for brucellosis surveillance and international trade in these species.


Trophic niches, diversity and community composition of invertebrate top predators (Chilopoda) as affected by conversion of tropical lowland rainforest in Sumatra (Indonesia).
Conversion of tropical rainforests into plantations fundamentally alters ecological niches of animal species. Generalist predators such as centipedes (Chilopoda) may be able to persist in converted ecosystems due to their ability to adapt and switch to alternative prey populations. We investigated variations in community composition and trophic niches of soil and litter living centipedes in a range of ecosystems including rainforests, jungle rubber agroforests, and rubber and oil palm monocultures in two landscapes in Sumatra, Indonesia. Including information on environmental factors in the soil and litter habitat, we explored drivers shaping ecological niches of soil living invertebrate predators in one of the world's hotspots of rainforest conversion. Conversion of rainforests into agroforests and plantations was associated with a marked change in the composition of centipede communities. However, irrespective of major differences in habitat characteristics, changes in total abundances were small and the overall diversity and biomass of centipedes was similar in each of the systems investigated, suggesting that the number of ecological niches for this group of predators remains unchanged. By using stable isotope analysis (15N and 13C), we investigated trophic niche shifts of the centipede community; lower δ13C values of centipedes in oil palm plantations as compared to other ecosystems suggests that centipedes switch from decomposer prey to other prey, presumably understory associated herbivores, due to reduced availability of litter associated prey species. The results suggest that the ability to utilize alternative prey is a key feature enabling invertebrate predators to persist in ecosystems undergoing major structural changes due to anthropogenic land use change.


Bovine serum albumin decreases Km values of human UDP-glucuronosyltransferases 1A9 and 2B7 and increases Vmax values of UGT1A9.
The human UDP-glucuronosyltransferase (UGT) enzymes UGT1A9 and UGT2B7 play important roles in the hepatic glucuronidation of many drugs. The presence of bovine serum albumin (BSA) during in vitro assays was recently reported to lower the K(m) values of both these UGTs for their aglycone substrates without affecting the corresponding V(max) values. Nonetheless, using the specific substrates entacapone and zidovudine (AZT) for UGT1A9 and UGT2B7, respectively, and using an improved ultrafiltration method for measuring drug binding to BSA and to biological membranes, we found that the presence of BSA during the glucuronidation reaction leads to a large increase in the V(max) value of UGT1A9, in addition to lowering its K(m) value. On the other hand, in the case of UGT2B7, our results agree with the previously described effect of BSA, namely lowering the K(m) value without a large effect on the enzyme's V(max) value. The unexpected BSA effect on UGT1A9 was independent of the expression system because it was found in a recombinant enzyme that was expressed in baculovirus-infected insect cells as well as in the native enzyme in human liver microsomes. Moreover, the effect of BSA on the kinetics of 4-methylumbelliferone glucuronidation by recombinant UGT1A9 was similar to its effect on entacapone glucuronidation. Contrary to the aglycone substrates, the effect of BSA on the apparent K(m) of UGT1A9 for the cosubstrate UDP-α-D-glucuronic acid was nonsignificant. Our findings call for further investigations of the BSA effects on different UGTs and the inhibitors that it may remove.


[Perioperative management of Parkinson's disease].
Several studies have demonstrated the serious impact of surgeries on patients with Parkinson's disease (PD). In addition, PD is a risk factor for postoperative complications and prolonged hospital stays. Discontinuation of anti-Parkinsonian drugs due to surgery causes an exacerbation of Parkinsonism and sometimes Parkinsonism-hyperpyrexia syndrome (PHS). Therefore, surgeries involving patients with PD require careful perioperative management. During the preoperative period, cooperation among neurologists, surgeons, and anesthesiologists is imperative. Administration of the same oral anti-Parkinsonian drug regimen that was prescribed during home care is important. Methods of both general and regional anesthesia should be chosen based on general health status and symptoms of Parkinsonism and agents should be selected with due consideration of their possible interaction with anti-Parkinsonian drugs. In patients with PD showing autonomic disturbance, changes in blood pressure and body temperature should be monitored. During the postoperative phase, postoperative pain, aspiration pneumonia, ileus, and psychotic symptoms should be managed, taking into consideration the interactions between anti-Parkinsonian drugs and therapeutic agents. Currently, new anti-Parkinsonian drugs, such as rotigotine and apomorphine are available for patients with PD requiring parenteral treatment. It is important that medical experts share awareness about perioperative problems and their management in patients with PD.


