Urinary 8-hydroxy-2'-deoxyguanosine as a novel biomarker of inflammatory activity in patients with cardiac sarcoidosis.
Inflammation and oxidative stress play a crucial role in the pathogenesis of cardiac sarcoidosis (SAR). We investigated whether urinary (U) 8-hydroxy-2'-deoxyguanosine (8-OHdG)--an oxidative DNA damage marker--was related to SAR inflammatory activity. U-8-OHdG levels were measured in 31 SAR patients, classified as active (n=17) or non-active (n=14) based on (18)F-fluorodeoxyglucose positron emission tomography-computed tomography ((18)F-FDG-PET/CT), 28 dilated cardiomyopathy (DCM) patients, and 30 controls. In active SAR patients, U-8-OHdG levels were reexamined and compared with (18)F-FDG-PET/CT results at 6 months after corticosteroid treatment to assess therapeutic response. Immunohistochemical examination of left ventricle (LV) autopsy samples from SAR patients revealed positive 8-OHdG staining in cardiomyocyte nuclei from LV sections showing (18)F-FDG accumulation on PET/CT, while serum 8-OHdG levels were significantly higher in the coronary sinus than in the aortic root only in active SAR patients. U-8-OHdG levels in SAR patients were higher than those in controls, and significantly higher in active SAR patients than in non-active SAR and DCM patients. U-8-OHdG was a powerful predictor of active SAR in receiver operating characteristic curve analysis (AUC, 0.98; 95% CI, 0.94-1.02; optimal cutoff value, 13.1 ng/mg creatinine), with a sensitivity of 88.2% and a specificity of 92.9%. U-8-OHdG levels in responders significantly decreased at 6 months after corticosteroid treatment initiation, in proportion with the decrease in the focal cardiac uptake of (18)F-FDG. U-8-OHdG is a potentially clinically useful biomarker for evaluating inflammatory activity and monitoring the effectiveness of corticosteroid therapy in SAR patients.


Increased gut cholinergic activity and antagonism of 5-hydroxytryptamine M-receptors by BRL 24924: potential clinical importance of BRL 24924.
The mechanisms by which BRL 24924 ([(+/-)- (endo)])-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo-[3.3.1]-non- 4-yl) benzamide hydrochloride stimulates gut motility and the relationships between BRL 24924 and 5-hydroxytryptamine (5-HT) receptors have been studied. In guinea-pig isolated ileum, BRL 24924 (10(-14)-10(-6) M) increased electrically-evoked, cholinergically-mediated contractions, probably by increasing acetylcholine (ACh) release. This action of BRL 24924 was prevented by the presence of high concentrations of 5-HT, but not by hexamethonium, phentolamine and propranolol, methysergide or ICS 205-930. The mechanism by which BRL 24924 can increase gut ACh release is not certain, but most likely involves activation of an enteric 5-HT receptor which differs from those 5-HT M-receptors antagonized by ICS 205-930 or by higher concentrations of BRL 24924 in other test systems. BRL 24924 antagonized 5-HT-evoked, cholinergically-mediated contractions of guinea-pig isolated ileum (pA2 = 7.56 +/- 0.12). Similar and higher concentrations of BRL 24924 did not antagonize contractions evoked by nicotinic receptor stimulation. In rabbit isolated heart, BRL 24924 1-10 nM reduced the tachycardia evoked by 5-HT. In anaesthetized rats, BRL 24924 0.3-83 nmol kg-1 i.v. antagonized the Bezold-Jarisch reflex evoked by 5-HT; the ID50 for BRL 24924 was 10.2 +/- 3.0 nmol kg-1 (3.7 +/- 1.1 microgram kg-1). A direct action of BRL 24924 on nerve function was excluded. In rat cortex, BRL 24924 10(-6) M did not displace [3H]-5-HT or [3H]-ketanserin binding to 5-HT1 and 5-HT2 receptors. The actions of BRL 24924 are discussed in terms of its potential clinical use as a stimulant of gastric motility and as a 5-HT M-receptor antagonist.


The effects of an angiotensin-converting inhibitor (enalapril) on patients with mild cardiac failure--evaluating cardiac function based on the relationship between daily walking pace and heart rate.
Heart failure has been evaluated by several methods, the New York Heart Association (NYHA) classification of heart failure based on symptoms being used most frequently. However, the degree of heart failure assessed by these criteria does not always correlate with cardiac function in daily life. The aim of the study was to evaluate cardiac function based on the walking pace/heart rate (HR) relationship to assess the effects of enalapril, an angiotensin-converting enzyme inhibitor, in patients with mild to moderate cardiac function. To evaluate cardiac function objectively, we developed a method using a pedometer to count the steps walked while simultaneously recording HR using a Holter electrocardiograph (ECG). Step-count walk rate (WR) was recorded on the magnetic tape of the Holter apparatus, and both HR and walking pace were calculated automatically by the Holter ECG analysis system. Data were determined every hour, and mean pace and HR were plotted along the x and y axes, respectively. The slope of HR x WR was calculated using the least squares method. The slope and the total number of steps were regarded as indicators of cardiac function and quality of life, respectively. We analyzed 36 subjects, consisting of 8 normal volunteers, 8 patients in New York Heart Association (NYHA) class I. 11 in class II, and 9 in class III chronic mild heart failure, during maximal exercise work load by bicycle ergometer; furthermore, fractional shortening of the left ventricle on echocardiogram was determined in 14 patients with chronic mild heart failure and was compared with the slope of HR x WR. Enalapril was administered at a daily dose of 2.5-10 mg for 1-24 months (mean 6 months) in 60 patients to evaluate the effects of this drug on these parameters. There was a significant inverse relationship between maximal work load and the HR x WR slope, and also between the fractional shortening and the slope, suggesting that the slope may reflect the severity of cardiac dysfunction. Furthermore, the slope decreased significantly from 1.8 +/- 1.26 before enalapril to 1.0 +/- 0.94 (mean +/- standard deviation) after drug administration, while the total number of steps increased significantly from 4842 +/- 3581 to 7804 +/- 4793. The slope of the graph relating step count and HR proved to be a good, objective indicator of cardiac function, and enalapril therapy improved this parameter.


Deep venous thrombosis in a patient with Behçet's disease and homozygous prothrombin (factor II) G20210A mutation on oral contraceptive pills.
Behçet's disease (BD) is a multisystemic disease of unknown aetiology characterized by chronic relapsing oral aphthous lesions, genital ulcers, uveitis, and vasculopathy of both arteries and veins of all sizes. We present the case of a female patient, with BD on oral contraceptive pills, who sustained deep venous thrombosis of the long saphenous vein. The patient was found to be a carrier of a homozygous mutation of the prothrombin (factor II) G20210A gene. Our case suggests that a thrombophilia work-up may be warranted in BD patients, especially young women before they are prescribed oral contraceptives.


EEG oscillations and recognition memory: theta correlates of memory retrieval and decision making.
Studies of memory retrieval have identified electroencephalographic (EEG) correlates of a test item's old-new status, reaction time, and memory load. In the current study, we used a multivariate analysis to disentangle the effects of these correlated variables. During retrieval, power of left-parietal theta (4-8 Hz) oscillations increased in proportion to how well a test item was remembered, and theta in central regions correlated with decision making. We also studied how these oscillatory dynamics complemented event-related potentials. These findings are the first to demonstrate that distinct patterns of theta oscillations can simultaneously relate to different aspects of behavior.


Early weight bearing in tibial shaft fractures protected with wooden splints.
Evaluation of the rate of union of 40 adult tibial shaft fractures treated in below-knee wooden splints together with early weight bearing showed that fractures healed faster and patients returned to normal activity earlier than patients who were allowed early weight bearing in above-knee casts. Shortening was not increased.


Body Worlds: looking back and looking ahead.
After 10 years of intensive debate about Gunther von Hagens' "Body Worlds" exhibition, this article systematically analyses the arguments that have been raised. Two elements of the debate are critical: the donor's self-determination and consideration for the family and acquaintances. However, the arguments for and against the public exhibition of human remains, and the unusual positioning of the figurative plastinates seems to be amenable to discussion and also seems to allow different ethical weighing. Perhaps this can be understood as an indicator that, to start with, discussion is necessary in regard to our general burial culture.


Externalizing psychopathology and persistence of offending in childhood first-time arrestees.
This study aims to investigate the predictive validity of externalizing psychopathology for persistence in delinquent behavior when controlling for socio-demographic and first arrest characteristics in childhood first-time arrestees. A sample of first-time arrestees aged under 12 (n = 192) was assessed using the Diagnostic Interview Schedule for Children (DISC-IV) parent-version on attention deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD). Based on child and parent reports of offending as obtained at arrest and at 2-year follow-up, three groups of offenders were differentiated: (1) persistent high (n = 48), (2) occasional (n = 62), and (3) persistent low offenders (n = 82). Over one-third of the sample (33.9%) was diagnosed with an externalizing disorder, and 13.5% with both ADHD and ODD or CD. Higher levels of externalizing psychopathology distinguished persistent high offenders from occasional (comorbid ADHD and ODD/CD: OR 8.2, CI 2.6-25.5) and persistent low offenders (comorbid ADHD and ODD/CD: OR 18.2, CI 4.6-72.3; ADHD: OR 4.1, CI 1.3-13.0), over and above socio-demographic and first offense characteristics. Living with both biological parents distinguished the persistent low offenders from the occasional offenders (OR 2.5, CI 1.2-5.0). Since the prevalence of externalizing disorders was high and predicted re-offending, mental health screening and intervention initiatives, aiming at these conditions, should be investigated for this high-risk sample.


Gene-based sequence-tagged-sites (STSs) as the basis for a human gene map.
Using our data set of 3,143 single pass sequences from human brain cDNA libraries, we have developed a strategy in which gene-based sequence-tagged-sites (STSs), derived from 3'untranslated regions of human cDNAs, are rapidly assigned to megabase-insert yeast artificial chromosomes and somatic cell hybrids to generate regional gene mapping data. Employing this approach, we have mapped 318 cDNAs, representing 308 human genes. Ninety-two of these mapped to regions implicated in human genetic diseases, identifying them as candidate genes. Extension of this strategy has the potential to result in virtually every human gene having, at its 3' end, its own associated STS, with each STS in turn specifying both a corresponding genomic clone and a specific regional location in the genome.


