Effect of inhibition of glutathione synthesis on insulin action: in vivo and in vitro studies using buthionine sulfoximine.
Decreased cellular GSH content is a common finding in experimental and human diabetes, in which increased oxidative stress appears to occur. Oxidative stress has been suggested to play a causative role in the development of impaired insulin action on adipose tissue and skeletal muscle. In this study we undertook to investigate the potential of GSH depletion to induce insulin resistance, by utilizing the GSH synthesis inhibitor, L-buthionine-[S,R]-sulfoximine (BSO). GSH depletion (20-80% in various tissues), was achieved in vivo by treating rats for 20 days with BSO, and in vitro (80%) by treating 3T3-L1 adipocytes with BSO for 18 h. No demonstrable change in the GSH/GSSG ratio was observed following BSO treatment. GSH depletion was progressively associated with abnormal glucose tolerance test, which could not be attributed to impaired insulin secretion. Skeletal muscle insulin responsiveness was unaffected by GSH depletion, based on normal glucose response to exogenous insulin, 2-deoxyglucose uptake measurements in isolated soleus muscle, and on normal skeletal muscle expression of GLUT4 protein. Adipocyte insulin responsiveness in vitro was assessed in 3T3-L1 adipocytes, which displayed decreased insulin-stimulated tyrosine phosphorylation of insulin-receptor-substrate proteins and of the insulin receptor, but exaggerated protein kinase B phosphorylation. However, insulin-stimulated glucose uptake was unaffected by GSH depletion. In accordance, normal adipose tissue insulin sensitivity was observed in BSO-treated rats in vivo, as demonstrated by normal inhibition of circulating non-esterified fatty acid levels by endogenous insulin secretion. In conclusion, GSH depletion by BSO results in impaired glucose tolerance, but preserved adipocyte and skeletal muscle insulin responsiveness. This suggests that alternative oxidation-borne factors mediate the induction of peripheral insulin resistance by oxidative stress.


Fabrication of a polymer brush-functionalized porphyrin-based covalent organic framework for enrichment of N-glycopeptides.
A surface-initiated atom transfer radical polymerization method combining click chemistry was employed to prepare a novel porphyrin-based covalent organic framework composite grafted with polymer brushes (TAPBB@GMA@AMA@Cys) for the specific enrichment of N-glycopeptides. The material successfully realized the high efficiency enrichment of N-glycopeptides with good selectivity (1:1000), low detection limit (0.2 fmol/μL), and high loading capacity (133.3 mg·g-1). The TAPBB@GMA@AMA@Cys was successfully applied to actual sample analysis; 235 N-glycopeptides related to 125 glycoproteins and 210 N-glycopeptides related to 121 glycoproteins were recognized from the serum of normal individuals and Alzheimer's disease patients, respectively. Gene ontology studies of molecular functions, cellular components, and biological processes have revealed that identified glycoproteins are strongly associated with neurodegenerative diseases involving innate immune responses, basement membranes, calcium binding, and receptor binding. The above results confirm the surprising potential of materials in glycoproteomics research and practical sample applications.


Residents' Procedural Experience Does Not Ensure Competence: A Research Synthesis.
Many medical certifying bodies require that a minimum number of clinical procedures be completed during residency training to obtain board eligibility. However, little is known about the relationship between the number of procedures residents perform and their clinical competence. This study evaluated associations between residents' medical procedure skills measured in a simulation laboratory and self-reported procedure experience and year of training. This research synthesis extracted and summarized data from multiple cohorts of internal medicine, emergency medicine, anesthesiology, and neurology resident physicians who performed simulated clinical procedures. The procedures were central venous catheter insertion, lumbar puncture, paracentesis, and thoracentesis. We compared residents' baseline simulated performance to their self-reported procedure experience using data from 7 research reports written by Northwestern University investigators between 2006 and 2016. We also evaluated how performance differed by postgraduate year (PGY). A total of 588 simulated procedures were performed during the study period. We found significant associations between passing the skills examinations and higher number of self-reported procedures performed (P = .011) and higher PGY (P < .001). However, performance for all procedures was poor, as only 10% of residents passed the assessments with a mean of 48% of checklist items correct (SD = 24.2). The association between passing the skills examination and year of training was mostly due to differences between PGY-1 and subsequent years of training. Despite positive associations between self-reported experience and simulated procedure performance, overall performance was poor. Residents' clinical experience is not a proxy for skill.


Brain hemispheric structural efficiency and interconnectivity rightward asymmetry in human and nonhuman primates.
Evidence for interregional structural asymmetries has been previously reported for brain anatomic regions supporting well-described functional lateralization. Here, we aimed to investigate whether the two brain hemispheres demonstrate dissimilar general structural attributes implying different principles on information flow management. Common left hemisphere/right hemisphere structural network properties are estimated and compared for right-handed healthy human subjects and a nonhuman primate, by means of 3 different diffusion-weighted magnetic resonance imaging fiber tractography algorithms and a graph theory framework. In both the human and the nonhuman primate, the data support the conclusion that, in terms of the graph framework, the right hemisphere is significantly more efficient and interconnected than the left hemisphere, whereas the left hemisphere presents more central or indispensable regions for the whole-brain structural network than the right hemisphere. From our point of view, in terms of functional principles, this pattern could be related with the fact that the left hemisphere has a leading role for highly demanding specific process, such as language and motor actions, which may require dedicated specialized networks, whereas the right hemisphere has a leading role for more general process, such as integration tasks, which may require a more general level of interconnection.


[Molecular biological detection of tissues of central nervous system in meat products].
In principle, molecular biological methods can be used for the detection of specified risk material (SRM) in meat products. We were able to identify suitable target mRNAs for the marker proteins glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) of tissues of the central nervous system (CNS). The selected primers for GFAP ("GFAP87") and MBP ("MBP51") facilitated the detection of CNS in non-heated and heated standards of emulsion type (and raw) sausages with defined addition of brain by reverse transcription and polymerase chain reaction (RT-PCR). Stability of the mRNA proved to be given over a minimum of 48 hours. First results indicate an even higher stability of the target mRNAs over time and an ample stability against meat technological influences such as storage, temperature, and ripening. RT-PCR with GFAP87 facilitates the detection of CNS of all relevant slaughter animals in meat products. Thus it can be applied in food labeling control. Using RT-PCR and MBP51 as primer we were able to detect selectively the CNS of bovines, ovines and caprines but not CNS of porcines and poultry. Thus we have a second RT-PCR detection procedure for CNS in meat products which, however, yields results equivalent to the legal definition of SRM. The further development of these molecular biological methods would be of considerable importance for routine food control and reduction of human TSE-exposure risk.


Novel escape mutants suggest an extensive TRIM5α binding site spanning the entire outer surface of the murine leukemia virus capsid protein.
After entry into target cells, retroviruses encounter the host restriction factors such as Fv1 and TRIM5α. While it is clear that these factors target retrovirus capsid proteins (CA), recognition remains poorly defined in the absence of structural information. To better understand the binding interaction between TRIM5α and CA, we selected a panel of novel N-tropic murine leukaemia virus (N-MLV) escape mutants by a serial passage of replication competent N-MLV in rhesus macaque TRIM5α (rhTRIM5α)-positive cells using a small percentage of unrestricted cells to allow multiple rounds of virus replication. The newly identified mutations, many of which involve changes in charge, are distributed over the outer 'top' surface of N-MLV CA, including the N-terminal β-hairpin, and map up to 29 A(o) apart. Biological characterisation with a number of restriction factors revealed that only one of the new mutations affects restriction by human TRIM5α, indicating significant differences in the binding interaction between N-MLV and the two TRIM5αs, whereas three of the mutations result in dual sensitivity to Fv1(n) and Fv1(b). Structural studies of two mutants show that no major changes in the overall CA conformation are associated with escape from restriction. We conclude that interactions involving much, if not all, of the surface of CA are vital for TRIM5α binding.


Colonization resistance of the digestive tract and the spread of bacteria to the lymphatic organs in mice.
After oral contamination of conventional mice with high doses of Escherichia coli, Klebsiella pneumoniae or Pseudomonas aeruginosa the contaminant was recovered in abnormally high concentrations from the duodenum and caecum during the first few days. In this initial colonization phase, evidence of spread was obtained by culturing the cervical and mesenteric lymph nodes and spleen. Longer after contamination the intestinal concentration decreased to normal and spread stopped. In orally antibiotic-treated mice, the situation seen during the initial colonization phase in conventional mice occurred after a much lower oral contamination dose and persisted during the entire observation period of 2 weeks.


Reversed root for entirely biological aortic valve and ascending aorta replacement in a patient with endocarditis and mediastinitis.
A 59-year-old patient developed endocarditis with coagulase-negative staphylococci after aortic composite graft replacement and pacemaker implantation. She underwent complete pacemaker removal and tricuspid valve reconstruction. Pus was present in and around the aortic graft. Re-replacement of the aortic root and ascending aorta using only biological material was performed. A 23-mm full root stentless prosthesis (Vascutek Root Elan, Vascutec, Terumo, Leeds, UK) was used for aortic root replacement, and a second 25-mm full root prosthesis with removed cusps implanted in a reversed fashion was used for ascending aorta and proximal aortic arch replacement.


