Analysis of risk factors for axial symptoms after posterior cervical open-door laminoplasty.
Laminoplasty (LP), a procedure commonly used to treat cervical spondylotic myelopathy (CSM), often results in the development of axial symptoms (AS) postoperatively. This study aims to analyze the risk factors associated with the occurrence of AS after LP. We collected and evaluated clinical data from 264 patients with CSM who underwent LP treatment at our institution from January 2018 to January 2022 through a single-center retrospective study. Of the patients, 153 were male and 111 were female, with an average age of 58.1 ± 6.7 years. All patients underwent C3-7 posterior laminoplasty. Based on the occurrence of postoperative axial symptoms, the patients were divided into an AS group and a non-AS group. General information, including age, gender, disease duration, Japanese Orthopaedic Association (JOA) score, postoperation early function training, and collar-wearing time, was recorded and compared between the two groups. Surgical-related data, such as operative segments, surgical time, intraoperative blood loss, intraoperative facet joint destruction, and destruction of the C7 spinous process muscle insertion, were also compared. Imaging data, including preoperative cervical curvature, cervical range of motion, preoperative encroachment rate of the anterior spinal canal, and angle of laminar opening, were collected. Univariate and multivariate logistic regression analyses were used to identify risk factors for the development of AS after LP, and receiver operator characteristic (ROC) curves were utilized to explore the optimal preoperative parameters. All 264 patients successfully underwent surgery and were followed up for an average of 19.5 ± 6.8 months. At the 6-month follow-up, 117 patients were diagnosed with AS, resulting in an incidence rate of 40.2%. The multivariate logistic regression analysis identified that preoperative encroachment rate of anterior spinal canal (Pre-op ERASC), intraoperative facet joints destruction (Intra-op FJD), intraoperative open-door angle (Intra-op OA), destroy the C7 spinous process muscle insertion (Destroy C7 SPMI), postoperative loss of cervical curvature (Post-op LCC), and postoperative loss of cervical range of motion (Post-op LCROM) were independent risk factors for AS. Conversely, preoperative cervical curvature (Pre-op CC) and postoperation early function training (Post-op EFT) were protective factors against AS. According to the ROC curve, the cutoff values for preoperative anterior spinal canal occupation rate and preoperative cervical curvature were 28.5% and 16.5°, respectively. When the preoperative anterior spinal canal occupation rate was greater than 28.5% or the preoperative cervical curvature was less than 16.5°, AS was more likely to occur after surgery. High preoperative anterior spinal canal occupation rate, facet joint damage during surgery, C7 spinous process muscle stop point damage, larger angle of laminar opening, and greater postoperative cervical curvature loss and cervical range of motion loss are associated with an increased risk of developing AS after cervical laminoplasty. Conversely, a larger preoperative cervical curvature and early postoperative functional exercises can help reduce the occurrence of AS.


[Operative and interventional therapy of lung metastases].
Almost every third patient succumbing to a malignant disease has metastases in the lungs. However, these are often asymptomatic and are detected fortuitously during a routine examination. Today, the surgical removal of lung metastases is associated with a risk of less than 1%, but only one-third of the patients meet the criteria for such a procedure. The long-term outcome after resection of lung metastases depends in particular on the nature of the primary tumor, the number of metastases, the duration of the period between the occurrence of the primary and development of metastases, and the completeness of the resection. In the case of inoperable metastases, interventional measures may suffice to achieve local tumor control. For the treatment of lung metastases, radiofrequency ablation in particular is currently being investigated.


Discovery of regulatory elements in human ATP-binding cassette transporters through expression quantitative trait mapping.
ATP-binding cassette (ABC) membrane transporters determine the disposition of many drugs, metabolites and endogenous compounds. Coding region variation in ABC transporters is the cause of many genetic disorders, but much less is known about the genetic basis and functional outcome of ABC transporter expression level variation. We used genotype and mRNA transcript level data from human lymphoblastoid cell lines to assess population and gender differences in ABC transporter expression, and to guide the discovery of genomic regions involved in transcriptional regulation. Nineteen of 49 ABC genes were differentially expressed between individuals of African, Asian and European descent, suggesting an important influence of race on expression level of ABC transporters. Twenty-four significant associations were found between transporter transcript levels and proximally located genetic variants. Several of the associations were experimentally validated in reporter assays. Through influencing ABC expression levels, these single-nucleotide polymorphisms may affect disease susceptibility and response to drugs.


Ellagic acid and urolithin A modulate the immune response in LPS-stimulated U937 monocytic cells and THP-1 differentiated macrophages.
Dietary polyphenols are subjected, following ingestion, to an extensive metabolism, and the molecules that act at the cellular and tissue level will be, most likely, metabolites rather than native polyphenols. The mechanisms behind the positive effects exerted by polyphenols are not yet completely elucidated, since most in vitro studies use unmetabolised polyphenols rather than the metabolites present in the body. The aim of this study was to investigate and compare the potential effect of phenolic metabolites on the immune response using U937 monocyte and THP-1 macrophage cell cultures. Of the 16 metabolites tested, urolithins (Uro), and Uro A, in particular were the most potent, showing a modest increase in basal NF-κB activity and a reduction in lipopolysaccaride (LPS)-induced NF-κB activity, gene expression and secretion of pro-inflammatory cytokines. Protocatechuic acid and its sulfate/glucuronide metabolites reduced LPS-induced NF-κB activity, but not IL-6 and TNF-α cytokine secretion. Interestingly, both ellagic acid and its metabolite Uro A had immunomodulating effects, although they regulated the immune response differently, and both reduced LPS-induced NF-κB activity in U937 cells. However, while Uro A dramatically reduced IL-6 and IL-10 mRNA expression, no effect could be observed with ellagic acid. In THP-1 cells, treatment with ellagic acid dramatically reduced the expression of Toll-like receptor 4, while Uro A had no effect. The dual role observed for Uro A, showing both a modest increase in basal NF-κB activity and a reduction in LPS-induced NF-κB activity, as well as a reduction in LPS-induced pro-inflammatory cytokine secretion, makes this metabolite particularly interesting for further studies in animals and humans.


Photosynthetic and molecular markers of CO₂-mediated photosynthetic downregulation in nodulated alfalfa.
Elevated CO₂ leads to a decrease in potential net photosynthesis in long-term experiments and thus to a reduction in potential growth. This process is known as photosynthetic downregulation. There is no agreement on the definition of which parameters are the most sensitive for detecting CO₂ acclimation. In order to investigate the most sensitive photosynthetic and molecular markers of CO₂ acclimation, the effects of elevated CO₂, and associated elevated temperature were analyzed in alfalfa plants inoculated with different Sinorhizobium meliloti strains. Plants (Medicago sativa L. cv. Aragón) were grown in summer or autumn in temperature gradient greenhouses (TGG). At the end of the experiment, all plants showed acclimation in both seasons, especially under elevated summer temperatures. This was probably due to the lower nitrogen (N) availability caused by decreased N₂-fixation under higher temperatures. Photosynthesis measured at growth CO₂ concentration, rubisco in vitro activity and maximum rate of carboxylation were the most sensitive parameters for detecting downregulation. Severe acclimation was also related with decreases in leaf nitrogen content associated with declines in rubisco content (large and small subunits) and activity that resulted in a drop in photosynthesis. Despite the sensitivity of rubisco content as a marker of acclimation, it was not coordinated with gene expression, possibly due to a lag between gene transcription and protein translation.


Dynamic compression plate and cancellous bone graft for aseptic nonunion after intramedullary nailing of femoral fracture.
We evaluated the effect of revision with dynamic compression plate and cancellous bone graft for aseptic nonunion after intramedullary nailing of femoral shaft fracture. Fifty patients with aseptic nonunion of femoral shaft fracture after intramedullary nailing were reviewed and analyzed retrospectively between 1996 and 2007. There were 40 men and 10 women with an average age of 44 years (range, 19-76 years). Thirty-five were diaphyseal fractures, 8 were distal fractures, and 7 were proximal fractures. Twenty-eight fractures were defined as atrophic nonunion, 13 fractures were hypertrophic nonunion, and 9 fractures could not be defined clearly. All fractures were managed by retaining previous implants, open reduction and internal fixation with dynamic compression plate, and supplementation by cancellous bone graft. The average follow-up period was 76 months (range, 24-128 months). Functional evaluations were done by Harris Hip score and Hospital for Special Surgery knee score. All nonunions united on average at 24 weeks (range, 18-32 weeks). One superficial wound infection occurred. At follow-up, each patient was evaluated to have satisfactory function results, with near normal hip/knee functions without noticeable pain, and full return to preinjury activities/work without pain.Augmentative dynamic compression plate with cancellous bone graft is a reliable and effective treatment for revision of aseptic nonunion of femoral shaft fracture after intramedullary nailing.


Pessimistic outcome expectancy does not explain ambiguity aversion in decision-making under uncertainty.
When faced with a decision, most people like to know the odds and prefer to avoid ambiguity. It has been suggested that this aversion to ambiguity is linked to people's assumption of worst possible outcomes. We used two closely linked behavioural tasks in 78 healthy participants to investigate whether such pessimistic prior beliefs can explain ambiguity aversion. In the risk-taking task, participants had to decide whether or not they place a bet, while in the beliefs task, participants were asked what they believed would be the outcome. Unexpectedly, we found that in the beliefs task, participants were not overly pessimistic about the outcome in the ambiguity condition and in fact closer to optimal levels of decision-making than in the risk conditions. While individual differences in pessimism could explain outcome expectancy, they had no effect on ambiguity aversion. Consequently, ambiguity aversion is more likely caused by general caution than by expectation of negative outcomes despite pessimism-dependent subjective weighting of probabilities.


