Short-term effect of ovariectomy on measures of insulin sensitivity and response to dexamethasone administration in horses.
To evaluate the effect of ovariectomy on insulin sensitivity in horses and determine whether the effects of suppression of the hypothalamo-pituitary-adrenal axis differ before and after ovariectomy. 6 healthy mares. The horses underwent an IV glucose tolerance test (IVGTT), an insulin sensitivity test, and a dexamethasone suppression test before and 5 weeks after ovariectomy. Body weight, serum cortisol and plasma ACTH concentrations, serum insulin-to-blood glucose concentration ratios, and changes in blood glucose concentration with time after injection of glucose or insulin were compared before and after ovariectomy. The dexamethasone injection resulted in a decrease in serum cortisol concentration before and after ovariectomy. In all horses, baseline plasma ACTH concentrations were within the reference range before and after ovariectomy. For each mare, results of an IVGTT before and after ovariectomy were considered normal. No significant differences in basal blood glucose concentration or time to reach baseline glucose concentration after an IVGTT were observed. Basal serum insulin concentration and serum insulin-to-blood glucose concentration ratios were not significantly different before or after ovariectomy, nor was the mean time to attain a 50% decrease in blood glucose concentration after insulin injection. Results indicated that ovariectomy does not appear to modify dexamethasone response in horses and that it does not modify short-term measures of insulin sensitivity. Findings suggested that horses undergoing ovariectomy are not at higher risk of developing equine metabolic syndrome or hypothalamo-pituitary-adrenal axis dysfunction and associated morbidity.


Investigating transcriptional regulation by fluorescence spectroscopy, from traditional methods to state-of-the-art single-molecule approaches.
Gene expression regulation, in particular at the level of transcription, has been demonstrated to play a key role in the development of human diseases, including cancer, and in bacteria it is crucial for proliferation as well as for pathogenicity. Transcriptional regulation is based on complex networks of interactions, including those of the regulatory proteins with the operator DNAs, which are further modulated by ligands. Thus, understanding transcriptional regulation mechanisms requires a thorough analysis of the physical parameters underlying the interactions involved. Among the panoply of methods available, fluorescence spectroscopy-based approaches have been widely used for the assessment of the thermodynamics and structural dynamics of biomolecular interactions. Here we will discuss the application of three fluorescence spectroscopy methods--fluorescence anisotropy and fluorescence correlation and cross-correlation spectroscopy--for the investigation of protein-DNA, protein-protein, and protein-ligand interactions. The weaknesses and the strengths of each method will be highlighted on the basis of our experience in the analysis of the interactions of bacterial repressors implicated in transcriptional regulation in bacilli.


Naringenin ameliorates insulin resistance by modulating endoplasmic reticulum stress in hepatitis C virus-infected liver.
Hepatitis C virus (HCV) infection may lead to hepatic insulin resistance (IR), and endoplasmic reticulum (ER) stress has been found to induce IR. In our previous study, naringenin (NGEN) had an insulin sensitization effect on the HCV core protein (HCVCP) infected mouse livers. In the present study, we examined the effects of NGEN on HCVCP infection-induced ER stress and investigated the insulin sensitization mechanism involved. We found that XBP1s was up-regulated in the livers of HCV-infected patients, in hepatocytes with HCV infection, and in HCVCP-infected mice. HCVCP induces ER stress in the mouse liver and hepatocytes by increasing XBP1s and downstream gene expression. Pre-treatment with NGEN inhibited the ER stress and downstream gene expression both in vivo and in vitro. Similar to the HCVCP infection results, NGEN also inhibited the ER stress in tunicamycin-treated Huh-7.5.1 cells. In addition, the role of IRE1α in HCVCP-induced IR was detected, and knockdown of IRE1α abolished HCVCP-stimulated IR. Overexpression induced IR but could be abolished by NGEN. NGEN also blocked the HCVCP-induced IRE1α expression levels that were up-regulated in vivo. Our data reveal that ER stress may be associated with HCV-induced IR, and NGEN treatment inhibited ER stress activity and increased insulin sensitivity by decreasing the expression of IRE1α.


Increased circulating microparticles in streptozotocin-induced diabetes propagate inflammation contributing to microvascular dysfunction.
Circulating microparticles (MPs) are elevated in many cardiovascular diseases and have been considered as biomarkers of disease prognosis; however, current knowledge of MP functions has been mainly derived from in vitro studies and their precise impact on vascular inflammation and disease progression remains obscure. Using a diabetic rat model, we identified a >130-fold increase in MPs in plasma of diabetic rats compared to normal rats, the majority of which circulated as aggregates, expressing multiple cell markers and largely externalized phosphatidylserine; vascular images illustrate MP biogenesis and their manifestations in microvessels of diabetic rats. Using combined single microvessel perfusion and systemic cross-transfusion approaches, we delineated how diabetic MPs propagate inflammation in the vasculature and transform normal microvessels into an inflammatory phenotype observed in the microvessels of diabetic rats. Our observations derived from animal studies resembling conditions in diabetic patients, providing a mechanistic insight into MP-mediated pathogenesis of diabetes-associated multi-organ microvascular dysfunction. In various cardiovascular diseases, microparticles (MPs), the membrane-derived vesicles released during cell activation, are markedly increased in the circulation. These MPs have been recognized to play diverse roles in the regulation of cellular functions. However, current knowledge of MP function has been largely derived from in vitro studies. The precise impact of disease-induced MPs on vascular inflammation and disease progression remains obscure. In this study we investigated the biogenesis, profile and functional roles of circulating MPs using a streptozotocin-induced diabetic rat model with well-characterized microvascular functions. Our study revealed a >130-fold increase in MPs in the plasma of diabetic rats compared to normal rats. The majority of these MPs originate from platelets, leukocytes and endothelial cells (ECs), and circulate as aggregates. Diabetic MPs show greater externalized phosphatidylserine (PS) than normal MPs. When diabetic plasma or isolated diabetic MPs were perfused into normal microvessels or systemically transfused into normal rats, MPs immediately adhered to endothelium and subsequently mediated leukocyte adhesion. These microvessels then exhibited augmented permeability responses to inflammatory mediators, replicating the microvascular manifestations observed in diabetic rats. These effects were abrogated when MPs were removed from diabetic plasma or when diabetic MPs were pre-coated with a lipid-binding protein, annexin V, suggesting externalized PS to be key in mediating MP interactions with endothelium and leukocytes. Our study demonstrated that the elevated MPs in diabetic plasma are actively involved in the propagation of vascular inflammation through their adhesive surfaces, providing mechanistic insight into the pathogenesis of multi-organ vascular dysfunction that commonly occurs in diabetic patients.


Lethal poisoning with theophylline in the form of rectally administered tablets.
The paper discusses the case of death of a 56-year-old man who died in a municipal hospital from which his body was taken to the Chair and Department of Forensic Medicine, Jagiellonian University Medical College, Krakow. The man was said to have been found unconscious by accidental passers-by. While being transported to the hospital's emergency department, he suffered an attack of convulsions and went into cardiac arrest. He was subsequently successfully resuscitated. A physical examination performed at the hospital revealed the presence of multiple, only slightly dissolved tablets in the man's rectum. The patient died on the 25th day of hospitalization. A toxicological analysis showed a toxic concentration of theophylline (25 mg/l) in the man's blood. Theophylline was identified as the main ingredient of the tablets. The cause of death was thus given as theophylline poisoning. The reported case is unusual in that the poisoning occurred as a result of overdosing on an oral drug which was administered by the victim rectally, and in that the chosen substance currently is not very commonly used in medicine, and does not cause symptoms of intoxication.


[Cloning and functional analysis of the cotton Trihelix transcription factor GhGT29].
Trihelix transcription factors are important proteins involved in response to abiotic stresses in plants. Understanding the molecular mechanisms of Trihelix in cottons will lay the foundation to improve stress tolerance by gene engineering. In this study, a gene encoding Trihelix transcription factor was isolated in upland cottons using reverse transcription PCR according to bioinformatic analysis. The gene was named as GhGT29 (GenBank accession No. JQ013097), which was 1 092 bp, contained a 1 089 bp open reading frame and encoded a protein of 363 amino acids with a predicted molecular weight of 40.9 kDa and a isoelectric point of 5.45. SMART analysis showed GhGT29 contained one typical SANT motif. Phylogenetic analysis showed that GhGT29 belonged to the SH4 subfamily of the Trihelix family and was most closely related to AtSH4-like1 and AtSH4-like2. Quantitative real-time PCR (qRT-PCR) analysis revealed that GhGT29 was induced by high salt, drought, cold and abscisic acid. The expression profile also revealed that GhGT29 was constitutively expressed in all tested tissues, such as roots, stems, leaves, flowers, ovules (0 DPA) and fibers (12 DPA). The expression level of GhGT29 was the highest in flowers and the lowest in stems. Using the Arabidopsis protoplasts assay system, we found that the GhGT29 protein was located in cell nuclei and had trans-activation activity. These results revealed that GhGT29 might be involved in the regulation of stress resistance-related genes in stress signaling pathways in upland cottons.


Clinical features and neuropsychiatric comorbidities in pediatric patients with tic disorders: a retrospective chart review study from South Korea.
Tic disorders are childhood-onset neuropsychiatric disorders characterized by multiple motor or vocal tics with frequent comorbidities and a broad spectrum of phenotypic presentations. In this study, we aimed to investigate the clinical characteristics and comorbid neuropsychiatric conditions in pediatric patients with tic disorders. We retrospectively reviewed the medical records of 119 pediatric patients (89 males, 30 females) who were diagnosed with tic disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) at Uijeongbu St. Mary's Hospital, Republic of Korea, between January 2012 and July 2019. The mean age of tic onset was 6.9 years (range, 1-14) and the mean age at diagnosis was 8 years (range, 1-17). The mean lag between tic onset and diagnosis was 13.3 months (range, 0.25-132). The most common, first-presenting tics were eye blinking (50.4%), followed by jaw or lip movement (29.4%) and throat clearing (29.4%). Thirty-seven (31.1%) patients had at least one co-occurring neuropsychiatric disorder at the time of tic diagnosis. Subtypes of tic disorders, types of initial tics, and presence of neuropsychiatric comorbidities were not associated with tic severity. Tic severity was associated with greater functional impairment and tic noticeability (p < 0.05). A relatively shorter time to diagnosis was associated with tic severity (Spearman's ρ = - 0.14, p = 0.11). The evolving nature of tic expression and severity, high prevalence of neuropsychiatric comorbidities, and associated functional impairments emphasize the importance of comprehensive assessment during the disease course for determining and prioritizing goals of treatment.