Generalization of the right acute stroke promotive strategies in reducing delays of intravenous thrombolysis for acute ischemic stroke: A meta-analysis.
The generalization of successful efforts for reducing time delays in intravenous thrombolysis (IVT) could help facilitate its utility and benefits in acute ischemic stroke (AIS) patients.We searched the PubMed and Embase databases for articles reporting interventions to reduce time delays in IVT, published between January 1995 and September 2017. The IVT rate was chosen as the primary outcome, while the compliance rates of onset-to-door time (prehospital delay) and door-to-needle time (in-hospital delay) within the targeted time frame were the secondary outcomes. Interventions designed to reduce prehospital, in-hospital, or total time delays were quantitatively described in meta-analyses. The efficacy of postintervention improvement was illustrated as odds ratios (ORs) and 95% confidence intervals (95% CIs).In total, 86 papers (17 on prehospital, 56 on in-hospital, and 13 on total delay) encompassing 17,665 IVT cases were enrolled, including 28 American, 23 Asian, 30 European, and 5 Australian studies. The meta-analysis revealed statistically significant improvement in promoting IVT delivery after prehospital improvement interventions with an OR of 1.45 (95% CI, 1.23-1.71) for the new transportation protocol, 1.38 (95% CI, 1.11-1.73) for educational and training programs, and 1.83 (95% CI, 1.44-2.32) for comprehensive prehospital stroke code. The benefits of reducing in-hospital delay were much greater in developed western countries than in Asian countries, with ORs of 2.90 (95% CI, 2.51-3.34), 2.17 (95% CI, 1.95-2.41), and 1.89 (95% CI, 1.74-2.04) in American, European, and Asian countries, respectively. And telemedicine (OR, 2.26; 95% CI, 2.08-2.46) seemed to work better than pre-notification alone (OR, 1.94; 95% CI, 1.74-2.17) and in-hospital organizational improvement programs (OR, 2.10; 95% CI, 1.97-2.23). Mobile stroke treatment unit and use of a comprehensive stroke pathway in the pre- and in-hospital settings significantly increased IVT rates by reducing total time delay, with ORs of 2.01 (95% CI, 1.60-2.51) and 1.77 (95% CI, 1.55-2.03), respectively.Optimization of the work flow with organizational improvement or novel technology could dramatically reduce pre- and in-hospital time delays of IVT in AIS. This study provided detailed information on the net and quantitative benefits of various programs for reducing time delays to facilitate the generalization of appropriate AIS management.


Meta-research evaluating redundancy and use of systematic reviews when planning new studies in health research: a scoping review.
Several studies have documented the production of wasteful research, defined as research of no scientific importance and/or not meeting societal needs. We argue that this redundancy in research may to a large degree be due to the lack of a systematic evaluation of the best available evidence and/or of studies assessing societal needs. The aim of this scoping review is to (A) identify meta-research studies evaluating if redundancy is present within biomedical research, and if so, assessing the prevalence of such redundancy, and (B) to identify meta-research studies evaluating if researchers had been trying to minimise or avoid redundancy. Meta-research studies (empirical studies) were eligible if they evaluated whether redundancy was present and to what degree; whether health researchers referred to all earlier similar studies when justifying and designing a new study and/or when placing new results in the context of earlier similar trials; and whether health researchers systematically and transparently considered end users' perspectives when justifying and designing a new study. The initial overall search was conducted in MEDLINE, Embase via Ovid, CINAHL, Web of Science, Social Sciences Citation Index, Arts & Humanities Citation Index, and the Cochrane Methodology Register from inception to June 2015. A 2nd search included MEDLINE and Embase via Ovid and covered January 2015 to 26 May 2021. No publication date or language restrictions were applied. Charting methods included description of the included studies, bibliometric mapping, and presentation of possible research gaps in the identified meta-research. We identified 69 meta-research studies. Thirty-four (49%) of these evaluated the prevalence of redundancy and 42 (61%) studies evaluated the prevalence of a systematic and transparent use of earlier similar studies when justifying and designing new studies, and/or when placing new results in context, with seven (10%) studies addressing both aspects. Only one (1%) study assessed if the perspectives of end users had been used to inform the justification and design of a new study. Among the included meta-research studies evaluating whether redundancy was present, only two of nine health domains (medical areas) and only two of 10 research topics (different methodological types) were represented. Similarly, among the included meta-research studies evaluating whether researchers had been trying to minimise or avoid redundancy, only one of nine health domains and only one of 10 research topics were represented. Even with 69 included meta-research studies, there was a lack of information for most health domains and research topics. However, as most included studies were evaluating across different domains, there is a clear indication of a high prevalence of redundancy and a low prevalence of trying to minimise or avoid redundancy. In addition, only one meta-research study evaluated whether the perspectives of end users were used to inform the justification and design of a new study. Protocol registered at Open Science Framework: https://osf.io/3rdua/ (15 June 2021).


Personality Profile of Male Adolescents With Tourette Syndrome: A Controlled Study.
Tourette syndrome is a neurodevelopmental disorder characterized by multiple tics and commonly associated with behavioral problems, especially obsessive-compulsive disorder and attention-deficit hyperactivity disorder (ADHD). The presence of specific personality traits has been documented in adult clinical populations with Tourette syndrome but has been underresearched in younger patients. We assessed the personality profiles of 17 male adolescents with Tourette syndrome and 51 age- and gender-matched healthy controls using the Minnesota Multiphasic Personality Inventory-Adolescent version, along with a standardized psychometric battery. All participants scored within the normal range across all Minnesota Multiphasic Personality Inventory-Adolescent version scales. Patients with Tourette syndrome scored significantly higher than healthy controls on the Obsessiveness Content Scale only (P = .046). Our findings indicate that younger male patients with Tourette syndrome do not report abnormal personality traits and have similar personality profiles to healthy peers, with the exception of obsessionality traits, which are likely to be related to the presence of comorbid obsessive compulsive symptoms rather than tics.


On the path to understanding the nature of cancer.
In this essay crucial problems of the origin of cancer and the development of malignancy are discussed. The problem of precancer and three ways leading to malignancy are considered: induction of tumor precursors, accumulation of genetic traits common for tumor growth, and the role of inflammation in tumor induction. The nature of viral oncogenes and modes of their action are described in the context of their origin as a component of the viral genome. Oncogenes of RNA-containing viruses and DNA-containing tumorigenic viruses are described together with cellular protooncogenes, which are progenitors of RNA-containing viral oncogenes. Hematological malignancies are described as an intermediate form between simple tumors induced by a single oncogene and more complicated epithelial tumors. The roles of tumor suppressor genes and the interaction of several oncogenes in the formation of carcinomas and also the role of progression in tumor evolution are discussed.


Mechanistic study of silver-mediated furan formation by oxidative coupling.
Density functional calculations and experiments have been carried out to unravel the mechanism of a silver-mediated furan formation by oxidative coupling. Various possible reaction paths were considered and the most favorable channel has been identified on the basis of the calculated solvent-corrected Gibbs free-energy profiles. The mechanism represented by this route consists of a radical and a subsequent ionic route. The silver cation has a double role in the mechanism: it is the oxidant in the radical steps and the catalyst for the ionic steps, which is in accordance with the experimental observations. The two most important aspects of the optimal route are the formation of a silver-acetylide, reacting subsequently with the enolate radical, and the aromatic furan-ring formation in a single step at the latter, ionic segment of the reaction path. Our findings could explain several experimental observations, including the "key-promoter role" of silver, the preference for ionic cyclization, and the reduced reactivity of internal acetylides.


The effect of lower inter-limb asymmetries on athletic performance: A systematic review and meta-analysis.
Inter-limb asymmetry refers to an imbalance in performance between the left and right limbs. Discrepancies throughout asymmetry research does not allow practitioners to confidently understand the effect of inter-limb asymmetries on athletic performance. Therefore, this review summarized the current literature using a meta-analytic approach, conforming to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines to identify the association between inter-limb asymmetry and athletic performance. A literature search using PubMed, Web of Science and SPORTDiscus databases yielded 11-studies assessing the effect of inter-limb asymmetries, measured via unilateral jump performance, on bilateral jump, change of direction (COD) and sprint performance in adult sports players. The quality of evidence was assessed via a modified Downs and Black checklist and in compliance with the Grading of Recommendations Assessment Development and Evaluation. Correlation coefficients were transformed via Fishers z (Zr), meta-analysed and then re-converted to correlation coefficients. Egger's regression presented no significant risk of bias. Vertical jump performance was not significantly affected by asymmetry (Zr = 0.053, r = 0.05; P = 0.874), whereas COD and sprint both presented significant weak associations (COD, Zr = 0.243, r = 0.24; Sprint, Zr = 0.203, r = 0.2; P < 0.01). The results demonstrate that inter-limb asymmetries seem to present a negative impact to COD and sprint performance but not vertical jump performance. Practitioners should consider implementing monitoring strategies to identify, monitor and possibly address inter-limb asymmetries, specifically for performance tests underpinned by unilateral movements such as COD and sprint performance.


Ionic versus nonionic paramagnetic contrast media in differentiating between scar and herniated disk.
To compare the MR contrast enhancement produced by ionic and nonionic paramagnetic contrast media in herniated disk fragments with that in epidural scar tissue. A recurrent herniated disk was modeled in canines by using laminectomy to place a fragment of disk cartilage in the epidural space. The dogs were studied 88 and 90 days after laminectomy with MR imaging enhanced with an ionic or a nonionic paramagnetic contrast medium. Contrast enhancement of the epidural scar tissue and the epidural disk fragment was measured at 2, 22, and 45 minutes after the injection. Contrast enhancement was consistently and significantly higher in scar tissue than in disk fragments, although the difference decreased between 2 and 45 minutes after administration of contrast medium. Enhancement of disk fragments was less with the ionic than with the nonionic contrast medium. Contrast between the disk fragments and scar was also greater with the ionic than with the nonionic medium. The contrast between recurrent disk fragments and scar tissue is affected by the timing of the scan and the choice of contrast medium. Scans obtained immediately after the injection of contrast medium show more contrast between disk fragment and scar than do delayed scans. Recurrent herniated disk fragments are more effectively shown by ionic than by nonionic media.


Challenges of Clinical Education.
As we celebrate the 50th anniversary of the physician assistant (PA) profession and specifically PA education, think of the tens of thousands of clinical preceptors who were or currently still are involved in the education of PA students. The clinical phase of PA programs has become the rate-limiting issue in PA education. For decades, developing clinical education sites was relatively easy. Over the last decade, rapid expansion in medical, nurse practitioner, and PA education programs has resulted in greater challenges in obtaining necessary clinical training sites. This article attempts to address several of the current challenges in PA clinical education.