Systems approaches to preventing transplanted cell death in cardiac repair.
Stem cell transplantation may repair the injured heart, but tissue regeneration is limited by death of transplanted cells. Most cell death occurs in the first few days post-transplantation, likely from a combination of ischemia, anoikis and inflammation. Interventions known to enhance transplanted cell survival include heat shock, over-expressing anti-apoptotic proteins, free radical scavengers, anti-inflammatory therapy and co-delivery of extracellular matrix molecules. Combinatorial use of such interventions markedly enhances graft cell survival, but death still remains a significant problem. We review these challenges to cardiac cell transplantation and present an approach to systematically address them. Most anti-death studies use histology to assess engraftment, which is time- and labor-intensive. To increase throughput, we developed two biochemical approaches to follow graft viability in the mouse heart. The first relies on LacZ enzymatic activity to track genetically modified cells, and the second quantifies human genomic DNA content using repetitive Alu sequences. Both show linear relationships between input cell number and biochemical signal, but require correction for the time lag between cell death and loss of signal. Once optimized, they permit detection of as few as 1 graft cell in 40,000 host cells. Pro-survival effects measured biochemically at three days predict long-term histological engraftment benefits. These methods permitted identification of carbamylated erythropoietin (CEPO) as a pro-survival factor for human embryonic stem cell-derived cardiomyocyte grafts. CEPO's effects were additive to heat shock, implying independent survival pathways. This system should permit combinatorial approaches to enhance graft viability in a fraction of the time required for conventional histology.


ATP activation of plasma membrane yeast H(+)-ATPase shows complex kinetics independently of the degree of purification.
ATP stimulation of plasma membrane H(+)-ATPase activity from a wild baker's yeast (Saccharomyces cerevisiae) was followed under conditions of progressive degrees of purification. A particular emphasis was put to cover a wide range of concentrations which went from 2 microM up to 3000 microM ATP. The preparations used were (i) crude membrane fraction, (ii) untreated plasma membrane fraction obtained by differential centrifugation, (iii) residual plasma membrane treated with Triton X-100, (iv) enzyme solubilized with either Zwittergent 3-14 alone or after Triton X-100 treatment. Under all conditions the fitting of the dose-response curves required an equation composed by the sum of two Michaelian terms. Depending on the treatment, the Km values and Vmax values varied. The fitted curves displayed a high affinity-low Vmax (Km values of 7-60 microM and Vmax values of 0.03-0.50 mumol P(i)/mg per min) and a low affinity-high Vmax component (Km values of 408-1960 microM and Vmax values of 0.26-5.82 mumol P(i)/mg per min). The complex ATP activation curve of the yeast plasma membrane H(+)-ATPase is in line with similar behavior found for the H(+)-ATPase of higher plants and all known animal cation transport ATPases.


Hyperfractionation for head and neck cancer.
Between March 1978 and April 1984, 144 patients with 148 moderately advanced to advanced primary squamous cell carcinomas of the head and neck received treatment with curative intent with twice-a-day irradiation (120 cGy/fraction, 4-6 hour interfraction interval). Eighty-eight percent of the patients had AJCC Stage III-IV cancers. One hundred and thirty-two patients received irradiation alone to the primary site with or without radical neck dissection, with surgery reserved for salvage. The total doses administered were 7440-7920 cGy in the majority of instances. In 19 patients with oropharyngeal lesions, a 1000-1500 cGy radium needle boost was added after the basic dose. Twelve patients received preoperative irradiation (5040-6000 cGy) followed by primary resection and radical neck dissection. Local control results following irradiation alone to total doses of greater than 7000 cGy with minimum 2-year follow-up were 25/31 (81%), 38/50 (76%), and 5/25 (20%) for T2, T3, and T4 cancers, respectively. Local control rates did not correlate well with total dose. Local control following preoperative irradiation plus primary resection was obtained in 4 of 5 T3 and 2 of 3 T4 primary lesions. The 5-year actuarial rates of neck control were 100% for N0 (45 patients), 90% for N1 (25 patients), 77% for N2 (23 patients), 50% for N3A (9 patients), and 70% for N3B (42 patients). The 5-year actuarial rates of continuous disease control above the clavicles were 73% for Stage III, 64% for Stage IVA, and 32% for Stage IVB. The actuarial 4-year rate of continuous disease control above the clavicles was 78% for Stage II. For patients whose disease was controlled above the clavicles, distant metastases developed in 4% of patients with Stage II-III disease and in 18% of patients with Stage IV disease. Radiation complications following irradiation alone to the primary site correlated with total dose. Complications of planned neck dissection(s) were acceptable. Complications of salvage surgery at the primary site were similar to those seen in patients treated once a day. The actuarial 5-year survival rates, according to modified AJCC stage, were 59% for Stage III, 37% for Stage IVA, and 23% for Stage IVB. The actuarial 4-year survival rate for Stage II was 69%. Compared to historical control groups treated with once-a-day, continuous-course irradiation at our institution, twice-a-day treatment has produced local control results that are higher by 10-15 percentage points.


Prostacyclin biosynthesis and reduced 5-HT uptake after complement-induced endothelial injury in the dog isolated lung.
1. Pulmonary prostacyclin (PGI2) biosynthesis was evaluated in relation to endothelial integrity before and after complement activation in isolated plasma-perfused lung lobes of the dog. 2. The plasma was activated with zymosan (ZAP, n = 4), yeast cells (YAP, n = 4) or yeast with 3 microM indomethacin (Indo + YAP, n = 3). Immunoreactive 6-oxo-prostaglandin F1 alpha (i-6-oxo-PGF1 alpha) and thromboxane B2 (iTXB2) were measured to monitor PGI2 and TXA2 biosynthesis. 3. The kinetic parameters Km and Vmax of 5-hydroxytryptamine (5-HT) uptake were calculated on the basis of multiple indicator diffusion data to evaluate endothelial integrity. 4. YAP and ZAP induced a biphasic increase of the arterial perfusion pressure. The immediate pressure peak was partly mediated by TXA2 and the TXB2 was subsequently cleared by the lung. 5. The apparent Vmax of 5-HT uptake remained constant throughout the experiment. Thus, complement activation did not affect the number of endothelial 5-HT carrier sites available to the perfusate. 6. The apparent Km of 5-HT uptake was enhanced in 9 lungs exposed to activated plasma complement for 20 min. This decreased affinity for 5-HT probably reflects endothelial injury. It was transient as the apparent Km had returned to the baseline value after 60 min. 7. PGI2 clearance and biosynthesis were virtually absent in the control period. PGI2 formation increased drastically after infusion of ZAP or YAP and was proportional to the endothelial injury expressed as elevated Km or pulmonary oedema. Thus, PGI2 biosynthesis might be a marker of severe endothelial distress.


Quality of life of persons with epilepsy in Mahenge, an onchocerciasis-endemic area in Tanzania: A cross-sectional study.
This study investigated the quality of life (QoL) of adults with epilepsy living in Mahenge, an onchocerciasis-endemic area in Tanzania with a high prevalence of onchocerciasis-associated epilepsy (OAE). Between February and December 2020, persons with epilepsy (PWE) were recruited from four rural villages in Mahenge: Mdindo, Msogezi, Mzelezi, and Sali. For PWE who could not answer the questionnaire due to their mental or physical disability, a family member was asked to answer the questions instead. The Quality of Life in Epilepsy Inventory-31 (QOLIE-31) questionnaire used contained seven domains. The raw domain scores were transformed to 0-100% subscales, with higher scores indicating better QoL. The global QoL was calculated from the subscales using the overall QOLIE-31 score formula. In total, 96 PWE were enrolled in the study with a median age of 28 (range: 18-60) years, of whom 45 (47%) were male. The questionnaires were answered by PWE (54.8%) or one of their family members (45.2%). Most PWE were single (81%), and half never attended school. About two-thirds (65%) of PWE were suspected of having OAE, and a third (31%) had a history of head nodding seizures. Most PWE were treated with phenobarbital (85.4%) and had high treatment adherence (96.9%). Still, the number of seizures per week ranged from 0 to 7, with a median of one. The mean global QOLIE-31 score was 66.9 (range: 38.3-92.1) out of 100.0. Predictors of lower QoL were living in Sali Village and experiencing seizures the week before the interview. In contrast, completing primary school and switching to second-line anti-seizure medication were predictors of higher QoL. In order to improve the QoL of PWE in Mahenge, it is vital to optimize anti-seizure medication regimens to decrease the frequency of seizures and to increase the schooling of PWE.


Geochemical record of high emperor penguin populations during the Little Ice Age at Amanda Bay, Antarctica.
Emperor penguins (Aptenodytes forsteri) are sensitive to the Antarctic climate change because they breed on the fast sea ice. Studies of paleohistory for the emperor penguin are rare, due to the lack of archives on land. In this study, we obtained an emperor penguin ornithogenic sediment profile (PI) and performed geochronological, geochemical and stable isotope analyses on the sediments and feather remains. Two radiocarbon dates of penguin feathers in PI indicate that emperor penguins colonized Amanda Bay as early as CE 1540. By using the bio-elements (P, Se, Hg, Zn and Cd) in sediments and stable isotope values (δ(15)N and δ(13)C) in feathers, we inferred relative population size and dietary change of emperor penguins during the period of CE 1540-2008, respectively. An increase in population size with depleted N isotope ratios for emperor penguins on N island at Amanda Bay during the Little Ice Age (CE 1540-1866) was observed, suggesting that cold climate affected the penguin's breeding habitat, prey availability and thus their population and dietary composition.


