Isolation of human immune deficiency virus from African AIDS patients and from persons without AIDS or IgG antibody to human immune deficiency virus.
We previously reported a high incidence of acquired immune deficiency syndrome (AIDS) in Kinshasa, Zaire, as well as a high frequency of antibody to human immunodeficiency virus (HIV), which includes HTLV-III and LAV viruses, in persons without AIDS. In this report we assessed the frequency of HIV virus infection in persons with and without clinical AIDS and the association of virus isolation to presence of antibody. We isolated HIV from 27 (77%) of 35 patients with AIDS, and 5 of 9 patients with AIDS-related complex (ARC). Virus was also isolated from plasma and cerebrospinal fluid of patients in the study. The presence of antibody was a reliable marker for virus infection in African patients with AIDS. HIV was isolated from 5 of 27 control patients without AIDS, 3 of whom had normal T helper to T suppressor ratios and normal numbers of T helper cells. Two of these patients had no detectable antibody to HIV by ELISA or Western blot methods. In a population, such as the general heterosexual population of Kinshasa, with frequent infection by HIV and with few clearly definable risk groups, screening for antibodies to HIV may not be sufficient to identify some virus infected persons.


The impact of nonclinical factors on practice variations: the case of hysterectomies.
This study investigates the role of nonclinical factors (physician characteristics) in explaining variations in hysterectomy practice patterns. Patient discharge data are obtained from the Arizona state discharge database for the years 1989-1991. Physician data are obtained from the Arizona State Medical Association. The analyses are based on 36,104 cases performed by 339 physicians in 43 hospitals. This article measures the impact of physician factors on the decision to perform a hysterectomy, controlling for a host of patient and hospital characteristics. Physician factors include background characteristics and training, medical experience, and physician's practice style. Physician effects are evaluated in terms of their overall contribution to the explanatory power of regression models, as well as in terms of specific hypotheses to be tested. The sources of data were linked to produce one record per patient. As a set, physician factors account for a statistically significant increase in the explanatory power of the model after addition of patient and hospital effects. Parameter estimates provide further support for the hypothesized effects of physicians' background, experience, and practice characteristics. Overall, the results confirm that nonclinical (physician) factors play a statistically significant role in the hysterectomy decision. Substantively, however, these factors play a smaller, secondary role compared to that of clinical and patient factors in explaining practice variations in hysterectomies. The results suggest that efforts to reduce unnecessary hysterectomies should be directed at identifying the appropriate clinical indications for hysterectomy and disseminating this information to physicians and patients. This may require such intervention strategies as continuing clinical education, promulgation of explicit practice guidelines, peer review, public education, and greater understanding and inclusion of patient preference in the decision process.


Adding the value of the Charlson Comorbidity Index to the GRACE score for mortality prediction in acute coronary syndromes.
Scarce and conflicting data still exist about the role of the Charlson Comorbidity Index (CCI) when added to the traditional Global Registry of Acute Coronary Events (GRACE) risk score for outcome prediction in patients with acute coronary syndrome (ACS). All consecutive admissions due to ACS, from 1 January 2018 to 31 December 2020 were retrospectively reviewed from an internal database of a tertiary cardiac center in Salerno (Italy). Logistic and Cox proportional regression analyses were performed in order to assess the contribution of the CCI on 30-day and long-term mortality. The CCI adding value to the GRACE score was analyzed with several measures of improvement in discrimination: increase in the area under the receiver-operating characteristic curve (AUC), the integrated discrimination improvement (IDI), and the categorical and continuous net reclassification improvement (cNRI) more than 0. Robustness of the results was assessed through an internal validation procedure with bootstrapping. One thousand three hundred and ten patients were identified. The median age was 68 (58-78) years. One hundred and twenty (9.2%) and 113 (9.5%) deaths occurred, respectively, during the first 30 days from admission and during long-term follow-up (median follow-up time: 13 months; interquartile range: 9-24). After multivariate regression analysis, the CCI was not associated with short-term mortality, while it was significantly and independently associated with long-term mortality along with the GRACE score (hazard ratio: 1.34, 95% confidence interval: 1.22-1.47; P < 0.001). An additive effect of CCI with the GRACE risk score was observed in predicting long-term mortality: AUC from 0.768 to 0.819 (P = 0.003), category-based NRI: 0.215, cNRI>0: 0.669 (P < 0.001), IDI: 0.066 (P < 0.001). The CCI is a predictor of long-term mortality and improves risk stratification of patients with ACS over the GRACE risk score.


[Transgenic technology and soybean quality improvement].
Soybean is an important source of edible oil, protein and protein diet. The breeding process of high quality soybean can be accelerated via employment of transgenic technology, by which the key genes for soybean quality traits could be directly manipulated. Thus, various soybean varieties could be bred to fulfill different needs for specific consumers. Here, we reviewed the contribution of transgenic technology to improvement of soybean qualities in recent years. We also introduce some newly developed safe transgenic technologies and hope this information could relieve some concerns on the GM food.