Delta oscillation underlies the interictal spike changes after repeated transcranial direct current stimulation in a rat model of chronic seizures.
Transcranial direct current stimulation (tDCS) provides a noninvasive polarity-specific constant current to treat epilepsy, through a mechanism possibly involving excitability modulation and neural oscillation. To determine whether EEG oscillations underlie the interictal spike changes after tDCS in rats with chronic spontaneous seizures. Rats with kainic acid-induced spontaneous seizures were subjected to cathodal tDCS or sham stimulation for 5 consecutive days. Video-EEG recordings were collected immediately pre- and post-stimulation and for the subsequent 2 weeks following stimulation. The acute pre-post stimulation and subacute follow-up changes of interictal spikes and EEG oscillations in tDCS-treated rats were compared with sham. Ictal EEG with seizure behaviors, hippocampal brain-derived neurotrophic factor (BDNF) protein expression, and mossy fiber sprouting were compared between tDCS and sham rats. Interictal spike counts were reduced immediately following tDCS with augmented delta and diminished beta and gamma oscillations compared with sham. Cathodal tDCS also enhanced delta oscillations in normal rats. However, increased numbers of interictal spikes with a decrease of delta and theta oscillations were observed in tDCS-treated rats compared with sham during the following 2 weeks after stimulation. Resuming tDCS suppressed the increase of interictal spike activity. In tDCS rats, hippocampal BDNF protein expression was decreased while mossy fiber sprouting did not change compared with sham. The inverse relationship between the changes of delta oscillation and interictal spikes during tDCS on and off stimulation periods indicates that an enhanced endogenous delta oscillation underlies the tDCS inhibitory effect on epileptic excitability.


Hormonal Regulation and Stimulation Response of Jatropha curcas L. Homolog Overexpression on Tobacco Leaf Growth by Transcriptome Analysis.
The Flowering locus T (FT) gene encodes the florigen protein, which primarily regulates the flowering time in plants. Recent studies have shown that FT genes also significantly affect plant growth and development. The FT gene overexpression in plants promotes flowering and suppresses leaf and stem development. This study aimed to conduct a transcriptome analysis to investigate the multiple effects of Jatropha curcas L. homolog (JcFT) overexpression on leaf growth in tobacco plants. The findings revealed that JcFT overexpression affected various biological processes during leaf development, including plant hormone levels and signal transduction, lipid oxidation metabolism, terpenoid metabolism, and the jasmonic-acid-mediated signaling pathway. These results suggested that the effects of FT overexpression in plants were complex and multifaceted, and the combination of these factors might contribute to a reduction in the leaf size. This study comprehensively analyzed the effects of JcFT on leaf development at the transcriptome level and provided new insights into the function of FT and its homologous genes.


Correlation with a spatial light modulator having phase and amplitude cross coupling.
In correlation filtering a spatial light modulator is traditionally modeled as affecting only the phase or only the amplitude of light. Usually, however, a single operating parameter affects both phase and amplitude. An integral constraint is developed that is a necessary condition for optimizing a correlation filter having single parameter coupling between phase and amplitude. The phase-only filter is shown to be a special case.


Trends in suicide death risk in transgender people: results from the Amsterdam Cohort of Gender Dysphoria study (1972-2017).
This study explored the overall suicide death rate, the incidence over time, and the stage in transition where suicide deaths were observed in transgender people. A chart study, including all 8263 referrals to our clinic since 1972. Information on death occurrence, time, and cause of death was obtained from multiple sources. Out of 5107 trans women (median age at first visit 28 years, median follow-up time 10 years) and 3156 trans men (median age at first visit 20 years, median follow-up time 5 years), 41 trans women and 8 trans men died by suicide. In trans women, suicide deaths decreased over time, while it did not change in trans men. Of all suicide deaths, 14 people were no longer in treatment, 35 were in treatment in the previous two years. The mean number of suicides in the years 2013-2017 was higher in the trans population compared with the Dutch population. We observed no increase in suicide death risk over time and even a decrease in suicide death risk in trans women. However, the suicide risk in transgender people is higher than in the general population and seems to occur during every stage of transitioning. It is important to have specific attention for suicide risk in the counseling of this population and in providing suicide prevention programs.


The role of cytotoxic T lymphocytes in corneal allograft rejection.
Immunologic rejection constitutes a major barrier to the success of allogeneic corneal transplants, but the specific mediators and mechanisms of graft rejection are poorly understood. Several studies have implicated cytotoxic T-lymphocyte (CTL) responses, typically associated with CD8(+) T cells, in promoting corneal graft rejection. This study sought to test the hypothesis that CTLs are essential in promoting corneal graft rejection. BALB/c donor corneas were grafted orthotopically onto C57BL/6, perforin knockout, or CD8(+) T-cell knockout mice. The tempo and incidence of graft rejection were observed for each group. In separate experiments, donor-specific CTL and delayed-type hypersensitivity (DTH) responses were tested at the time of graft rejection by a standard chromium release assay and an ear swelling assay, respectively. Perforin knockout and CD8(+) T-cell knockout mice were as effective as wild-type C57BL/6 control mice in rejecting BALB/c donor corneas. Furthermore, animals in all three groups were found to develop robust donor-specific DTH, not CTL, responses at the time of graft rejection. Histopathologically, the rejected corneas from all three groups contained a predominantly mononuclear cellular infiltrate. This study rejects the hypothesis that CD8(+) CTLs are essential in promoting corneal graft rejection and instead further implicates donor-specific DTH reactions as the relevant immune response during graft failure.


Luminal tachykinin receptors on canine tracheal epithelium: functional subtyping.
Luminal addition of tachykinins to the open-circuited canine tracheal epithelium produces a biphasic response in the transmucosal potential difference (PD). A rapid, transient decrease is followed by a subsequent rise, both phases being associated with changes in conductance. Concentration-response curves demonstrated the following orders of potency: substance P greater than physalaemin greater than eledoisin = kassinin for the tachykinins, and substance P greater than substance P-(4-11) greater than substance P-(6-11) using the C-terminal fragments. Both sequences are similar to those reported for the dog carotid artery. These observations were confirmed by cross-tachyphylaxis experiments. SP-O-methyl ester, a selective agonist for the SP-P (or NK-1) receptor, elicited identical responses, and exhibited cross-tachyphylaxis to substance P. Bradykinin produced similar luminal responses, though different receptors are involved, since no cross-tachyphylaxis was observed between bradykinin and the tachykinins.


Comparison of Hip- and Back-Muscle Activity and Pelvic Compensation in Healthy Subjects During 3 Different Prone Table Hip-Extension Exercises.
Prone hip extension has been recommended for strengthening the back and hip muscles. Previous studies have investigated prone hip extension conducted with subjects on the floor in the prone position. However, no study has compared 3 different table hip-extension (THE) positions in terms of the activities of the back- and hip-joint muscles with lumbopelvic motion. To identify more effective exercises for strengthening the gluteus maximus (GM) by comparing 3 different exercises (THE alone, THE with the abdominal drawing-in maneuver [THEA], and THEA with chair support under the knee [THEAC]) based on electromyographic muscle activity and pelvic compensation. Repeated-measure within-subject intervention. University research laboratory. 16 healthy men. Surface electromyography (EMG) was used to obtain data on the GM, erector spinae (ES), multifidus, biceps femoris (BF), and semitendinosus (ST). Pelvic compensation was monitored using an electromagnetic motion-tracking device. Exertion during each exercise was recorded. Any significant difference in electromyographic muscle activity and pelvic motion among the 3 conditions (THE vs THEA vs THEAC) was assessed using a 1-way repeated-measures analysis of variance (ANOVA) with Bonferroni post hoc test. The muscle activities recorded by EMG differed significantly among the 3 exercises (P < .01). GM activity was increased significantly during THEAC (P < .01). There was a significant difference in lumbopelvic kinematics in terms of anterior tilting (F = 19.49, P < .01) and rotation (F= 27.38, P < .01) among the 3 exercises. The THEAC exercise was the most effective for strengthening the GM without overactivity of the ES, BF, and ST muscles and lumbopelvic compensation compared with THE and THEA.


[A comparative study of 4 sequential first-line chemotherapy protocols in locally advanced breast cancer].
Between 1977 and 1994, our center administered successively 4 different chemotherapy regimens to 242 evaluable patients with locally advanced breast cancer. Patients with inflammatory signs were excluded. Sixty-eight patients were treated by AVCF (A (adriamycine) + V (vincristine) + C (cytoxan) + F (5FU)), 47 by AECF (A + E (vindesine) + C + F), 81 by CAFP (C + A + F + P (prednisone)) and 46 by AN (A + N (vinorelbine)). The mean number of cycle was 3. One hundred and twenty-five patients (52.5%) responded to chemotherapy and we recorded 35 complete response (14.7%). The response rates at the different combinations were respectively: AVCF: 29.4%, AECF: 53.2%, CAFP: 64.9%, AN: 65.2%, and were independent of tumor size, grade and receptor status. The response rate at the AVCF regimen was significantly worse than the others (p = 0.0005). Breast conserving surgery was performed in 31 patients (14%) and 17 patients (8%) had a complete response. Among the 35 patients with complete response, 21 were treated by radiotherapy alone. Local recurrence occurred in 19 patients (7.9%) and 96 (40%) had advanced disease. The mean follow-up of AVCF regimen was 150 months, 115 months for AECF, 111 for CAFP and 42 months for AN. The disease-free survival and the overall survival were significantly better with AECF, CAFP and AN regimens (DFS p < 0.04, OS p < 0.02). Survival was better in those patients with an objective response (p = 0.002) or with non-affected axillary node at the time of surgery. Our study showed already that AVCF combination was significantly lower than AECF, CAFP, AN in terms of response rate, disease-free survival and overall survival. Waiting the results of randomized studies about the impact of neoadjuvant chemotherapy on survival, we look for chemotherapy regimen improving the rate of conservative surgery.