Hyaluronic scaffold transplantation with bone marrow concentrate for the treatment of osteochondral lesions of the talus: durable results up to a minimum of 10 years.
The aim of this study was to evaluate the long-term clinical results of the transplantation of a hyaluronic acid membrane augmented with bone marrow aspirate concentrate (BMAC) in an one-step technique for the treatment of patients affected by osteochondral lesions of the talus (OLT). A total of 101 patients (64 men, 37 women, age 32.9 ± 10.9) were evaluated for a minimum of 10 years of follow-up (151.5 ± 18.4 months) The mean lesion size was 2.2 ± 1.4 cm2, the lesion had a post-traumatic origin in 73 patients, 15 patients previously had an ankle fracture, 22 patients had ankle osteoarthritis. All patients were clinically evaluated at baseline and at 2, 5, and a minimum of 10 years after treatment using the AOFAS score, the NRS for pain, and the Tegner score. A survival analysis was performed to check the survival to failure up to the last follow-up. The AOFAS score significantly improved from baseline (59.6 ± 13.9) to the final follow-up (82.3 ± 14.2) (p < 0.0005). A significant reduction in the AOFAS score was found from 2 to 10 years (p < 0.0005). The NRS for pain changed from 7.0 ± 1.3 at baseline to 3.9 ± 2.7 at the final follow-up (p < 0.0005). A significant worsening was documented between 5 years and the final follow-up (p < 0.0005). The Tegner score improved from the preoperative value of 2.0 (range 1-7) to 3.0 (range 1-7) at the final follow-up (p < 0.0005), although it remained lower as compared to the preinjury level of 4.0 (range 1-9) (p < 0.0005). Better results were documented in male and younger patients with smaller lesions, without the previous surgery, and without the previous ankle fractures or osteoarthritis. At the final follow-up, 85 patients considered their general health status "satisfactory" and 84 patients reported feeling "better" than the preoperative condition. Five patients were considered failures and underwent prosthetic ankle replacement or repeated the same surgery. This one-step technique showed to be an effective procedure for the treatment of OLT, providing a low failure rate and offering durable clinical improvements up to a minimum of 10 years of follow-up. However, this technique demonstrated a small yet significant decrease over the years in terms of pain and function and poor results in terms of sports activity level. Level IV.


Illness and health in the ancient world.
This is the first in a series of vignettes about health, disease and care giving practices in the ancient worlds of Greece (1000 BC-100 BC) and Rome (1st AD-500 AD). Attention is directed to what the better known conditions were, what structures existed for the delivery of care, what the commonly held health beliefs were, who the most likely care attendants were and what psych-cultural changes occurred which brought about improvements in health care. Thus the series is about the early origins and development of the Western cultural tradition of health care practices. They demonstrate that there was a recognised community need for health care structures to exist and that the association between healing and religious belief began very early.


Role of High Mobility Group Box 1 in Cardiovascular Diseases.
High Mobility Group Box 1 (HMGB1) is a ubiquitous, highly conserved nuclear and cytosolic protein that has diverse biological roles depending on its cellular location and posttranslational modifications. The HMGB1 is localized in the nucleus but can be translocated to the cytoplasm to modulate the intracellular signaling and eventually secreted outside the cells. It is widely established that HMGB1 plays a key role in inflammation; however, the role of HMGB1 in the cardiovascular diseases is not well understood. In this review, we will discuss the latest reports on the pathophysiological link between HMGB1 and cardiovascular complications, with special emphasis on the inflammation. Thus, the understanding of the role of HMGB1 may provide new insights into developing new HMGB1-based therapies.


Ferroptosis Mechanisms Involved in Neurodegenerative Diseases.
Ferroptosis is a type of cell death that was described less than a decade ago. It is caused by the excess of free intracellular iron that leads to lipid (hydro) peroxidation. Iron is essential as a redox metal in several physiological functions. The brain is one of the organs known to be affected by iron homeostatic balance disruption. Since the 1960s, increased concentration of iron in the central nervous system has been associated with oxidative stress, oxidation of proteins and lipids, and cell death. Here, we review the main mechanisms involved in the process of ferroptosis such as lipid peroxidation, glutathione peroxidase 4 enzyme activity, and iron metabolism. Moreover, the association of ferroptosis with the pathophysiology of some neurodegenerative diseases, namely Alzheimer's, Parkinson's, and Huntington's diseases, has also been addressed.


What do children need to know about dementia? The perspectives of children and people with personal experience of dementia.
ABSTRACTBackground:The vision for dementia-friendly communities is challenged by limited public awareness and stigma about dementia. The study aim was to elicit stakeholder priorities for the message content of an education program to improve dementia awareness among youth; specifically, what do children need to know about dementia? A qualitative inquiry using interviews and focus groups was used. Purposive sampling achieved maximum variation in dementia experience and participant characteristics. Focus groups with Scouts in the community aged 9-12 years old (n = 22) used innovative techniques to explore children's attitudes towards people with dementia. Participants with personal experience of dementia were five people with early-stage dementia; 12 adult primary carers; four non-primary carers; and six grandchildren of a person with dementia. They were asked what is important for children to understand about dementia and what attitudes they may like an education program to confer. Content analysis was performed using NVivo10. Strong themes to emerge were that children need to know the whole truth about dementia; that individuals with dementia are "still people," that it is "not the fault" of the person with dementia; and that dementia is different and typically unpredictable for everyone. Discussions also indicated a need to educate children about ways to relate to a person with dementia, and to appreciate "positives" within a relationship. Children are our future citizens. Developing an education program for children with this message content may be fundamental to de-stigmatizing dementia and laying the foundation to dementia-friendly communities.


Direct sagittal CT scan: a new diagnostic approach for surgical neonates.
Because of their small body size, neonates can be placed in the plane of the CT scanner gantry (aperture diameter 70 cm) instead of across it. This direct sagittal scanning technique allows accurate delineation of surgical lesions, particularly midline ones, unobtainable with conventional axial imaging. In addition, the sagittal image provides a perspective of anatomic arrangement more familiar to the surgeon than that provided by axial sections and therefore allows for easier interpretation. In imperforate anus, sagittal CT identifies the blind rectal end by the meconium tissue interphase and therefore avoids the pitfalls of invertogram, which depends on the bowel gas pattern for interpretation. With this new approach, we correctly classified six cases of imperforate anus into high types (3) and low types (3), visualized the associated fistula and had knowledge of the exact distance of the blind rectal end from the skin level preoperatively. In tracheoesophageal fistula (2), sagittal CT demonstrated the air-filled blind pouch and fistula to allow preoperative classification and assessment of the gap distance. In sacrococcygeal teratoma (3) and laryngeal cyst (1), its use allowed an accurate assessment of possible extension of the lesion into neighboring structures. Our experience with direct sagittal CT scan therefore suggests that this new and noninvasive technique is a useful adjunct in the management of a variety of common neonatal surgical problems.


Kis antitoxin couples plasmid R1 replication and parD (kis,kid) maintenance modules.
The coupling between the replication and parD (kis, kid) maintenance modules of R1 has been revisited here by the isolation of a significant collection of conditional replication mutants in the pKN1562 mini-R1 plasmid, and in its derivative, pJLV01, specifically affected in the RNase activity of the Kid toxin. This new analysis aims to identify key factors in this coupling. For this purpose we have quantified and characterized the restriction introduced by parD to isolate conditional replication mutants of this plasmid, a signature of the modular coupling. This restriction depends on the RNase activity of the Kid toxin and it is relieved by either over-expression of the Kis antitoxin or by preventing its degradation by Lon and ClpAP proteases. Based on these data and on the correlation between copy numbers and parD transcriptional levels obtained in the different mutants, it is proposed that a reduction of Kis antitoxin levels in response to inefficient plasmid replication is the key factor for coupling plasmid replication and parD modules.


Cannabis Use Is Associated With Depression Severity and Suicidality in the National Comorbidity Survey-Adolescent Supplement.
To investigate the association of cannabis use with major depression and suicidal behavior in adolescence. Data are from the National Comorbidity Survey-Adolescent Supplement N=10,123, a nationally representative survey of adolescents aged 13 to 18 years. Weighted logistic regression and ordinal regression analyses of major depression and suicidal behavior outcomes were conducted on cannabis variables, incorporating sociodemographic characteristics. Adolescents with lifetime cannabis use have 2.07 times higher odds of mild/moderate (adjusted odds ratio [aOR]; 95% CI=1.69, 2.53) and 3.32 times higher odds of severe major depressive disorder (MDD; aOR; 95% CI=2.31, 4.75). Cannabis use (aOR 6.90, 95% CI=4.67,10.19), mild/moderate MDD (aOR 4.10, 95% CI=2.82, 5.98), and severe MDD (aOR 13.97, 95% CI = 7.59, 25.70) were associated with higher odds of suicide attempt. Past 12-month cannabis use (aOR 3.70, 95% CI = 2.16, 6.32), mild/moderate major depressive episodes (MDE) (aOR 7.85, 95% CI=3.59, 17.17), and severe MDE (aOR 36.36, 95% CI=13.68,96.64) were associated with higher odds of suicide attempt. The frequency of past 12-month cannabis use was associated with higher odds of suicide attempt and with MDE severity, with higher odds among individuals who use cannabis 3 or more days than among individuals who use cannabis less frequently, suggesting a dose effect. Among cannabis users, older age of onset of cannabis use was associated with lower odds of suicidal behaviors. Cannabis use is associated with higher odds of depression and depression severity in adolescence. Furthermore, depression and cannabis use are independently associated with higher odds of suicide attempt. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.


Randomized phase II trial of different schedules of administration of rebeccamycin analogue as second line therapy in non-small cell lung cancer.
Rebeccamcyin analogue (RA) is an antitumor antibiotic that results in DNA intercalation and topoisomerase I and II inhibition. Phase I trials of the daily x 5 schedule and once every 3 week schedule have been completed. Antitumor activity was observed during the phase I trials. The purpose of this study is to primarily determine the response rate of 2 different schedules of administration of RA in patients with advanced non-small cell lung cancer (NSCLC) who had progressed on one prior chemotherapy regimen. Secondary endpoints were median and 1-year survival rates. A two-stage Simon design was employed for both arms of the study. Patients were randomly assigned to either of two RA treatment schedules of 500 mg/m(2) as a 1 hr infusion repeated every 3 weeks (Arm A) or 140 mg/m(2)/day x 5 days repeated every 3 weeks (Arm B). Forty-two patients were randomized. No confirmed objective responses were seen. Stable disease was seen in 52% of patients on arm A and 37% on arm B. Median survival and 1 year survival rates were 5.6 months and 33.3% for arm A, 9.7 months and 42.1% for arm B respectively. Cox regression model demonstrated increased risk of death in patients younger than the age of 61 and for patients treated on arm A. RA failed to demonstrate a significant response rate in this disease setting, although the proportion of patients with stable disease and 1-year survival were encouraging and similar to other published studies of approved single agents for second-line therapy of NSCLC.