Functional outcome of AO type C distal humeral fractures.
To review the functional outcome of AO type C distal humeral fractures (bicondylar fractures) managed with dual orthogonal plate fixation. Twenty-three patients were reviewed retrospectively at a mean of 45.1 months. Patient-rated outcomes (Disabilities of the Arm Shoulder and Hand [DASH], Patient Rated Ulnar Nerve Evaluation [PRUNE], American Shoulder and Elbow Surgeons Elbow form [ASES-e], and Short Form-36 [SF-36]), clinical, radiographic, and objective evaluations were used to assess outcomes. Almost 40% of patients required a third plate for adequate fixation. Patients identified minimal subjective deficits (10%) with a mean satisfaction of 93%. The arc of motion was decreased in the flexion-extension plane (122 degrees relative to 138 degrees, p <.01), whereas strength was lower for both elbow flexion-extension and forearm rotation (p <.05). The overall complication rate was 48%, however, most were minor and resolved without further surgery. No ulnar neuropathies were identified at follow-up after routine ulnar nerve transposition. Outcomes of AO type C distal humeral fractures were good with dual orthogonal plating, ulnar nerve transposition, and early motion. Additional plating may be required with distal fracture patterns or osteopenic bone.


Transurethral versus open enucleation of the prostate in Sweden - a retrospective comparative cohort study.
To investigate if treatment with transurethral enucleation of the prostate (TUEP) during the learning curve is as efficient and safe in the short term as transvesical open prostate enucleation (OPE), in patients with benign prostatic obstruction (BPO) > 80 ml in a population in Sweden. Methods: 54 patients with ultrasound verified BPO > 80 ml and indication for surgery underwent TUEP or OPE between 2013 and 2019. Peri- and postoperative outcome variables regarding voiding efficiency and morbidity from 20 OPE at Skåne University Hospital (SUS) and from the first 34 TUEP performed at SUS and Ystad Hospital were retrospectively assembled. Follow-up data from the first 6 postoperative months were collected by chart review. Intraoperative bleeding during TUEP was less than in OPE (225 ml vs. 1,000 ml). TUEP took longer surgery time than OPE (210 vs. 150 min.). Within 30 days postoperatively, bleeding occurred less often after TUEP (23% vs. 40%), requiring one fourth of the blood transfusions given after OPE. After TUEP, patients had shorter hospitalisation (3 days vs. 7 days) and catheterisation time (3 days vs. 12 days). During the 6-month follow-up period, incontinence and UTI defined as symtomatic significant bacteriuria (urinary culture) were observed as main complications after TUEP and OPE. Functional outcome data availability (International Prostate Symptom Score [IPSS] questionnaire, uroflowmetry, residual urine) were limited. Treatment with TUEP during the learning curve led to less bleeding, shorter hospitalisation- and catheterisation time than treatment with OPE. However, surgery time was shorter with OPE. There were no major differences between the groups concerning mid-term functional outcomes, with the reservation of an inconsistent follow-up.


Temperature effects on emission of quantum dots embedded in polymethylmethacrylate.
We successfully used CdSe/ZnS quantum dots (QDs) as a dopant within a polymethylmethacrylate (PMMA) matrix. This doped material was used in the fabrication of a microstructured polymer optical fiber whose photoluminescence was characterized. A detailed analysis of the emission properties of the QDs as a function of temperature is presented, with the temperature dependence of this emission broken into components to show contributions from the thermo-optic effect of the PMMA and the temperature-dependence of the bandgap of the QDs.


Efficacy and Safety of Vandetanib in Progressive and Symptomatic Medullary Thyroid Cancer: Post Hoc Analysis From the ZETA Trial.
We conducted a post hoc analysis of the vandetanib phase III trial involving patients with advanced medullary thyroid cancer (MTC) to assess the efficacy and safety of vandetanib in patients with progressive and symptomatic MTC. The primary objective of the analysis was to determine progression-free survival (PFS) of these patients. Eligible patients from the ZETA trial were divided into 4 disease severity subgroups: progression and symptoms, symptoms only, progression only, and no progression and no symptoms assessed at baseline. PFS, determined from objective tumor measurements performed by the local investigator, overall survival (OS), time to worsening of pain (TWP), and objective response rate (ORR) were evaluated. Of the 331 patients in this trial, 184 had symptomatic and progressive disease at baseline. In this subgroup, results were similar in magnitude to those observed in the overall trial for PFS (hazard ratio [HR], 0.43; 95% CI, 0.28 to 0.64; P < .0001), OS (HR, 1.08; 95% CI, 0.72 to 1.61; P = .71), and TWP (HR, 0.67; 95% CI, 0.43 to 1.04; P = .07), and the observed adverse events were consistent with the known safety profile of vandetanib. In this subgroup, the ORR was 37% in the treatment arm versus 2% in the placebo arm. Vandetanib demonstrated clinical benefit-specifically, increased PFS-in patients with symptomatic and progressive MTC.