Postinfarction ventricular aneurysm. Successful surgical treatment.
Over a two-year period, 18 patients with postinfarction ventricular aneurysms were treated surgically. There were no operative or early deaths, and only one (5.5%) late (20 months) death. The indications for surgery included angina, congestive heart failure, and serious arrhythmias. Electrocardiograms and plain chest roentgenograms were unreliable in making the diagnosis. All patients had cardiac catheterization and, at operation, a definite localized aneurysm was demonstrable. In 15 patients (83%), coronary artery bypass grafts were performed at the time the aneurysm was excised. Good results should be expected from surgical treatment of symptomatic ventricular aneurysms. Simultaneous bypass grafting should be performed when indicated.


Sickness absence in a municipal public service of Goiânia, Brazil.
Sickness absence, as work absenteeism justified by medical certificate, is an important health status indicator of the employees and, overall, sociodemographic and occupational characteristics are among the main factors associated with sickness absence. Public administration accounts for 21.8% of the formal job positions in Brazil. This population allows the study of a wide range of professional categories. To assess the profile and indicators of sickness absence among public workers from the municipality of Goiania, in the State of Goiás, Brazil. A cross-sectional study on certified sick leaves, lasting longer than three days, of all civil servants from January 2005 to December 2010. Prevalence rates were calculated using as main criteria the number of individuals, episodes and sick days. 40,578 certified sick leaves were granted for health treatment among 13,408 public workers, in an annual average population of 17,270 people, which resulted in 944,722 days of absenteeism. The cumulative prevalence of sick leave for the period was of 143.7%, with annual average of 39.2% and duration of 23 days per episode. The cumulative prevalence of sickness absence was higher among women (52.0%), older than 40 years old (55.9%), with a partner (49.9%), low schooling (54.4%), education professionals (54.7%), > 10 years of service (61.9%), and with multiple work contracts (53.7%). Diagnoses groups (ICD-10) with higher cumulative prevalence of sick leaves were those with mental disorders (26.5%), musculoskeletal diseases (25.1%), and injuries (23.6%). Indicators of sickness absence express the magnitude of this phenomenon in the public sector and can assist in planning health actions for the worker, prioritizing the most vulnerable occupational groups.


Psychodynamic theory and narcissistically related personality problems: support from case study research.
An introductory overview of central psychodynamic theories relevant to narcissistically related personality problems and disorders of the self is provided, focusing on the central role of the child's relationship with primary care givers in the development of the self. A psychodynamic formulation is described for a 45-year-old woman experiencing depression, anxiety and despair following a severe rift in her previously enmeshed/merged relationship with her teenage daughter. The subsequent two and a half years of therapy were monitored using the Brief Symptom Inventory (BSI), the Dysfunctional Attitudes Scale (DAS) and the Object Relations Technique (ORT), producing data supportive of psychodynamic theory and therapy. A pattern of depression emerged during therapy which was in keeping with the concept of abandonment depression, as the client came to experience herself as more separate from her daughter and others. Changes in the functioning of primitive defences were also illustrated, plus the expression of previously denied anger, and increased abilities to be assertive, set limits and take care of herself.


Meiotic pairing of B chromosomes, multiple sexual system, and Robertsonian fusion in the red brocket deer Mazama americana (Mammalia, Cervidae).
Deer species of the genus Mazama show significant inter- and intraspecific chromosomal variation due to the occurrence of rearrangements and B chromosomes. Given that carriers of aneuploidies and structural rearrangements often show anomalous chromosome pairings, we here performed a synaptonemal complex analysis to study chromosome pairing behavior in a red brocket deer (Mazama americana) individual that is heterozygous for a Robertsonian translocation, is a B chromosome carrier, and has a multiple sex chromosome system (XY₁Y₂). The synaptonemal complex in spermatocytes showed normal chromosome pairings for all chromosomes, including the autosomal and sex trivalents. The electromicrographs showed homology among B chromosomes since they formed bivalents, but they also appeared as univalents, indicating their anomalous behavior and non-Mendelian segregation. Thus, synaptonemal complex analysis is a useful tool to evaluate the role of B chromosomes and rearrangements during meiosis on the intraspecific chromosomal variation that is observed in the majority of Mazama species.


Patterns of DNA variability at X-linked loci in Mus domesticus.
Introns of four X-linked genes (Hprt, Plp, Glra2, and Amg) were sequenced to provide an estimate of nucleotide diversity at nuclear genes within the house mouse and to test the neutral prediction that the ratio of intraspecific polymorphism to interspecific divergence is the same for different loci. Hprt and Plp lie in a region of the X chromosome that experiences relatively low recombination rates, while Glra2 and Amg lie near the telomere of the X chromosome, a region that experiences higher recombination rates. A total of 6022 bases were sequenced in each of 10 Mus domesticus and one M. caroli. Average nucleotide diversity (pi) for introns within M. domesticus was quite low (pi = 0.078%). However, there was substantial variation in the level of heterozygosity among loci. The two telomeric loci, Glra2 and Amg, had higher ratios of polymorphism to divergence than the two loci experiencing lower recombination rates. These results are consistent with the hypothesis that heterozygosity is reduced in regions with lower rates of recombination, although sampling of additional genes is needed to establish whether there is a general correlation between heterozygosity and recombination rate as in Drosophila melanogaster.


Drug delivery via lipoprotein-based carriers: answering the challenges in systemic therapeutics.
Plasma lipoproteins are transporters of lipids and other hydrophobic molecules in the mammalian circulation. Lipoproteins also have a strong potential to serve as drug-delivery vehicles due to their small size, long residence time in the circulation and high-drug payload. Consequently, lipoproteins and synthetic/reconstituted lipoprotein preparations have been evaluated with increasing interest towards clinical applications, particularly for cancer diagnostics/imaging and chemotherapy. In this review, past and current studies on lipoproteins and similar alternative drug carriers are discussed regarding their suitability as agents to deliver drugs, primarily to cancer cells and tumors. A lipoprotein-based delivery strategy may also provide a novel platform for improving the therapeutic efficacy of drugs that have previously been judged unsuitable or had only limited application due to poor solubility. An additional, and perhaps the most important aspect of the drug-delivery process via lipoprotein-type carriers, is the receptor-mediated uptake of the payload from the lipoprotein complex. Monitoring the expression of specific receptors prior to treatment could, thus, give rise to efficient selection of optimally responsive patients, resulting in a successful personalized therapy regimen.


"She's on her own": a thematic analysis of clinicians' comments on abortion referral.
The objective was to understand the motivations around and practices of abortion referral among women's health providers. We analyzed the written comments from a survey of Nebraska physicians and advanced-practice clinicians in family medicine and obstetrics-gynecology about their referral practices and opinions for a woman seeking an abortion. We analyzed clinician's responses to open-ended questions on abortion referral thematically. Of the 496 completed surveys, 431 had comments available for analysis. We found four approaches to abortion referral: (a) facilitating a transfer of care, (b) providing the abortion clinic name or phone number, (c) no referral and (4) misleading referrals to clinicians or facilities that do not provide abortion care. Clinicians described many motivations for their manner of referral, including a fiduciary obligation to refer, empathy for the patient, respect for patient autonomy and the lack of need for referral. We found that abortion stigma impacts referral as clinicians explained that patients often desire additional privacy and clinicians themselves seek to avoid tension among their staff. Other clinicians would not provide an abortion referral, citing moral or religious objections or stating they did not know where to refer women seeking abortion. Some respondents would refer women to other providers for additional evaluation or counseling before an abortion, while others sought to dissuade the woman from obtaining an abortion. While practices and motivations varied, few clinicians facilitated referral for abortion beyond verbally naming a clinic if an abortion referral was made at all. Interprofessional leadership, enhanced clinician training and public policy that addresses conscientious refusal of abortion referral are needed to reduce abortion stigma and ensure that women can access safe care.


Comparison of different maximum safe levels in fortified foods and supplements using a probabilistic risk assessment approach.
Different European institutions have developed mathematical models to propose maximum safe levels either for fortified foods or for dietary supplements. The objective of the present study was to compare and check the safety of these different maximum safe levels (MSL) by using a probabilistic risk assessment approach. The potential maximum nutritional intakes were estimated by taking into account all sources of intakes (base diet, fortified foods and dietary supplements) and compared with the tolerable upper intake levels for vitamins and minerals. This approach simulated the consequences of both food fortification and supplementation in terms of food safety. Different scenarios were tested. They are the result of the combination of several MSL obtained using the previous models. The study was based on the second French Individual and National Study on Food Consumption performed in 2006-7, matched with the French food nutritional composition database. The analyses were based on a sample of 1918 adults aged 18-79 years. Some MSL in fortified foods and dietary supplements obtained independently were protective enough, although some others could lead to nutritional intakes above the tolerable upper intake levels. The simulation showed that it is crucial to consider the inter-individual variability of fortified food intakes when setting MSL for foods and supplements. The risk assessment approach developed here by integrating the MSL for fortified foods and dietary supplements is useful for ensuring consumer protection. It may be subsequently used to test any other MSL for vitamins and minerals proposed in the future.