Possible Correlation Between Kyphosis of Lumbar Osteoporosis Fractures and the Spinal Signal Intensity Ratio (SSIR).
The aim of this study was to examine the correlation between the risk of increasing kyphosis as well as collapse of the osteoporotic vertebral body fractures and the intensity of the bone edema in magnetic resonance imaging (MRI) scans. Inclusion criteria included the following: age >18 years and osteoporotic vertebral body fracture grade I-IV according to OF classification. Exclusion criteria included the following: other pathological fractures due to primary tumors or metastasis, OF grade V fractures, and AO type B or C fractures. This was a retrospective study from pseudonymized data of a tertiary spine center. No additional imaging were performed. Measurements of bisegmental kyphosis angle of the fracture for involvement of both endplates and monosegmental angle for involvement of 1 endplate, as well as vertebral body height loss in initial radiographs and at follow-ups after 3 and 6 months have been performed. Also, the initial signal intensity of the vertebral body edema was measured using integrated tool of the DICOM viewer (Impax V6.5 Agfa, Brentford, UK) in addition to the signal intensity of the cerebrospinal fluid (CSF) as reference for T1, T2, and separate target illumination radar (STIR) sequences of the MRI scans. A quotient from the signal intensity of the vertebral body edema and the reference (CSF) has been generated. Patients have been divided to 4 groups according to the ratio (<1, 1-2, 2-3, >3) and compared in regards to the results of the degree of kyphosis and vertebral collapse at follow-ups and final examination. The statistical analysis was performed using linear regression using statistic software SPSS version 26. Forty-four patients have been included: 9 males and 35 females with an average age of 71.5 years. The analysis showed a significant correlation between the increasing kyphosis at follow-ups and the quotient of the signal intensity for STIR and T2 weighing with P = .002 (SD ±2.664) for STIR and P = .001 (SD ±1.616) for T2 sequences. Furthermore, there was only a correlation between the intensity ratio and kyphosis for STIR weighting at last examination (P = .017; SD ±1.360). There was no correlation between the height loss and the signal intensity. Level 2.


Wave-front aberrations in the anterior corneal surface and the whole eye.
In order to investigate the sources of wave-front aberrations in the human eye, we have measured the aberrations of the anterior cornea and the whole eye using a topographic system and a psychophysical wave-front sensor. We have also calculated the aberrations for the internal optics of both eyes of 45 young subjects (aged 9 to 29 years). The mean rms for the anterior cornea was similar to that for the internal optics and thewhole eye when astigmatism was included, but less than that for both the internal optics and the whole eye with astigmatism removed. For eyes with low whole-eye rms values, mean rms for the anterior cornea was greater than that for the whole eye, suggesting that the anterior corneal aberration is partially compensated by the internal optics of the eye to produce the low whole-eye rms. For eyes with larger whole-eye rms values, the rms values for both the anterior cornea and the internal optics were less than that for the whole eye. Thus the aberrations for the two elements tend to be primarily additive. This pattern exists whether or not astigmatism was included in the wave-front aberration rms. For individual Zernike terms, astigmatism and spherical aberration in the anterior cornea were partially compensated by internal optics, while some other Zernike terms showed addition between the anterior cornea and internal optics. Individual eyes show different combinations of compensation and addition across different Zernike terms. Our data suggest that the reported loss of internal compensation for anterior corneal aberrations in elderly eyes with large whole-eye aberrations [J. Opt. Soc. Am. A 19, 137 (2002)] may also occur in young eyes.


Phytochemical Composition, Antioxidant, and Antimicrobial Attributes of Different Solvent Extracts from Myrica esculenta Buch.-Ham. ex. D. Don Leaves.
Background: Plant diversity is a basic source of food and medicine for local Himalayan communities. The current study was designed to assess the effect of different solvents (methanol, ethyl acetate, and water) on the phenolic profile, and the corresponding biological activity was studied. Methods: Antioxidant activity was investigated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2″-azino-bis(3-ethylbenzothiazoline-6-sulphonic) acid (ABTS) assay, while the antimicrobial activity was evaluated by disk diffusion method using various bacterial and fungal strains. Results: The outcomes demonstrated that methanol acted as the most effective solvent for polyphenols extraction, as strengthened by the liquid chromatography and mass spectroscopy (LC-MS) and fourier transform infrared spectroscopy (FTIR) analysis. M. esculenta methanol extract showed the highest DPPH and ABTS radical scavenger antioxidant activity with IC50 values of 39.29 μg/mL and 52.83 μg/mL, respectively, while the ethyl acetate and aqueous extracts revealed minimum antioxidant potential. Methanol extract also revealed higher phenolic content, 88.94±0.24 mg of equivalent gallic acid (GAE)/g), measured by the Folin-Ciocalteu method, while the minimum content was recorded for aqueous extract (62.38±0.14 GAE/g). The highest flavonoid content was observed for methanol extract, 67.44±0.14 mg quercetin equivalent (QE)/g) measured by an aluminum chloride colorimetric method, while the lowest content was recorded for aqueous extract (35.77±0.14 QE/g). Antimicrobial activity findings also reveal that the methanol extract led to a higher inhibition zone against bacterial and fungal strains. FTIR analysis reveals the presence of various functional groups, viz. alkenes, amines, carboxylic acids, amides, esters, alcohols, phenols, ketones, carboxylic acids, and aromatic compounds. This FTIR analysis could serve as a basis for the authentication of M. esculenta extracts for future industrial applications. Compounds identified by LC-MS analysis were gallic acid, myricanol, myricanone, epigallocatechin 3-O-gallate, β-sitosterol, quercetin, p-coumaric acid, palmitic acid, n-pentadecanol, n-octadecanol, stigmasterol, oleanolic acid, n-hexadecanol, cis-β-caryophyllene, lupeol, and myresculoside. Conclusion: This study suggests that the methanolic extract from M. esculenta leaves has strong antioxidant potential and could be a significant source of natural antioxidants and antimicrobials for functional foods formulation.


Beyond Hours Worked and Dollars Earned: Multidimensional EQ, Retirement Trajectories and Health in Later Life.
The working lives of Americans have become less stable over the past several decades and older adults may be particularly vulnerable to these changes in employment quality (EQ). We aimed to develop a multidimensional indicator of EQ among older adults and identify EQ and retirement trajectories in the United States. Using longitudinal data on employment stability, material rewards, workers' rights, working-time arrangements, unionization, and interpersonal power relations from the Health and Retirement Study (HRS), we used principal component analysis to construct an EQ score. Then, we used sequence analysis to identify late-career EQ trajectories (age 50-70 years; N = 11,958 respondents), overall and by sociodemographics (race, gender, educational attainment, marital status). We subsequently examined the sociodemographic, employment, and health profiles of these trajectories. We identified 10 EQ trajectories; the most prevalent trajectories were Minimally Attached and Wealthy (13.9%) and Good EQ to Well-off Retirement (13.7%), however, 42% of respondents were classified into suboptimal trajectories. Those in suboptimal trajectories were disproportionately women, people of color, and less-educated. Individuals in the Poor EQ to Delayed and Poor Retirement and Unattached and Poor clusters self-reported the greatest prevalence of poor health and depression, while individuals in the Wealthy Business Owners and Great EQ to Well-off Retirement clusters self-reported the lowest prevalence of poor health and depression at baseline. Trajectories were substantially constrained for women of color. Although our study demonstrates EQ is inequitably distributed in later life, labor organizing and policy change may afford opportunities to improve EQ and retirement among marginalized populations.


Neuropsychology of early-treated phenylketonuria: specific executive function deficits.
This study explored the hypothesis that children with early-treated phenylketonuria (PKU) are selectively impaired on executive function measures, even when still on diet. The rationale for this hypothesis is that even mild elevations in phenylalanine (Phe) can lead to lower central levels of biogenic amines, including dopamine (DA). We hypothesize that this mild DA depletion causes subtle prefrontal dysfunction, which in turn affects executive functions such as set maintenance, planning, and organized search. 11 preschool early-treated PKU children (M age = 4.64) and a sample of age- and IQ-matched unaffected peers (n = 11) were evaluated on a battery of executive function (EF) measures. In addition, a "non-executive function" task, recognition memory, was administered to all subjects. Group comparisons demonstrated that PKU children were significantly impaired on an executive function composite score; there were no group differences, however, in recognition memory. These results supported the hypothesized specific deficit in executive function. Furthermore, within the PKU group the executive function composite score was significantly negatively correlated with concurrent phenylalanine levels, even after controlling for the correlation between IQ and executive function skills. This second finding provides support for the proposed biochemical mechanism underlying the specific cognitive deficits.


Obesity Is Associated with Altered Tumor Metabolism in Metastatic Melanoma.
Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI). Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts (n = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x = 36) by LC/MS, and in flow-sorted melanoma tumor cells (x = 37) and patient-derived melanoma cell lines (x = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n = 371). DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased central carbon metabolism in OW/OB metastatic melanoma tumors and patient-derived cell lines. The overall structure, diversity, and taxonomy of the fecal microbiome did not differ by BMI. These findings suggest that the host metabolic phenotype influences melanoma metabolism and provide insight into the improved outcomes observed in OW/OB patients with metastatic melanoma treated with ICIs and targeted therapies. See related commentary by Smalley, p. 5.


COMT inhibition with tolcapone in the treatment algorithm of patients with Parkinson's disease (PD): relevance for motor and non-motor features.
Levodopa is the most effective treatment in Parkinson's disease and the association with COMT inhibitors widens its plasma bioavailability and effectiveness. Tolcapone is a potent COMT inhibitor whose utilization in PD is limited due to safety concerns on liver toxicity. However, recent data indicate that if liver function is actively monitored, tolerability is no worse than other currently available therapies. By contrast, administration of tolcapone is associated with significant clinical improvement and benefit involves also non-motor features. In this review we discuss the rationale for the use of tolcapone in association with levodopa and other treatments in PD, and we provide an indirect comparison of current strategies to reduce "off" time. We propose that future guidelines include a trial with tolcapone in all PD patients who continue to complain about motor fluctuations despite treatment with entacapone and/or MAO-B inhibitors. Moreover, we suggest that tolcapone should be considered before surgical or infusional strategies are applied.