Building the Future: Post-transcriptional Regulation of Cell Fate Decisions Prior to the Xenopus Midblastula Transition.
In all animals, a critical period in early development is when embryonic cells switch from relying solely upon maternally deposited RNAs and proteins to relying upon molecules encoded by the zygotic genome. Xenopus embryos have served as a model for examining this switch, as well as the maternally controlled stages that prepare for it. In Xenopus, the robust activation of zygotic transcription occurs at the 12th cleavage division and is referred to as the midblastula transition (MBT). Prior to MBT, gene expression is regulated by post-transcriptional events including mRNA and protein localization, protein post-translational modification, and mRNA translation. After the MBT, appropriate transcriptional regulation of the zygotic genome becomes critical and predominates. However, it is important to realize that the first key cell fate decisions that have profound impacts on development occur prior to the MBT and these are governed by regulating the expression of maternally deposited regulatory mRNAs and proteins. In this chapter, I will discuss post-transcriptional mechanisms that function during the maternal stages of Xenopus development with an emphasis on mechanisms known to directly modulate cell fate decisions. Emerging approaches and technologies that will help better understand this phase of development will also be discussed.


The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery.
The polycystic ovary syndrome (PCOS) is frequently associated with obesity. However, there are very few data about PCOS in morbid obesity, especially with regard to its evolution after bariatric surgery. The objective of this study was to evaluate the response of PCOS to the sustained and marked weight loss achieved by bariatric surgery in morbidly obese women. This was a longitudinal prospective nonrandomized evaluation. The study was performed at an academic hospital. Thirty-six consecutive premenopausal women submitted to bariatric surgery were screened for PCOS, which was present in 17. Bariatric surgery was performed. Hyperandrogenism, menstrual function, and insulin resistance were estimated before and at least 6 months after bariatric surgery in 12 patients with PCOS. Weight loss (41 +/- 9 kg after 12 +/- 5 months) was paralleled by decreases in the hirsutism score (from 9.5 +/- 6.8 to 4.9 +/- 4.2; P = 0.001), total (69 +/- 32 to 42 +/- 19 ng/dl; P < 0.02) and free testosterone (from 1.6 +/- 0.7 to 0.6 +/- 0.3 ng/dl; P < 0.005), androstenedione (from 4.1 +/- 1.5 to 3.0 +/- 0.9 ng/ml; P < 0.02), and dehydroepiandrosterone sulfate (from 2000 +/- 1125 to 1353 +/- 759 ng/ml; P < 0.005); amelioration of insulin resistance estimated by homeostasis model assessment (from 6.0 +/- 3.0 to 1.6 +/- 1.0; P < 0.001); and restoration of regular menstrual cycles and/or ovulation in all patients. The PCOS is a frequent finding in women with morbid obesity and may resolve after weight loss induced by bariatric surgery.


Changes in cortical and subcortical levels of monoamines and their metabolites following unilateral ventrolateral cortical lesions in the rat.
Suction lesions were made in the anterior, posterior or both halves of the right ventrolateral cortex in rats. Six days later, levels of the monoamine neurotransmitters, norepinephrine (NE), dopamine (DA) and serotonin (5-HT), and their metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA), were measured in cortical and subcortical regions of lesioned rats and compared to values in sham-operated animals. NE and 5-HT were decreased in sections of ipsilateral (right) cortex including, and posterior to lesions, while 5-HIAA was increased throughout the ipsilateral cortex. Decreases in monoamines and increases in metabolites and metabolite:monoamine ratios (especially 5-HIAA:5-HT) were found in ipsilateral subcortical structures, including striatum, nucleus accumbens, hippocampus, hypothalamus, midbrain and brainstem, depending on the type of lesion. Subacutely, focal ventrolateral cortical lesions may profoundly alter the levels and utilization rates of monoamine neurotransmitters in widespread regions of the ipsilateral hemisphere.


Endoflip vs high-definition manometry in the assessment of fecal incontinence: A data-driven unsupervised comparison.
How much anal sphincter dysfunction contributes to fecal incontinence (FI) is not clear. High-definition anorectal manometry (HDAM) and functional luminal imaging probe (Endoflip) are two new techniques to study anal sphincter function. The goal was to compare the diagnostic utility of HDAM and Endoflip using optimal feature(s) in each modality for FI diagnosis. Blinded classification was carried out on 70 female subjects (32 FI & 38 controls), using 3 prominent machine-learning clustering techniques, with 3 distance metrics. For HDAM, descriptive statistics, shape, and textural features characterizing the spatial relationship of pixels in the HDAM high-pressure zone, and for Endoflip, permutations of pressure and CSA combinations (ie, multiplication, division, or individually) at rest and squeeze were tested. Intramodality: (a) Endoflip: Best clustering was obtained using the combination of the ratio of CSA over pressure at 40 and 50 mL at rest, which had significantly better specificity (P < 0.001) than using only pressure at 50 mL, no difference in sensitivity (P = 0.68). (b) HDAM: clustering using textural information at rest had significantly higher specificity compared to using only the maximal pressure at rest (P < 0.001). Intermodality: Clustering results using optimal features were not significantly different with respect to sensitivity or specificity (P > 0.05). Optimal Endoflip feature set differed significantly in specificity compared to HDAM maximal pressure at both rest (P < 0.001) and squeeze (P < 0.001). Defective anal closure function is fairly sensitive and highly specific in diagnosing FI. Using optimal feature sets, HDAM and Endoflip perform in a similar fashion in diagnosing FI, but are not complementary.


Corrigendum to "The incidence of hip fracture and mortality rate after hip fracture in Korea: A nationwide population-based cohort study" [Osteoporos Sarcopenia 5 (2019) 38-43].
[This corrects the article DOI: 10.1016/j.afos.2019.06.003.].


RANKL inhibition halts lesion progression and promotes bone remineralization in mice with fibrous dysplasia.
Fibrous dysplasia (FD) is a rare bone disease caused by GNAS mutation in skeletal stem cells, typically originating from and worsening in childhood. Till now, no cure for FD exists despite the well-recognized etiology. Studies have demonstrated that osteoclastogenesis hyperactivity is caused by elevated RANKL expression, making RANKL inhibition a potential therapy. Although a human monoclonal anti-RANKL antibody, denosumab, has been used in FD patients, the effects and mechanisms of RANKL inhibition for FD treatment require assessment. Denosumab is expensive and can only be injected. Therefore, formulating an oral-administered, cost-effective medicine is encouraged. In the current study, we evaluated the effects of a small-molecule RANKL inhibitor, AS2676293, on a transgenic FD mouse model. AS2676293 effectively suppressed osteoclastogenesis and halted FD progression. The pre-existing bone defects were primarily replaced by newly formed mineralized bone after two weeks of AS2676293 administration. The potent RANKL inhibitory effect and easier route of delivery make AS2676293 a promising target therapy of FD. Results from our study suggested that RANKL inhibition is effective in halting FD progression and promoting bone remineralization, which could benefit the patients with early onset of FD.


Ferrocenyl Quinone Methide-Thiol Adducts as New Antiproliferative Agents: Synthesis, Metabolic Formation from Ferrociphenols, and Oxidative Transformation.
Ferrociphenols (FCs) and their oxidized, electrophilic quinone methide metabolites (FC-QMs) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC-QMs toward cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FC-SR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of the FC-SR adducts exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either revert to their FC-QM precursors or transform into new quinone methides (QMs) containing the SR moiety, FC-SR-QM. These results provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs, and also open the way to a new series of organometallic antitumor compounds.


Synthesis and evaluation of 1,3,5-triazine derivatives as sunscreens useful to prevent skin cancer.
The incidence of skin cancers such as non-melanoma skin cancer and malignant melanoma has increased in the last few years mainly because of chronic exposure to ultraviolet (UV) radiation. Sunscreens protect the skin against harmful UV radiations; however, some limitations of these products justify the discovery of new UV filters. Novel 1,3,5-triazine derivatives (12a-h) obtained by the optimization of prototype resveratrol were synthesized and characterized. All compounds exhibited sun protection factor (SPF) and UVA protection factor (UVAPF) in the range of 3-17 and 3-13, respectively. These values were superior to resveratrol and the UV filter ethylhexyl triazone (EHT) currently available on the market. In addition, all compounds demonstrated in vitro antioxidant activity and thermal stability with the decomposition at temperatures above 236 °C. In conclusion, the novel 1,3,5-triazine derivatives have emerged as new UV filters with antioxidant effect useful to prevent skin cancer.


Associations of impulsivity, hyperactivity, and inattention with nonsuicidal self-injury and suicidal behavior: longitudinal cohort study following children at risk for neurodevelopmental disorders into mid-adolescence.
The knowledge of how the separate Attention-Deficit/Hyperactivity Disorder (ADHD) subdimensions (impulsivity, hyperactivity, and inattention) are associated with nonsuicidal self-injury (NSSI) and suicidal behavior (SB) is limited. The objective of this study was to investigate the associations of childhood ADHD subdimensions with NSSI and SB in children at risk of neurodevelopmental disorders (NDDs; including ADHD). The sample (N = 391) included twin pairs where at least one twin screened positive for at least one NDD or common comorbidity at age 9 or 12. Data on ADHD subdimensions was collected through a telephone interview with a caregiver/legal guardian at age 9 or 12, and data on NSSI and SB was collected through an in-person clinical assessment at age 15. The associations between the ADHD subdimensions and NSSI or SB were tested in three different models: (1) univariable, (2) together with the other ADHD subdimensions, and (3) in a confounder-adjusted model including other NDD symptoms in addition to ADHD subdimensions, for NSSI and SB separately. A total of 32 (8.2%) adolescents reported life-time engagement of NSSI, and 18 (4.6%) SB. Childhood impulsivity was associated with SB and childhood inattention with NSSI, in all models. Hyperactivity was not meaningfully associated with any of the outcomes. Impulsivity and inattention, but not hyperactivity, may be of particular importance in understanding SB and NSSI. Brief screening for impulsivity and inattention in childhood could facilitate detection of children vulnerable to NSSI and SB and indicate valuable information for preventive and intervention strategies.


The preparation of stable enzyme-coenzyme complexes with endogenous catalytic activity.
N6-(6-Aminohexylcarbamoylmethyl)-NAD+ was coupled to lactate dehydrogenase by using glutaraldehyde to form an active complex. The stability of this complex could be considerably improved by reduction with KBH4, although this treatment caused a partial decrease in specific activity. NAD+ was also coupled directly to the enzyme by this method. All of these complexes exhibited an intrinsic activity in the absence of exogenous NAD+.