Third molar surgery--a preliminary report on aspects affecting quality of life in the early postoperative period.
The issue of quality of life has largely been neglected within oral surgical practice. A questionnaire was designed to assess the effect of third molar surgery on a number of measures of health care outcome within the first postoperative week, that appeared not to have been previously addressed. These included level of physical discomfort, oral and vocal function, patients' perception of their appearance and social interaction. Patients were asked to complete the questionnaire one day following surgery and again 7 days after surgery. For each question they recorded the answer best describing how they felt, on a 4-point scale. Twenty-nine paired returns were received, for which the results for day 1 and day 7 were summated and compared. A two sample t-test revealed a small but significant improvement in the patients' perception of their quality of life over that time period. When a subset of 11 questions relating to physical wellbeing were analysed using the Wilcoxon Signed Rank Test, a significant improvement in only two of the 11 parameters (ability to masticate and perception of appearance) was found. These results show that within the first postoperative week some patients can experience a deterioration in their quality of life, that extends beyond the traditionally recognized side effects and which shows little improvement in the first postoperative week. It has been stated that patients have a right to know if their lifestyles are to be compromised by the effects of their treatment. We suggest that consideration be given to including reference at the preoperative assessment to some of these outcomes.


Ethical sensitivity and the goals of medicine: resisting the tides of medical deprofessionalisation.
There is a growing concern that, like in many developed countries, medical practice in Singapore is fast losing its role and status as a profession. The commodification and industrialisation of health care, and weakening of its ethical foundations are among the main forces threatening to deprofessionalise the practice of medicine. To overcome these challenges, an honest and introspective review of the goals of medicine and an affirmation of the ethical values of medicine are needed in order to reinstate the unique role of medicine in our society. Important steps to take include adopting a patient-centred philosophy and practice culture, promoting and emphasising ethical awareness and sensitivity among physicians, and active participation in constructive dialogues to negotiate the social contract of the profession. A more permanent impact may be achieved through cultivation of medical virtues in physicians, and the integration of core elements of medical professionalism into the ethical systems and mission statement of today's health care organisations.


Executive summary of the workshop on the border of viability.
One of the most complex areas in perinatal-neonatal medicine remains the care of the mother delivering a newborn infant at the border of viability, referred to as "periviable" gestation. To address the knowledge gaps that preclude optimal, evidence-based care in this critical field of perinatal medicine, the National Institute of Child Health and Human Development organized a workshop in March 2004. This article provides a summary of the discussions, focusing on major knowledge gaps and prioritized suggestions for studies in this area.


Kinetic effect of oestrogen on secretion of prostaglandins E2 and F2α in bovine oviduct epithelial cells.
This study aimed to investigate the effect of oestrogen on prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) secretion in bovine oviduct epithelial cells. Bovine oviduct epithelial cells were obtained from the lumen of fresh bovine oviducts. Quantitative real-time polymerase chain reaction and in-cell western assays were used to measure PGE2 and PGF2α synthase activity and enzyme-linked immunosorbent assays were used to detect the concentrations of the two prostaglandins in extracellular fluid. We observed that oestradiol caused a short-term increase in cyclo-oxygenase-2 (COX-2), which stimulated PGE2 and PGF2α secretion, and that a subsequent decrease in COX-2 and an increase in cyclo-oxygenase-1 (COX-1) produced a high PGE2:PGF2α ratio. These findings reflect the dynamic change in PGE2 and PGF2α levels under the influence of oestrogen, which may be essential for fertilisation.