Forest corridors maintain historical gene flow in a tiger metapopulation in the highlands of central India.
Understanding the patterns of gene flow of an endangered species metapopulation occupying a fragmented habitat is crucial for landscape-level conservation planning and devising effective conservation strategies. Tigers (Panthera tigris) are globally endangered and their populations are highly fragmented and exist in a few isolated metapopulations across their range. We used multi-locus genotypic data from 273 individual tigers (Panthera tigris tigris) from four tiger populations of the Satpura-Maikal landscape of central India to determine whether the corridors in this landscape are functional. This 45 000 km(2) landscape contains 17% of India's tiger population and 12% of its tiger habitat. We applied Bayesian and coalescent-based analyses to estimate contemporary and historical gene flow among these populations and to infer their evolutionary history. We found that the tiger metapopulation in central India has high rates of historical and contemporary gene flow. The tests for population history reveal that tigers populated central India about 10 000 years ago. Their population subdivision began about 1000 years ago and accelerated about 200 years ago owing to habitat fragmentation, leading to four spatially separated populations. These four populations have been in migration-drift equilibrium maintained by high gene flow. We found the highest rates of contemporary gene flow in populations that are connected by forest corridors. This information is highly relevant to conservation practitioners and policy makers, because deforestation, road widening and mining are imminent threats to these corridors.


Growth hormone is effective in the treatment of severe growth retardation in children with juvenile chronic arthritis. Double blind placebo-controlled followup study.
To assess the efficacy of growth hormone (GH) treatment in severe growth retardation in prepubertal children with juvenile chronic arthritis (JCA). In a randomized, double-blind placebo-controlled study, we treated 25 prepubertal children (7 boys, 18 girls, mean age 9.0 yrs) with severe growth retardation due to JCA with human recombinant GH (6 months) and placebo (6 months). A significant response to GH treatment, compared with placebo, was seen in most children. The median height velocity standard deviation score was +2.09 (range -7.18 to +9.49) during the 6 month period of GH therapy and -1.11 (range -10.00 to +1.11) during placebo treatment (p = 0.0002). The median height standard deviation score increased from -2.08 to -1.79 during GH treatment and from -2.18 to -2.02 during placebo (p = 0.0268). All children except one completed the study, showing high compliance. The treatment was well tolerated, and no significant alterations in the disease activity were recorded during the study. We conclude that human recombinant GH may be of benefit in the treatment of severe growth retardation in children with JCA. The response was seen after only 6 months and was independent of initial growth hormone status of the child.


Dominant optic atrophy.
DEFINITION OF THE DISEASE: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts. Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis. Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically occurring in the context of a family history of DOA. Optical Coherence Tomography further discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene (1% of patients). Visual loss in DOA may progress during puberty until adulthood, with very slow subsequent chronic progression in most of the cases. On the opposite, in DOA patients with associated extra-ocular features, the visual loss may be more severe over time. To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids. Genetic counseling is commonly offered and patients are advised to avoid alcohol and tobacco consumption, as well as the use of medications that may interfere with mitochondrial metabolism. Gene and pharmacological therapies for DOA are currently under investigation.


[Crohn's disease associated with Berger's disease. A rare complication].
We report the case of a male patient with Crohn's disease associated with IgA nephropathy. He was treated surgically for the intestinal disorder and then with corticoids and sulfasalazine. Six years after treatment the patient was asymptomatic. As the intestinal situation improved there was concomitant normalization of urinary sediment, maintaining renal function. The fact that the digestive mucosa is one of the body's major sources of secretory IgA may account for the existence of a common for Crohn's disease and certain forms of IgA nephropathy.


Survival and management considerations in postirradiation osteosarcoma and Paget's osteosarcoma.
Postirradiation and Paget's osteosarcomas are high-grade malignancies. The five-year survival was only 10% in recent experience at the author's institution. Progressive pain is an important clinical feature in both conditions. Careful roentgenographic studies demonstrate cortical destruction and a soft-tissue mass in virtually all patients. Metastasis was present in 25% of both groups of patients at presentation. In contrast to previous series, more than 80% of the patients with postirradiation osteosarcoma had had irradiation for malignant entities and more than 70% had been treated with modern radiotherapy regimens (cobalt-60 or linear accelerator). Twice as many patients with postirradiation osteosarcoma were evaluated and treated in the 1980s than in the previous decade. The initial indication for irradiation often was carcinoma of the breast, uterus, or cervix, or lymphoma. Two-thirds of the patients had progressive disease that was not controllable within six months after diagnosis. Early detection may be the only effective means of improving survival with postirradiation or Paget's osteosarcoma. These patients require lifelong follow-up evaluations.


Anticoagulant effect of sulphated poly/vinyl alcohol-acrylic acid/copolymers.
Copolymers of poly/vinyl alcohol-acrylic acid/ with various content of sulphate and carboxyl groups have been synthetized and tested for their in vitro effect on blood coagulation. The results indicate that the sulphated copolymers display an inhibitory effect but there is a requirement in the charged groups of about 20% in the molecule to possess effective anticoagulation. The biochemical mechanism of their actions is complex, i.e. the inhibition of blood clotting is a consequence of both the accelerated inactivation rate of thrombin by antithrombin-III and a direct inhibitory effect on the thrombin-fibrinogen reaction. Moreover, additional effects may occur on other blood coagulation enzymes than thrombin, depending on the chemical composition of the copolymers.


Esch. coli infections in childhood. Significance of bacterial virulence and immune defence.
The Esch. coli harboured in the gut constitute a reservoir of potential pathogens in the infant and child. The conditions required for these intestinal inhabitants to cause infection are not well understood. The presence of virulence factors such as capsular antigens, especially K1, may be of significance for the ability of Esch. coli to cause neonatal meningitis. The capacity of certain Esch. coli to attach to epithelial cells of mucous membranes may be important for their infective powers in the urinary as well as the intestinal tract. Furthermore, the ability of certain Esch. coli to produce enterotoxins similar to that of V. cholerae is of importance for their capacity to provoke diarrhoea. The importance of the immune defence mechanisms for prevention of these Esch. coli infections is suggested, especially in the form of local immunity provided by secretory IgA antibodies. Such antibodies directed against Esch. coli O and K antigens as well as enterotoxins are present in large amounts in human milk and may be of considerable importance for protection against Esch. coli in the breast-fed baby. Breast feeding may be of special significance until the baby has built up its own local immune defence preventing the micro-organisms from attaching to and invading the intestinal mucous membranes. SIgA antibodies in urine may have a similar protective effect against urinary tract infections. The variable pictures of Esch. coli infections in childhood are striking, ranging from severe sepsis/meningitis or diarrhoea to "asymptomatic" bacteriuria. This variability is obviously closely connected with the presence of various virulence factors and the function of different components of the immune defence.


The induction of a ribosomal ribonuclease in Saccharomyces cerevisiae.
The ribosomal ribonuclease of yeast is induced after a withdrawal of glucose. Cycloheximide inhibits the synthesis of the enzyme under conditions of induction but antimycin shows no effect. Hence, the increase of the ribonuclease activity during growth of yeast is due to newly synthesized enzyme, and the induction does not depend on respiration.


Naturally occurring extracellular matrix as a scaffold for musculoskeletal repair.
The use of naturally occurring extracellular matrix materials as scaffolds for the repair and regeneration of tissues is receiving increased attention. The present study evaluates the use of the extracellular matrix derived from porcine small intestinal submucosa as a scaffold for anterior cruciate ligament replacement in a goat model. Sixty healthy adult female goats were divided into two equal groups of 30 each. The right anterior cruciate ligament of each goat was removed surgically and replaced with either a patellar tendon autograft or a small intestinal submucosa anterior cruciate ligament scaffold. Three animals from each group were sacrificed at 6 weeks, 3 months, 6 months, and 1 year after surgery and grafts were harvested for histopathologic examination. Six animals from each group were sacrificed immediately after surgery, 3 months, and 1 year after surgery and the grafts were harvested for biomechanical testing. There was no evidence for an adverse clinical response to the xenogeneic small intestinal submucosa scaffold. Anterior drawer values were not different between the two groups at any point. The failure force of the patellar tendon autograft increased from 253 N at Time 0 to 879 N at 12 months. The failure force for the small intestinal submucosa repair device was 721 N at Time 0, decreased to 293 N at 3 months, followed by an increase to 706 N at 12 months. Histopathologic analysis showed a mixed inflammatory cell presence within the small intestinal submucosa scaffold including macrophages and lymphocytes in the early months after surgery. The inflammatory cells disappeared in the later stages of remodeling and the histologic appearance of the small intestinal submucosa remodeled grafts and the patellar tendon autografts were indistinguishable at 12 months. Xenogeneic small intestinal submucosa holds promise as a resorbable bioscaffold for anterior cruciate ligament repair in the goat model.


Effect of different humic substances on the fate of diuron and its main metabolite 3,4-dichloroaniline in soil.
Humic substances (HS) are the dominant constituents of soil organic matter (SOM). The interactions between the phenylurea herbicide 3-(3,4-dichlorophenyl)-1,1-dimethylurea (diuron) and several HS fractions, purified from various soil horizons, were studied. One commercial humic acid (HA) was included for comparison. Diuron was shown to adsorb significantly, but reversibly, to purified HA while sorption to fulvic acid (FA) was less pronounced. The sorption abilities of the purified HS fractions were correlated with their total aromatic content. In natural soils, SOM was the main adsorbent of diuron, but the organic matter partition coefficient was larger in sandy compared to clayey soils. Degradation of diuron in natural soils was slow and incomplete. Inoculation of a sandy C-horizon with a diuron-degrading bacterial strain led to substantial diuron degradation, but the addition of purified FA and HA to these inoculated soils decreased this degradation. The main metabolite produced during diuron degradation, 3,4-dichloroaniline, was bound irreversibly to HS within days after formation.


Long-term culture of normal and cystic fibrosis epithelial cells grown under serum-free conditions.
The understanding of pathways associated with differentiated function in human epithelial cells has been enhanced by the development of methods for the short-term culture of human epithelial cells. In general these methods involve the use of serum. The subculture and maintenance of epithelial cells in long-term culture has been more problematic. A serum-free medium developed for human bronchial epithelial cells was slightly modified and found to be useful for the subculture and long-term maintenance of not only bronchial epithelial cells, but also tracheal, nasal polyp, and sweat gland epithelial cells from either normal or cystic fibrosis individuals. The cells maintained epithelial-specific characteristics after multiple subcultures. Monolayers of epithelial cells showed junctional complex formation, the presence of keratin, and micro villi. Functional studies with Ussing chambers showed short circuit current (Isc) responses to isoproterenol, bradykinin, or calcium ionophore (A23187) in subcultured tracheal and bronchial cells.