Platelets and coronary artery disease: Interactions with the blood vessel wall and cardiovascular devices.
In view of the rare presence of studies concerning platelet function as risk factor in atherosclerotic patients, processes underlying thromboembolic events are reviewed in this paper. The morphology and the structural organization-membrane receptors, the open canalicular and dense tubular systems, the cytoskeleton, mitochondria, granules, lysosomes, and peroxisomes-of platelets are described. Platelet function under physiological conditions in atherosclerosis and after implantation of cardiovascular devices is summarized.


Some observations of a correlation between the symmetry of large heavy-atom complexes and their binding sites on proteins.
Two large, electron dense heavy-metal complexes were found to bind to crystals of heavy riboflavin synthase. The crystallographic analysis by difference Fourier methods shows that the tungsten cluster compound [(W3O2(O2CCH3)6]2+, which has trigonal symmetry, binds to a site on the 3-fold axis of the protein. The heteropolytungstate compound [NaP5W30O110]14-, which has pentagonal symmetry, binds to a site on the 5-fold axis of the protein.


Visceral fat predominance is associated with non-alcoholic fatty liver disease in Japanese women with metabolic syndrome.
Metabolic syndrome (MS) is likely to be associated with non-alcoholic fatty liver disease (NAFLD). The prevalence of NAFLD in visceral fat type MS (V-type MS) is known to be higher than in subcutaneous fat type MS (S-type MS) in men with MS, and a larger subcutaneous fat area is reported to be not associated with NAFLD in women. We elucidated differences between V-type S-type MS in Japanese women with MS. The subjects were 276 women with MS who underwent a medical checkup including abdominal ultrasonography. We examined for the prevalence of fatty liver and investigated biochemical parameters, and we also made a distinction between V-type and S-type MS. Triglyceride, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase, the frequency of fatty liver and impaired glucose tolerance (IGT) were significantly higher in V-type MS than in S-type MS. On logistic regression analysis with NAFLD (in our study, fatty liver with ALT ≥31 IU/L was defined as NAFLD) as a dependent variable, body mass index, dyslipidemia, AST and V-type MS were significant predictors of an increased prevalence of NAFLD (odds ratios [OR] = 18.85, 3.119, 59.77 and 3.205; 95% confidence intervals [CI] = 3.585-99.15, 1.195-8.142, 18.03-198.2 and 1.198-8.573; P < 0.001, <0.05, <0.001 and <0.05, respectively). Women with V-type MS are more likely to have fatty liver, IGT and liver dysfunction than those with S-type MS. V-type MS is one of the significant predictors for NAFLD in Japanese women with MS.


Transport of a hydrophobic biosynthetic precursor by lipophorin in the hemolymph of a geometrid female moth which secretes an epoxyalkenyl sex pheromone.
Previous experiments with a geometrid species, Ascotis selenaria cretacea, have suggested that a pheromonal C19 3,4-epoxy-6,9-diene is biosynthesized from the corresponding 3,6,9-triene produced outside a pheromone gland and transported to it via hemolymph after association with lipophorin. In order to clarify this transport, high-density lipophorin (HDLp) in the female moths showing two bands (apoLp I with ca. 250 kDa and apoLp II with ca. 80 kDa) on an SDS-PAGE was purified by KBr equilibrium density-gradient ultracentrifugation, and the association of the triene was confirmed by GC-MS analysis of a solvent extract from the isolated protein. Next, the role of HDLp was revealed by a topical application of the deuterated trienyl precursor to the abdomens of the females. The trienyl precursor was associated with HDLp. In their pheromone glands, the triene and the deuterated epoxy pheromone were detected, indicating movement of the triene via the hemolymph. Experiments with male moths of A. s. cretacea and female moths of Bombyx mori showed the same association of HDLp with the triene topically applied. This result suggested that the adult females of A. s. cretacea did not develop HDLp specialized in the triene transport. Furthermore, the topical application of a mixture including the trienyl precursor and two other related hydrocarbons showed equal amounts of association by HDLp but selective delivery of the precursor to pheromone glands in the A. s. cretacea females.


The clinical value of ceMRA versus DSA for follow-up of intracranial aneurysms treated by coil embolization: an assessment of occlusion classifications and impact on treatment decisions.
The aim of this study was a detailed analysis of the value of contrast-enhanced magnetic resonance angiography (ceMRA) compared to digital subtraction angiography (DSA) for follow-up imaging of intracranial aneurysms treated by coil embolization. Patients with coiled aneurysms and follow-up exams including both DSA and 3 T ceMRA were retrospectively identified. In blinded readings, both modalities were graded according to the modified Raymond-Roy classification (MRRC) and the Meyers scale. Additionally, readers were asked to make a decision regarding retreatment/follow-up based on the respective imaging findings. The study comprised 92 patients harboring 102 coiled aneurysms. There was good intermethod agreement of DSA and ceMRA concerning both the MRRC (κ = 0.64) and the Meyers scale (κ = 0.74). Agreement regarding occlusion of < 90% of the aneurysm (Meyers grade ≥ 2) was very good (κ = 0.87). Regarding the detection of a remnant with contrast between the coil mass and the aneurysm wall (MRRC IIIb), there were 12 discrepant findings and agreement was good (κ = 0.70). Comparing treatment/follow-up decisions, the two methods agreed very well (κ = 0.92). In seven patients with discrepant treatment decisions, the authors concurred with DSA in four cases and with ceMRA in three cases when evaluating both modalities together. Interval aneurysm growth was found in more cases with ceMRA (n = 19) than with DSA (n = 16). CeMRA is very unlikely to miss a relevant aneurysm remnant and thus could be suitable as the primary follow-up method. In case of remnant growth or recurrence, however, additional DSA might be required to guide treatment decisions. • There is high accordance between ceMRA and DSA regarding the evaluation of intracranial aneurysms treated by endovascular coil embolization, but closer analysis also revealed relevant differences. • CeMRA could be suitable as the primary follow-up imaging modality, potentially eliminating the need for routine DSA. • DSA will still be required in case of aneurysm remnant growth or recurrence as detected by ceMRA.


The effect of cell membrane alteration on glucocorticoid uptake by the AtT-20/D-1 target cell.
The glucocorticoid-sensitive AtT-20/D-1 cell line was used to study cellular uptake of glucocorticoids. A previous observation that glucocorticoid uptake by these cells was temperature dependent had prompted us to postulate that glucocorticoids entered the cell by a temperature-sensitive transport process located in the cell membrane. Attempts were then made to perturb the membrane mechanism. In some of these experiments, intact cells were treated with neuraminidase or pronase. The release of sialic acid in the case of neuraminidase treatment and of sialic acid and cell surface peptides in the case of pronase treatment demonstrated that the enzymes were effective. Approx. 60% of total cellular sialic acid was released by a 15 min incubation with 20 microng/ml neuraminidase at 25 degrees C. The treated cells appeared to be viable, in that they continued to produce corticotropin at a normal rate, yet intact cell glucocorticoid binding at both 4 and 25 degrees C was only 20-30% of that of untreated cells. Treatment with pronase also caused steroid uptake at 4 and 25 degrees C to be reduced, although the extent of reduction was less than that seen following neuraminidase treatment. In other experiments, the effect of exposure of AtT-20/D-1 cells to ethanol or dimethyl sulfoxide was determined. The solvent concentrations used (0.5-10%) did not alter cell viability significantly, and the ability of the cytosol receptor to bind steroid in a cell-free preparation was unimpaired. However, incubation of intact cells with 10% (v/v) dimethyl sulfoxide or ethanol resulted in an 80-90% decrease in steroid uptake at 25 degrees C. We conclude that steroid uptake by the intact cell can be perturbed by treatments which do not affect the cytosol receptor or alter cell viability. These results support the postulate that glucocorticoids enter the AtT-20/D-1 cell by a specific membrane-associated mechanism.


Modification on Direct Agglutination Antigen Preparation for Simplified Sero-Diagnosis of Human and Canine Visceral Leishmaniasis.
Visceral leishmaniasis is systematic serous parasitic disease with public health importance. Zoonotic form of visceral leishmaniasis is wide spread in Mediterranean basin and South America regions. Direct agglutination test (DAT) is an accurate, reliable and non-expensive serological test for the diagnosis of visceral leishmaniasis in human and canines but the antigen preparation involves some limitations. This study aimed to compare the conventional production of DAT antigen with our modified DAT antigen and then assessed on human and dog pooled sera. Conventional DAT antigen has been prepared at the School of Public Health, Tehran University of Medical Sciences and some modifications were carried out on it, which named as modified DAT antigen. Three positive and one negative human and dog pooled serum were separately used for the comparison of modified DAT with conventional DAT antigen batches with one-month interval for a period of 9 months. A good concordance was observed between modified DAT compared to conventional DAT antigens for the detection of visceral leishmaniasis on human (100%) and dog (94.4%) pooled sera, respectively. Since the modified DAT antigen could be reduced the preparation time from 3 days to several hours and a good degree of agreement was found between modified DAT and convention DAT antigen batches, it can be used as a simple and easy tool for screening and serodiagnosis of human and canine L. infantum infection.


TLR9 turns the tide on Treg cells.
In this issue of Immunity, Hall et al. (2008) demonstrate that commensal bacterial DNA can suppress Treg cell conversion via TLR9-mediated activation of lamina propria dendritic cells and thus potentially disrupt intestinal homeostasis.


Characterization of a novel anti-DR5 monoclonal antibody WD1 with the potential to induce tumor cell apoptosis.
TNF-related apoptosis-inducing ligand (TRAIL) is a TNF family member capable of inducing apoptosis. Death receptor 5 (DR 5) is a key receptor of TRAIL and plays an important role in TRAIL-induced apoptosis. To prepare monoclonal antibodies (mAbs) against DR5, cDNA encoding soluble DR5 (sDR5) was firstly amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) with specific primers, and then inserted into a prokaryotic expression vector pET-30a. The recombinant plasmid was expressed in Escherichia coli strain BL21 (DE3), and sDR5 was purified by nickel affinity chromatography. As an antigen, sDR5 was used to immunize mice. Hybridomas secreting antibodies against sDR5 were identified. One positive clone was selected to produce antibody, WD1. ELISA and immunofluorescence demonstrated that WD1 could bind recombinant sDR5 and membrane-bound DR5 (mDR5) on Jurkat and Molt-4 cells. ATPLite assays showed that Jurkat and Molt-4 cells were sensitive to the antibody in a dose dependent manner. The Annexin V/PI assays and Giemsa's staining both showed that WD1 could induce Jurkat cell apoptosis efficiently. Transient transfection of 293T cells and indirect immunofluorescence assay demonstrated that mAb (WD1) couldn't cross-react with DR4. Our findings indicated that the novel antibody, WD1 could act as a direct agonist, bind DR5 characteristically, and initiate efficient apoptotic signaling and tumor regression. Thus, WD1 would be a leading candidate for potential cancer therapeutics.