Barriers to HIV Treatment Adherence: A Qualitative Study of Discrepancies Between Perceptions of Patients and Health Providers in Tanzania and Uganda.
Previous qualitative studies about antiretroviral therapy (ART) adherence have largely focused on patient experiences. Less is known about the perspective of health care providers-particularly in low-income countries-who serve as gatekeepers and influencers of patients' HIV care experiences. This study explored patients' and providers' perceptions of important ART adherence determinants. Interviews were conducted at HIV treatment sites in Tanzania and Uganda, with adult patients on ART (n = 148), and with health care providers (n = 49). Patients were asked about their experiences with ART adherence, and providers were asked about their perceptions of what adherence challenges are faced by their patients. All interviews were conducted in local languages; transcripts were translated into English and analyzed using a codebook informed by the social ecological model. Themes were examined across and within countries. Adherence-related challenges were frequently reported, but patients and providers did not often agree about the reasons. Many patients cited challenges related to being away from home and therefore away from their pill supply; and, in Uganda, challenges picking up refills (access to care) and related to food sufficiency/diet. Providers also identified these access to care barriers, but otherwise focused on different key determinants (e.g., they rarely mentioned food/diet); instead, providers were more likely to mention alcohol/alcoholism, stigma, and lack of understanding about the importance of adhering. These findings suggest areas of opportunity for future research and for improving clinical care by aligning perceptions of adherence challenges, to deliver better-informed and useful ART counseling and support.


Multiple primary syphilis on the lip, nipple-areola and penis: An immunohistochemical examination of Treponema pallidum localization using an anti-T. pallidum antibody.
Primary syphilis caused by Treponema pallidum usually develops after sexual contact as an initial solitary sclerosis or hard chancre in the genital region. We describe a case of primary syphilis at three sites in genital and extragenital regions of a man who had sex with men. A 29-year-old man visited our hospital for skin lesions on his lower lip, nipple-areola and penis. A positive syphilis serological test for rapid plasma reagin had a titer of 1:16; the patient also tested positive for specific antibodies against T. pallidum, with a cut-off index of 39.0. Histopathological examination of a nipple-areola biopsy specimen revealed a thickened epidermis and dense infiltration of inflammatory cells extending from the upper dermal layers to the deep dermis. The inflammatory cells were composed of abundant lymphocytes, plasma cells, histiocytes and neutrophils. Immunohistochemical staining for T. pallidum using an anti-T. pallidum antibody showed numerous spirochetes in the lower portion of the epidermis, scattered inside inflammatory cell infiltrate and perivascular sites throughout the dermis. Based on these findings, the patient was diagnosed with primary syphilis. Treatment with oral amoxicillin hydrate was started. Five days after starting treatment, a diffuse maculopapular rash (syphilitic roseola) occurred on his trunk and extremities. Perivascular cuffing due to T. pallidum was present throughout the dermis in the biopsy specimen of a localized lesion of primary syphilis. Moreover, syphilitic roseola, which indicates generalized dissemination of T. pallidum, developed during the course of treatment for primary syphilis. Therefore, we considered perivascular cuffing to be indicative of the dissemination phase.


Evaluation of bovine milk extracellular vesicles for the delivery of locked nucleic acid antisense oligonucleotides.
The natural capacity of extracellular vesicles (EVs) to transport their payload to recipient cells has raised big interest to repurpose EVs as delivery vehicles for xenobiotics. In the present study, bovine milk-derived EVs (BMEVs) were investigated for their potential to shuttle locked nucleic acid-modified antisense oligonucleotides (LNA ASOs) into the systemic circulation after oral administration. To this end, a broad array of analytical methods including proteomics and lipidomics were used to thoroughly characterize BMEVs. We found that additional purification by density gradients efficiently reduced levels of non-EV associated proteins. The potential of BMEVs to functionally transfer LNA ASOs was tested using advanced in vitro systems (i.e. hPSC-derived neurons and primary human cells). A slight increase in cellular LNA ASO internalization and target gene reduction was observed when LNA ASOs were delivered using BMEVs. When dosed orally in mice, only a small fraction (about 1% of total administered dose) of LNA ASOs was recovered in the peripheral tissues liver and kidney, however, no significant reduction in target gene expression (i.e. functional knockdown) was observed.


Granulomatous tracheo-bronchitis associated with Crohn's disease.
We report a rare case of diffuse tracheo-bronchitis as a complication of Crohn's disease. A young man with a long-standing history of Crohn's enterocolitis initially presented with epigastric pain and melena. Upper endoscopy revealed erythematous, edematous, and friable mucosa with erosions, particularly in the pyloric channel, causing gastric outlet obstruction, and a nonbleeding ulcer in the corpus of stomach. Biopsy of these lesions showed chronic gastritis and a noncaseating epithelioid granuloma, consistent with active Crohn's disease. The patient was treated with a course of corticosteroids and the gastric symptoms resolved. A few months later, he developed fever, cough, hemoptysis, and rash. Bronchoscopy demonstrated a markedly thickened and very inflamed trachea with extensive friable, whitish lesions and ulcerations. Histology showed severe noncaseating granulomatous inflammation. The patient improved with a 6-week oral, followed by an additional 4-week inhaled, corticosteroid treatment. Since then, he has been doing well without relapse of pulmonary symptoms for 2 years.


Membrane-bound cytochrome b5 reductase (methemoglobin reductase) in human erythrocytes. Study in normal and methemoglobinemic subjects.
In this study we present evidence that in human erythrocytes NADH-cytochrome b5 reductase (methemoglobin reductase) is not only soluble but also tightly bound to the membrane. The membrane methemoglobin reductase-like activity is unmasked by Triton X-100 treatment, and represents about half of the total activity in the erythrocytes. Like the amphiphilic microsomal-bound cytochrome b5 reductase, the erythrocyte membrane-bound enzyme is solubilized by cathepsin D. Because this treatment is effective on unsealed ghosts but not on resealed (inside-in) ghosts, it is concluded that the enzyme is strongly bound to the inner face of the membrane. The erythrocyte membrane enzyme is antigenically similar to the soluble enzyme. The two forms of enzyme are specified by the same gene, in that both were found defective in six patients with recessive congenital methemoglobinemia. We suggest that the cytochrome b5 reductase of the erythrocyte membrane is the primary gene product. A posttranslational partial proteolysis probably gives rise to the soluble form of the enzyme, which serves as a methemoglobin reductase.


Identifying barriers to referrals in preschool-age ocular screening in Southern India.
The aim of this study was to identify barriers to follow-up among children aged 0-5 years who failed ocular screening. A cross-sectional, descriptive study was conducted for screening children aged 0-5 years, covering three districts of South India from January 2012 to December 2012. Screening was performed under Lavelle Paediatric Eye Care Project, included under Integrated Child Development Services (ICDS) program. A survey was conducted within 60 days of the screening, with the parents of children who failed to follow up at base hospital. Family demographics, parental awareness of childhood eye diseases and eye care for children, and barriers to follow up eye care were assessed. A total of 19,408 children were screened. Among them, 913 (4.7%) failed screening and were referred. 319 (35%) of those referred attended the base hospital, of which 133 (41.6%) had no abnormality on detailed examination. 111 (34.7%) had refractive errors, 10 (3%)) had strabismus, and three (1%) had amblyopia. 62 (19.4%) had other ocular conditions. Parents of 324/594 (65%) children who did not attend the base hospital were traced and completed the questionnaire. Low level of education, low income, types of occupation, and distance factors were the main barriers to follow-up of referral in preschool children. Factors such as cost of time taking off from work and monthly family income were statistically significant (P < 0.001). Education, financial status, and distance factors were the main barriers to follow up of referral in preschool children. Identification of these barriers to follow up and improving the referral services could help in detecting visual problem effectively.


Purification and characterization of antibacterial compounds of Pseudoalteromonas flavipulchra JG1.
Pseudoalteromonas flavipulchra JG1 produces a protein PfaP and a range of small-molecule compounds with inhibitory activities against Vibrio anguillarum. The PfaP protein was purified from the extracellular products of JG1 by electroelution, and antibacterial activity was observed by an in-gel antibacterial assay. The complete amino acid sequence (694 aa) of PfaP was determined by de novo peptide sequencing and subsequent alignment with the proteome sequence of strain JG1. The calculated molecular mass of PfaP was 77.0 kDa. PfaP was 58 % identical to l-lysine oxidase AlpP of Pseudoalteromonas tunicata D2, and 54 % identical to the marinocine antimicrobial protein of Marinomonas mediterranea MMB-1. Five small molecules (compounds 1-5) with antibacterial activity, which were identified as p-hydroxybenzoic acid (1), trans-cinnamic acid (2), 6-bromoindolyl-3-acetic acid (3), N-hydroxybenzoisoxazolone (4) and 2'-deoxyadenosine (5), were purified by sequential column chromatography over silica gel, Sephadex LH-20 and RP-18 from ethyl acetate extract of strain JG1, and their structures were determined by NMR and MS. Brown compound 3, the only brominated compound, showed antibacterial activity against both Gram-positive and Gram-negative bacteria.


Nucleotide sequence of the melA gene, coding for alpha-galactosidase in Escherichia coli K-12.
Melibiose uptake and hydrolysis in E.coli is performed by the MelB and MelA proteins, respectively. We report the cloning and sequencing of the melA gene. The nucleotide sequence data showed that melA codes for a 450 amino acid long protein with a molecular weight of 50.6 kd. The sequence data also supported the assumption that the mel locus forms an operon with melA in proximal position. A comparison of MelA with alpha-galactosidase proteins from yeast and human origin showed that these proteins have only limited homology, the yeast and human proteins being more related. However, regions common to all three proteins were found indicating sequences that might comprise the active site of alpha-galactosidase.


Superoxide dismutase and superoxide radical in Morris hepatomas.
Total superoxide dismutase (SOD) and manganese superoxide dismutase (Mn SOD) specific activities were measured in tissue homogenates and in isolated mitochondria from normal rat liver and three Morris hepatomas of different growth rates. Total SOD and Mn SOD specific activities were decreased in all tumor homogenates when compared to normal liver; the lowest activity was associated with the fastest growing tumor. These results are consistent with the hypothesis that total Mn SOD specific activity is decreased in all tumors. The Mn SOD specific activity was similar to the total SOD specific activity of isolated mitochondria, indicating that mitochondrial SOD is almost entirely manganese containing. This activity was decreased in the fast- and medium-growth-rate hepatomas but was slightly increased in the tumor with the slowest growth rate when compared to liver. The normal or higher than normal mitochondrial Mn SOD specific activity indicates that decreased mitochondrial SOD specific activity is not a characteristic of all tumors. Superoxide radical (O2-.) formation was measured in submitochondrial particles obtained by sonication of isolated mitochondria and subsequent washings to remove the SOD. The difficulty encountered in reducing the SOD activity suggests that at least part of the mitochondrial SOD might be associated with the mitochondrial membrane. In liver submitochondrial particles, O2-. was formed only when succinate and antimycin A were used together, as substrate and inhibitor of the electron transport chain, respectively. In the hepatomas studied for O2-. production (slow- and fast-growth rates), the formation of the radical was detected in the presence of succinate even when no inhibitor was present. Antimycin A stimulated the production of O2-. in normal rat liver and slow-growth-rate tumor, but not in fast-growth-rate tumor submitochondrial particles. Reduced nicotinamide adenine dinucleotide did not lead to the production of O2-. by normal liver or hepatoma submitochondrial particles. Mitochondrial membrane damage was seen in micrographs of the medium- and fast-growing hepatomas. This could be a consequence of low mitochondrial SOD concomitant with a flux of superoxide, if the radical is produced in vivo by these mitochondria.