Rye flour enriched with arabinoxylans in rye bread making.
The aim of the study was to investigate physical and chemical properties of preparations of water soluble arabinoxylans (arabinoxylan-enriched flour) obtained by industrial method and their derivatives (obtained by hydrolysis and cross-linking of aranbinoxylans), as well as their impact on baking properties of rye flours. Additionally, these results were compared with highly purified arabinoxylans prepared by laboratory method and well characterized in the literature. Flour enriched with arabinoxylans was obtained by industrial method involving air separation of flour particles. It was characterized by 8.6% arabinoxylan content, lack of insoluble material and substantial residue (67%) of starch and dextrins. The addition of all industrial method preparations in amount of 10% (i.e. approx. 1% water soluble arabinoxylans), to rye flours resulted in an increase in water absorption, bread volume and decrease in hardness of the bread crumb and the effect was especially strong in the case of flour type 720. Due to the easiness of isolation procedure, industrial method preparation could be advised as an improver for rye bread making.


Allelic analysis of sheath blight resistance with association mapping in rice.
Sheath blight (ShB) caused by the soil-borne pathogen Rhizoctonia solani is one of the most devastating diseases in rice world-wide. Global attention has focused on examining individual mapping populations for quantitative trait loci (QTLs) for ShB resistance, but to date no study has taken advantage of association mapping to examine hundreds of lines for potentially novel QTLs. Our objective was to identify ShB QTLs via association mapping in rice using 217 sub-core entries from the USDA rice core collection, which were phenotyped with a micro-chamber screening method and genotyped with 155 genome-wide markers. Structure analysis divided the mapping panel into five groups, and model comparison revealed that PCA5 with genomic control was the best model for association mapping of ShB. Ten marker loci on seven chromosomes were significantly associated with response to the ShB pathogen. Among multiple alleles in each identified loci, the allele contributing the greatest effect to ShB resistance was named the putative resistant allele. Among 217 entries, entry GSOR 310389 contained the most putative resistant alleles, eight out of ten. The number of putative resistant alleles presented in an entry was highly and significantly correlated with the decrease of ShB rating (r = -0.535) or the increase of ShB resistance. Majority of the resistant entries that contained a large number of the putative resistant alleles belonged to indica, which is consistent with a general observation that most ShB resistant accessions are of indica origin. These findings demonstrate the potential to improve breeding efficiency by using marker-assisted selection to pyramid putative resistant alleles from various loci in a cultivar for enhanced ShB resistance in rice.


Cysteinyl leukotriene receptor 1 gene variation and risk of asthma.
Although it has been recognised that genetics plays an important role in the development of asthma, important causal loci remain to be identified. The aim of the present study was to examine the association of known and novel candidate genes with asthma. Two independent samples, including 170 asthmatic cases and 347 controls in the initial sample, and 202 asthmatic cases and 332 controls in the confirmation sample, were recruited from the same region of China. Functional single nucleotide polymorphisms (SNPs; n = 129) from 105 genes were genotyped using MassARRAY technology, and 119 SNPs were used for the subsequent analysis. In the initial sample, three SNPs, rs320995 in the cysteinyl leukotriene receptor 1 gene, rs1047266 in the tumour necrosis factor receptor superfamily, member 10b, gene and rs40401 in the interleukin-3 gene, were associated with risk of asthma. Notably, under the recessive genetic model, subjects without the thymidine allele in SNP rs320995 had a 3.1 times higher risk of asthma, which remained significant after accounting for multiple testing. This association was replicated in the confirmation sample and validated by meta-analysis. Further, sex-specific analysis was performed, but no sex difference was found. The present study provided coherent evidence that cysteinyl leukotriene receptor 1 gene variation is associated with risk of asthma.


A Visual Leaf Zymography Technique for the In Situ Examination of Plant Enzyme Activity under the Stress of Environmental Pollution.
This study established a high-efficiency fluorescence quenching approach for the in situ visualization and modeling of the spatial distribution of xylanase, β-glucosidase, and phosphatase activities in plant leaves under pollution stress (namely, the leaf zymography technique, LZT). In the LZT, a membrane saturated with an enzyme-specific fluorescent substrate on the leaf surface was incubated and the fluorescence image generated on the membrane under ultraviolet light was recorded. An image-based modeling method for restoring the morphological traits of the true image by reducing noise was developed to ensure the accurate estimation of enzyme activities. The LZT could simultaneously measure 48 samples within 2 h, with good reproducibility. The results obtained by the LZT were comparable to those obtained by a conventional biochemical analysis method and presented low-cost and convenient advantages. This paper explains the theoretical basis required to investigate the realistic application of the LZT for assessing ecotoxicity in large-scale monitoring.


Pharmacogenomics and adverse effects of anti-infective drugs in children.
Children, as a special group, have their own peculiarities in terms of individualized medication use compared to adults. Adverse drug reactions have been an important issue that needs to be addressed in the hope of safe medication use in children, and the occurrence of adverse drug reactions is partly due to genetic factors. Anti-infective drugs are widely used in children, and they have always been an important cause of the occurrence of adverse reactions in children. Pharmacogenomic technologies are becoming increasingly sophisticated, and there are now many guidelines describing the pharmacogenomics of anti-infective drugs. However, data from paediatric-based studies are scarce. This review provides a systematic review of the pharmacogenomics of anti-infective drugs recommended for gene-guided use in CPIC guidelines by exploring the relationship between pharmacogenetic frequencies and the incidence of adverse reactions, which will help inform future studies of individualized medication use in children.


Study of prevalence of ocular manifestations in HIV positive patients.
HIV/AIDS is a disorder which affects multiple systems in our body but ophthalmic manifestations do occur in 70-80% of patients sometime during their lifetime. Eye is affected either directly by HIV virus or indirectly through various opportunistic infections. HIV related ophthalmic manifestations are wide and can affect any part of eye from a dnexal disorders to posterior segment diseases including the optic nerve and the optic tract. This study was done to know the prevalence of ocular manifestations in the known HIV positive case & to correlate the ocular manifestations in HIV positive patients with their CD4+ lymphocyte count and duration of disease. In the present study, we examined 200 known cases of HIV infection who attended the Out Patient Department of Government Eye Hospital, Amritsar, Punjab. Detailed ocular examination was done and the findings were correlated with CD4+ count and duration of the disease. In the present study it was found that dry eye and HIV retinopathy were amongst the most common ocular manifestations accounting for 20.5% and 20% of the total cases. Next in the series was neuro ophthalmic complications which include dpapilledema, optic nerve atrophy, papillitis and also third nerve abnormalities. It consisted of 5.5% of the total cases. Almost equal in incidence was anterior uveitis consisting of 5% of the total. Next of importance was CMV retinitis of which 5 cases were seen which constituted 2.5% of the total and all these cases were observed in the patients with CD4+ count less than 50/mm3. p value for this was 0.008 which was statistically significant. Few cases of blephar it is, conjunctivitis, cellulitis, herpes zoster ophthalmic us and keratitis were also found which consisted of 2.5%, 0.5%, 1%,3%, and 2% respectively. Any HIV-infected person who at any stage experiences ocular symptoms also should get competent ophthalmologic care at the earliest. Any delay in treatment can lead to permanent visual loss. An improved coordination between two branches of ophthalmology and HIV medicine will need long coordination against this dreadful disease.


Activity of Antibiotics against Staphylococcus aureus in an In Vitro Model of Biofilms in the Context of Cystic Fibrosis: Influence of the Culture Medium.
Staphylococcus aureus is a highly prevalent pathogen in the respiratory tract of young patients with cystic fibrosis (CF) and causes biofilm-related infections. Here, we set up an in vitro model of a biofilm grown in Trypticase soy broth supplemented with glucose and NaCl (TGN) or in artificial sputum medium (ASM) and used it to evaluate on a pharmacodynamic basis the activity of antibiotics used in CF patients and active on staphylococci (meropenem, vancomycin, azithromycin, linezolid, rifampin, ciprofloxacin, tobramycin). Rheological studies showed that ASM was more elastic than viscous, as was also observed for sputa from CF patients, with elastic and viscous moduli being, respectively, similar to and slightly lower than those of CF sputa. Biofilms formed by methicillin-sensitive S. aureus strain ATCC 25923 and methicillin-resistant S. aureus strain ATCC 33591 reached maturity after 24 h, with biomass (measured by crystal violet staining) and metabolic activity (assessed by following resazurin metabolization) being lower in ASM than in TGN and viability (assessed by bacterial counts) being similar in both media. Full concentration-response curves of antibiotics obtained after 24 h of incubation of biofilms showed that all antibiotics were drastically less potent and less efficient in ASM than in TGN toward viability, metabolic activity, and biomass. Tobramycin selected for small-colony variants, specifically in biofilms grown in ASM; the auxotrophism of these variants could not be established. These data highlight the major influence exerted by the culture medium on S. aureus responsiveness to antibiotics in biofilms. The use of ASM may help to determine effective drug concentrations or to evaluate new therapeutic options against biofilms in CF patients.


Endovascular treatment of a noninfected anastomotic juxtarenal aortic aneurysm.
An 82-year-old man underwent an endovascular procedure with a commercially available endovascular graft for an anastomotic juxtarenal abdominal aortic aneurysm. The anastomotic aneurysm, which showed no sign of infection, developed 4 years after implantation of an aortic end-to-end graft for an infrarenal aortic aneurysm. The aneurysm was diagnosed during routine ultrasonographic follow-up; there was no apparent infection of the graft. Aortography confirmed the diagnosis and also revealed a small pseudoaneurysm at the level of the distal aortic anastomosis. Endovascular surgery was performed in the operating room with the guidance of C-arm fluoroscopy and intravascular ultrasound. Two Vanguard Straight Endovascular Aortic Graft Cuffs (26 x 50 mm and 24 x 50 mm) were implanted, successfully excluding both the anastomotic juxtarenal aortic aneurysm and the distal pseudoaneurysm. The renal arteries were preserved and no early or late endoleaks were observed. The patient was discharged 2 days after the procedure. Sixteen months later, he was alive and well, with no endovascular leakage, no enlargement of the aortic aneurysms, and no sign of infection. In our opinion, this experience shows that commercially available endovascular grafts may be used successfully to treat anastomotic aortic aneurysms and pseudoaneurysms.