Incarcerated umbilical hernia in a super-super-obese patient.
Abdominal wall hernias are more prevalent in the morbidly obese. Incarceration of external hernias is a relatively common process in adults and is associated to a high rate of complications and mortality. We present the case of a morbidly super-super-obese patient (body mass index, 80 kg/m(2)) who underwent emergency surgery for an incarcerated umbilical hernia; the patient died despite segmental intestinal resection, hernia repair using mesh, and intensive care.


[Neuroimaging Characteristics of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Korean Based on Jeju Cohort: A Pictorial Essay].
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small artery vasculopathy caused by mutations in the NOTCH3 gene on chromosome 19. Jeju Island has the highest reported prevalence of CADASIL patients in the world. Even though most studies on the neuroimaging characteristics of CADASIL have focused on Western populations, there are notable differences in Korean CADASIL patients compared to those in Western countries, which may impact their clinical manifestations and prognosis. Herein, this pictorial essay presents the neuroimaging patterns of CADASIL in patients in Korea, with an emphasis on the differences observed from previous reports based on a Western patient population.


The march from early life food sensitization to allergic disease: a systematic review and meta-analyses of birth cohort studies.
There is growing evidence for an increase in food allergies. The question of whether early life food sensitization, a primary step in food allergies, leads to other allergic disease is a controversial but important issue. Birth cohorts are an ideal design to answer this question. We aimed to systematically investigate and meta-analyse the evidence for associations between early food sensitization and allergic disease in birth cohorts. MEDLINE and SCOPUS databases were searched for birth cohorts that have investigated the association between food sensitization in the first 2 years and subsequent wheeze/asthma, eczema and/or allergic rhinitis. We performed meta-analyses using random-effects models to obtain pooled estimates, stratified by age group. The search yielded fifteen original articles representing thirteen cohorts. Early life food sensitization was associated with an increased risk of infantile eczema, childhood wheeze/asthma, eczema and allergic rhinitis and young adult asthma. Meta-analyses demonstrated that early life food sensitization is related to an increased risk of wheeze/asthma (pooled OR 2.9; 95% CI 2.0-4.0), eczema (pooled OR 2.7; 95% CI 1.7-4.4) and allergic rhinitis (pooled OR 3.1; 95% CI 1.9-4.9) from 4 to 8 years. Food sensitization in the first 2 years of life can identify children at high risk of subsequent allergic disease who may benefit from early life preventive strategies. However, due to potential residual confounding in the majority of studies combined with lack of follow-up into adolescence and adulthood, further research is needed.


Water-borne fungi in the River Inn, Innsbruck (Austria).
Pythium, Saprolegnia and Achlya were the basic components of the river mycoflora. Occurrence and periodicity of the fungal genera and species exhibited three different patterns during the different months of this investigation.


Metabolic risk factors in children with kidney stone disease: an update.
The prevalence of kidney stones in children has significantly increased in the past few decades, with concomitant increased morbidity and healthcare costs worldwide. Assessing metabolic risk factors is essential for diagnosis and specific treatment. The objective of this retrospective study is to identify the epidemiological and clinical characteristics of children under 17 years of age, as well as the metabolic risk factors of nephrolithiasis. A total of 300 children with kidney stone disease were included to undergo several clinical tests using a standardized protocol. The mean age was 11.2 years, and the male:female ratio was 1.15:1.0. Biochemical abnormalities were found in 89.3% of all cases. A single urine metabolic risk factor was present in 52.6% (n = 141) of the patients, and multiple risk factors were present in 36.7% (n = 106). Idiopathic hypercalciuria (alone or in combination) and hypocitraturia (alone or in combination) were the most frequent risk factors identified in 47.0% and 39.6% of these patients, respectively. Renal colic and/or unspecified abdominal pain were the most frequent forms of presentation (76.9%), followed by hematuria in 64.4% with 97.5% of stones located in the upper urinary tract. A positive family history in first-degree and second-degree relatives was found in 64.8% of boys and 61.8% of girls. We conclude that specific urinary metabolic risk factors can be found in most children with kidney stones, with hypercalciuria and hypocitraturia being the most common diagnoses. Graphical abstract .


Does the single-limb stance reflect chronic ankle instability in an athlete?
The single-limb stance with closed eyes has been widely used to evaluate chronic ankle instability as static balance; however, there was lack of consideration of whether difference in age, frequency of previous ankle sprain or physical ability influenced single-limb stance. We hypothesized that the single-limb stance might not reflect subjective ankle instability and function on physical activity in people who perform sports activities. In total, 102 high school basketball players were recruited to evaluate their physical performance at the beginning of the season. Participants were divided into five groups based on the frequency of previous ankle sprain. Karlsson ankle function score (K score) was considered as a subjective ankle function score, that was divided into various components. Each component and the single-limb stance test with center of pressure (COP) analysis was observed between the frequency of ankle sprains with one-way ANOVA and compared using Spearman's rank correlation coefficient to verify the relationship between the K score and COP. For COP parameters, no difference was observed in the history of ankle sprains. The K score was lower in participants with three previous ankle sprains than in those with a different number of ankle sprains for instability, stiffness, running, work activities, support, and total K score for all parameters. There were weak negative correlations (r = -0.19∼-0.35) between K score and COP parameters among participants with no history of ankle sprain or only once. In contrast, there were strong positive correlations (r = 0.69∼0.87) among history of ankle sprain at third. The single-limb stance might not accurately reflect an athlete's ankle instability and function on physical activity. Clinically, therapists should choose suitable evaluation tools depending on the athlete's activity level to check for chronic ankle instability.


Failure of melatonin to influence endogenous opioid effects on LH secretion in the anoestrous ewe.
In May mature seasonally anoestrous ewes were implanted with melatonin which advanced the onset of cycles by about 1 month. The LH response to an opioid antagonist, WIN-3, was determined 5, 15, 25 and 60 days after melatonin implantation, by intravenous administration of WIN-3 (12.5 mg/dose) 4 times at 15-min intervals during both the 1st and the 5th hour of an 8-h treatment period. There was no effect of WIN-3 at 5, 15 and 25 days after melatonin implantation. At 60 days LH concentration and pulse frequency were significantly increased (P less than 0.05 and less than 0.01 respectively) in response to WIN-3 treatment, but only in those animals which had begun reproductive cycles, an effect known to be mediated by the presence of progesterone. We were therefore unable to find evidence to support the hypothesis that the influence of melatonin in advancing the breeding season may be via an opioidergic pathway.


Kinetic-effect models and their applications.
This article focuses on mathematical models that analyze the time course of drug effects in humans. Any such model, whether parametric or nonparametric, is termed a kinetic-effect model (KEM). These models serve to describe (interpolation) and to predict (extrapolation) the effect-time profile. KEMs are applicable to many problems in pharmaceutics, pharmacology, and clinical pharmacology.


The prognostic value of peripheral blood parameters on all-frequency sudden sensorineural hearing loss.
To determine whether peripheral blood parameters have any predictive value for all-frequency Sudden Sensorineural Hearing Loss (SSNHL). We chose 78 individuals with all-frequency SSNHL who had been admitted to our department. They were divided into two groups: the effective group and the ineffective group. In patients with all-frequency SSNHL, the prognostic variables, including peripheral blood tests and clinical traits, were examined by a logistic regression analysis. In addition, the predictive value was carried out. The effective rate of all-frequency SSNHL was 61.5%. Pre-treatment hearing level and the proportion of patients with diabetes were both significantly lower in the effective group than in the ineffective group (p = 0.024 and 0.000, respectively). The levels of fibrinogen and C-reactive protein were also significantly different between the two groups (p = 0.001 and 0.025, respectively). Pre-treatment hearing level and fibrinogen level both significantly impacted the prognosis of all-frequency SSNHL (p = 0.032 and 0.002, respectively), according to a logistic regression analysis. Furthermore, the prognosis was significantly predicted by both fibrinogen level and pre-treatment hearing level (p = 0.001 and 0.0002, respectively). The receiver operating characteristic curve showed that the fibrinogen level had a sensitivity of 85.4% and a specificity of 60.0% for predicting the prognosis of all-frequency SSNHL. For the prognosis of all-frequency SSNHL, the fibrinogen level can be regarded as a useful predictor. The level of C-reactive protein, however, does not have a significant prognostic effect on predicting all-frequency SSNHL. Therefore, more attention should be devoted to the level of fibrinogen in the acute period of all-frequency SSNHL.


Endoscopy training in the UK pre-COVID-19 environment: a multidisciplinary survey of endoscopy training and the experience of reciprocal feedback.
Training in gastrointestinal endoscopy in the UK occurs predominantly in a real world one-to-one trainer to trainee interaction. Previous surveys have shown surgical and gastroenterology trainees have had mixed experiences of supervision and training, and no surveys have explored specifically the role of trainee to trainer feedback. This study aimed to explore the experience of training and of providing trainer feedback for all disciplines of endoscopy trainees. An online survey designed in collaboration with Joint Advisory Committee training committee and trainee representatives was distributed from January 2020 but was interrupted by the COVID-19 pandemic and hence terminated early. There were 129 responses, including trainees from all disciplines and regions, of which 86/129 (66.7%) rated the culture in their endoscopy units favourably-either good or excellent. 65/129 (50.4%) trainees reported having one or more training lists allocated per week, with 41/129 (31.8%) reporting only ad hoc lists. 100/129 (77.5%) respondents were given feedback and 97/129 (75.2%) were provided with learning points from the list. 65/129 (50.4%) respondents reported their trainer completed a direct observation of procedure or direct observation of polypectomies. 73/129 (56.6%) respondents reported that they felt able to give feedback to their trainer, with 88/129 (68.2%) feeling they could do this accurately. Barriers to trainer feedback cited included time constraints, lack of anonymity and concerns about affecting the trainer-trainee relationship. Overall, the training environment has improved since previous surveys. There are still issues around interdisciplinary differences with some surgical trainees finding the training environment less welcoming, and trainee perceptions of hierarchical barriers and trainer responsiveness to feedback limiting the accuracy of their feedback.