Prognostic Indicators of Response to Plasmapheresis in Patients of Guillain Barre Syndrome.
Plasmapheresis is an important modality for the treatment of GBS. Moreover the response to this treatment modality is not same in all cases. We therefore studied the various prognostic indicators of response to plasmapheresis in patients of Guillain Barre Syndrome. 40 patients were included in the study. Thorough clinical examination was done. Nerve conduction was done to find out the type of neuropathy. All were then given plasmapheresis. Prognostic indicators with reference to Age, sex, presenting severity, time between onset of illness and arrival to hospital, time taken to start plasmapheresis, number of plasmapheresis cycles, respiratory involvement, and type of neuropathy were studied. There were 57.5% females and 47.5% males. Majority (82%) patients were in the age group of 20 to 60 years. All the patients had power grade 1 or 2 on admission but on discharge the power was grade 3 to 5 in 29 (80.55%) patients. The number of patients who received 5 cycles was 34(85%) and those who received 4 cycles of plasmapheresis was 6(15%). AIDP (acute inflammatory demyelinating polyneuropathy) was seen in 36 (90%) pts and AMAN (Acute Motor axonal Neuropathy) was seen in 4 (10%) patients. The severity at presentation and improvement was similar for all ages. Those who received plasmapheresis late showed power improvement of 2 to 3 grade in (50%) whereas those who received early showed improvement of 2 or 3 grade power in 82.14% patients indicating better improvement with early plasmapheresis. No difference was seen in grade of power improvement in 4 or 5 cycles of plasmapheresis. The number of patients on mechanical ventilation were 13 (40.62%) AIDP cases and 4 (100%) AMAN cases indicating more respiratory involvement in AMAN patients. All four patients of AMAN put on mechanical ventilation died of Ventilator associated pneumonia. Early treatment with plasmapheresis has better outcome in patients of GBS.four and five cycles of plasmapheresis are equally beneficial.


Endoscopic Versus Open Excision of Os Trigonum for the Treatment of Posterior Ankle Impingement Syndrome in an Athletic Population: A Randomized Controlled Study With 5-Year Follow-up.
Open surgical excision of the os trigonum has been the traditional treatment for posterior ankle impingement syndrome (PAIS). However, the endoscopic excision has recently become quite popular. Purpose/Hypothesis: The purpose of our study was to compare the results of endoscopic versus open excision of a symptomatic os trigonum for the treatment of PAIS in an athletic population. It was hypothesized that the endoscopic technique would be superior to the open technique regarding functional outcomes, pain, and time to return to training and the previous sports level. Randomized controlled trial; Level of evidence, 2. From 2008 to 2011, 52 athletes underwent a symptomatic os trigonum excision; 26 athletes had an open procedure (group A) and 26 had an endoscopic procedure (group B). The American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score and the Visual Analog Score-Foot and Ankle (VAS-FA) were obtained, and the time to return to training and to previous sports level was recorded. Patients in group B appeared to have significant improvement of AOFAS hindfoot score compared with those in group A ( P < .05), whereas no statistical significance was found for the postoperative VAS-FA scores between the 2 groups. The mean ± SD time to return to training was 9.58 ± 3.98 weeks for group A and 4.58 ± 1.47 weeks for group B ( P < .001). The time to return to previous sports level was 11.54 ± 3.89 weeks for group A and 7.12 ± 2.25 weeks for group B ( P < .001). The overall complication rate was 23% for group A (6 cases) and 3.8% for group B (1 case). Both the open procedure and the endoscopic approach yielded acceptable outcomes in terms of function and pain. However, complication rates were remarkably lower with endoscopic treatment, and the time to return to full activities was much shorter. Endoscopic excision of the os trigonum is a safe and effective treatment option for athletes who require early return to their previous sports level.


A comparison of US and Australian men's values and preferences for PSA screening.
Patient preferences derived from an assessment of values can help inform the design of screening programs, but how best to do so, and whether such preferences differ cross-nationally, has not been well-examined. The objective of this study was to compare the values and preferences of Australian and US men for PSA (prostate specific antigen) screening. We used an internet based survey of men aged 50-75 with no personal or family history of prostate cancer recruited from on-line panels of a survey research organization in the US and Australia. Participants viewed information on prostate cancer and prostate cancer screening with PSA testing then completed a values clarification task that included information on 4 key attributes: chance of 1) being diagnosed with prostate cancer, 2) dying from prostate cancer, 3) requiring a biopsy as a result of screening, and 4) developing impotence or incontinence as a result of screening. The outcome measures were self reported most important attribute, unlabelled screening test choice, and labelled screening intent, assessed on post-task questionnaires. We enrolled 911 participants (US:456; AU:455), mean age was 59.7; 88.0% were white; 36.4% had completed at least a Bachelors' degree; 42.0% reported a PSA test in the past 12 months. Australian men were more likely to be white and to have had recent screening. For both US and Australian men, the most important attribute was the chance of dying from prostate cancer. Unlabelled post-task preference for the PSA screening-like option was greater for Australian (39.1%) compared to US (26.3%) participants (adjusted OR 1.68 (1.28-2.22)). Labelled intent for screening was high for both countries: US:73.7%, AUS:78.0% (p = 0.308). There was high intent for PSA screening in both US and Australian men; fewer men in each country chose the PSA-like option on the unlabelled question. Australian men were somewhat more likely to prefer PSA screening. Men in both countries did not view the increased risk of diagnosis as a negative aspect, suggesting more work needs to be done on communicating the concept of overdiagnosis to men facing a PSA screening decision. This trial was registered at ClinicalTrials.gov (NCT01558583).


Central as well as Peripheral Attentional Bottlenecks in Dual-Task Performance Activate Lateral Prefrontal Cortices.
Human information processing suffers from severe limitations in parallel processing. In particular, when required to respond to two stimuli in rapid succession, processing bottlenecks may appear at central and peripheral stages of task processing. Importantly, it has been suggested that executive functions are needed to resolve the interference arising at such bottlenecks. The aims of the present study were to test whether central attentional limitations (i.e., bottleneck at the decisional response selection stage) as well as peripheral limitations (i.e., bottleneck at response initiation) both demand executive functions located in the lateral prefrontal cortex. For this, we re-analyzed two previous studies, in which a total of 33 participants performed a dual-task according to the paradigm of the psychological refractory period (PRP) during functional magnetic resonance imaging (fMRI). In one study (N = 17), the PRP task consisted of two two-choice response tasks known to suffer from a central bottleneck (CB group). In the other study (N = 16), the PRP task consisted of two simple-response tasks known to suffer from a peripheral bottleneck (PB group). Both groups showed considerable dual-task costs in form of slowing of the second response in the dual-task (PRP effect). Imaging results are based on the subtraction of both single-tasks from the dual-task within each group. In the CB group, the bilateral middle frontal gyri and inferior frontal gyri were activated. Higher activation in these areas was associated with lower dual-task costs. In the PB group, the right middle frontal and inferior frontal gyrus (IFG) were activated. Here, higher activation was associated with higher dual-task costs. In conclusion we suggest that central and peripheral bottlenecks both demand executive functions located in lateral prefrontal cortices (LPFC). Differences between the CB and PB groups with respect to the exact prefrontal areas activated and the correlational patterns suggest that the executive functions resolving interference at least partially differ between the groups.


Surgical treatment of juvenile rheumatoid arthritis.
Juvenile rheumatoid arthritis is rare and only affects a small number of children but can lead to severe crippling of adolescents or adults unless they are treated early. In this review the problems encountered in the surgical treatment, particularly those caused by skeletal stunting are discussed. The results of synovectomy of the knee and elbow are valuable procedures in suitably selected patients. Stapling of the knee in young children with genu valgum gave good correction in the majority. Soft tissue operation on the hip and knee in young children with severe deformities have given encouraging results. Complications and the results of reconstructive surgery for the hip and knee are discussed, and it was found that total joint replacement in these young patients with badly damaged hips is fully justified before they become chairbound.


Approaching the free rotor limit: extremely low methyl torsional barrier observed in the microwave spectrum of 2,4-dimethylfluorobenzene.
The microwave spectrum of 2,4-dimethylfluorobenzene was recorded using a molecular jet Fourier transform microwave spectrometer in the frequency range from 2.0 to 26.5 GHz. The spectral assignment and modeling were challenging due to the large tunnelling splittings resulting from the very low barrier to internal rotation of the p-methyl group that approaches the free rotor limit. Internal rotation splittings arising from two inequivalent o- and p-methyl groups were observed, analysed and modelled using the modified version of the XIAM code and the BELGI-Cs-2Tops code, giving a root-mean-square deviation of 549.1 kHz and 4.5 kHz, respectively, for a data set of 885 rotational lines. The torsional barriers of the o- and p-methyl groups were determined to be 227.039(51) cm-1 and 3.23(40) cm-1, respectively. The V3 barrier observed for the p-methyl group is lower than in any other para-methyl substituted toluene derivatives with coupled internal rotations, becoming the lowest value ever observed to date. The barrier to internal rotation of the o-methyl group next to a fluorine atom is consistently around 220 cm-1, as confirmed by comparing it to barriers observed in other toluene derivatives. The experimental rotational constants were compared to those obtained by quantum chemical calculations.


Behavioral and brain measures (N400) of semantic priming in patients with schizophrenia: test-retest effect in a longitudinal study.
The purpose of this study was to investigate whether deficits in the behavioral and/or N400 semantic priming (SP) effect observed in patients with schizophrenia constitute a stable cognitive feature of the disorder or whether they may be influenced by the severity of each individual's symptomatology. A 1-year test-retest study was conducted on 15 patients with schizophrenia and 10 healthy participants who performed an SP task. Both behavioral measures and event-related potentials measures of SP were recorded twice (test and retest sessions). At test, patients exhibited a deficit in SP as was revealed by both the behavioral and the event-related potentials measures of the amplitude of the N400 component. At retest, behavioral SP remained impaired, whereas N400 SP was significantly improved. These results provide evidence that SP impairments in schizophrenia as measured by N400 should not be considered as stable cognitive markers of the disorder. The behavioral and the N400 measures of SP indicated different levels of sensitivity to subtle cognitive and brain processes, which are subject to change over the clinical course of schizophrenic disorder.


Antipsychotic drug side effects: their relationship to dose.
The risk of adverse side effects of neuroleptic agents must be considered carefully in the treatment of acute and long-term psychotic states. Consequences should be assessed by analysis of dose-response relationships, risk factors, and central nervous system (especially extrapyramidal) side effects, as well as the influence of neuroleptics on neurotransmitter systems. Appropriate minimum dosages of neuroleptics must be further evaluated as an effective measure in reducing these side effects.