Collagenous colitis: a retrospective study of clinical presentation and treatment in 163 patients.
Data on collagenous colitis have been based on a limited number of patients. To obtain more information on this disease from a register set up at Orebro Medical Center Hospital. Twenty five Swedish hospitals have contributed to this patient register, which comprises 163 histopathologically verified cases. Clinical data were retrospectively analysed. Collagenous colitis followed a chronic intermittent course in most cases (85%) with a sudden onset in 42%. Symptoms were chronic watery diarrhoea, often nocturnal (27%), abdominal pain (41%), and weight loss (42%). Sixty six patients (40%) had one or more associated diseases. Routine laboratory data were mostly normal. The median age at diagnosis was 55 (range 16-86) years, but 25% of the patients were younger than 45 years. Seven patients died of unrelated diseases. The response rate for sulphasalazine was 59%, and 50% and 40% for mesalazine and olsalazine. Prednisolone was most effective with a response rate of 82%, but the required dose was often high and the effect was not sustained after withdrawal. Antibiotics were efficient in 63%. Cholestyramine and loperamide had response rates of 59% and 71% respectively. Collagenous colitis follows a chronic continuous course. Symptoms can be socially disabling, but the disease does not seem to have a malignant potential. A plan for the treatment of a newly diagnosed patient with collagenous colitis is proposed.


Activation of Nrf2 by Electrophiles Is Largely Independent of the Selenium Status of HepG2 Cells.
Selenoenzymes, whose activity depends on adequate selenium (Se) supply, and phase II enzymes, encoded by target genes of nuclear factor erythroid 2-related factor 2 (Nrf2), take part in governing cellular redox homeostasis. Their interplay is still not entirely understood. Here, we exposed HepG2 hepatoma cells cultured under Se-deficient, Se-adequate, or Se-supranutritional conditions to the Nrf2 activators sulforaphane, cardamonin, or diethyl maleate. Nrf2 protein levels and intracellular localization were determined by immunoblotting, and mRNA levels of Nrf2 target genes and selenoproteins were assessed by qRT-PCR. Exposure to electrophiles resulted in rapid induction of Nrf2 and its enrichment in the nucleus, independent of the cellular Se status. All three electrophilic compounds caused an enhanced expression of Nrf2 target genes, although with differences regarding extent and time course of their induction. Whereas Se status did not significantly affect mRNA levels of the Nrf2 target genes, gene expression of selenoproteins with a low position in the cellular "selenoprotein hierarchy", such as glutathione peroxidase 1 (GPX1) or selenoprotein W (SELENOW), was elevated under Se-supplemented conditions, as compared to cells held in Se-deficient media. In conclusion, no major effect of Se status on Nrf2 signalling was observed in HepG2 cells.


Detoxification of hydrogen sulfide and methanethiol in the cecal mucosa.
Colonic bacteria liberate large quantities of the highly toxic gases hydrogen sulfide (H(2)S) and methanethiol (CH(3)SH). The colonic mucosa presumably has an efficient means of detoxifying these compounds, which is thought to occur through methylation of H(2)S to CH(3)SH and CH(3)SH to dimethylsulfide (CH(3)SCH(3)). We investigated this detoxification pathway by incubating rat cecal mucosal homogenates with gas containing H(2)S, CH(3)SH, or CH(3)SCH(3). Neither CH(3)SH nor CH(3)SCH(3) was produced during H(2)S catabolism, whereas catabolism of CH(3)SH liberated H(2)S but not CH(3)SCH(3). Thus, H(2)S and CH(3)SH are not detoxified by methylation to CH(3)SCH(3). Rather, CH(3)SH is demethylated to H(2)S, and H(2)S is converted to nonvolatile metabolites. HPLC analysis of the homogenate showed the metabolite to be primarily thiosulfate. Analysis of cecal venous blood obtained after intracecal instillation of H(2)(35)S revealed that virtually all absorbed H(2)S had been oxidized to thiosulfate. The oxidation rate of H(2)S by colonic mucosa was 10,000 times greater than the reported methylation rate. Conversion to thiosulfate appears to be the mechanism whereby the cecal mucosa protects itself from the injurious effects of H(2)S and CH(3)SH, and defects in this detoxification possibly could play a role in colonic diseases such as ulcerative colitis.


A fourth Escherichia coli gene system with the potential to evolve beta-glucoside utilization.
Escherichia coli K12 is being used to study the potential for adaptive evolution that is present in the genome of a single organism. Wild-type E. coli K12 do not utilize any of the beta-glucoside sugars arbutin, salicin or cellobiose. It has been shown that mutations at three cryptic loci allow utilization of these sugars. Mutations in the bgl operon allow inducible growth on arbutin and salicin while cel mutations allow constitutive utilization of cellobiose as well as arbutin and salicin. Mutations in a third cryptic locus, arbT, allow the transport of arbutin. A salicin+ arbutin+ cellobiose+ mutant has been isolated from a strain which is deleted for the both the bgl and cel operons. Because the mutant utilized salicin and cellobiose as well as arbutin, it is unlikely it is the result of a mutation in arbT. A second step mutant exhibited enhanced growth on salicin and a third step mutant showed better growth on cellobiose. A fourfold level of induction in response to arbutin and a twofold level of induction in response to salicin was observed when these mutants were assayed on the artificial substrate p-nitrophenyl-beta-D-glucoside. Although growth on cellobiose minimal medium can be detected after prolonged periods of time, these strains are severely inhibited by cellobiose in liquid medium. This system has been cloned and does not hybridize to either bgl or cel specific probes. We have designated this gene system the sac locus. The sac locus is a fourth set of genes with the potential for evolving to provide beta-glucoside utilization.


[Phenomenon of w-reactivation in plasmids].
An analysis of the action of the bacterial repair system on the UV-irradiated pMB9 plasmid has been carried out. It has been shown that the UV-irradiated plasmid is repaired in the bacteria similarly to the DNA of bacteriophage (lambda): the effectiveness of the UVR-system is lowered two-three times, and the postreplicativing REC system acts only at low doses of the UV-light. The phenomenon of omega-reactivation is observed both with plasmid and phage DNAs.


Lrrk promotes tau neurotoxicity through dysregulation of actin and mitochondrial dynamics.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson disease. Genetics and neuropathology link Parkinson disease with the microtubule-binding protein tau, but the mechanism of action of LRRK2 mutations and the molecular connection between tau and Parkinson disease are unclear. Here, we investigate the interaction of LRRK and tau in Drosophila and mouse models of tauopathy. We find that either increasing or decreasing the level of fly Lrrk enhances tau neurotoxicity, which is further exacerbated by expressing Lrrk with dominantly acting Parkinson disease-associated mutations. At the cellular level, altering Lrrk expression promotes tau neurotoxicity via excess stabilization of filamentous actin (F-actin) and subsequent mislocalization of the critical mitochondrial fission protein dynamin-1-like protein (Drp1). Biochemically, monomeric LRRK2 exhibits actin-severing activity, which is reduced as increasing concentrations of wild-type LRRK2, or expression of mutant forms of LRRK2 promote oligomerization of the protein. Overall, our findings provide a potential mechanistic basis for a dominant negative mechanism in LRRK2-mediated Parkinson disease, suggest a common molecular pathway with other familial forms of Parkinson disease linked to abnormalities of mitochondrial dynamics and quality control, and raise the possibility of new therapeutic approaches to Parkinson disease and related disorders.


Drug Sensitivity Prediction Models Reveal a Link between DNA Repair Defects and Poor Prognosis in HNSCC.
Head and neck squamous cell carcinoma (HNSCC) is characterized by the frequent manifestation of DNA crosslink repair defects. We established novel expression-based DNA repair defect markers to determine the clinical impact of such repair defects. Using hypersensitivity to the DNA crosslinking agents, mitomycin C and olaparib, as proxies for functional DNA repair defects in a panel of 25 HNSCC cell lines, we applied machine learning to define gene expression models that predict repair defects. The expression profiles established predicted hypersensitivity to DNA-damaging agents and were associated with mutations in crosslink repair genes, as well as downregulation of DNA damage response and repair genes, in two independent datasets. The prognostic value of the repair defect prediction profiles was assessed in two retrospective cohorts with a total of 180 patients with advanced HPV-negative HNSCC, who were treated with cisplatin-based chemoradiotherapy. DNA repair defects, as predicted by the profiles, were associated with poor outcome in both patient cohorts. The poor prognosis association was particularly strong in normoxic tumor samples and was linked to an increased risk of distant metastasis. In vitro, only crosslink repair-defective HNSCC cell lines are highly migratory and invasive. This phenotype could also be induced in cells by inhibiting rad51 in repair competent and reduced by DNA-PK inhibition. In conclusion, DNA crosslink repair prediction expression profiles reveal a poor prognosis association in HNSCC. SIGNIFICANCE: This study uses innovative machine learning-based approaches to derive models that predict the effect of DNA repair defects on treatment outcome in HNSCC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/21/5597/F1.large.jpg.