Collaborative evolution of regional green innovation system under the influence of high-speed rail based on Belousov-Zhabotinsky reaction.
As a green transportation mode and carrying factors with high knowledge-intensive characteristics, high-speed rail (HSR) has contributed to the improvement of regional green innovation. However, the relationship between HSR and regional green innovation is still limited. Based on the Belousov-Zhabotinsky (B-Z) reaction model, this study establishes a three-dimensional logistic dynamic evolution model for factor flow, knowledge spillover and green innovation performance. Through linear stability analysis, the threshold conditions for the evolution of the regional green innovation system under the influence of HSR are explored, and the impact of HSR policy on the regional green innovation system under four different initial states is examined. The results reveal four major points: (1) Factor flow is the order parameter and shows a significant collaborative relationship with green innovation performance. (2) The opening of HSR can effectively promote the evolution of the regional green innovation system, and the powerful stimulus of HSR contributes to shortening its evolutionary cycle. (3) The initial state of the regional green innovation system plays a crucial role in the green innovation performance. (4) In the process of collaborative evolution of regional green innovation system, factor flow and knowledge spillover serve as the premise and foundation, respectively, to jointly promote green innovation performance enhancement. Findings not only provide references for decision-makers to implement green innovation strategy and boost the green innovation performance, but also extend the theoretical system of HSR effect and collaborative evolution.


The cost-effectiveness of treating triple coinfection with HIV, tuberculosis and hepatitis C virus.
The objective of this study was to estimate the cost-effectiveness of treating patients infected with HIV and simultaneously coinfected with tuberculosis (TB) and hepatitis C virus (HCV). A mathematical model for HIV coinfection with TB and HCV is introduced. The model was designed to incorporate parameters of control for the coverage of care, which makes it useful for performing cost-effectiveness analysis of public policies. A cost-effectiveness analysis of early medical care of patients with TB and HCV coinfection, with coverage of 0 (basal), 25, 50, 75 and 100%, was performed for the whole cohort of patients and a special analysis was performed in a selected population with triple infection. The cost per resolved infection and the cost per year of life gained were found to be very cost-effective for the population with triple infection, for all different coverages. It is known that treating patients with HIV who are coinfected with TB or HCV implies high cost and low efficacy, but it is possible that the population with triple infections could achieve important benefits in terms of years of life gained.


The complexity of medicinal plants: the traditional Artemisia annua formulation, current status and future perspectives.
Artemisia annua has a long tradition of use for the treatment of intermittent fevers which we now relate to malarial infections. The active principle artemisinin has been isolated from Artemisia annua and today forms the backbone of the global fight against malaria. The traditionally prepared Artemisia annua formulation is however still being used on a global scale for the treatment of malaria, and it is claimed that its action is superior to the single purified drug. Artemisia annua is therefore on the forefront of the heated debate between the single drug-single target approach of western based medicine and the holistic approach of traditional medicinal systems. This review aims to highlight the complexities we face in the general study of medicinal plants at the hand of three levels of complexity. These levels consist of (a) the chemistry of the medicinal plant, (b) the influence of the preparation method on the chemistry of the final formulation and (c) the influence of metabolism on the chemistry of the formulation. We also aim to provide an up-to-date report on all scientific work that has been conducted and published in English on the traditional formulation of Artemisia annua. All English scientific literatures published until the first quarter of 2013 were retrieved from well-known scientific databases (Scifinder scholar, Web of Science, PubMed, Google scholar) and Non-governmental organisations active in this field were consulted. A draft version of this manuscript was sent to the African office of the World Health Organisation (WHO), and to the Non-governmental organisations "Action Médicine Naturelle" (ANAMED) and "Iwerliewen fir bedreete Volleker - Réseau belgo-luxembourgeois pour la valorisation des herbes médicinales" (IFBV-BELHERB) for comments. Very little scientific work has been conducted on the Artemisia annua formulation. The available literature contains many discrepancies which are unfortunately selectively being used by the two different sides in this debate to further their arguments. On one side of the argument we have the low content of artemisinin in Artemisia annua, the low bioavailability of artemisinin when the traditional formulation is administered and the high levels of recrudescence, which are being emphasised, while on the other side the possible role of synergism and prodrugs are being highlighted. This review reports that there are still too many gaps in our existing knowledge to provide conclusive evidence for either of the two sides of the argument. Much more research is needed into Artemisia annua formulations. We stand to gain invaluable knowledge into how traditional medicinal plant works, discover the identities of new active compounds (which can be used against other diseases such as HIV, diarrhoea, and cancer) and possibly bring both sides of this debate closer together.


Intake of antioxidants and subsequent decline in physical function in a racially/ethnically diverse population.
Oxidative stress is considered a risk factor for physical function (PF) decline with aging. The objective of this study was to examine the relationship between antioxidant intake and change in PF over a 5-year period. The Boston Area Community Health (BACH) Survey is a population-based longitudinal study including 5,502 racially/ethnically diverse and randomly selected participants aged 30-79 years. In total, 2828 persons aged 30-79 years completed the validated Block Food Frequency Questionnaire (FFQ) and participated in the follow-up study. Change in PF from baseline (2002-2005) to follow-up (2006-2010) was assessed using the validated SF-12 questionnaire. Linear models were used to examine the association between energy-adjusted quartiles of vitamins C, E and carotenoids and change in PF. A low intake (first quartile) of vitamin E was associated with a greater decline in PF compared with the highest quartile, with a mean difference in change in PF of -1.73 (95%CI:-3.31,-0.15). Notably, this mean difference was clinically meaningful as it was equivalent to the effect estimate we found for participants who were approximately 15 years apart in age in our cohort, as 1 year increase in age was associated with a mean difference in change in PF of -0.11 (95%CI:-0.16,-0.06). PF decline was not significantly different in the lowest compared with the highest quartile of vitamin C (mean difference=-1.29, 95%CI:-2.61, 0.03) or carotenoids (mean difference=-0.62, 95%CI:-2.22,0.99). Low intake of vitamin E was significantly associated with decline in PF with aging. These results are clinically meaningful, extend previous findings that oxidative stress contributes to PF decline, and may inform the development of future prevention strategies aimed at reducing this clinical and public health problem.


[Other forms of hyperthyroidism: indications and operative procedures (author's transl)].
Hyperthyroid hot nodules, toxic nodular goiter, and rarely thyroid cancer with thyrotoxicosis represent the majority of hyperthyroid cases in goiter areas. Even though these patients usually fall into higher age groups, surgery after thyrostatic premedication is usually the optimal form of therapy if there are no serious medical risks. While toxic adenomas possibly require only unilateral procedures, toxic nodular goiters should be bilaterally resected; thyroid cancer with thyrotoxicosis is treated as other forms of thyroid cancer.


Positive and negative early life experiences differentially modulate long term survival and amyloid protein levels in a mouse model of Alzheimer's disease.
Stress has been implicated as a risk factor for the severity and progression of sporadic Alzheimer's disease (AD). Early life experiences determine stress responsivity in later life, and modulate age-dependent cognitive decline. Therefore, we examined whether early life experiences influence AD outcome in a bigenic mouse model which progressively develops combined tau and amyloid pathology (biAT mice).Mice were subjected to either early life stress (ELS) or to 'positive' early handling (EH) postnatally (from day 2 to 9). In biAT mice, ELS significantly compromised long term survival, in contrast to EH which increased life expectancy. In 4 month old mice, ELS-reared biAT mice displayed increased hippocampal Aβ levels, while these levels were reduced in EH-reared biAT mice. No effects of ELS or EH were observed on the brain levels of APP, protein tau, or PSD-95. Dendritic morphology was moderately affected after ELS and EH in the amygdala and medial prefrontal cortex, while object recognition memory and open field performance were not affected. We conclude that despite the strong transgenic background, early life experiences significantly modulate the life expectancy of biAT mice. Parallel changes in hippocampal Aβ levels were evident, without affecting cognition of young adult biAT mice.


Dual-bioactive molecules loaded aligned core-shell microfibers for tendon tissue engineering.
Development of a controlled delivery ultrafine fibrous system with two bioactive molecules is required to stimulate tendon healing in different phase. In this study, we used emulsion stable jet electrospinning to fabricate aligned poly(L-lactic acid) (PLLA) based ultrafine fibers with two small bioactive molecules of L-Arginine (Arg) and low molecular weight hyaluronic acid (HA). The results demonstrated that the aligned Arg/HA/PLLA microfibrous scaffold showed core-shell structure and allowed sequential release of Arg and HA due to their different electric charge. The scaffold also showed enhanced hydrophilicity, cell migration, spread and proliferation. Using an Achilles tendon repair model in rats, we demonstrated that this novel fibrous scaffold can prevent adhesion and promote tendon regeneration. Additionally, two p53 and ER-α-mediated signalling pathways were described as the probable main path of synergistic effects of the novel scaffold on tendon generation. Thus, this study may provide an important strategy for developing biofunctional and biomimetic tendon scaffolds.


Analysis of EIF4G1 in ethnic Chinese.
Eukaryotic translation initiation factor 4-gamma 1 (EIF4G1) gene mutations have recently been reported in autosomal dominant, late-onset Parkinson's disease (LOPD). We carried out genetic analysis to determine the prevalence of EIF4G1 variants in an ethnic Chinese population and to better understand the association between EIF4G1 and PD. We conducted a comprehensive genetic analysis of EIF4G1 in a cohort of 29 probands of autosomal dominant, LOPD families. Polymerase chain reaction (PCR) analysis and sequencing was carried out of the entire EIF4G1 exonic regions and exon-intron boundaries. Specific mutation and exonic variants were chosen for further sequencing in a case-control study including 503 sporadic PD and 508 healthy controls. Statistical significance was analyzed by the Chi-square test. Our analysis revealed three exonic variants (rs2230571, rs13319149 and rs2178403) and eight intronic variants across the entire EIF4G1 gene. No reported mutations were detected in EIF4G1 exonic regions. The synonymous coding variant rs2230571 in exon 27 and the eight intronic variants were not used for further sequencing, but the specific mutation c.3614G > A (p.R1205H) and the two nonsynonymous variants (rs13319149 and rs2178403) were chosen for further analysis in a case-control study. None of the 503 sporadic PD or 508 healthy controls carried p.R1205H, and there was no statistical significance in rs2178403 genotype or allele frequencies in EIF4G1 between the PD cases and the healthy controls (p = 0.184 and p = 0.774, respectively; Chi-square test). The rs13319149 genotype in all PD cases and healthy controls was GG. Our data indicate that in an ethnic Chinese population, the pathogenic mutation p.R1205H in EIF4G1 is not common and that EIF4G1 exonic variants rs2178403 and rs13319149 are not associated with PD. EIF4G1 does not appear to be a frequent cause of PD in this ethnic Chinese population.