Advances of peripheral nerve repair techniques to improve hand function: a systematic review of literature.
Concepts of neuronal damage and repair date back to ancient times. The research in this topic has been growing ever since and numerous nerve repair techniques have evolved throughout the years. Due to our greater understanding of nerve injuries and repair we now distinguish between central and peripheral nervous system. In this review, we have chosen to concentrate on peripheral nerve injuries and in particular those involving the hand. There are no reviews bringing together and summarizing the latest research evidence concerning the most up-to-date techniques used to improve hand function. Therefore, by identifying and evaluating all the published literature in this field, we have summarized all the available information about the advances in peripheral nerve techniques used to improve hand function. The most important ones are the use of resorbable poly[(R)-3-hydroxybutyrate] (PHB), epineural end-to-end suturing, graft repair, nerve transfer, side to side neurorrhaphy and end to side neurorrhaphy between median, radial and ulnar nerves, nerve transplant, nerve repair, external neurolysis and epineural sutures, adjacent neurotization without nerve suturing, Agee endoscopic operation, tourniquet induced anesthesia, toe transfer and meticulous intrinsic repair, free auto nerve grafting, use of distal based neurocutaneous flaps and tubulization. At the same time we found that the patient's age, tension of repair, time of repair, level of injury and scar formation following surgery affect the prognosis. Despite the thorough findings of this systematic review we suggest that further research in this field is needed.


[Interaction of succinate dehydrogenase with succinate and oxaloacetate during enzyme activation-deactivation].
The interaction of succinate dehydrogenase from the bovine adrenal cortex with succinate and oxaloacetate was studied in the process of its activation-deactivation. It is supposed that an intermediate unstable complex of succinate dehydrogenase with oxaloacetate plays an important role in the changed enzymic activity.


Phylogenetic weighting does little to improve the accuracy of evolutionary coupling analyses.
Homologous sequence alignments contain important information about the constraints that shape protein family evolution. Correlated changes between different residues, for instance, can be highly predictive of physical contacts within three-dimensional structures. Detecting such co-evolutionary signals via direct coupling analysis is particularly challenging given the shared phylogenetic history and uneven sampling of different lineages from which protein sequences are derived. Current best practices for mitigating such effects include sequence-identity-based weighting of input sequences and post-hoc re-scaling of evolutionary coupling scores. However, numerous weighting schemes have been previously developed for other applications, and it is unknown whether any of these schemes may better account for phylogenetic artifacts in evolutionary coupling analyses. Here, we show across a dataset of 150 diverse protein families that the current best practices out-perform several alternative sequence- and tree-based weighting methods. Nevertheless, we find that sequence weighting in general provides only a minor benefit relative to post-hoc transformations that re-scale the derived evolutionary couplings. While our findings do not rule out the possibility that an as-yet-untested weighting method may show improved results, the similar predictive accuracies that we observe across distinct weighting methods suggests that there may be little room for further improvement on top of existing strategies.


Analysis of NTSB Aircraft-Assisted Pilot Suicides: 1982-2014.
On March 24, 2015, a Germanwings aircraft crashed in the Alps. The suicidal copilot killed himself and 150 others. Pilot suicide is rare, but does happen. This research analyzed the National Transportation Safety Board's accident database (eADMS) looking for pilots who died by suicide in flight. Fifty-one suicides were identified. Gender, age, and other characteristics were examined. Average age of suicidal pilots was 38, significantly different from the average age of 45 for all male pilots involved in aircraft accidents. A discriminant function accurately identified suicidal incidents at 96%. There was a high false-positive rate limiting the usefulness of the discriminant function.


Cost of gastro-oesophageal reflux disease to the employer: a perspective from the United States.
Employers pay more than just salary for their employees. Previous studies have largely focused on direct medical and prescription drug costs of gastro-oesophageal reflux disease (GERD), and few have reported on total absenteeism costs. To examine the annual cost of illness of GERD in an employed US population by benefit category and by place of service for direct medical costs. Retrospective data analysis from 2001 to 2004. International Classification of Diseases (ICD)-9 codes (530.1, 530.10, 530.11, 530.12, 530.19, 530.81, 787.1x, 787.2x or 251.5x) were used to identify employees with and without GERD (the control group). Measures included medical and prescription drug claims, plus indirect costs for sick leave, short- and long-term disability, and workers' compensation. For a subset of the population, the direct medical claims were analysed by place of service. Data were available for 267,269 eligible employees of which 11,653 had gastro-oesophageal reflux disease. GERD was associated with a mean incremental cost of US $3,355 per employee of which direct medical costs accounted for 65%, prescription drug costs 17%, and indirect costs 19%. The place of service 'out-patient hospital or clinic' accounted for the largest part (47%) of the difference in medical costs. GERD is associated with substantial direct and indirect costs, which highlight the importance of managing the disease effectively.


Heme oxygenase-1 in SJL mice with experimental allergic encephalomyelitis.
The expression of heme oxygenase-1 (HO-1) is increased in the CNS of mice and rats with experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). To investigate the role of HO-1 in EAE, a putative inhibitor [tin-protoporphyrin IX (Sn-PP IX)] of HO-1 was administered to SJL mice during active disease. Sn-PP IX (200 micromol/kg) attenuated clinical scores, weight loss, and some signs of pathology in comparison to vehicle treatment. Glutathione levels were greater in treated EAE mice than in those receiving vehicle, indicating lower oxidative stress in the former group. These data suggest that inhibition of HO-1 attenuated disease and suppressed free radical production. In the SJL model of EAE, extravasated blood is present in the CNS, and iron released by HO-1 from this heme source may not be adequately sequestered by ferritin, allowing for iron-mediated tissue damage. Thus, HO-1 may act to amplify the disease process in this model.


Carrot Juice Intake Affects the Cytokine and Chemokine Response in Human Blood after Ex Vivo Lipopolysaccharide-Induced Inflammation.
In vitro and animal studies have shown that carrot juice containing bioactive natural products, such as falcarinol (FaOH) and falcarindiol (FaDOH), can affect inflammation. The present study was designed to test whether oral intake of carrot juice containing the bioactive acetylenic oxylipins FaOH and FaDOH affects mediators of acute inflammation or the innate immune response in human blood. Carrot juice (500 mL) was administered orally to healthy volunteers, and blood samples were drawn before and 1 h after juice intake. Next, the blood samples were split in two, and one sample was stimulated ex vivo with lipopolysaccharide (LPS) and incubated at 37 °C for 24 h. The concentrations of 44 inflammatory cytokines and chemokines were examined using multiplex electrochemiluminescence analysis. In blood samples not stimulated with LPS, a significant increase in IL-15 was measured 1 h after carrot juice intake. Cytokines like IFN-ɣ, IL-12/IL-23(p40), IL-23, IL-17A, IL-17B, IL-17D, and IL-22 were significantly increased in LPS-stimulated blood samples after carrot juice intake. The upregulation of the immunostimulating cytokines belonging to the IL-23/IL-17 Th17 axis suggests that carrot juice intake could benefit diseases where inflammation plays a role, like in the early stages of diabetes or cancers.


Phosphorylation of eIF2α Promotes Schwann Cell Differentiation and Myelination in CMT1B Mice with Activated UPR.
Myelin Protein Zero (MPZ/P0) is the most abundant glycoprotein of peripheral nerve myelin. P0 is synthesized by myelinating Schwann cells, processed in the endoplasmic reticulum (ER) and delivered to myelin via the secretory pathway. The mutant P0S63del (deletion of serine 63 in the extracellular domain of P0), that causes Charcot-Marie-Tooth type 1B (CMT1B) neuropathy in humans and a similar demyelinating neuropathy in transgenic mice, is instead retained the ER where it activates an unfolded protein response. Under ER-stress conditions, protein kinase R-like endoplasmic reticulum kinase (PERK) phosphorylates eukaryotic initiation factor 2α (eIF2α) to attenuate global translation, thus reducing the misfolded protein overload in the ER. Genetic and pharmacological inactivation of Gadd34 (damage-inducible protein 34), a subunit of the PP1 phosphatase complex that promotes the dephosphorylation of eIF2α, prolonged eIF2α phosphorylation and improved motor, neurophysiological, and morphologic deficits in S63del mice. However, PERK ablation in S63del Schwann cells ameliorated, rather than worsened, S63del neuropathy despite reduced levels of phosphorylated eIF2α. These contradictory findings prompted us to genetically explore the role of eIF2α phosphorylation in P0S63del-CMT1B neuropathy through the generation of mice in which eIF2α cannot be phosphorylated specifically in Schwann cells. Morphologic and electrophysiological analysis of male and female S63del mice showed a worsening of the neuropathy in the absence of eIF2α phosphorylation. However, we did not detect significant changes in ER stress levels, but rather a dramatic increase of the MEK/ERK/c-Jun pathway accompanied by a reduction in expression of myelin genes and a delay in Schwann cell differentiation. Our results support the hypothesis that eIF2α phosphorylation is protective in CMT1B and unveil a possible cross talk between eIF2α and the MEK/ERK pathway in neuropathic nerves.SIGNIFICANCE STATEMENT In the P0S63del (deletion of serine 63 in the extracellular domain of P0) mouse model of Charcot-Marie-Tooth type 1B (CMT1B), the genetic and pharmacological inhibition of Gadd34 (damage-inducible protein 34) prolonged eukaryotic initiation factor 2α (eIF2α) phosphorylation, leading to a proteostatic rebalance that significantly ameliorated the neuropathy. Yet, ablation of protein kinase R-like endoplasmic reticulum kinase (PERK) also ameliorated the S63del neuropathy, despite reduced levels of eIF2α phosphorylation (P-eIF2α). In this study, we provide genetic evidence that eIF2α phosphorylation has a protective role in CMT1B Schwann cells by limiting ERK/c-Jun hyperactivation. Our data support the targeting of the P-eIF2α/Gadd34 complex as a therapeutic avenue in CMT1B and also suggest that PERK may hamper myelination via mechanisms outside its role in the unfolded protein response.


[Neuropsychology in epilepsy].
Neuropsychological assessment has become an essential tool for the diagnosis and outcome control in the clinical management of epilepsy. However, only a few attempts have been made to formulate explicit guidelines about which cognitive domains should be addressed in epilepsy patients and which of the various coexisting neuropsychological tests would provide an appropriate and evidence-based assessment. The present survey among 14 epilepsy centres in German-speaking countries indicates that there is at least some consensus concerning the cognitive domains which need to be addressed. However, concerning test selection a large diversity of more than 200 applied psychometric tests among the different epilepsy centres becomes evident. Evidence-based test selection was only seen in 25 % of the applied instruments. One-third of the tests are conducted because of pragmatic reasons or due to subjective preferences, whereas for the majority of tests no justification is provided. Taking into consideration the bulk of publications on cognition and epilepsy, it is time to establish an evidence-based core test battery for the use in epilepsy patients. Therefore a closer communication between centres is needed to come to an agreement and to accumulate experience with already established and newly developed tests in order to promote evidence-based neuropsychology in the field of epilepsy.