Beyond just "flattening the curve": Optimal control of epidemics with purely non-pharmaceutical interventions.
When effective medical treatment and vaccination are not available, non-pharmaceutical interventions such as social distancing, home quarantine and far-reaching shutdown of public life are the only available strategies to prevent the spread of epidemics. Based on an extended SEIR (susceptible-exposed-infectious-recovered) model and continuous-time optimal control theory, we compute the optimal non-pharmaceutical intervention strategy for the case that a vaccine is never found and complete containment (eradication of the epidemic) is impossible. In this case, the optimal control must meet competing requirements: First, the minimization of disease-related deaths, and, second, the establishment of a sufficient degree of natural immunity at the end of the measures, in order to exclude a second wave. Moreover, the socio-economic costs of the intervention shall be kept at a minimum. The numerically computed optimal control strategy is a single-intervention scenario that goes beyond heuristically motivated interventions and simple "flattening of the curve". Careful analysis of the computed control strategy reveals, however, that the obtained solution is in fact a tightrope walk close to the stability boundary of the system, where socio-economic costs and the risk of a new outbreak must be constantly balanced against one another. The model system is calibrated to reproduce the initial exponential growth phase of the COVID-19 pandemic in Germany.


Leukotoxin confers beta-hemolytic activity to Actinobacillus actinomycetemcomitans.
Actinobacillus actinomycetemcomitans is the etiologic agent of localized aggressive periodontitis, a rapidly progressing oral disease that occurs in adolescents. A. actinomycetemcomitans can also cause systemic disease, including infective endocarditis. In early work on A. actinomycetemcomitans workers concluded that this bacterium is not beta-hemolytic. More recent reports have suggested that A. actinomycetemcomitans does have the potential to be beta-hemolytic. While growing A. actinomycetemcomitans on several types of growth media, we noticed a beta-hemolytic reaction on media from one manufacturer. Beta-hemolysis occurred on Columbia agar from Accumedia with either sheep or horse blood, but not on similar media from other manufacturers. A surprising result was that mutants of A. actinomycetemcomitans defective for production of leukotoxin, a toxin that is reportedly highly specific for only human and primate white blood cells, are not beta-hemolytic. Purified leukotoxin was able to lyse sheep and human erythrocytes in vitro. This work showed that in contrast to the accepted view, A. actinomycetemcomitans leukotoxin can indeed destroy erythrocytes and that the production of this toxin results in beta-hemolytic colonies on solid medium. In light of these results, the diagnostic criteria for clinical identification of A. actinomycetemcomitans and potentially related bacteria should be reevaluated. Furthermore, in studies on A. actinomycetemcomitans leukotoxin workers should now consider this toxin's ability to destroy red blood cells.


Cloning of the gene encoding a novel thermostable alpha-galactosidase from Thermus brockianus ITI360.
An alpha-galactosidase gene from Thermus brockianus ITI360 was cloned, sequenced, and expressed in Escherichia coli, and the recombinant protein was purified. The gene, designated agaT, codes for a 476-residue polypeptide with a calculated molecular mass of 53, 810 Da. The native structure of the recombinant enzyme (AgaT) was estimated to be a tetramer. AgaT displays amino acid sequence similarity to the alpha-galactosidases of Thermotoga neapolitana and Thermotoga maritima and a low-level sequence similarity to alpha-galactosidases of family 36 in the classification of glycosyl hydrolases. The enzyme is thermostable, with a temperature optimum of activity at 93 degrees C with para-nitrophenyl-alpha-galactopyranoside as a substrate. Half-lives of inactivation at 92 and 80 degrees C are 100 min and 17 h, respectively. The pH optimum is between 5.5 and 6.5. The enzyme displayed high affinity for oligomeric substrates. The K(m)s for melibiose and raffinose at 80 degrees C were determined as 4.1 and 11.0 mM, respectively. The alpha-galactosidase gene in T. brockianus ITI360 was inactivated by integrational mutagenesis. Consequently, no alpha-galactosidase activity was detectable in crude extracts of the mutant strain, and it was unable to use melibiose or raffinose as a single carbohydrate source.


A method for objective evaluation of functional images.
A method is described for characterizing functional maps by means of a frequency distribution function (DF) of pixels. The method makes use of a map of the standard deviation of the functional parameter. By use of this map the method (a) becomes less sensitive to imprecise definition of the organ borders, (b) compensates for random fluctuations in the functional map, and (most importantly) (c) permits spatial information to be included in the DF. This spatial information is included by performing spatial cluster weighting--a procedure that emphasizes regional dysfunction over global dysfunction. The method is illustrated by applying it to phase maps of the left ventricle. In this example, it is shown that analysis of the DF permits detection of regional abnormalities of LV wall motion and that an improvement in detectability is obtained with cluster weighting.


Response of the mouse circadian system to serotonin 1A/2/7 agonists in vivo: surprisingly little.
Serotonin (5-HT) is thought to play a role in regulating nonphotic phase shifts and modulating photic phase shifts of the mammalian circadian system, but results with different species (rats vs. hamsters) and techniques (in vivo vs. in vitro; systemic vs. intracerebral drug delivery) have been discordant. Here we examined the effects of the 5-HT1A/7 agonist 8-OH-DPAT and the 5-HT1/2 agonist quipazine on the circadian system in mice, with some parallel experiments conducted with hamsters for comparative purposes. In mice, neither drug, delivered systemically at a range of circadian phases and doses, induced phase shifts significantly different from vehicle injections. In hamsters, quipazine intraperitoneally (i.p.) did not induce phase shifts, whereas 8-OH-DPAT induced phase shifts after i.p. but not intra-SCN injections. In mice, quipazine modestly increased c-Fos expression in the SCN (site of the circadian pacemaker) during the subjective day, whereas 8-OH-DPAT did not affect SCN c-Fos. In hamsters, both drugs suppressed SCN c-Fos in the subjective day. In both species, both drugs strongly induced c-Fos in the paraventricular nucleus (within-subject positive control). 8-OH-DPAT did not significantly attenuate light-induced phase shifts in mice but did in hamsters (between-species positive control). These results indicate that in the intact mouse in vivo, acute activation of 5-HT1A/2/7 receptors in the circadian system is not sufficient to reset the SCN pacemaker or to oppose phase-shifting effects of light. There appear to be significant species differences in the susceptibility of the circadian system to modulation by systemically delivered serotonergics.


Disparities in Pancreatic Cancer Outcomes in the Disaggregated Asian American Population.
The Asian American, Native Hawaiian, and Pacific Islander (AANHPI) population is among the fastest-growing population in the USA. However, this is not reflected in scientific research, in which ethnic groups are often combined. We identified trends in treatment and outcomes for pancreatic cancer in a disaggregated AANHPI population. We hypothesize that patients from different AANHPI groups have differences in survival. A retrospective analysis of the National Cancer Database between 2010 and 2019 identified patients treated for pancreatic cancer. We identified demographic factors for patients of Caucasian, African American, and disaggregated Asian subpopulations. Survival curves were generated and multivariate analysis was performed to help determine which factors impacted overall survival. A total of 296,448 patients met the inclusion criteria. Of those, 8568 (3%) patients were Asian. Median survival of AANHPI patients was 11.3 months, as compared with Caucasians (8.9 months) and African Americans (8.1 months) (p < 0.0001). Asian Indians had the highest median survival (14.3 months), whereas the Japanese subpopulation had the lowest (7.6 months) (p < 0.0001). There were significant differences in median survival between the different AANHPI subpopulations irrespective of stage. Multivariate analysis demonstrated that belonging to an AANHPI racial/ethnic group, excluding Japanese and Filipino, was associated with decreased risk of overall mortality. Significant differences were identified in the overall median survival for patients with pancreatic cancer between AANHPI subpopulations. Disparities in socioeconomic factors may have played a role in overall survival. This study highlights the need to include disaggregated data in future studies to subdue disparities in cancer care for patients.


In vitro inhibition of matriptase prevents invasive growth of cell lines of prostate and colon carcinoma.
Matriptase, also known as membrane-type-serine-protease 1 (MT-SP 1), is a type II transmembrane serine protease involved in the activation of the precursor form of hepatocyte growth factor/scatter factor (pro-HGF/SF). Since HGF/SF is a well-known extracellular signal, which plays a key role in the control of invasive growth, we investigated the effects of matriptase inhibition in cell lines derived from colon (DLD-1) or prostate (PC-3) carcinomas. Biochemical analysis showed that matriptase was very efficient in the proteolytic conversion of the inactive HGF/SF precursor into HGF/SF. Inhibition of endogenous matriptase synthesis in DLD-1 or PC-3 cells by specific small interfering RNAs impaired the conversion of pro-HGF/SF into HGF/SF at the cell surface and inhibited cell scattering upon pro-HGF/SF stimulation. The same effect was observed after treatment of these cells with matriptase inhibitors of the 3-amidinophenylalanine-type, CJ-697 or CJ-730. Inhibition of matriptase significantly reduced invasion of the extracellular matrix as well. Interestingly, this reduction was observed even in the presence of pre-activated HGF/SF. It is concluded that matriptase plays a dual-role in the events unleashing the invasive phenotype, one 'upstream' from the HGF/SF signalling cascade and one 'downstream', most likely at the level of the plasminogen activation system. These data provide a proof of concept for the targeting of matriptase in the search for anti-invasive drugs.


Effects of 12-O-tetradecanoylphorbol-13-acetate on the differentiation of avian melanocytes.
12-O-Tetradecanoylphorbol-13-acetate (TPA) has been reported to inhibit and/or delay the terminal differentiation of a variety of cell types. More recently, TPA has been reported to enhance melanogenesis in cultured human melanoma cells. This study focuses on the effect of TPA on the differentiation of normal avian melanocytes. TPA blocked melanogenesis in normal replicating presumptive melanoblasts, as well as in replicating pigmented melanocytes derived from the neural crest, the retinal pigment epithelium, and the pecten oculi. These normal embryonic cells not only failed to synthesize melanin but also failed to assemble premelanosomes and to assume either the characteristic dendritic processes of normal trunk melanocytes or the epithelioid morphology of the normal retinal pigment epithelial cell. This inhibition was remarkably reversible. Following removal of TPA, the previously blocked neural crest cells became pigmented and formed their characteristic dendritic processes, whereas the previously blocked retinal cells formed a pigmented epithelium. The effect of TPA on these normal cells was dependent on duration of exposure and degree of differentiation of the cells at the time of exposure. TPA induced the formation of elongated neurite-like processes in the amelanotic neural crest cells which differed in their cytoskeletal structure from the dendritic processes of normal trunk melanocytes. These TPA-blocked pigment cells with elongated processes bear a striking morphological resemblance to presumptive myoblasts, chondroblasts, and fibroblasts treated with the tumor promoter.