[Abnormal infrared effects (AIREs) of nm-Ru/GC electrode towards CO adsorption in alkaline solutions].
The adsorption of CO on electrode of nanometer thin film of Ru in 0.1 mol.L-1 NaOH solution was studied by using in-situ FTIR spectroscopy. The results revealed that the adsorbed CO in alkaline solutions is mainly in linear bonded from that yields IR absorption at around 1,960 cm-1, and a small portion of bridge bonded CO was also determined near 1,780 cm-1. The band centers of COL and COB have been red-shifted respectively about 50 and 60 cm-1 in comparison with the values measured in acid medium. The enhancement factor of IR absorption of CO on nm-Ru/GC electrode has been measured at 33 in 0.1 mol.L-1 NaOH solution, which is more than 2 times larger than the value determined in a 0.1 MH2SO4 solution.


Intelligence with representation.
Behaviour-based robotics has always been inspired by earlier cybernetics work such as that of W. Grey Walter. It emphasizes that intelligence can be achieved without the kinds of representations common in symbolic AI systems. The paper argues that such representations might indeed not be needed for many aspects of sensory-motor intelligence but become a crucial issue when bootstrapping to higher levels of cognition. It proposes a scenario in the form of evolutionary language games by which embodied agents develop situated grounded representations adapted to their needs and the conventions emerging in the population.


Upper Blepharoplasty for Areola Reconstruction.
Blepharoplasty is one of the most common rejuvenating facial plastic surgery procedures. The procedure has been described many times and has very few complications. The tissue removed from the upper eyelid during blepharoplasty can be used as a skin graft for areola reconstruction due to the tissue's similarity to the areola's natural skin. The present study investigated the use of upper blepharoplasty for areola reconstruction. Criteria were patient satisfaction, objective measurements and the assessment of cosmesis by a panel of physicians. All eight patients included in the study were very satisfied with the cosmetic result. Objective measurements and assessment by a panel of physicians using photographs of the reconstructed nipple-areola complex showed very good aesthetic results.


Association Between Air Pollution and Coronary Heart Disease Hospitalizations in Lanzhou City, 2013-2020: a Time Series Analysis.
Coronary heart disease (CHD) is one of the most serious public health problems. However, few studies have focused on the effects of exposure to particulate matter and gaseous air pollutants on CHD. This study aimed to explore the relationship between air pollutants and the number of hospitalized patients with CHD in Lanzhou, and we collected daily data on the number of hospitalized patients with CHD, daily air pollutants, and meteorological factors from 2013 to 2020. A distributed lag nonlinear model (DLNM) combined with a quasi-Poisson regression model was applied to evaluate the relationship between air pollutants and the number of hospitalized patients with CHD. The results indicated that the hysteresis effect of all pollutants except O38h reached its maximum at lag3, and the relative risk of coronary heart disease admission was 1.0014 (95%CI: 1.0004, 1.0023), 1.0003 (95%CI: 1.0000, 1.0006), 1.0020 (95%CI: 1.0004, 1.0035), and 1.0053 (95%CI: 1.0026, 1.0080) when PM2.5, PM10, NO2, and SO2 concentrations were increased by 10 μg/m3, respectively. Each 1 mg/m3 increase in CO concentration was associated with a relative risk of coronary heart disease; hospitalization risk was 1.1076 (95%CI: 1.0530, 1.1650). We observed a relative risk of 0.9991 (95%CI: 0.9986, 0.9999) for each 10 μg/m3 increase in O38h for coronary heart disease admission at lag1. Women and elderly were more susceptible to the impact of air pollution, and the impact was greater during cold seasons. Our results indicate that air pollution increased the risk of hospitalization for CHD in a short term. The research findings can provide strategic insights into the impact of current and future air pollution on CHD.


Mental toughness in sport: motivational antecedents and associations with performance and psychological health.
We argue that basic psychological needs theory (BPNT) offers impetus to the value of mental toughness as a mechanism for optimizing human functioning. We hypothesized that psychological needs satisfaction (thwarting) would be associated with higher (lower) levels of mental toughness, positive affect, and performance and lower (higher) levels of negative affect. We also expected that mental toughness would be associated with higher levels of positive affect and performance and lower levels of negative affect. Further, we predicted that coaching environments would be related to mental toughness indirectly through psychological needs and that psychological needs would indirectly relate with performance and affect through mental toughness. Adolescent cross-country runners (136 male and 85 female, M(age) = 14.36) completed questionnaires pertaining to BPNT variables, mental toughness, and affect. Race times were also collected. Our findings supported our hypotheses. We concluded that BPNT is generative in understanding some of the antecedents and consequences of mental toughness and is a novel framework useful for understanding mental toughness.


Effect of probiotics on thymus size and markers of infection in late infancy: a randomized controlled trial.
Probiotics are known to stimulate the immune system but the effect on thymus size in late infancy is unknown. We examined the effect of probiotics on thymus size and C-reactive protein (CRP) in healthy Danish infants starting daycare. We further examined associations between thymus size, CRP and recent infections. The study included 186 children randomized to a combination of Lactobacillus rhamnosus, LGG® and Bifidobacterium animalis spp. lactis, BB-12® or placebo for 6 months. Thymus size, assessed as thymus index (TI) and thymus weight index (TWI), was measured by ultrasound at baseline and at endpoint. Blood samples were drawn to measure CRP. Infections were parent-reported. There was no significant difference in thymus size between the probiotic group and placebo (p ≥ 0.248) but TWI tended to be higher in the probiotic group corresponding to 5% higher than placebo (p = 0.068) in an adjusted model. There was no effect of probiotics on CRP (p = 0.331). At the endpoint, thymus size was inversely associated with CRP (p ≤ 0.040), diarrhea (p ≤ 0.050), and TI was also associated with the absence from daycare due to respiratory or gastrointestinal infections (p = 0.010). The probiotic intervention had no effect on thymus size or CRP in Danish children at the age of starting daycare. Overall there was no effect on thymus size of a combination of Lactobacillus rhamnosus, LGG® and Bifidobacterium animalis spp. lactis, BB-12® administered to Danish children starting daycare. This study examines the effect of probiotics on thymus size in healthy children when they start daycare thus exposed for infections while their immune system is still developing. This has to our knowledge not been described before. We found no significant difference in thymus size between the probiotic and placebo groups, but for thymus weight index, there was a trend. This should be investigated further in studies designed for this as primary outcome.


[Use of buffalo milk as raw material in the processing of Mozzarella cheese].
The present research aimed to compare the physico-chemical, and organoleptic properties of Mozzarella cheese prepared with buffaloes' milk, cow's milk or blending of equal parts of both types. The manufactured cheeses were evaluated for their organoleptic characteristics as well as for pH value, acidity, moisture, fat, ash, protein, and soluble nitrogen contents. It was verified that buffaloes' milk alone or combined with cow's milk is feasible for preparing Mozzarella cheese, since no differences were found in taste, aroma nor texture as compared with cheeses manufactured with cow's milk alone. Cheeses from buffaloes' milk presented higher yields and higher fat content than the others. Their levels of titratable acidity, moisture, protein and soluble nitrogen were the lowest and their ash content and pH value were the highest. Chemical and physico-chemical characteristics of cheeses manufactured by blending buffaloes' and cow's milk were intermediate in relation to those made with any type of milk alone.


Improved analysis on the viewing angle of integral imaging.
There have already been several analyses about the viewing angle of integral imaging (InIm). However, they can be applied only under the assumption that the original image is merely a single point source and are not suitable for application to an actual condition. We propose an improved analysis based on the actual InIm image, not on a single point source. It is possible to analyze and predict the viewing angle of an InIm system with good accuracy with the new analytic method because almost all the parameters of the InIm system such as the size and focal length of the lens array, image distance, the size and resolution of the image, and the location of the observers are included in this analysis.


Spread of Highly Pathogenic Avian Influenza (HPAI) H5N5 Viruses in Europe in 2016-2017 Appears Related to the Timing of Reassortment Events.
During the epizootic of highly pathogenic avian influenza (HPAI) H5N8 virus in Europe in 2016-2017, HPAI viruses of subtype H5N5 were also isolated. However, the detection of H5N5 viruses was limited compared to H5N8. In this study, we show that the genetic constellation of a newly isolated H5N5 virus is different from two genotypes previously identified in the Netherlands. The introduction and spread of the three H5N5 genotypes in Europe was studied using spatiotemporal and genetic analysis. This demonstrated that the genotypes were isolated in distinguishable phases of the epizootic, and suggested multiple introductions of H5N5 viruses into Europe followed by local spread. We estimated the timing of the reassortment events, which suggested that the genotypes emerged after the start of autumn migration. This may have prevented large-scale spread of the H5N5 viruses on wild bird breeding sites before introduction into Europe. Experiments in primary chicken and duck cells revealed only minor differences in cytopathogenicity and replication kinetics between H5N5 genotypes and H5N8. These results suggest that the limited spread of HPAI H5N5 viruses is related to the timing of the reassortment events rather than changes in virus pathogenicity or replication kinetics.