Extended sacropelvic resection for locally recurrent rectal cancer: can it be done safely and with good oncologic outcomes?
A multimodality approach to patients with locally recurrent rectal cancer that includes surgery is associated with a significant survival advantage when tumor-free margins are achieved. Patients with advanced tumors will require extended sacropelvic resection to optimize oncologic outcomes. The aim of this study was to assess the safety, feasibility, and oncologic outcomes of extended sacropelvic resection for locally recurrent rectal cancer at our institution. A retrospective review identified 406 patients who had surgery for locally recurrent rectal cancer between 1997 and 2007. From this group, all patients who underwent a curative-intent sacropelvic resection were analyzed. This investigation was conducted at an academic tertiary referral center. Thirty patients (24 male) were identified. Median age was 59 years (range, 25-84). Operations were performed for a first local recurrence (n = 24), a second recurrence (n = 5) and for a third recurrence (n = 1). Twenty-six patients underwent neoadjuvant radiation, and 20 received intraoperative radiation therapy. All patients underwent extended sacropelvic resection. The primary outcomes measured were early (<30 days) and late (>30 days) surgical complications. Overall and disease-free survivals were estimated by using the Kaplan-Meier technique. Margin-negative resection was achieved in 93%. The most proximal level of spinal transection was the fourth lumbar space, and 4 patients underwent lower extremity amputation. There was no mortality, and early morbidity was seen in 76%. Median follow-up was 2.7 years (range, 2 months to 10.8 years). Overall survival at 2 and 5 years was 86% and 46%. Disease-free survival at 2 and 5 years was 79% and 43%. This study was limited by its retrospective nature and the limited number of patients. We found extended sacropelvic resection for locally recurrent rectal cancer to be feasible and safe with overall and disease-free survival rates in comparison with survival rates seen in patients undergoing nonsacropelvic resections for locally recurrent rectal cancer.


Incidence and severity of short-term complications after breast augmentation: results from a nationwide breast implant registry.
The frequency and severity of local complications remain the primary safety issues with silicone breast implants. The Danish Registry for Plastic Surgery of the Breast (DPB), established in 1999, prospectively collects pre-, peri- and postoperative information regarding Danish women undergoing breast augmentation. Through DPB, we conducted a prospective follow-up study of short-term local complications among 1090 women who underwent cosmetic breast implantation from June 1999 through October 2002. Nineteen percent of women who underwent initial implantation developed at least 1 adverse effect. Forty percent of the adverse effects occurred within 3 months of implantation; 79%, within 6 months. Capsular contracture grade II-IV was observed among 4.1% of women in the 2-year follow-up period. Overall, 97 (29%) of the 344 adverse effects among 55 (6%) of the 971 women required surgical intervention. A higher incidence of adverse effects typically occurred after subsequent implantations. According to the DPB experience, we conclude that most short-term postoperative adverse effects following cosmetic implantation are clinically insignificant and do not require treatment and that short-term complications requiring adjuvant treatment are rare.


Detection of a novel type of RET rearrangement (PTC5) in thyroid carcinomas after Chernobyl and analysis of the involved RET-fused gene RFG5.
A novel type of RET rearrangement, PTC5, was detected in papillary thyroid carcinomas of two patients exposed to radioactive fallout after Chernobyl. Reverse transcription-PCR and rapid amplification of 5'-cDNA ends revealed a fusion of the ret tyrosine kinase (TK) domain with a sequence identical to that described previously as ret-II. Ret-II is a transfection artifact in NIH3T3 cells and has not yet been detected in any human tumor. Overlapping sequences found in the expressed sequence tag databases enabled us to sequence the COOH terminus of the ret-fused gene 5 (RFG5). The combined data made it possible to assemble a full-length rfg5 protein sequence. Computer-assisted analysis of this sequence reveals four putative coiled-coil structures, possibly involved in dimerization, but no membrane-binding sequences. Northern blots show a ubiquitous RFG5 expression in various normal tissues, including the thyroid gland. In addition to the RFG5/RET, we also detected the reciprocal RET/RFG5 transcript in both tumor samples, suggesting that the rearrangement is based on a balanced reciprocal translocation. In agreement with other rearranged TKs, it is concluded that the transforming action of the new fusion protein rfg5/ret in thyroid tumors may be due to an activation of the ret TK by constitutive expression and dimerization potential of the 5'-fused rfg5 protein. Ret immunohistochemistry indicates that the fusion protein is expressed in all cells of PTC5 tumors, suggesting that RFG5/RET rearrangement is an early event in thyroid carcinogenesis.


Oligospecificity of the cellular adhesion receptor Mac-1 encompasses an inducible recognition specificity for fibrinogen.
Mitogenesis, cellular aggregation, and motility follow upon the interaction of fibrinogen with certain defined cell surface receptors. In addition to circulating platelets and vascular endothelium, monocytes express what appears to be a receptor for fibrinogen. Evidence is presented here that the leukocyte adhesion receptor Mac-1 can be specifically induced to bind fibrinogen with characteristics immunochemically and functionally distinct from the established Arg-Gly-Asp-directed fibrinogen receptors. The competence of Mac-1 as a fibrinogen receptor is a general property of cells of monocyte and myeloid lineage acquired after maturational changes of some regions of the alpha subunit of Mac-1 during the process of cell differentiation. This ligand recognition specificity of Mac-1 is lacking for the resting cell. Rather, induction of fibrinogen binding capacity of Mac-1 is due to a cellular response to selected agonists characterized by inducing rapid transients of cytosolic Ca2+. Although different in activation pathways and recognition specificity, Mac-1 exhibits an oligospecific ligand versatility characteristic of other homologous Arg-Gly-Asp-directed adhesion receptors.


Yogurt Prevents Colitis-Associated Colorectal Cancer in Mice.
Epidemiological studies indicate an inverse correlation between yogurt consumption and colorectal cancer (CRC), but whether there is a cause-and-effect relationship has not yet been validated. This study aims to investigate the effects and possible mechanisms of yogurt on colitis-associated colorectal cancer (CAC) in mice. Experimental CAC is induced by azoxymethane (AOM, 10 mg kg-1 , ip) followed by three cycles of dextran sulfate sodium (DSS, 3%) treatment. Colitis is induced by adding DSS (3%) in drinking water for 5 days. Primary mouse macrophages are isolated for mechanistic studies. Data clearly show that yogurt (15 g kg-1 body weight) significantly reduces the multiplicity of colonic neoplasms by 38.83% in mice. Yogurt protects mice from colitis dependent on lactate receptor GPR81. The deficiency of Gpr81 exacerbates colitis and CAC in mice. Further investigation reveals that GPR81 may be dispensable for gut barrier function but essential for colonic mucosal repair. d-lactate in yogurt can activate GPR81 to suppress proinflammatory macrophage polarization, thereby facilitating inflammatory resolution after colonic injury and consequently suppressing CAC progression. Yogurt effectively protects against colitis-associated colorectal tumorigenesis in mice, and this study provides a rationale for introducing yogurt supplementation to patients with chronic inflammatory bowel diseases.


Looking ahead: the SSAT strategic plan for the next decade.
The Society for Surgery of the Alimentary Tract's (SSAT) mission is to advance the science and practice of surgery in the treatment of digestive disease. An essential core value of the SSAT is multidisciplinary collaboration with both its sister societies in the Digestive Disease Week (DDW) Council and other surgical societies in Gastrointestinal Surgery. In order to achieve the society's goals, the strategic plan rests on the society's values of interdisciplinary collaboration, scholarship, education, and discovery. The strategic plan also creates a meritocracy system to foster the development of future leaders for both the SSAT and the broader house of surgery. In the short term, this plan will: Re-organize committee structure and reporting responsibilities; Clarify committee goals and deliverables; Facilitate member participation in the committees and governance of the society; Enhance member services by utilizing enhanced communication strategies; Accelerate efforts to meet the Maintenance of Certification needs of the membership; Re-focus the SSAT's energy on Quality and Outcome Assessment of GI surgery; Clarify and standardize the methodology for allocating funds for new projects. Over the course of the next few years, the SSAT will: Develop a financial model that increases revenue to support the expanded tasks the society intends to undertake; Play an active role in developing the evolving training paradigms for gastrointestinal surgeons through the continuum from residency, fellowship, and early mentored practice; Continue to support development of surgeon scientists through Career Development Award; Enhance relationship with the SSAT Foundation; Continue to improve the experience of members attending DDW; Develop surgeons interested in public policy to be leaders at a national level. The strategic plan is ambitious, and the current leadership realizes that all the tasks and objectives cannot be accomplished in 1 year. There is much to do in order to keep the SSAT the premier professional society for gastrointestinal surgery. Changes in the external environment may require modifications of the priorities or the plan itself in the coming years. Implicit in this plan is the need for annual review by the Board of Trustees at the May Board Meeting so that modifications can be made as the world around us changes.


Fluorescence-guided resection of intradural spinal tumors: a systematic review and meta-analysis.
Intradural spinal tumors present significant challenges due to involvement of critical motor and sensory tracts. Achieving maximal resection while preserving functional tissue is therefore crucial. Fluorescence-guided surgery aims to improve resection accuracy and is well studied for brain tumors, but its efficacy has not been fully assessed for spinal tumors. This meta-analysis aims to delineate the efficacy of fluorescence guidance in intradural spinal tumor resection. The authors performed a systematic review in four databases. We included studies that have utilized fluorescence agents, 5-aminolevulinic acid (5-ALA) or sodium fluorescein, for the resection of intradural spinal tumors. A meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 12 studies involving 552 patients undergoing fluorescence-guided intradural spinal tumor resection were included. Meningiomas demonstrated a 98% fluorescence rate and were associated with a homogenous florescence pattern; however, astrocytomas had variable fluorescence rate with pooled proportion of 70%. There was no significant difference in gross total resection (GTR) rates between fluorescein and 5-ALA (94% vs 84%, p = .22). Pre-operative contrast enhancement was significantly associated with intraoperative fluorescence with fluorescein. Intramedullary tumors with positive intraoperative fluorescence were significantly associated with higher GTR rates (96% vs 73%, p = .03). Utilizing fluorescence guidance during intradural spinal tumor resection holds promise of improving intraoperative visualization for specific intradural spinal tumors. Meningiomas and ependymomas have the highest fluorescence rates especially with sodium fluorescein; on the other hand, astrocytomas have variable fluorescence rates with no superiority of either agent. Positive fluorescence of intramedullary tumors is associated with a higher degree of resection.