Coverage, quality of and barriers to postnatal care in rural Hebei, China: a mixed method study.
Postnatal care is an important link in the continuum of care for maternal and child health. However, coverage and quality of postnatal care are poor in low- and middle-income countries. In 2009, the Chinese government set a policy providing free postnatal care services to all mothers and their newborns in China. Our study aimed at exploring coverage, quality of care, reasons for not receiving and barriers to providing postnatal care after introduction of this new policy. We carried out a mixed method study in Zhao County, Hebei Province, China from July to August 2011. To quantify the coverage, quality of care and reasons for not using postnatal care, we conducted a household survey with 1601 caregivers of children younger than two years of age. We also conducted semi-structured interviews with 24 township maternal and child healthcare workers to evaluate their views on workload, in-service training and barriers to postnatal home visits. Of 1442 (90% of surveyed caregivers) women who completed the postnatal care survey module, 8% received a timely postnatal home visit (within one week after delivery) and 24% of women received postnatal care within 42 days after delivery. Among women who received postnatal care, 37% received counseling or guidance on infant feeding and 32% on cord care. 24% of women reported that the service provider checked jaundice of their newborns and 18% were consulted on danger signs and thermal care of their newborns. Of 991 mothers who did not seek postnatal care within 42 days after birth, 65% of them said that they did not knew about postnatal care and 24% of them thought it was unnecessary. Qualitative findings revealed that staff shortages and inconvenient transportation limited maternal and child healthcare workers in reaching out to women at home. In addition, maternal and child healthcare workers said that in-service training was inadequate and more training on postnatal care, hands-on practice, and supervision were needed. Coverage and quality of postnatal care were low in rural Hebei Province and far below the targets set by Chinese government. We identified barriers both from the supply and demand side.


Local Analysis of Heterogeneous Intracellular Transport: Slow and Fast Moving Endosomes.
Trajectories of endosomes inside living eukaryotic cells are highly heterogeneous in space and time and diffuse anomalously due to a combination of viscoelasticity, caging, aggregation and active transport. Some of the trajectories display switching between persistent and anti-persistent motion, while others jiggle around in one position for the whole measurement time. By splitting the ensemble of endosome trajectories into slow moving subdiffusive and fast moving superdiffusive endosomes, we analyzed them separately. The mean squared displacements and velocity auto-correlation functions confirm the effectiveness of the splitting methods. Applying the local analysis, we show that both ensembles are characterized by a spectrum of local anomalous exponents and local generalized diffusion coefficients. Slow and fast endosomes have exponential distributions of local anomalous exponents and power law distributions of generalized diffusion coefficients. This suggests that heterogeneous fractional Brownian motion is an appropriate model for both fast and slow moving endosomes. This article is part of a Special Issue entitled: "Recent Advances In Single-Particle Tracking: Experiment and Analysis" edited by Janusz Szwabiński and Aleksander Weron.


Effects of Estradiol Therapy on Resting-State Functional Connectivity of Transgender Women After Gender-Affirming Related Gonadectomy.
An extreme incongruence between sex and gender identity leads individuals with gender dysphoria (GD) to seek cross-sex hormone therapy (CSHT), and gender-affirming surgery (GAS). Although few studies have investigated the effects of CSHT on the brain prior to GAS, no studies in the extant literature have evaluated its impact during hypogonadism in post-GAS individuals. Here, we aimed to evaluate the effects of estradiol on resting-state functional connectivity (rs-FC) of the sensorimotor cortex (SMC) and basal ganglia following surgical hypogonadism. Eighteen post-GAS (male-to-female) participants underwent functional magnetic resonance imaging (fMRI) and neuropsychiatric and hormonal assessment at two time points (t1, hormonal washout; t2, CSHT reintroduction). Based on the literature, the thalamus was selected as a seed, while the SMC and the dorsolateral striatum were targets for seed-based functional connectivity (sbFC). A second sbFC investigation consisted of a whole-brain voxel exploratory analysis again using the thalamus as a seed. A final complementary data-driven approach using multivoxel pattern analysis (MVPA) was conducted to identify a potential seed for further sbFC analyses. An increase in the rs-FC between the left thalamus and the left SCM/putamen followed CSHT. MVPA identified a cluster within the subcallosal cortex (SubCalC) representing the highest variation in peak activation between time points. Setting the SubCalC as a seed, whole-brain analysis showed a decoupling between the SubCalC and the medial frontal cortex during CSHT. These results indicate that CSHT with estradiol post-GAS, modulates rs-FC in regions engaged in cognitive, emotional, and sensorimotor processes.


Atypical primary pulmonary meningioma: a report of a case suspected of being a lung metastasis.
Primary extracranial and extraspinal meningiomas are very rare tumours, and primary pulmonary ones are even more uncommon. They present as a solitary pulmonary nodule, and most of them are benign, except for three cases. We describe a primitive atypical pulmonary meningioma first suspected of being a metastasis in a patient during follow-up ten years after therapy for breast cancer.


International Society for Clinical Densitometry 2007 Adult and Pediatric Official Positions.
The International Society for Clinical Densitometry (ISCD) periodically convenes Position Development Conferences (PDCs) in order to establish standards and guidelines for the assessment of skeletal health. The most recent Adult PDC was held July 20-22, 2007, in Lansdowne, Virginia, USA; the first Pediatric PDC was June 20-21, 2007 in Montreal, Quebec, Canada. PDC topics were selected according to clinical relevancy, perceived need for standardization, and likelihood of achieving agreement. Each topic area was assigned to a task force for a comprehensive review of the scientific literature. The findings of the review and recommendations were presented to adult and pediatric international panels of experts. The panels voted on the appropriateness, necessity, quality of the evidence, strength, and applicability (worldwide or variable according to local requirements) of each recommendation. Those recommendations that were approved by the ISCD Board of Directors become Official Positions. This is a review of the methodology of the PDCs and selected ISCD Official Positions.


Streptozotocin-induced changes in cardiac gene expression in the absence of severe contractile dysfunction.
Diabetes mellitus alters energy substrate metabolism and gene expression in the heart. It is not known whether the changes in gene expression are an adaptive or maladaptive process. To answer this question, we determined both the time-course and the extent of the alteration of gene expression induced by insulin-deficient diabetes. Transcript analysis with real-time quantitative polymerase chain reaction (PCR) was performed in rat hearts 1 week (acute group) or 6 months (chronic group) after administration of streptozotocin (55 mg/kg). In the acute group, insulin-dependent diabetes induced a 55-70% decrease of both glucose transporter 1 (GLUT1) and GLUT4 transcripts, a slight decrease of liver-specific carnitine palmitoyltransferase I (CPT I), and no change in muscle-specific CPT I. The uncoupling protein UCP-3 increased three-fold, with no change in UCP-2. These metabolic alterations were accompanied by an isoform switching from the normally expressed alpha myosin heavy chain (MHC) to the fetal isoform betaMHC mRNA, by a 50% decrease of cardiac alpha-actin mRNA, a 30% decrease of the sarcoplasmic Ca++-ATPase mRNA, and a 50% decrease of muscle creatine kinase (P<0.01 v controls). All genomic changes were also present in the chronic group. Genomic markers of ventricular dysfunction [tumor necrosis factor alpha (TNF-alpha), inducible nitric oxide synthase, cyclo-oxygenase-2] were not affected by chronic diabetes. In both groups, there were no changes in resting left ventricular function by echocardiography. The heart adapts to insulin-deficient diabetes by a rapid and simultaneous response of multiple genes involved in cardiac metabolism and function. This genomic adaptation resembles the adaptation of cardiac hypertrophy, remains stable over time, and does not lead to major contractile dysfunction.


[Properties and biosynthesis of acetyl-CoA-carboxylase from chicken liver with administration of nicotinic acid during stimulation of lipogenesis].
Acetyl-CoA-carboxylase is isolated and purified to a homogeneous state from the chicken liver with alimentary lipogenesis stimulation. Under the action of nicotinic acid in vivo the specific enzyme activity is shown to decrease considerably followed by some variations in its properties. According to the results obtained during ultracentrifugation and PAAG electrophoresis nicotinic acid causes partial enzyme deaggregation with simultaneous increase of its phosphorylation. The latter is accompanied by a rise in the content of phosphate labile to alkali on acetyl-CoA-carboxylase subunits. Nicotinic acid in vivo has practically no effect on acetyl-CoA-carboxylase synthesis and decay rate. Its inhibiting action is induced by stimulation of enzyme phosphorylation.


Use of magnetic resonance imaging to assess blood-brain/blood-glioma barrier opening during conformal radiotherapy.
For chemotherapy to act synergistically and safely with radiation against high-grade gliomas, drugs must pass the endothelial junctions of the blood-tumor barrier (BTB) to reach all tumor cells, and should not pass the blood-brain barrier (BBB) to cause toxicity to normal brain. The objective of this study was to assess BBB/BTB status using magnetic resonance imaging (MRI) during a course of radiotherapy of high-grade gliomas. Sixteen patients with grade 3 or 4 supratentorial malignant glioma receiving conformal radiotherapy (RT) underwent contrast-enhanced MRI before, during, and after completion of RT. A gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) uptake index was analyzed with respect to the tumor and RT dose received. In the nonenhanced tumor region, contrast uptake increased significantly after the receipt of approximately 10 Gy (P < .01), and reached a maximum after the receipt of approximately 30 Gy. In the initially contrast-enhanced tumor region, contrast uptake decreased over the course of RT and became significant after completion of RT in patients without progressive disease. The healthy brain showed only nonsignificant changes during and after irradiation. Contrast MRI reveals increases in Gd-DTPA uptake in the initially nonenhanced tumor region but not in the remaining brain during the course of RT, suggesting opening of the BTB. This finding suggests that the effect of conformal radiation is more selective on the BTB than the BBB, and there may be a window extending from 1 week after the initiation of radiotherapy to 1 month after the completion of treatment during which a pharmaceutical agent has maximum access to high-grade gliomas.