Quantification of the effect of system and object parameters on edge enhancement in phase-contrast radiography.
The purpose of this study was to evaluate the effects of system parameters (focal spot size, tube voltage, geometry, detector resolution, and image noise) and object characteristics (edge gradient/ shape, composition, thickness, and overlying attenuating material) upon the edge enhancement effect in phase-contrast radiography. Each variable of interest was adjusted and images of a 3 mm lucite phantom were obtained with the other variables remaining constant. A microfocus x-ray source coupled to a CCD camera with an intensifying screen was used to acquire the digital images. Two parameters of image analysis were used to quantify the effects. The edge enhancement index (EEI) was used to measure the absolute degree of edge enhancement, while the edge enhancement to noise ratio (EE/N) was used to measure the conspicuity of the edge enhancement relative to image noise. Little effect on EEI was seen from tube voltage, object thickness, overlying attenuating material, while focal spot size and system geometry demonstrated measurable effects upon the degree of edge enhancement. It was also shown that while the edge enhancement effect over straight edges is highly dependent upon how the edge aligns with the x-ray beam, rounded edges, which better model biological objects, do not suffer from this dependence and the EEI reaches its maximal level at any alignment. Decreasing detector resolution diminished the EEI slightly, but even with pixel sizes of 0.360 x 0.360 mm edge enhancement effects were readily visible. The effect of image noise on EE/N was evaluated using different exposure times showing an expected improvement with longer exposure time with EE/N approaching a plateau at 5 min. Many of the parameters that will go into the design of a future PC-R imaging system have been quantified in terms of their effect on the degree of edge enhancement in the acquired image. These results, taken together, indicate that either a specimen or even clinical breast imaging system could be created with currently available technology. The major limitation to a clinical system would be the low x-ray flux from the microfocal x-ray source.


Estimating prevalence of alcohol abuse and dependence in one general hospital: an approach to reduce sample selection bias.
Prevalence estimates of alcohol abuse or dependence in general hospitals are often limited to single wards, small data collecting periods or insufficient diagnostic procedures. Therefore, the present study aimed to ascertain alcohol abuse or dependence in one general hospital, to compare prevalence data for all the 11 wards and 6 intake months, to establish if screening is sufficient or if a two-step diagnostic procedure is needed, and to determine whether information for an alcohol diagnosis on suspicion is available. A sample of 1309 medical or surgical in-patients were screened by questionnaires or medication for withdrawal, and, if screening-positive, were interviewed with the alcohol section of a standardized psychiatric interview. In screening-negative patients, a diagnosis on suspicion was given if medication to treat withdrawal had been used, or if there was evidence of single criteria of alcohol dependence, somatic disorders from alcohol drinking, raised laboratory parameters on grounds of alcohol drinking or of self-reported high alcohol consumption. Of the medical and surgical in-patients, 20.7 and 16.0% respectively were alcohol abusers or dependents, with a range of prevalence rates of alcohol abuse or dependence among wards of 11.1-32.9% and among intake months between 11.3 and 28.7%. Of the medical department in-patients, 1.9%, and of the surgical in-patients, 2.1%, were screened as false-positive cases. In addition, 5.5% of the medical and 12.0% of the surgical patients were given a diagnosis on suspicion. It is concluded that all general wards and different intake months should be taken into account when estimating prevalence of alcohol abuse or dependence in a general hospital.


[Extensive xanthelasma--a surgical solution: case report].
Xanthelasma can be treated with acids, laser or primary suture, all presenting frequent relapses besides being inefficacious in extensive cases. The authors present the functional and esthetic result of a female patient's case with extensive xanthelasmas on the upper and lower eyelids which were removed combined with upper and lower blepharoplasty, using the skin removed from the upper eyelids to cover the defect in the lower, and vice-versa.


Avoidance of harvesting and sampling artefacts in hydraulic analyses: a protocol tested on Malus domestica.
A prerequisite for reliable hydraulic measurements is an accurate collection of the plant material. Thereby, the native hydraulic state of the sample has to be preserved during harvesting (i.e., cutting the plant or plant parts) and preparation (i.e., excising the target section). This is particularly difficult when harvesting has to be done under transpiring conditions. In this article, we present a harvesting and sampling protocol designed for hydraulic measurements on Malus domestica Borkh. and checked for possible sampling artefacts. To test for artefacts, we analysed the percentage loss of hydraulic conductivity, maximum specific conductivity and water contents of bark and wood of branches, taking into account conduit length, time of day of harvesting, different shoot ages and seasonal effects. Our results prove that use of appropriate protocols can avoid artefactual embolization or refilling even when the xylem is under tension at harvest. The presented protocol was developed for Malus but may also be applied for other angiosperms with similar anatomy and refilling characteristics.


Postoperative Pulmonary Complications after Percutaneous Nephrolithotomy Under Spinal Anesthesia.
To evaluate risk factors and outcomes of Pulmonary Complications (PCs) in Percutaneous Nephrolithotomy (PCNL) under Spinal anesthesia (SA). 286 patients who underwent PCNL under SA between 2017 and 2021 were identified retrospectively and divided into group 1 (clinically significant PCs) and group 2 (no clinically significant PCs). Demographic, preoperative, and intraoperative variables and postoperative outcomes were compared between both groups. Independent risk factors for PCs were evaluated by univariable and multivariable logistic regression analyses. PCs were noted in 90 patients (31.5%). Advanced age (P = .011), high body mass index (BMI) (P < .001), and the presence of chronic obstructive pulmonary disease (COPD) (P < .001) were risk factors for PCs. SA is an effective method of anesthesia for all PCNL patients and carries a lower rate of PCNL-associated PCs. Risk factors for PCs after PCNL were advanced age, obesity, and preoperative COPD.


Analytical Solutions of Three-Dimensional Contaminant Transport Models with Exponential Source Decay.
Despite the availability of numerical models, interest in analytical solutions of multidimensional advection-dispersion systems remains high. Such models are commonly used for performing Tier I risk analysis and are embedded in many regulatory frameworks dealing with groundwater contamination. In this work, we develop a closed-form solution of the three-dimensional advection-dispersion equation with exponential source decay, first-order reaction, and retardation, and present an approach based on some ease of use diagrams to compare it with the integral open form solution and with earlier versions of the closed-form solution. The comparison approach focuses on the relative differences associated with source decay and the effect of simulation time. The analysis of concentration contours, longitudinal sections, and transverse sections confirms that the closed-form solutions studied can be used with acceptable approximation in the central area of a plume bound transversely within the source width, both behind and beyond the advective front and for concentration values up to two orders of magnitude less than the initial source concentration. As the proposed closed-form model can be evaluated without nested numerical computations and with simple mathematical functions, it can be very useful in risk assessment procedures.


Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation-Mediated Repression of the Hedgehog/Gli1 Pathway.
Purpose: Agents extracted from natural sources with antitumor property have attracted considerable attention from researchers and clinicians because of their safety, efficacy, and immediate availability. Degalactotigonin (DGT), extracted from Solanum nigrum L, has anticancer properties without serious side effects. Here, we explored whether DGT can inhibit the growth and metastasis of osteosarcoma.Experimental Design: MTT, colony formation, and apoptosis assays were performed to analyze the effects of DGT on osteosarcoma cell viability in vitro The migration and invasion abilities were measured using a Transwell assay. Animal models were used to assess the roles of DGT in both tumor growth and metastasis of osteosarcoma. Gli1 expression and function were measured in osteosarcoma cells and clinical samples. After DGT treatment, Gli1 activation and the phosphorylation status of multiple cellular kinases were measured with a luciferase reporter and phospho-kinase antibody array.Results: DGT inhibited proliferation, induced apoptosis, and suppressed migration and invasion in osteosarcoma cells. DGT, injected intraperitoneally after tumor inoculation, significantly decreased the volume of osteosarcoma xenografts and dramatically diminished the occurrence of osteosarcoma xenograft metastasis to the lungs. Mechanistically, DGT inhibited osteosarcoma growth and metastasis through repression of the Hedgehog/Gli1 pathway, which maintains malignant phenotypes and is involved in the prognosis of osteosarcoma patients. DGT decreased the activity of multiple intracellular kinases that affect the survival of osteosarcoma patients, including GSK3β. In addition, DGT represses the Hedgehog/Gli1 pathway mainly through GSK3β inactivation.Conclusions: Our studies provide evidence that DGT can suppress the growth and metastasis of human osteosarcoma through modulation of GSK3β inactivation-mediated repression of the Hedgehog/Gli1 pathway. Clin Cancer Res; 24(1); 130-44. ©2017 AACR.


Pirfenidone: a novel pharmacological agent that inhibits leiomyoma cell proliferation and collagen production.
There are currently no effective, long-term drug therapies for the treatment of leiomyomas. Pirfenidone (Marnac, Inc.) is an antifibrotic agent that is being tested for use in patients with pulmonary fibrosis. Because leiomyomas are characterized also by increased cell proliferation and tissue fibrosis, we examined the effects of pirfenidone on cell proliferation and collagen expression in cultured myometrial and leiomyoma smooth muscle cells. Effects of pirfenidone on proliferation of myometrial and leiomyoma cells were measured using tritiated thymidine incorporation assays and changes in actual cell numbers. Possible cytotoxic effects were examined using lactate dehydrogenase assays and trypan blue exclusion. Effects on collagen type I and type III production were assessed by Northern blotting. Doses of pirfenidone tested were: 0, 0.01, 0.1, 0.3, and 1.0 mg/mL. Serum-stimulated increases in DNA synthesis and cell proliferation by myometrial and leiomyoma cells were significantly inhibited in a dose-dependent manner by pirfenidone. Densitometric analysis of Northern blots showed significantly decreased expression of collagen type I and type III messenger RNAs in both leiomyoma and myometrial cells. Lactate dehydrogenase assays and trypan blue exclusion measurements showed no cytotoxic effect of pirfenidone at concentrations that inhibited cell proliferation and collagen production. Pirfenidone is an effective inhibitor of myometrial and leiomyoma cell proliferation in vitro and reduces the messenger RNA levels of collagen types I and III in a dose-dependent manner. This compound may prove to be an effective nonsteroidal therapy for treatment of uterine leiomyomas.