The impact of the number of lifetime stone events on quality of life: results from the North American Stone Quality of Life Consortium.
To evaluate the impact of chronic stone recurrence on an individual's quality of life using the validated Wisconsin Stone Quality of Life (WISQOL) questionnaire. We collected cross-sectional data on patients with kidney stones from 14 institutions in North America. A stone event was defined as renal colic, stone-related procedure or emergency department visit. The regression analyses using general linear models and pairwise comparison determined the impact of the number of stone events on quality of life. The median number of stone events among the 2205 patients who completed the questionnaire was 3 (IQR 1-6). The mean total score was 107.4 ± 28.7 (max 140 points). The number of lifetime stone events was an independent predictor of lower quality of life (p < 0.001), specifically, score declined significantly beyond five events. Compared with patients who experienced a single stone event, there was a 0.4, 2.5, and 6.9 point decline in the adjusted mean WISQOL score after 2-5, 6-10, or > 10 events, respectively. The cumulative number of lifetime stone events was associated with a lower quality of life when more than five stone events were occurred. These findings underscore the importance of efforts to determine the underlying metabolic etiology of urolithiasis in the recurrent stone former, and the institution of a regimen to place their stone disease in remission.


Pure and Hybrid SCAN, rSCAN, and r2SCAN: Which One Is Preferred in KS- and HF-DFT Calculations, and How Does D4 Dispersion Correction Affect This Ranking?
Using the large and chemically diverse GMTKN55 dataset, we have tested the performance of pure and hybrid KS-DFT and HF-DFT functionals constructed from three variants of the SCAN meta-GGA exchange-correlation functional: original SCAN, rSCAN, and r2SCAN. Without any dispersion correction involved, HF-SCANn outperforms the two other HF-DFT functionals. In contrast, among the self-consistent variants, SCANn and r2SCANn offer essentially the same performance at lower percentages of HF-exchange, while at higher percentages, SCANn marginally outperforms r2SCANn and rSCANn. However, with D4 dispersion correction included, all three HF-DFT-D4 variants perform similarly, and among the self-consistent counterparts, r2SCANn-D4 outperforms the other two variants across the board. In view of the much milder grid dependence of r2SCAN vs. SCAN, r2SCAN is to be preferred across the board, also in HF-DFT and hybrid KS-DFT contexts.


Bioprostheses for cardiac valve replacement.
Biologic tissue has been used successfully for cardiac valve substitutes since the introduction of glutaraldehyde preservation in 1969. Assessment of the clinical performance of prosthetic valves requires consideration of thromboembolism, anticoagulant-related hemorrhage, prosthetic valve endocarditis, periprosthetic leak and prosthesis failure. Two methods of assessment of valve performance, linearized occurrence rates and multiple decrement analysis of valve-related complications, are illustrated in evaluation of previous and new-generation Carpentier-Edwards porcine bioprostheses. The standard valve has a valve-related complication rate of 2.9% per patient-year over 5 years, while the rate for the new-generation supra-annular prosthesis is 4.3% per patient-year in the 2-year interval. Thromboembolism has been 1.6% and 1.7% per patient-year, respectively, for the previous and new-generation prostheses. Primary tissue failure has occurred only in the standard prosthesis, 0.6% per patient-year. The freedom from all valve-related complications is 93.1% at 2 years and 87.5% at 6 years with the standard valve and 95.1% at 2 years with the new-generation prosthesis. Standardized assessment of prosthetic performance should provide physicians and surgeons with the knowledge to optimize patient management. The new-generation biologic prostheses with improved preservation should reduce calcification and fatigue lesions. Tissue valves have afforded patients an excellent quality of life with a low incidence of valve-related complications.


Simple, efficient and open-source CRISPR/Cas9 strategy for multi-site genome editing in Populus tremula × alba.
Although the CRISPR/Cas9 system has been successfully used for crop breeding, its application remains limited in forest trees. Here, we describe an efficient gene editing strategy for hybrid poplar, (Populus tremula × alba INRA clone 717-1B4) based on the Golden Gate MoClo cloning. To test the system efficiency for generating single gene mutants, two single guide RNAs (sgRNAs) were designed and incorporated into the MoClo Tool Kit level 2 binary vector with the Cas9 expression cassette to mutate the SHORT ROOT (SHR) gene. Moreover, we also tested its efficiency for introducing mutations in two genes simultaneously by expressing one sgRNA targeting a single site of the YUC4 gene and the other sgRNA targeting the PLT1 gene. For a robust evaluation of the approach, we repeated the strategy to target the LBD12 and LBD4 genes simultaneously, using an independent construct. We generated hairy roots by Agrobacterium rhizogenes-mediated leaf transformation. Sequencing results confirmed the CRISPR/Cas9-mediated mutation in the targeted sites of PtaSHR. Biallelic and homozygous knockout mutations were detected. A deletion spanning both target sites and small insertions/deletions were the most common mutations. Out of the 22 SHR alleles sequenced, 21 were mutated. The phenotype's characterization showed that transgenic roots with biallelic mutations for the SHR gene lacked a defined endodermal single cell layer, suggesting a conserved gene function similar to its homolog in Arabidopsis Arabidopsis thaliana (L.) Heynh. Sequencing results also revealed the high efficiency of the system for generating double mutants. Biallelic mutations for both genes in the yuc4/plt1 and lbd12/lbd4 roots were detected in three (yuc4/plt1) and two (lbd12/lbd4) out of four transgenic roots evaluated. A small deletion or a single nucleotide insertion at the single target site was the most common mutations. This CRISPR/Cas9 strategy arises as a rapid, simple and standardized gene-editing tool to evaluate the gene role in essential developmental programs such as radial cell differentiation of poplar roots.


Elucidation of conformational states, dynamics, and mechanism of binding in human κ-opioid receptor complexes.
Opioid G protein-coupled receptors (GPCRs) have been implicated in modulating pain, addiction, psychotomimesis, mood and memory, among other functions. We have employed the recently reported crystal structure of the human κ-opioid receptor (κ-OR) and performed molecular dynamics (MD), free energy, and ab initio calculations to elucidate the binding mechanism in complexes with antagonist JDTic and agonist SalA. The two systems were modeled in water and in DPPC lipid bilayers, in order to investigate the effect of the membrane upon conformational dynamics. MD and Atoms in Molecules (AIM) ab initio calculations for the complexes in water showed that each ligand was stabilized inside the binding site of the receptor through hydrogen bond interactions that involved residues Asp138 (with JDTic) and Gln115, His291, Leu212 (with SalA). The static description offered by the crystal structure was overcome to reveal a structural rearrangement of the binding pocket, which facilitated additional interactions between JDTic and Glu209/Tyr139. The role of Glu209 was emphasized, since it belongs to an extracellular loop that covers the binding site of the receptor and is crucial for ligand entrapment. The above interactions were retained in membrane complexes (SalA forms additional hydrogen bonds with Tyr139/312), except the Tyr139 interaction, which is abolished in the JDTic complex. For the first time, we report that JDTic alternates between a "V-shape" (stabilized via a water-mediated intramolecular interaction) and a more extended conformation, a feature that offers enough suppleness for effective binding. Moreover, MM-PBSA calculations showed that the more efficient JDTic binding to κ-OR compared to SalA (ΔGJDTic = -31.6 kcal mol(-1), ΔGSalA = -9.8 kcal mol(-1)) is attributed mostly to differences in electrostatic contributions. Importantly, our results are in qualitative agreement with the experiments (ΔGJDTic,exp = -14.4 kcal mol(-1), ΔGSalA,exp = -10.8 kcal mol(-1)). This study provides previously unattainable information on the dynamics of human κ-OR and insight on the rational design of drugs with improved pharmacological properties.


Targeted agents for second-line treatment of advanced hepatocellular carcinoma.
Over the past ten years, sorafenib, a multikinase inhibitor, has been the standard of care for patients with unresectable hepatocellular carcinoma (HCC) and well-preserved liver function. Recently, lenvatinib, a different multikinase inhibitor, was shown to be non-inferior to sorafenib, in terms of survival, while all other agents previously tested failed to prove non-inferiority (or superiority) when compared to sorafenib. Similarly, in the second-line setting, most investigational drugs failed to provide better survival outcomes than placebo. However, in the last 2 years three positive phase III trials have been published in this setting. The RESORCE trial, a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib, showed better outcomes with regorafenib compared to placebo. More recently, the phase III CELESTIAL trial demonstrated the superiority of cabozantinib, a multikinase inhibitor targeting vascular endothelial growth factor receptor, MET, and AXL, vs placebo in the second- and third-line setting in patients progressing on or intolerant to sorafenib. The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels. Overall, the adverse events reported in these trials were in line with the known safety profiles of the tested agents. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.


Trends and Outcomes of Infective Endocarditis in Adults With Tetralogy of Fallot: A Review of the National Inpatient Sample Database.
Lesion complexity and prosthetic valves are known risk factors for infective endocarditis in patients with congenital heart disease. Tetralogy of Fallot (TOF) is the most common complex/cyanotic congenital heart disease and often requires prosthetic valve implantation. Population-based risk of endocarditis in TOF patients is unknown. We reviewed the National Inpatient Sample (NIS) and identified admissions in TOF patients (>18 years), 2000 to 2014. The primary outcome was to describe incidence of endocarditis-related admissions. To assess trends, we divided the study period into tertiles: early (2000 to 2004), mid (2005 to 2009) and late (2010 to 2014) eras. The secondary outcome was to compare in-hospital mortality, complications, and health care resource utilization between admissions with and without endocarditis. There were 393 (2.1%) endocarditis-related admissions among 18,353 admissions, and the incidence of endocarditis-related admissions increased over time: 1.9% (early era) vs 2.2% (mid-era) vs 2.4% (late era), P < 0.001. Overall in-hospital mortality was 6%. In addition to previously described risk factors for endocarditis, such as previous pacemaker/defibrillator or prosthetic valve implantation, we observed an association between endocarditis-related admissions and male gender, black race, and lower socioeconomic class. In comparison with admissions without endocarditis, the endocarditis-related admissions had higher in-hospital mortality, complications, and health care resource utilization measured by length of stay, inflation-adjusted hospitalization cost, and type of hospital discharge. Incidence of endocarditis-related admissions increased over time and was associated with higher mortality, complications, and health care resource utilization. Further studies are required to investigate the observed temporal increase in incidence of endocarditis and explore new strategies to improve outcomes.