ECMO for Pediatric Lung Transplantation.
Extracorporeal membrane oxygenation (ECMO) has been reported as an alternative to cardiopulmonary bypass during lung transplantation. The reports in the literature have been limited to adult practice and associated with decreased pulmonary and renal complications, lower mortality, and lower in-hospital mortality. We present four pediatric lung transplantations performed on ECMO and discuss relevant perfusion management.


Thermal antinociception after dexmedetomidine administration in cats: a dose-finding study.
The optimum dose of dexmedetomidine for antinociception to a thermal stimulus was determined in a crossover study of 12 cats. In five treatment groups (n = 10 per group), dexmedetomidine was administered intramuscularly (i.m.) at 2, 5, 10, 20 and 40 microg/kg; positive and negative controls were administered buprenorphine (20 microg/kg, i.m.) and 0.9% saline (0.006 mL/kg, i.m.) respectively. Baseline thermal thresholds and visual analogue scale (VAS) sedation scores were obtained prior to drug treatment and then at regular intervals until 24 h after administration. The summary measures of overall mean thresholds and overall mean VAS scores were investigated using a univariate general linear model for multiple factors with post hoc Tukey's tests (P < 0.05). Only dexmedetomidine at 40 microg/kg displayed an analgesic effect (less than that of buprenorphine). The VAS for sedation did not significantly affect the thresholds obtained and treatment was the only significant factor to influence VAS. Dexmedetomidine resulted in higher VAS for sedation than saline and buprenorphine. Dexmedetomidine at 40 microg/kg significantly increased nociceptive thresholds compared with saline control, but less than buprenorphine. Dexmedetomidine produced dose-dependent sedation, but only the highest dose produced analgesia, suggesting that induction of analgesia requires the highest dose (or an additional analgesic) in the clinical setting.


When distress does not become depression: emotion context sensitivity and adjustment to bereavement.
Recent evidence suggests that the sensitivity of emotion responses to changing context may be a key element of psychological adjustment and psychopathology (Bonanno et al., 2007; Rottenberg, Kasch, Gross, & Gotlib, 2002). However, there have been no previous investigations to examine emotion context sensitivity and adjustment following stressful life events. This investigation addressed this deficit in a sample of middle-aged bereaved adults (N = 48) whose emotion responses were measured as they described loss and non-loss-related events during a laboratory interview 4 months after the death of their spouse or child. Symptoms of depression were assessed using structured clinical interviews at 4 and 18 months postloss. Although positive emotions were beneficial regardless of context, context sensitivity for negative emotions at 4 months predicted fewer depression symptoms at 18 months. These findings suggest that the capacity to shift negative emotion responses according to changing context may differentiate those individuals who will show improvements in depression symptoms over time from those who will show chronic impairments. Implications for future research and clinical intervention are discussed.


Energy Drinks and Their Impact on the Cardiovascular System: Potential Mechanisms.
Globally, the popularity of energy drinks is steadily increasing. Scientific interest in their effects on cardiovascular and cerebrovascular systems in humans is also expanding and with it comes a growing number of case reports of adverse events associated with energy drinks. The vast majority of studies carried out in the general population report effects on blood pressure and heart rate. However, inconsistencies in the current literature render it difficult to draw firm conclusions with regard to the effects of energy drinks on cardiovascular and cerebrovascular variables. These inconsistencies are due, in part, to differences in methodologies, volume of drink ingested, and duration of postconsumption measurements, as well as subject variables during the test. Recent well-controlled, randomized crossover studies that used continuous beat-to-beat measurements provide evidence that cardiovascular responses to the ingestion of energy drinks are best explained by the actions of caffeine and sugar, with little influence from other ingredients. However, a role for other active constituents, such as taurine and glucuronolactone, cannot be ruled out. This article reviews the potentially adverse hemodynamic effects of energy drinks, particularly on blood pressure and heart rate, and discusses the mechanisms by which their active ingredients may interact to adversely affect the cardiovascular system. Research areas and gaps in the literature are discussed with particular reference to the use of energy drinks among high-risk individuals.