Phencyclidine dependence: the relationship of dose and serum concentrations to operant behavioral effects.
The dependence-producing properties of 10 days of chronic i.v. infusions of phencyclidine (PCP) and the relationship between PCP serum concentrations and behavioral effects were studied in Sprague-Dawley rats. For dependence studies, rats were trained to respond for food under a fixed-ratio 30 schedule during half-hour response periods every 6 hr. After training, implantation of jugular catheters, and restabilization of behavior, the rats were infused with PCP.HCl at 3.2, 5.6, 10.0 or 17.8 mg/kg/day (n = 5 or 6 per dose). The two higher doses initially decreased response rates, but tolerance developed within 4 to 5 days. When PCP infusions were terminated, dose-dependent decreases in session response rate occurred in the three highest dose groups (P less than .05). Mild, overt signs of abstinence were observed only in the highest dose group. Response rates returned to base line within 2 to 3 days after stopping PCP infusions. PCP serum concentrations in rats infused with 10 mg of PCP.HCl/kg/day for 10 days were stable from hour 24 to day 10 (mean steady-state concentration (+/- S.D.) = 97 (+/- 20) ng of PCP/ml; n = 4). The average terminal elimination half-life after stopping infusions on day 10 was 4.6 hr. Comparison of the average response rates with the average serum concentrations showed that during the first 24 hr of infusions, the rate of responding for food decreased as PCP concentrations increased; however, once the animals became tolerant to PCP there was no relationship. In contrast, during the first 24 hr after stopping infusions, response rates decreased as serum concentrations decreased.


Evidence of changing migratory patterns of wild Atlantic salmon Salmo salar smolts in the River Bush, Northern Ireland, and possible associations with climate change.
The migration patterns, timing and biological characteristics of wild Atlantic salmon Salmo salar smolts in the River Bush, Northern Ireland, were examined over the period 1978-2008. A distinct change in the timing of the smolt run was detected with progressively earlier emigration periods evident across the time series. The shift in run timing ranged from 3.6 to 4.8 days 10 years(-1) for a range of standard migratory audit points. The timing of smolt emigration has been linked to ambient river temperature patterns. Distinct seasonal patterns were evident for biological characteristics of River Bush smolts with mean age and fork length decreasing throughout the emigration period. Marine survival patterns in 1 sea winter River Bush S. salar were strongly influenced by the run timing of the preceding smolt year such that later emigrating cohorts demonstrated increased survival. Possible mechanisms for this relationship based on local climatic variation have been explored, including the effect of potential thermal mismatch between freshwater and marine environments.


Computer-assisted navigation in complex cervical spine surgery: tips and tricks.
Stereotactic navigation is quickly establishing itself as the gold standard for accurate placement of spinal instrumentation and providing real-time anatomic referencing. There have been substantial improvements in computer-aided navigation over the last decade producing improved accuracy with intraoperative scanning while shortening registration time. The newest iterations of modeling software create robust maps of the anatomy while tracking software localizes instruments in multiple display modes. As a result, stereotactic navigation has become an effective adjunct to spine surgery, particularly improving instrumentation accuracy in the setting of atypical anatomy. This article provides an overview of stereotactic navigation applied to complex cervical spine surgery, details the means for registration and direct referencing, and shares our preferred methods to implement this promising technology.


Variation in AUDIT (Alcohol Use [correction of Used] Disorder Identification Test) scores within the first weeks of imprisonment.
Although the prevalence of alcohol problems amongst detainees is suspected to be high, often only more flagrant problems are detected, restricting the possibilities for intervention in alcohol misuse and reducing opportunities for preventive efforts. This study examined the re-test reliability of AUDIT (the Alcohol Use Disorder Identification Test) in screening prisoners AUDIT was administered for the first time on the day of entry to prison and again about 15 days later. The results were analysed according to two AUDIT thresholds: a score of 8 or higher and 12 or higher. Of 75 consecutive entrants tested, 47 male prisoners completed the study. At the first administration, 19.1% of these 47 men met criteria for a probable alcohol problem but this percentage rose to 59.6% on the second occasion (P = 0.0001). The proportion of subjects with a score 12 or higher (probably dependent) was 10.6% the first time versus 42.6% the second time (P = 0.0001). In the 19 who scored positive at the second administration only, changes in answers to the 10 items were coherent with a total score growing from 3.0 to 18.1 (P = 0.0001). No prisoner had a lower AUDIT score on the second administration. As alcohol problems are not routinely considered during the medical and biological examination at entry, no confirmation of the AUDIT results could be obtained, although those obtained at the second administration fitted well with the prevalence rates in previous reports. AUDIT, for the purpose of giving a prevalence estimate or to enter appropriate prisoners into more detailed assessment or interventions, should not be conducted immediately at entry, but some weeks later.


IFN-gamma and TNF regulate macrophage expression of the chemotactic S100 protein S100A8.
The murine calcium-binding protein S100A8 is a potent chemoattractant for neutrophils and monocytes in vivo and in vitro but may also play a protective role. We show that the kinetics of induction of S100A8 mRNA in elicited murine macrophages (Mac) by LPS, IFN-gamma, and TNF were distinct from the C-C chemokines monocyte chemoattractant protein-1 (MCP-1), macrophage-inflammatory protein-1alpha (MIP-1alpha), and RANTES. Monomeric S100A8 was predominantly secreted. IFN substantially increased S100A8 mRNA levels after 1 h with optimal induction after 12 h; induction by TNF was slower and more sustained. TNF did not up-regulate MCP-1 and MIP-1alpha mRNA in these cells. Luciferase reporter assays confirmed that LPS and IFN induce S100A8 gene transcription and mRNA in LPS-treated Mac showed little decay over 16 h, whereas transcripts induced by IFN and TNF were markedly less stable. Newly synthesized proteins may be required for mRNA transcription and stabilization in response to LPS. S100A9 associates with A8 in neutrophils, but was not coinduced with S100A8. S100A8 gene induction in Mac stimulated with LPS and IFN may be modulated by mobilization of intracellular Ca2+ concentration from distinct intracellular stores and/or the extracellular compartment and by distinct pathways involving protein kinase C and leading to activation of mitogen-activated protein kinase.


Vasculitis associated with tumor necrosis factor-α inhibitors.
To describe the clinical characteristics, histopathologic features, and outcomes of patients in whom vasculitis developed in association with use of tumor necrosis factor-α (TNF-α) inhibitors. This is a retrospective review of patients evaluated at Mayo Clinic, Rochester, Minnesota, from January 1, 1998, through March 31, 2011, with a diagnosis of vasculitis induced by anti-TNF-α therapy. Of 8 patients with vasculitis associated with anti-TNF-α therapy (mean age, 48.5 years), 6 (75%) were female. Four (50%) had rheumatoid arthritis, 1 (13%) had Crohn disease, and 3 (38%) had ulcerative colitis. Five (63%) were treated with infliximab, 2 (25%) with etanercept, and 1 (13%) with adalimumab. The mean duration of treatment before development of vasculitis was 34.5 months. The skin was the predominant organ affected (5 patients [63%]), with the most common cutaneous lesion being palpable purpura (4 of 5 [80%]). Two organs involved in systemic vasculitis were the peripheral nervous system (4 patients [50%]) and kidney (1 patient [13%]). All cases of vasculitis were histopathologically confirmed. Seven of 8 patients improved with discontinuation of therapy (mean time to resolution, 6.9 months) and adjuvant treatment (all 8 received prednisone; another agent was also used in 7); rechallenge with anti-TNF-α therapy was not attempted in any patient. At last follow-up, no patients had experienced a recurrence of vasculitis after therapy discontinuation. Cutaneous small-vessel vasculitis was the most common finding, but systemic vasculitis, including peripheral nerve and renal vasculitis, was also frequently observed.


Hepatitis-B virus: replication cycle, targets, and antiviral approaches.
An estimated 257 million people are chronic carriers of hepatitis-B virus (HBV) infection, which resulted in around 1 million deaths, mainly due to hepatocellular carcinoma (HCC). Long-term nucleotide analog treatment of HBV infection is associated with favorable prognosis, no disease progression, and a reduction of HCC risk, but lifelong treatments are required. A better understanding of HBV replication cycle and the host immune response will likely improve the identification of new targets for drug development. Studies are ongoing to determine if it is possible to successfully combine direct-acting antivirals (DAA) with an immunomodulatory therapy to allow increased cure rates. This review will start with summarizing the HBV replication cycle, recall current treatments, and then discuss potential targets and antiviral approaches in development to optimistically reach the HBV cure.


CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: regulation by BET.
Asthma is characterized by airway inflammation and remodeling and CXCL8 is a CXC chemokine that drives steroid-resistant neutrophilic airway inflammation. We have shown that airway smooth muscle (ASM) cells isolated from asthmatic individuals secrete more CXCL8 than cells from nonasthmatic individuals. Here we investigated chromatin modifications at the CXCL8 promoter in ASM cells from nonasthmatic and asthmatic donors to further understand how CXCL8 is dysregulated in asthma. ASM cells from asthmatic donors had increased histone H3 acetylation, specifically histone H3K18 acetylation, and increased binding of histone acetyltransferase p300 compared with nonasthmatic donors but no differences in CXCL8 DNA methylation. The acetylation reader proteins Brd3 and Brd4 were bound to the CXCL8 promoter and Brd inhibitors inhibited CXCL8 secretion from ASM cells by disrupting Brd4 and RNA polymerase II binding to the CXCL8 promoter. Our results show a novel dysregulation of CXCL8 transcriptional regulation in asthma characterized by a promoter complex that is abnormal in ASM cells isolated from asthmatic donors and can be modulated by Brd inhibitors. Brd inhibitors may provide a new therapeutic strategy for steroid-resistant inflammation.


Effect of hormonal contraceptive use on HIV progression in female HIV seroconverters in Rakai, Uganda.
To assess the association between hormonal contraceptive use and HIV progression. A retrospective analysis of 625 female HIV seroconverters from a Ugandan cohort study. Multivariate Cox regression analyses incorporating time-varying hormonal contraceptive exposure were used to estimate the adjusted hazard ratios of death, and a composite outcome of AIDS or death, associated with hormonal contraceptive use. Sensitivity analyses included lagging hormonal contraceptive exposure, varying comparison groups, and separately assessing effects of oral and injectable contraceptives. A total of 27.5% of women reported ever using hormonal contraception. Of 625 women, 104 (16.6%) died and 291 (46.6%) progressed to AIDS or death during observation. Time-varying hormonal contraceptive use was not associated with an increased hazard of death as compared with nonuse of hormonal contraception (adjusted hazard ratio 0.76, 95% confidence interval 0.41-1.39, P = 0.37), and was associated with a significantly reduced hazard of progression to AIDS or death (adjusted hazard ratio 0.70, 95% confidence interval 0.50-0.97, P = 0.03). None of the sensitivity analyses suggested an adverse effect of hormonal contraception on HIV progression. Hormonal contraceptive use was not associated with faster progression to death, and was associated with a reduced hazard of progression to the composite outcome of AIDS or death.


IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4-CD8- IL-17-producing T cells.
IL-2, a cytokine with pleiotropic effects, is critical for immune cell activation and peripheral tolerance. Although the therapeutic potential of IL-2 has been previously suggested in autoimmune diseases, the mechanisms whereby IL-2 mitigates autoimmunity and prevents organ damage remain unclear. Using an inducible recombinant adeno-associated virus vector, we investigated the effect of low systemic levels of IL-2 in lupus-prone MRL/Fas(lpr/lpr) (MRL/lpr) mice. Treatment of mice after the onset of disease with IL-2-recombinant adeno-associated virus resulted in reduced mononuclear cell infiltration and pathology of various tissues, including skin, lungs, and kidneys. In parallel, we noted a significant decrease of IL-17-producing CD3(+)CD4(-)CD8(-) double-negative T cells and an increase in CD4(+)CD25(+)Foxp3(+) immunoregulatory T cells (Treg) in the periphery. We also show that IL-2 can drive double-negative (DN) T cell death through an indirect mechanism. Notably, targeted delivery of IL-2 to CD122(+) cytotoxic lymphocytes effectively reduced the number of DN T cells and lymphadenopathy, whereas selective expansion of Treg by IL-2 had no effect on DN T cells. Collectively, our data suggest that administration of IL-2 to lupus-prone mice protects against end-organ damage and suppresses inflammation by dually limiting IL-17-producing DN T cells and expanding Treg.


Bioavailability of dietary (poly)phenols: a study with ileostomists to discriminate between absorption in small and large intestine.
A feeding study was carried out in which six healthy ileostomists ingested a juice drink containing a diversity of dietary (poly)phenols derived from green tea, apples, grapes and citrus fruit. Ileal fluid and urine collected at intervals over the ensuing 24 h period were then analysed by HPLC-MS. Urinary excretions were compared with results obtained in an earlier study in which the juice drink was ingested by ten healthy control subjects with an intact colon. Some polyphenol components, such as (epi)catechins and (epi)gallocatechin(s), were excreted in urine in similar amounts in ileostomists and subjects with an intact colon, demonstrating that absorption took place principally in the small intestine. In the urine of ileostomists, there were reduced levels of other constituents, including hesperetin-7-O-rutinoside, 5-O-caffeoylquinic acid and dihydrochalcones, indicating their absorption in both the small and large intestine. Ileal fluid analysis revealed that even when absorption occurred in the small intestine, in subjects with a functioning colon a substantial proportion of the ingested components still pass from the small into the large intestine, where they may be either absorbed before or after catabolism by colonic bacteria.


[Ultrastructural and biochemical evidence of brain damage by the serum IgG fraction of the blood of schizophrenics].
Using electron microscopic and biochemical studies, the rat brain was examined following the intracisternal administration of IgG obtained from schizophrenics' blood serum. The resultant ultrastructural impairments of the sensorimotor cortex and activation of lipid peroxidation processes were similar to the alterations detected in the brain of the schizophrenic patients. The results suggest that the circulating cerebral antibodies in schizophrenics possess a membranotropic effect and may induce various structural and functional disorders in the central nervous system of these patients.


P4 suicidality screener: Literature synthesis and results from two randomized trials.
To synthesize the literature on use of the P4 suicidality screener since its introduction in 2010 and to summarize results from 2 randomized clinical trials. A PubMed search was conducted from 2010 to 2023 to retrieve studies reporting on use of the P4. Also, data was extracted from the CAMMPS and SCOPE trials in which the P4 was periodically administered over 12 months when the 9th item of the PHQ-9 was endorsed. A total of 21 research studies using the P4 were found, of which 12 provided some data on P4 findings. Additionally, another 7 protocol papers reported intended use of the P4 as a study measure. In our 2 trials, the 9th item was endorsed 259 (12.5%) times in 2068 administrations of the PHQ-9. Higher risk suicidal ideation was identified in 4.1% (12/294) of CAMMPS participants and 2.8% (7/250) of SCOPE participants. No suicide attempts occurred over the 12 months in either trial. The P4 has had moderate use as a brief suicidality screener and is an efficient way to identify the small proportion of depressed patients with higher risk suicidality. Studies comparing the P4 with other common suicidality screeners would further inform use.


Consolidation with diffuse or focal high attenuation: computed tomography findings.
This pictorial essay aims to present various lesions that could present as consolidations with diffuse of focal high attenuation on computed tomography, helping to make the diagnosis more confident and specific. The radiologic literature has limited information about such findings and the role of computed tomography in the differential diagnosis. The following diseases are presented: metastatic pulmonary calcification, pulmonary alveolar microlithiasis, amiodarone lung, talcosis, iodinated oil embolism, tuberculosis, silicoproteinosis, and amyloidosis. In conclusion, air-space consolidations can be seen in a wide variety of diseases affecting the lungs. The identification of the different patterns of consolidation with focal high attenuation narrows the differential diagnosis. We present a diagnostic approach based on appearance and distribution of these lesions.


Osteopontin is a downstream effector of the PI3-kinase pathway in melanomas that is inversely correlated with functional PTEN.
The tumor suppressor PTEN antagonizes phosphatidylinositol 3-kinase (PI3K), which contributes to tumorigenesis in many cancer types. While PTEN mutations occur in some melanomas, their precise mechanistic consequences have yet to be elucidated. We sought to identify novel downstream effectors of PI3K using a combination of genomic and functional tests. Microarray analysis of 53 melanoma cell lines identified 610 genes differentially expressed (P<0.05) between wild-type lines and those with PTEN aberrations. Many of these genes are known to be involved in the PI3K pathway and other signaling pathways influenced by PTEN. Validation of differential gene expression by qRT-PCR was performed in the original 53 cell lines and an independent set of 18 melanoma lines with known PTEN status. Osteopontin (OPN), a secreted glycophosphoprotein that contributes to tumor progression, was more abundant at both the mRNA and protein level in PTEN mutants. The inverse correlation between OPN and PTEN expression was validated (P<0.02) by immunohistochemistry using melanoma tissue microarrays. Finally, treatment of cell lines with the PI3K inhibitor LY294002 caused a reduction in expression of OPN. These data indicate that OPN acts downstream of PI3K in melanoma and provides insight into how PTEN loss contributes to melanoma development.


Source identification of volcanic ashes by geochemical analysis of well preserved lacustrine tephras in Nahuel Huapi National Park.
Well preserved volcanic ashes produced in recent events, recovered from sedimentary sequences extracted from three lakes belonging to Nahuel Huapi National Park, Northern Patagonia, were geochemically characterized in order to reveal patterns that allow the identification of the source. Two water bodies are situated in the direct impact area of volcanoes Calbuco and Puyehue-Cordón Caulle, while the third, lake Moreno, is situated in-between. The sedimentary sequences were dated by (210)Pb and (137)Cs techniques; the elemental composition was determined by Instrumental Neutron Activation Analysis. Distinctive patterns were found out when comparing glass shards, and also white pumice but in a lesser degree, of tephra layers extracted from lake Ilón, related mostly to volcano Calbuco events, and lake Nahuel Huapi (Brazo Rincón site), associated to Puyehue-Cordón Caulle eruptions. The geochemical parameters that showed decisive differences were SiO(2) and Na(2)O+K(2)O contents, the Eu anomaly, Rare Earth element ratios; the concentration of incompatible elements Cs, Rb, Th, Hf, Ta and Zr, and the compatible elements Cr and V. The six upper tephra layers extracted from lake Moreno showed geochemical patterns that allowed clear association with Calbuco and Puyehue-Cordón Caulle sources. These results set up the base for tephrochronological applications in historical periods in Nahuel Huapi National Park area.


Improving the sustainability of ex situ populations with mate choice.
Many breeding programs managed by the Association of Zoos and Aquariums' (AZA) Species Survival Plans® (SSPs) are not meeting goals for population size and genetic diversity due to failure of recommended pairs to breed successfully. According to AZA Population Management Center analyses, as many as 80% of recommended breeding pairs fail to produce young before the next breeding and transfer plan is issued. Determining reasons for failure and ensuring that a specific pairing produces offspring can be challenging. Mate incompatibility, one possible reason for failure, might be addressed by allowing mate choice. Although many SSP® coordinators and breeding managers, who implement breeding recommendations at their institutions, recognize the potential benefits of mate choice, examples and models for presenting and assessing choice are lacking. Here we review examples from birds, rodents, lagomorphs, marsupials, carnivores, fishes, and insects where mate choice has been incorporated. These examples provide strong evidence that free mate choice and mating with preferred partners increase a variety of reproductive success measurements when compared to assigned mate pairings. We suggest innovative housing and breeding arrangements for better incorporating mate choice into the management strategies for species held ex situ. Further, we discuss the fitness consequences and welfare implications of allowing choice. We advocate for a more systematic use of behavioral research in cooperative breeding programs. Behavioral management for mating can yield more successful programs, thus ensuring SSP® genetic and demographic goals are met, while simultaneously improving welfare.


[Influence of fat diet in glicidic metabolism in obese women with Pro12Pro genotype in PPARgamma2 gene].
The peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) is an adipogenic transcription factor that influences in insulin resistance (IR) in the presence of agonists such as polyunsaturated fatty acids (PUFA). Evaluate the influence of dietary fat in glicidic metabolism in morbidly obese women with Pro12Pro genotype in the gene PPARgamma2. Were selected 25 women with genotype Pro12Pro. The fat intake was estimated by food records, being used for the division of groups, GA (until 30% of the total energy expenditure (TEE)) and GB (greater than 30% of the TEE). Biochemical and anthropometric evaluations were conducted in fasting, following the test meal high in n-6 PUFA and postprandial biochemical evaluations. IR and insulin sensitivity (IS) were assessed by HOMA-IR (Homeostasis Model Assessment) and QUICKI (Quantitative Insulin Sensitivity Check Index), respectively. GA presented normal HOMAIR and QUICKI. GB presented higher body mass index (BMI), HOMA-IR, saturated fatty acids (SFA) and monounsaturated (MUFA) intake higher, compared with GA (p < 0.05). In GA, the MUFA intake was negatively correlated with HOMA-IR, fasting glucose and insulin, and positively with QUICKI. The fat and SFA intake contributed to the increase in body mass and IR. However, MUFA intake may have reduced the impact of high fat diet in glicidic metabolism. It is suggested that obese women with Pro12Pro genotype in the PPARgamma2 gene avoid high fat and SFA diets, prioritizing MUFA for controlling obesity and improving the IS.