Impact of cartridge-based nucleic acid amplification test (CBNAAT) introduction on the detection of pulmonary and extra-pulmonary tuberculosis in Bhubaneswar, Odisha.
Compared to conventional microscopy, the cartridge-based nucleic acid amplification test (CBNAAT, Xpert MTB/RIF, Cepheid, USA) has the dual advantage of higher sensitivity to detect Mycobacterium tuberculosis (M. tb), and the ability to detect rifampicin resistance. To evaluate the impact of the CBNAAT on the detection of pulmonary and extra-pulmonary tuberculosis from private and public healthcare facilities in Bhubaneswar, Odisha. The study included specimens received between June 2015 to February 2017 from public and private health sectors for tuberculosis diagnosis at a national reference laboratory for tuberculosis in Bhubaneswar, where the CBNAAT was initiated in February 2016. We retrospectively collected the patients' socio-demographic characteristics from their test request form, CBNAAT results from the CBNAAT register and PMDT culture and drug susceptibility testing (DST) register and validated the data by comparing the patient details and test results from the CBNAAT software. From June 2015 to January 2016, 106 samples were received from Bhubaneswar at the reference laboratory, of which there were zero referrals from the private sector and zero referrals of extra-pulmonary tuberculosis (TB) samples. After initiation of the CBNAAT, from February 2016 to February 2017, 1262 specimens were received, of which 55.2% (696/1262), 17.8% (225/1262), 17.2% (217/1262), and 9.8% (124/1262) were from government hospitals and medical colleges, private hospitals, private practitioners, and district TB centers, respectively. The availability of TB diagnostics at public sector facilities to patients from private sectors and the rollout of the CBNAAT increased the referral of patients from private health facilities and the referral of paucibacillary non-sputum samples.


Inhaled corticosteroids and risk of pneumonia in patients with chronic obstructive pulmonary disease: A meta-analysis of randomized controlled trials.
Inhaled corticosteroids (ICS) are generally used to treat patients with chronic obstructive pulmonary disease (COPD) who suffer from repeated exacerbations. Recently, it was reported that ICS treatment increased the risk of pneumonia in COPD patients. But it is controversial.The objective of this paper is to clarify the associations between ICS treatment and the risk of pneumonia in COPD patients. PubMed, Cochrane Library, Clinical Trials.gov, and Embase were searched from February 2019 to June 2019. Randomized clinical trials (RCTs) were incorporatedthat compared ICS with non-ICS treatment on the risk of pneumonia in COPD patients. Meta-analyses were conducted by the Peto and Mantel-Haenszel approaches with corresponding 95% CIs. Twenty-five trials (N = 49,982 subjects) were included. Pooled results demonstrated a significantly increased risk of pneumonia with ICS use in COPD patients (RR, 1.59, 95% CI, 1.33-1.90; I2 = 51%). ICS treatment also increased the risk of severe pneumonia (RR, 2.17, 95% CI, 1.47-3.22; I2 = 29%). The results of subgroup analysis based on doses of ICS were consistent with the above. However, subgroup analyses based on types of ICS revealed that fluticasone therapy was associated with an increased risk of pneumonia but not budesonide. In addition, medium- and low-doses of budesonide treatment also did not increase the risk of pneumonia. Use of ICS increases the risk of pneumonia in patients with COPD. The above is prominent for fluticasone-containing ICSs but not for budesonide-containing ICSs.


On the selectivity of the NaChBac channel: an integrated computational and experimental analysis of sodium and calcium permeation.
Ion channel selectivity is essential for their function, yet the molecular basis of a channel's ability to select between ions is still rather controversial. In this work, using a combination of molecular dynamics simulations and electrophysiological current measurements we analyze the ability of the NaChBac channel to discriminate between calcium and sodium. Our simulations show that a single calcium ion can access the Selectivity Filter (SF) interacting so strongly with the glutamate ring so as to remain blocked inside. This is consistent with the tiny calcium currents recorded in our patch-clamp experiments. Two reasons explain this scenario. The first is the higher free energy of ion/SF binding of Ca2+ with respect to Na+. The second is the strong electrostatic repulsion exerted by the resident ion that turns back a second potentially incoming Ca2+, preventing the knock-on permeation mechanism. Finally, we analyzed the possibility of the Anomalous Mole Fraction Effect (AMFE), i.e. the ability of micromolar Ca2+ concentrations to block Na+ currents. Current measurements in Na+/Ca2+ mixed solutions excluded the AMFE, in agreement with metadynamics simulations showing the ability of a sodium ion to by-pass and partially displace the resident calcium. Our work supports a new scenario for Na+/Ca2+ selectivity in the bacterial sodium channel, challenging the traditional notion of an exclusion mechanism strictly confining Ca2+ ions outside the channel.


Phylogenetic relationships of Phytophthora andina, a new species from the highlands of Ecuador that is closely related to the Irish potato famine pathogen Phytophthora infestans.
Phylogenetic relationships of Phytophthora infestans sensu lato in the Andean highlands of South America were examined. Three clonal lineages (US-1, EC-1, EC-3) and one heterogeneous lineage (EC-2) were found in association with different host species in genus Solanum. The EC-2 lineage includes two mitochondrial (mtDNA) haplotypes, Ia and Ic. Isolates of P. infestans sensu lato EC-2 fit the morphological description of P. infestans but are different from any genotypes of P. infestans described to date. All isolates of P. infestans sensu lato from Ecuador were amplified by a P. infestans specific primer (PINF), and restriction fragment length patterns were identical in isolates amplified with ITS primers 4 and 5. The EC-1 clonal lineage of P. infestans sensu lato from S. andreanum, S. columbianum, S. paucijugum, S. phureja, S. regularifolium, S. tuberosum and S. tuquerense was confirmed to be P. infestans based on sequences of the cytochrome oxidase I (cox I) gene and intron 1 of ras gene. The EC-2 isolates with the Ic haplotype formed a distinct branch in the same clade with P. infestans and P. mirabilis, P. phaseoli and P. ipomoeae for both cox I and ras intron 1 phylogenies and were identified as the newly described species P. andina. Ras intron 1 sequence data suggests that P. andina might have arisen via hybridization between P. infestans and P. mirabilis.


Local determination of a moving contrast edge.
This paper proposes an intensity-based method for determining the spatial orientation and observed velocity of a continuously moving edge. Space-time relations arise from the translation of a straight edge across a fixed detector array; a tesselation unit comprised of three equidistant detectors is used to exploit these relationships. The time ordering of cells within this unit can estimate edge direction and velocity. More precise edge determination is possible when intercell times are available and constant edge velocity is assumed; a sensitivity analysis examines the effect of relaxing the velocity constraint. The simulation of a translating synthetic image over an array of detectors is presented in order to demonstrate the method.


Transcription Factor Pit-1 Affects Transcriptional Timing in the Dual-Promoter Human Prolactin Gene.
Gene transcription occurs in short bursts interspersed with silent periods, and these kinetics can be altered by promoter structure. The effect of alternate promoter architecture on transcription bursting is not known. We studied the human prolactin (hPRL) gene that contains 2 promoters, a pituitary-specific promoter that requires the transcription factor Pit-1 and displays dramatic transcriptional bursting activity and an alternate upstream promoter that is active in nonpituitary tissues. We studied large hPRL genomic fragments with luciferase reporters, and used bacterial artificial chromosome recombineering to manipulate critical promoter regions. Stochastic switch mathematical modelling of single-cell time-lapse luminescence image data revealed that the Pit-1-dependent promoter showed longer, higher-amplitude transcriptional bursts. Knockdown studies confirmed that the presence of Pit-1 stabilized and prolonged periods of active transcription. Pit-1 therefore plays an active role in establishing the timing of transcription cycles, in addition to its cell-specific functions.


Autonomy, power, and place: Ethical considerations at the intersections of substance use care, and the sex trade.
Substance use disorder (SUD) care among women in the sex trade poses multiple ethical challenges. We propose a framework with three lenses-autonomy, power, and place-that can inform and help improve more ethical clinical care for people who trade sex seeking SUD treatment. A relational perspective on autonomy, an analysis of power relations in the clinic, and a geographical analysis can inform how we create space for people with experience in the sex trade in substance use treatment facilities and beyond. We conclude with some practical applications of this framework, all while integrating a composite clinical vignette throughout our analysis. This analysis addresses a clinical and ethical gap in ways to provide better care for women in the sex trade, an understudied and chronically marginalized population deserving of care that meets them where they are.


Lung injury edema in dogs. Influence of sympathetic ablation.
Increased vascular permeability characterizes lung injury pulmonary edema and renders fluid balance in the injured lung especially sensitive to changes in hydrostatic pressure. Pulmonary edema is often associated with increased sympathetic nervous system activity which can lead to pulmonary venoconstriction. This postcapillary venoconstriction could raise microvascular pressure and might therefore increase edema in the injured lung. We produced lung injury edema in dogs with oleic acid and directly measured small (less than 2 mm) pulmonary vein pressure. We found that the small pulmonary vein pressure was increased from 9.8 +/- 0.5 mmHg to 12.6 +/- 0.5 mmHg (n = 10) by oleic acid injury edema. The increase was not due to a rise in left atrial pressure since the small pulmonary vein-left atrial pressure gradient also increased. To test if this increase in the postcapillary pressure gradient was sympathetically mediated, we either unilaterally ablated the stellate ganglion or produced unilateral alpha adrenergic blockade with phenoxybenzamine before giving oleic acid. Both of these "antisympathetic" interventions prevented the increase in pulmonary vein pressure caused by oleic acid edema in the protected lung but not in the intact contralateral lung. These interventions produced a 30 +/- 6.8% reduction in the amount of edema caused by oleic acid. Restoring the increase in small vein pressure by inflating a balloon in the left atrium of dogs with bilateral stellate ganglion ablations abolished the reduction in edema produced by antisympathetic treatment. However, the decrease in edema was not significantly correlated with the reduction in pulmonary vein pressure. Thus, the mechanism of the effects of these antisympathetic interventions remains unclear. We conclude that lung injury edema causes sympathetically mediated pulmonary venoconstriction and that antisympathetic interventions significantly reduce lung injury edema and microvascular pressure.