Frequency and severity of malocclusions in patients with statutory health insurance in a German orthodontic practice in North Rhine Westphalia - a multi-part cross-sectional study over a 20-year period.
Since 2002, patients with statutory health insurance in Germany must undergo an assessment of orthodontic treatment need using the "Kieferorthopädische Indikationsguppen" (KIG; orthodontic indication groups) classification system. According to this system, tooth and jaw misalignment are divided into 11 subgroups and five grades. The objectives of this study were to determine the distribution of KIG classifications in patients with statutory insurance of a German orthodontic practice (North Rhine, Germany) and to analyze changes over a 20-year period. Since the introduction of the KIG index in 2002, 4940 statutorily insured patients over a 20-year period (2330 m, 2610 f, min 3.2, max 49.5 years, peak between 10 and 12 years) were classified at their first appointment. According to the valid guidelines of the statutory health insurance (GKV), the division was made into the highest possible KIG classification. Multiple entries were thus not made. In accordance with the operating cycles of the practice, the progression was divided into four 5-year periods. Over a 20-year period, 24.98% of the patients were assigned to the classification "D". 86.52% of the patients were among the 6 most frequently ("D", "E", "K", "S", "P" and "M", > 10% each) and only 13.49% among the 5 least frequently recorded classifications ("U", "B", "T", "O" and "A", < 5% each). The distribution of the 6 most frequent and the 5 least frequent KIG classifications was constant over a 20-year-period. Among all possible tooth and jaw misalignment variants, the sagittal classifications "D" and "M" represent the most frequent malocclusions. The results and their comparison with historical data show that both frequency and severity of tooth and jaw misalignment with orthodontic treatment need appear identical for patients with statutory health insurance over a 20-year period.


Stick-Slip Motion of ssDNA over Graphene.
We have performed molecular dynamics simulations of nanomanipulation experiments on short single-stranded DNA chains elastically driven on a graphene surface. After a brief transient, reproducible stick-slip cycles are observed on chains made by 10 units of thymine, cytosine, adenine, and guanine. The cycles have the periodicity of the graphene substrate, and take place via an intermediate stage, appearing as a dip in the sawtooth variations of lateral force recorded while the chains are manipulated. Guanine presents remarkable differences from the other bases, since a lower number of nucleotides are prone to stick to the substrate in this case. Nevertheless, the magnitudes of static friction and lateral stiffness are similar for all chains (30 pN and 0.7 N/m per adsorbed nucleotide respectively).


Effect of Enteral and Parenteral Nutrition Support on Pulmonary Function in Elderly Patients with Chronic Obstructive Pulmonary Disease Complicated by Respiratory Failure.
To investigate the effect of enteral and parenteral nutrition support (EPNS) on pulmonary function in elderly patients with chronic obstructive pulmonary disease (COPD) complicated by respiratory failure (RF). A total of 127 patients who underwent treatment for elderly patients with COPD complicated by RF in our hospital from February 2020 to May 2022 were collected for a retrospective analysis. There were 41 patients with enteral nutrition support (group A), 46 with parenteral nutrition support (group B), and 40 with EPNS (group C). The levels of serum albumin (ALB), prealbumin (PA), serum hemoglobin (Hb), and serum transferrin (TRF) were measured before and after nutritional support in the three groups, and the changes in pulmonary function of patients were compared. The changes in the levels of inflammatory factors and markers of oxidative stress (OS) in serum were also detected, and the incidence of adverse reactions and length of stay (LOS) were counted. ALB, PA, Hb, and TRF levels were increased in all 3 groups after nutritional support, with the highest in group C (P < 0.05). Similarly, lung function was improved in all 3 groups and inflammatory factor levels and OS were suppressed, also most dramatically in group C (P < 0.05). There was no difference in the incidence of adverse reactions among the 3 groups, and the LOS in group C was shorter than those in groups A and B (P < 0.05). EPNS can effectively improve the lung function of patients with COPD combined with RF and reduce the inflammation and OS damage. It can effectively improve the therapeutic effect of patients and has great application prospects in the treatment of COPD combined with RH in the future.