Beta- and pre-beta-lipoproteins in coronary disease and hyperlipoproteinaemia.
A very high percentage of male patients with proven coronary disease and/or raised lipid levels had a pre-beta-hyperlipoproteinaemia (class P [6] or Fredrickson [3] type IV) and relatively few had a beta-hyperlipoproteinaemia (class B or Fredrickson type IIA). Mixed hyperlipoproteinaemia was found in a large number of male patients but these again had predominantly raised triglyceride. More female patients over 40 years had beta-hyperlipoproteinaemia. Our retrospective study shows that raised triglyceride levels are more often found in patients with coronary disease than raised cholesterol levels.


Experiences of households using integrated malaria prevention in two rural communities in Wakiso district, Uganda: a qualitative study.
The integrated approach to malaria prevention which advocates use of several methods in a holistic manner is being explored to complement existing strategies. A pilot project that promoted integrated malaria prevention established 40 demonstration households using the approach. As part of impact evaluation of the project 2 years after implementation, the experiences of these households using integrated malaria prevention were assessed. A qualitative cross-sectional survey was carried out in Wakiso district, Uganda which involved 40 in-depth interviews among households implementing integrated malaria prevention. The study assessed practices on malaria prevention, benefits and challenges of using integrated malaria prevention, preference of malaria prevention methods, and impact of the demonstration households on the community. Thematic analysis was employed using Atlas ti software. The households continued to use many of the malaria prevention methods in the integrated approach including sleeping under long-lasting insecticidal nets, screening in windows and ventilators, removing mosquito breeding sites, and closing of doors early in the evenings. The major benefits reported from using integrated malaria prevention were reduction in mosquito populations in their houses and less occurrence of malaria particularly among children. Although several community members learnt about and admired various malaria prevention methods from the demonstration households especially screening in windows and ventilators, the majority could not afford to implement some of them due to lack of resources. The main challenge established in using integrated malaria prevention was the much time required to implement the several methods some of which had to be done regularly such as early closing of windows. In addition, complacency had led to some households not utilizing a number of methods in the integrated approach because of using others. Use of the integrated approach to malaria prevention benefited the demonstration households mainly through observed reduction in mosquitoes indoors and malaria occurrence hence could be promoted in other areas. Other studies to quantify the protective effect of integrated malaria prevention particularly regarding malaria prevalence and contribution of each of the methods are required.


Reliability Assessment and Validation of the Skin Hyperpigmentation Index Compared to the Physician Global Assessment Score.
The skin hyperpigmentation index (SHI), a new objective method for measuring skin hyperpigmentation, needs validation. To gain evidence of the reliability and validity of the SHI. Fifteen raters were divided into 3 groups (5 dermatologists, 5 nondermatologist physicians, and 5 nonphysician clinicians). Each rated 5 pigmented mole lesions with mild-to-severe hyperpigmentation to determine intra- and interrater reliability. All raters photographed the lesions and rated them using the subjective Physician Global Assessment (PGA) score. The same photographs were then assessed based on automatic computer measurement software using the online SHI tool (https://shi.skinimageanalysis.com). The SHI reliability was excellent for all intra- and interrater assessments, while most PGA assessments showed good intra- and interrater agreement. Between-group reliability was excellent for SHI, while moderate-to-good for PGA evaluations. Concordance between the SHI and PGA assessments was strong across all groups of assessors. There is evidence that the SHI is a reliable instrument for measuring skin hyperpigmentation, and can be used by nonexperienced clinicians.


Was there an improvement in the years of life lost (YLLs) for non-communicable diseases in the Soma and Minamisoma cities of Fukushima after the 2011 disaster? A longitudinal study.
This study aimed to determine cause-specific years of life lost (YLL) changes between predisaster and postdisaster in disaster-affected municipalities, compared with the national average. We estimated the YLL in Soma and Minamisoma cities (the subject area) in Fukushima, Japan, where the tsunami and the nuclear accident hit in 2011. We used vital registration records from a national survey conducted between January 2006 and December 2015. We analysed 6369 death data in the predisaster period (2006-2010) and 6258 death data in the postdisaster period (2011-2015). We incorporated vital statistics data as follows: age-based, sex-based and International Classification of Diseases, 10th Revision-based cause-specific deaths and calculated YLLs by ages 0, 40, 65 and 75 and sex for attributable causes of death for heart diseases, cerebrovascular diseases, pneumonia, all cancers and specific cancers; breast cancer, colorectal cancer, leukaemia, lung cancer, stomach cancer and uterine cancer for predisaster and postdisaster in the subject area. YLL attributed to heart diseases for males showed no decrease and YLL postdisaster was 0.37 years larger than that of the national average at age 0. The difference was -0.17 (95% uncertainty interval: -0.40 to 0.05) years at age 65. It decreased for females; the difference was 0.37 (0.18-0.57) years after the disaster. YLL decrease (that is, difference) in cerebrovascular diseases at age 0 was 0.27 (0.09-0.44) years and 0.18 (0.04-0.32) years; however, the YLLs postdisaster were still 0.24 and 0.25 years larger than those for the national average for males and females, respectively. YLL attributed to cancer did not increase even after the nuclear disaster. We specified the causes of death to be reduced in disaster-affected areas in the future. This study emphasised the importance of understanding how the health situation changed for the whole society of the area from a comprehensive perspective, rather than focusing only on small mortality increases.


Methods to study motile ciliated cell types in the zebrafish brain.
Cilia are well conserved hair-like structures that have diverse sensory and motile functions. In the brain, motile ciliated cells, known as ependymal cells, line the cerebrospinal fluid (CSF) filled ventricles, where their beating contribute to fluid movement. Ependymal cells have gathered increasing interest since they are associated with hydrocephalus, a neurological condition with ventricular enlargement. In this article, we highlight methods to identify and characterize motile ciliated ependymal lineage in the brain of zebrafish using histological staining and transgenic reporter lines.


Manual stimulation of the orbicularis oculi muscle improves eyelid closure after facial nerve injury in adult rats.
We have shown that manual stimulation of rat whisker-pad muscles following facial-facial-anastomosis (FFA) restores normal whisking by lowering the proportion of polyinnervated motor endplates. Here we examined whether manual stimulation of the orbicularis oculi muscle (OOM) after FFA would also improve outcome. Blink responses to standardized air puffs were analyzed using video-based motion analysis. Two months after FFA, blink capacity was impaired, as indicated by a largely increased minimum distance between the eyelids after air-puff stimulation compared with intact rats (2.7 +/- 0.4 vs. 0.2 +/- 0.01 mm). Manual stimulation reduced this deficit by a factor of two (1.3 +/- 0.5 mm). The functional improvement after manual stimulation was associated with a 2-fold decrease in the proportion of polyinnervated OOM endplates (21 +/- 10% vs. 42 +/- 10% without manual stimulation, 0% in intact rats). We conclude that manual stimulation is a noninvasive and simple procedure with immediate potential for clinical rehabilitation of eyelid closure following facial nerve injury.


[The use of ultrasonographic 3D power Doppler to describe an ovarian Sertoli-Leydig cell tumor].
We report one case of unilateral ovarian Sertoli-Leydig tumor with intermediate grade and heterologous element, in a young woman with clinical and biological typical presentation. We discuss 2D and 3D ultrasonographic and doppler features.


Infection control by antibody disruption of bacterial quorum sensing signaling.
Quorum sensing (QS) is the process through which bacteria communicate utilizing small diffusible molecules termed autoinducers. It has been demonstrated that QS controls a plethora of microbial processes including the expression of virulence factors. Here we report an immunopharmacotherapeutic approach for the attenuation of QS in the Gram-positive human pathogen Staphylococcus aureus. An anti-autoinducer monoclonal antibody, AP4-24H11, was elicited against a rationally designed hapten, and efficiently inhibited QS in vitro through the sequestration of the autoinducing peptide (AIP)-4 produced by S. aureus RN4850. Importantly, AP4-24H11 suppressed S. aureus pathogenicity in an abscess formation mouse model in vivo and provided complete protection against a lethal S. aureus challenge. These findings provide a strong foundation for further investigations of immunopharmacotherapy for the treatment of bacterial infections in which QS controls the expression of virulence factors.


Interactions of the human telomeric DNA with terbium-amino acid complexes.
The human telomeric DNA can form four-stranded structures: the G-rich strand adopts a G-quadruplex conformation stabilized by G-quartets and the C-rich strand may fold into an I-motif based on intercalated C.C(+) base pairs. There is intense interests in the design and synthesis of compounds which can target telomeric DNA and inhibit the telomerase activity. Here we report the thermodynamic studies of the two newly synthesized terbium-amino acid complexes bound to the human telomeric G-quadruplex and I-motif DNA which were studied by means of UV-Visible, DNA meltings, fluorescence and circular dichroism. These two complexes can bind to the human telomeric DNA and have shown different features on DNA stability, binding stoichiometry, and sequence-dependent fluorescence enhancement. To our knowledge, this is the first report to show terbium-amino acid complexes can interact with the human telomeric DNA.


Chronic inflammation in the myocardium of patients with clinically suspected dilated cardiomyopathy.
Dilated cardiomyopathy continues to be an etiologically unknown heart muscle disease. Recent clinical and experimental data have suggested a causal relation to viral myocarditis. The clinical diagnosis, however, is unspecific, and diagnostic yield of the histologic evaluation of endomyocardial biopsies by light microscopy according to the Dallas classification is poor. The authors analyzed the biopsy specimens of 120 patients with suspected dilated cardiomyopathy by immunohistologic methods to obtain a more sensitive and specific identification and quantification of infiltrating lymphocytes, indicating an activated immunologic process within the myocardium. Increased lymphocytic infiltrates and inflammatory endothelial activation were demonstrated in patients with clinically suspected dilated cardiomyopathy. These findings are associated with the often seen progression of ventricular dysfunction. Further studies are necessary to prove whether these immunohistologically positive patients will improve under immunosuppressive therapy.