The expression profile of p14, p53 and p21 in tumour cells is associated with disease-specific survival and the outcome of postoperative chemotherapy treatment in muscle-invasive bladder cancer.
We investigated the effects of alterations in the biological markers p14, p53, p21, and p16 in relation to tumour cell proliferation, T-category, N- category, lymphovascular invasion, and the ability to predict prognosis in patients with muscle-invasive bladder cancer (MIBC) treated with cystectomy and, if applicable, chemotherapy. We prospectively studied patients with urinary bladder cancer pathological stage pT1 to pT4 treated with cystectomy, pelvic lymph node dissection and postoperative chemotherapy. Tissue microarrays from paraffin-embedded cystectomy tumour samples were examined for expression of immunostaining of p14, p53, p21, p16 and Ki-67 in relation to other clinical and pathological factors as well as cancer-specific survival. The median age of the 110 patients was 70 years (range 51-87 years), and 85 (77%) were male. Pathological staging was pT1 to pT2 (organ-confined) in 28 (25%) patients and pT3 to pT4 (non-organ-confined) in 82 (75%) patients. Lymph node metastases were found in 47 patients (43%). P14 expression was more common in tumours with higher T-stages (P = 0.05). The expression of p14 in p53 negative tumours was associated with a significantly shorter survival time (P=0.003). Independently of p53 expression, p14 expression was associated with an impaired response to chemotherapy (P=0.001). The expression of p21 in p53 negative tumours was associated with significantly decrease levels of tumour cell proliferation detected as Ki-67 expression (P=0.03). The simultaneous expression of the senescence markers involved in the p53-pathway shows a more relevant correlation to the pathological outcome of MIBC than each protein separately. P14 expression in tumours with non-altered (p53-) tumours is associated with poor prognosis. P14 expression is associated with impaired response to chemotherapy. P21 expression is related to decreased tumour cell proliferation.


The effects of expiratory positive airway pressure on functional residual capacity in normal subjects.
Functional residual capacity (FRC) was determined by constant volume, whole body plethysmography in seven normal subjects under resting conditions and following the addition of increasing levels of expiratory positive airway pressure (EPAP). There was a significant increase in FRC in six of the seven subjects studied. Grouped data showed a progressive increase in FRC with increasing EPAP (p less than 0.01). The highest level of EPAP (15 cm H2O) was associated with a 20% increase in FRC. We have been able to confirm that EPAP provides a simple and effective method of increasing FRC which could be applied to the treatment of conditions characterized by temporary and reversible reduction in lung volume.


C-Geranylated Flavanones from Paulownia tomentosa Fruits as Potential Anti-inflammatory Compounds Acting via Inhibition of TNF-α Production.
Eleven new C-geranylated flavonoids, tomentodiplacones L, M, and N (1, 2, 10), tomentodiplacol B (3), 3',4'-O-dimethyl-5'-hydroxydiplacone (4), mimulones F, G, and H (5, 6, 7), paulowniones A (8) and B (9), tomentone (11), and 3',4',5'-trimethoxyflavanone (12), together with 11 known flavonoids (13-23), were isolated from fruits of Paulownia tomentosa. The structures of the compounds isolated were determined by spectroscopic data interpretation. The ability of compounds 1-23, together with the nonprenylated flavanones eriodictyol (24) and naringenin (25), to reduce the production of the pro-inflammatory cytokine TNF-α in THP-1 cells after bacterial lipopolysaccharide stimulation was evaluated using an in vitro screening test. The preliminary structure-activity relationships of these derivatives were also studied, and the correlation of their TNF-α inhibitory activity with their lipophilicity was investigated. The mechanism of action of compounds with significant antiphlogistic potential (4, 7, 10, 14, 22) was investigated. These compounds reduced both the secretion of TNF-α and the level of its corresponding mRNA. Compounds 4, 7, 10, 14, and 22 inhibited the nuclear translocation of NF-κB, which controls the expression of TNF-α, by blocking the degradation of IκB.


Urinary Tract Infections and Preeclampsia among Pregnant Women Attending Two Hospitals in Mwanza City, Tanzania: A 1:2 Matched Case-Control Study.
Urinary tract infection (UTI) and preeclampsia are common among pregnant women and are associated with adverse maternal-fetal and neonatal outcomes. Despite this, limited information exists on the association between UTIs and preeclampsia in Tanzania to guide specific management and thereby averting the adverse outcomes. A 1:2 matched case-control study (by age and gravidity) involving 131 pregnant women with preeclampsia (cases) and 262 without preeclampsia (controls) was conducted. Sociodemographic and clinical information was collected using a questionnaire. Midstream urine samples were collected during admission for culture and antimicrobial susceptibility testing (AST). Out of 393 pregnant women enrolled, 110 (28.0%), 95% CI: 23.8%-32.7%, had significant bacteriuria [cases: 50.4% (66/131) and control: 16.8% (44/262)]. Pregnant women with preeclampsia had 7.7 odds of having significant bacteriuria than those without preeclampsia [OR=7.7, 95% CI (4.11-14.49); p-value <0.001]. Escherichia coli, 50 (45.5%), and Klebsiella spp., 25 (23.6%), predominated, and resistance to gentamicin, ceftriaxone, and piperacillin-tazobactam ranged from 9.0% to 29.0% in these dominant species. Extended spectrum beta lactamases (ESBL) production in Escherichia coli and Klebsiella spp. was 18.0% (9/50) and 15.4% (4/26), respectively. Routine urine culture and AST among pregnant women with preeclampsia should be introduced in the antenatal clinics to ensure prompt management. Delineation of maternal-fetal and neonatal outcomes among pregnant women with preeclampsia and UTIs would be of interest in future studies.


Modeling linear and variable growth in phosphate limited suspension cultures of Opium poppy.
In examining the growth kinetics of cell suspensions of opium poppy (Papaver somniferum), the increase in biomass with time was observed to be linear over the entire batch growth period of up to 20 days. Although batch growth profiles were reproducible utilizing the same inoculum, growth rates varied tremendously when experiments were inoculated with cells from different flasks. Both of these phenomena are difficult to explain with conventional batch growth models. In a series of a experiments, phosphate was determined to be the growth-rate-limiting substrate. By expressing growth rate in terms of the intracellular reserves of phosphorus, a growth model which expresses kinetics in terms of the intracellular phosphorus contents of the cells is shown to predict both linear growth character and inoculum dependent variability in growth. The stationary phase phosphate content of seven plant suspension cultures of different plant species was found to be comparable to phosphorus levels of phosphate-starved poppy cells, which suggests that phosphate limitation may be common for plant tissue culture. The applicability of this model to other biological systems which display similar batch growth patterns when subjected to inorganic nutrient deprivation is discussed.


Measuring critical care redesign: impact on satisfaction and quality.
This report describes restructuring on four critical care units at an acute, tertiary care hospital in South-east Pennsylvania. Utilizing a Patient Centered Care conceptual framework that had been successfully applied in the medical-surgical areas, restructuring involved three main areas: revamping of work processes, inclusive of redesigned staff roles; environmental and facility changes; and enhancement of telecommunication and information systems. Preliminary analyses six months post redesign revealed improvements and maintenance in four outcomes areas--satisfaction, quality and efficiency, and costs of care.


Pediatric airway study: Endoscopic grading system for quantifying tonsillar size in comparison to standard adenotonsillar grading systems.
Current grading systems may not allow clinicians to reliably document and communicate adenotonsillar size in the clinical setting. A validated endoscopic grading system may be useful for reporting tonsillar size in future clinical outcome studies. This is especially important as tonsillar enlargement is the cause of a substantial health care burden on children. To propose and validate an easy-to-use flexible fiberoptic endoscopic grading system that provides physicians with a more accurate sense of the three-dimensional relationship of the tonsillar fossa to the upper-airway. 50 consecutive pediatric patients were prospectively recruited between February 2015 and February 2016 at a pediatric otolaryngology outpatient clinic. The patients had no major craniofacial abnormalities and were aged 1 to 16years. Each patient had data regarding BMI, Friedman palate position, OSA-18 survey results collected. For each child, digital video clips of fiberoptic nasopharyngeal, oropharyngeal and laryngeal exams were presented to 2 examiners. Examiners were asked to independently use the proposed Endoscopic tonsillar grading system, the Brodsky tonsillar grading scale, the Modified Brodsky tonsillar grading scale with a tongue depressor, and the Parikh adenoid grading system to rate adenotonsillar hypertrophy. Cohen's Kappa and weighted Kappa scores were used to assess interrater reliability for each of the four grading scales. The Spearman correlation was used to test the associations between each scale and OSA-18 scores, as well as Body Mass Index (BMI). 50 pediatric patients were included in this study (mean age 6.1years, range of 1year to 16years). The average BMI was 20. The average OSA-18 score was 61.7. The average Friedman palate position score was 1.34. Twelve percent of the patients had a Friedman palate position score≥3, which made traditional Brodsky grading of their tonsils impossible without a tongue depressor. All four scales showed strong agreement between the two raters. The weighted Kappa was 0.83 for the Modified Brodsky scale, 0.89 for the Brodsky scale, 0.94 for the Parikh scale to 0.98 for the Endoscopic scale (almost perfect agreement). The Endoscopic scale showed the most consistent agreement between the raters during the study. There was a moderate association between the Parikh adenoid grading system with OSA-18 scores (Spearman's ρ=0.58, p<0.001) compared to a low association of the tonsillar grading systems with OSA- 18 scores. None of the scales correlated with patient BMI. The proposed Endoscopic tonsillar grading system is as reliable of a method of grading tonsillar size as conventional grading systems. It offers the advantage of allowing for critical evaluation of the tonsils without any anatomic distortion which may occur with the use of a tongue blade. This new validated endoscopic grading system provides a tool for communicating the degree of airway obstruction at the level of the oropharynx regardless of Friedman palate position and may be used in future outcomes projects.