[Character of changes in the rheological parameters of blood in patients with heart failure III-IV FC treated by the combination therapy with plasmapheresis].
The purpose of the investigation is to estimate the blood rheological parameters in patients with heart failure III-IV FC treated by the combination therapy (plasmapheresis with the standard therapy). There were 96 patients under the investigations, 69 men and 27 women. Age ranged from 55 to 75 years. All patients were divided into two groups: the 1st group--29 patients (20 men and 9 women) treated by standard therapy (ACE inhibitors, diuretics, digoxin and etc.), the 2nd group included 67 patients (49 men and 18 women), which received the combination therapy with plasmapheresis (2-4 times). The investigations of the blood rheological parameters in patients with heart failure III-IV FC treated by the standard therapy and by the combination therapy show the benefit of the combined one. It was proved by the statistically significant decrease of prothrombin time, fibrinogen, antithrombin III and haematocrit indicator in patients with heart failure treated with the combined therapy (in comparison with patients treated with standard therapy). Patients treated with the combined therapy demonstrated low blood viscosity levels -BV20, BV200 and high erythrocyte deformability index.


Exploring the chelation-based plant strategy for iron oxide nanoparticle uptake in garden cress (Lepidium sativum) using magnetic particle spectrometry.
Although iron is one of Earth's most abundant elements, its availability to plants remains an agricultural challenge, particularly in high pH environments. At high pH, iron forms insoluble ferric oxide-hydroxides that makes it inaccessible to plants. It is estimated that 30% of the world's cropland is too alkaline for optimal plant growth. Staple crops, like rice, are particularly susceptible to iron deficiency, thereby, necessitating the need for continued research in developing iron-based fertilizers. Recent studies have demonstrated the potential of using iron oxide nanoparticles (IONPs) as fertilizers to address iron deficiency in plants, but some studies have generated conflicting results. One of the major challenges associated in investigating IONP plant uptake and translocation is the inability to distinguish between intact IONPs versus leached iron ions. In this study, we utilized a new approach based on magnetic particle spectrometry (MPS) to monitor the uptake and distribution of different sized (10 and 20 nm) chelated IONPs in plants. We exposed garden cress (Lepidium sativum) plants to EDTA-capped IONPs and observed an 8-fold enhancement in total biomass and 1.4 times increase in chlorophyll production compared to plants treated with a commercial chelated iron fertilizer (Fe-EDTA). Moreover, we demonstrated that the uptake and tissue distribution of IONPs can be quantitatively monitored using MPS, and the results of the analysis were validated by atomic absorption spectroscopy, which is the conventional method used to study IONP plant uptake. Our study demonstrates that MPS is a reliable, sensitive, and effective analytical tool for the development of IONP-based fertilizers.


Unique Challenges of NIPT for Sex Chromosome Aneuploidy.
Noninvasive prenatal testing (NIPT) for the sex chromosome aneuploidies (45,X, 47,XXY, 47,XXX, and 47,XYY) differs significantly from that for the autosomal aneuploidies (trisomy 13, 18, and 21). As a group, sex chromosome aneuploidies occur more commonly (1/400) than any one isolated autosomal aneuploidy, the phenotypic variation is greater, the role of mosaicism more challenging, and the positive predictive value of a high-risk NIPT result is substantially lower. These considerations should be identified during pretest counseling, the inclusion of sex chromosome testing offered separately, and the differences from autosomal aneuploidy NIPT clearly delineated.