Extratemporal ictal clinical features in hippocampal sclerosis: their relationship to the degree of hippocampal volume loss and to the outcome of temporal lobectomy.
Since extratemporal clinical features in patients with unilateral hippocampal sclerosis (HS) are likely to indicate aberrant ictal spread or a more extensive epileptogenic zone, we asked whether such features are associated with more severe HS and a worse outcome following temporal lobectomy. We reviewed all patients (174) who had undergone temporal lobectomy for histologically proven unilateral HS related temporal lobe epilepsy between 1997-2005 at the National Hospital for Neurology and Neurosurgery. We divided patients into those with severe HS (side-to-side ratio < 0.6) and those with mild HS (side-to-side ratio > 0.75). We examined all seizures recorded on electroencephalography (EEG) video telemetry in these patients for clinical features of temporal lobe epilepsy. The postsurgical outcome was classified using the Engel classification at the time of follow up (median 4.7 years, range 1-9 years). Patients (28 out 39) with severe HS had atypical features compared to 7 out of 27 in the mild HS [Chi square (chi(2)) test, p = 0.0013]. The mean number of atypical clinical features was 2.2 in the severe HS group and 0.62 in the mild HS group (Mann Whitney U Test, p < 0.001). The percentage of postsurgery seizure freedom (class 1 Engel classification) was 87%, and there was no significant effect of the presence of atypical clinical features. This study shows that atypical (extratemporal) clinical features tend to occur more frequently in patients with severe HS and do not correlate with worse surgical outcome.


Mycotoxin production and postharvest storage rot of ginger (Zingiber officinale) by Penicillium brevicompactum.
Twenty naturally infected ginger (Zingiber officinale) rhizomes displaying visible mold growth were examined to identify the fungi and to evaluate the presence of fungal secondary metabolites. Penicillium brevicompactum was the predominant species isolated from 85% of the samples. Mycophenolic acid was identified from corresponding tissue extracts. Because mycophenolic acid is a potent immunosuppressant and synergistic mycotoxicosis studies involving human consumption have not been carried out on this metabolite, spoilage of commercially marketed produce caused by P. brevicompactum is a concern. This is the first reported occurrence of mycophenolic acid in commercially sold plant food products.


Opioid antagonists in the treatment of opioid-induced constipation and pruritus.
To describe the role of opioid antagonists in the treatment of opioid-induced constipation and pruritus. A MEDLINE search was performed (1966-February 2000) for narcotics and opioid antagonists. Results were limited to English-language and clinical trials. Background information was obtained from pharmacology and pharmacotherapy references and review articles. Hand searching of selected bibliographies yielded several references. Studies were reviewed that examined the use of naloxone, naltrexone, and methylnaltrexone for opioid-related constipation and pruritus. Selected citations included various clinical trials and case series. Opioid agents are used for cancer and nonmalignant pain. Peripheral opioid receptor stimulation due to endogenous (i.e., endorphins) or exogenous (i.e., morphine) stimulants may result in negative adverse effects, including constipation and pruritus. Adjuvant agents, such as laxatives and antihistamines, are often used to treat these adverse effects, but are themselves associated with adverse effects and are sometimes ineffective. Opioid antagonists have demonstrated reversal of peripheral opioid receptor stimulation. Clinical trials show adequate maintenance of pain control, as well as decreases in opioid-induced constipation and pruritus. Opioid antagonists offer a therapeutic alternative to conventional adjuvant agents, with the risk of loss of analgesia at higher doses. Methylnaltrexone offers the advantage of peripheral action only, therefore not reversing analgesia. Results are promising; however, larger clinical trials are necessary before opioid antagonists become the standard of care for opioid-induced constipation and pruritus.


Impact evaluation of a youth sexually transmissible infection awareness campaign using routinely collected data sources.
Young people are at high risk of sexually transmissible infections (STI) and notifications of chlamydia are rising rapidly. In 2007, a Victorian multimedia campaign aimed to increase STI testing and condom use among 18-25-year-olds. We conducted a retrospective impact evaluation using multiple sources of routinely collected data. Population-level chlamydia testing data from general practice, chlamydia testing data from five government primary care clinics with a high caseload of young people, and behavioural data from an annual youth behavioural survey were analysed. Analyses included time-series regression to assess trends in testing levels, Kruskal-Wallis tests to assess changes in positivity, and χ(2)-tests to assess knowledge and behaviour change. There was no significant difference in the slope of monthly chlamydia testing in population-level or clinic-based surveillance during the campaign compared with before or after the campaign, and no changes in chlamydia positivity. Between 2007 and 2008, there was a significant increase in STI knowledge among females (P<0.01) and in the proportion of females reporting always using a condom with casual (P=0.04) and new sexual partners (P<0.01) in the annual behavioural survey. Our findings suggest the campaign had no impact on STI testing but may have contributed to an increase in knowledge and condom use among females; however, this increase could not be directly attributed to the campaign. Future campaigns targeting young people for STI testing should consider alternative messages and approaches, and include robust evaluation mechanisms to measure campaign impact prospectively.


Maternal exposure to environmental endocrine disruptors during pregnancy is associated with pediatric germ cell tumors.
Environmental endocrine disruptors (EEDs) are natural or synthetic chemical compounds that interfere with normal endocrine function in both wildlife and humans. Previous studies have indicated that EEDs may contribute to oncogenesis. This study explores the relationship between EEDs and pediatric germ cell tumors (GCTs). A case-control study was conducted in 84 pediatric patients from 2014 to 2017, including 42 subjects with immature teratoma, yolk sac tumor, or germinoma, and 42 controls who experienced pneumonia or trauma. Serum PFASs, including PFBS, PFHpA, PFHxS, PFOA, PFOS, PFNA, PFDA, PFUA, PFOSA, and PFDoA, were measured in each subject, and their history of possible EED exposure was reviewed. Six of the 10 measured PFASs were significantly increased in the GCT group relative to the control group. With respect to lifestyle history, only PFHxS levels were statistically significantly associated with GCTs as determined by logistic regression analysis. The odds ratio for a 1 ng/L increase in PFHxS was 19.47 (95% CI: 4.20-90.26). Furthermore, in the GCT and control groups, both parental consumption of barbecued foods and hair dye use among parents were significantly correlated with elevated serum PFHxS levels (ρ = 0.383, 0.325 in the patient group and ρ = 0.370, 0.339 in the control group; p < 0.05). Our study confirmed that children with GCTs from our institute had relatively high serum levels of PFASs relative to those of tumor-free pediatric patients. Serum PFHxS levels were independently associated with germ cell tumor occurrence.


Identification of proteins containing cysteine residues that are sensitive to oxidation by hydrogen peroxide at neutral pH.
A procedure for detecting proteins that contain H(2)O(2)-sensitive cysteine (or selenocysteine) residues was developed as a means with which to study protein oxidation by H(2)O(2) in cells. The procedure is based on the facts that H(2)O(2) and biotin-conjugated iodoacetamide (BIAM) selectively and competitively react with cysteine residues that exhibit a low pK(a), and that the decrease in the labeling of cell lysate proteins with BIAM caused by prior exposure of cells to H(2)O(2) or to an agent that induces H(2)O(2) production can be monitored by streptavidin blot analysis. This procedure was applied to rat pheochromocytoma PC12 cells directly treated with H(2)O(2), mouse hippocampal HT22 cells in which H(2)O(2) production was induced by glutamate, and human erythroleukemia K562 cells in which H(2)O(2) production was induced by phorbol myristate acetate. It revealed that several cell proteins contain cysteine or selenocysteine residues that are selectively oxidized by H(2)O(2). Three of these H(2)O(2)-sensitive proteins were identified as a member of the protein disulfide isomerase family, thioredoxin reductase, and creatine kinase, all of which were previously known to contain at least one reactive cysteine or selenocysteine at their catalytic sites. This procedure should thus prove useful for the identification of proteins that are oxidized by H(2)O(2) generated in response to a variety of extracellular agents.


The Energy of Muscle Contraction. II. Transverse Compression and Work.
In this study we examined how the strain energies within a muscle are related to changes in longitudinal force when the muscle is exposed to an external transverse load. We implemented a three-dimensional (3D) finite element model of contracting muscle using the principle of minimum total energy and allowing the redistribution of energy through different strain energy-densities. This allowed us to determine the importance of the strain energy-densities to the transverse forces developed by the muscle. We ran a series of in silica experiments on muscle blocks varying in initial pennation angle, muscle length, and external transverse load. As muscle contracts it maintains a near constant volume. As such, any changes in muscle length are balanced by deformations in the transverse directions such as muscle thickness or muscle width. Muscle develops transverse forces as it expands. In many situations external forces act to counteract these transverse forces and the muscle responds to external transverse loads while both passive and active. The muscle blocks used in our simulations decreased in thickness and pennation angle when passively compressed and pushed back on the load when they were activated. Activation of the compressed muscle blocks led either to an increase or decrease in muscle thickness depending on whether the initial pennation angle was less than or greater than 15°, respectively. Furthermore, the strain energy increased and redistributed across the different strain-energy potentials during contraction. The volumetric strain energy-density varied with muscle length and pennation angle and was reduced with greater transverse load for most initial muscle lengths and pennation angles. External transverse load reduced the longitudinal muscle force for initial pennation angles of β0 = 0°. Whereas for pennate muscle (β0 > 0°) longitudinal force changed (increase or decrease) depending on the muscle length, pennation angle and the direction of the external load relative to the muscle fibres. For muscle blocks with initial pennation angles β0 ≤ 20° the reduction in longitudinal muscle force coincided with a reduction in volumetric strain energy-density.