An amylase gene from Drosophila pseudoobscura is expressed in Escherichia coli. Functional selection and biochemical comparisons of the fly- and clone-produced amylases.
An amylase gene from Drosophila pseudoobscura was isolated from a genomic library constructed in pBR322 and cloned in Escherichia coli by selecting for the ability of its product to hydrolyze starch, a carbon source not normally utilized by E. coli. Hybridization of pAMY17F to D. pseudoobscura polytene chromosomes shows a positive signal at the amylase pseudogene locus (bank 78, chromosome 3). The chimeric plasmid pAMY17F, has been altered in such a way as to increase amylase expression. Southern and Northern hybridizations to the cloned amylase DNA indicate that the source of the gene is from D. pseudoobscura. Biochemical properties such as pH optima, substrate specificities, electrophoretic analyses, inhibitor sensitivities, heat stabilities, temperature responsiveness and molecular weights indicate that the amylases produced by the fly and bacterial clone are similar and have similar properties. It appears that E. coli/pAMY17F is producing an amylase like that found in D. pseudoobscura.


Objective assessment of the effects of opicapone in Parkinson's disease through kinematic analysis.
Opicapone (OPC) is a third-generation, selective peripheral COMT inhibitor that improves peripheral L-DOPA bioavailability and reduces OFF time and end-of-dose motor fluctuations in Parkinson's disease (PD) patients. In this study, we objectively assessed the effects of adding OPC to L-DOPA on bradykinesia in PD through kinematic analysis of finger movements. We enrolled 20 treated patients with PD and motor fluctuations. Patients underwent two experimental sessions (L-DOPA, L-DOPA + OPC), separated by at least 1 week. In each session, patients were clinically evaluated and underwent kinematic movement analysis of repetitive finger movements at four time points: (i) before their usual morning dose of L-DOPA (T0), (ii) 30 min (T1), (iii) 1 h and 30 min (T2), and (iv) 3 h and 30 min after the L-DOPA intake (T3). Movement velocity and amplitude of finger movements were higher in PD patients during the session with OPC compared to the session without OPC at all the time points tested. Importantly, the variability of finger movement velocity and amplitude across T0-T3 was significantly lower in the L-DOPA + OPC than L-DOPA session. This study is the first objective assessment of the effects of adding OPC to L-DOPA on bradykinesia in patients with PD and motor fluctuations. OPC, in addition to the standard dopaminergic therapy, leads to significant improvements in bradykinesia during clinically relevant periods associated with peripheral L-DOPA dynamics, i.e., the OFF state in the morning, delayed-ON, and wearing-OFF periods.


Acemetacin antinociceptive mechanism is not related to NO or K+ channel pathways.
Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) used for the treatment of acute gout and inflammation. However, its use is limited due to side effects. Acemetacin is a prodrug of indomethacin that exhibits better gastric tolerability in preclinical and clinical trials. The aim of this study was to examine if the systemic administration of acemetacin involved the sequential participation of nitric oxide (NO) or K+ channel pathways to confer its antinociceptive effect, as compared to indomethacin. The antinociceptive effect of both drugs was studied with the formalin test. Equimolar doses of acemetacin or indomethacin were administered orally. The intraplantar administration of either L-NAME, glibenclamide, apamin or charybdotoxin plus indomethacin or acemetacin was studied using the formalin test and the anti-inflammatory and antihyperalgesic effects were measured. The antinociceptive effect of acemetacin or indomethacin was not significantly different when pretreatment with L-NAME, glibenclamide, apamin or charybdotoxin was done. The antihyperalgesic and antiinflammatory effects were also similar for both indomethacin and acemetacin. Our results suggest that the antinociceptive effect of indomethacin or acemetacin is not mediated by NO or K+ channel activation.


Influenza A virus infection of macrophages. Enhanced tumor necrosis factor-alpha (TNF-alpha) gene expression and lipopolysaccharide-triggered TNF-alpha release.
We have previously shown that infection of macrophages by influenza A virus is capable of priming for a high TNF-alpha production in response to LPS. The present study was designed to examine in more detail TNF-alpha gene expression and TNF-alpha protein release of virus-infected, murine PU5-1.8 macrophages in the presence or absence of low and by itself rather inefficient concentrations of LPS (10 ng/ml). Although influenza A virus infection alone induced a massive TNF-alpha mRNA accumulation, translation into the bioactive TNF-alpha protein was low as intra- and extracellularly determined by bioassay, specific ELISA and Western blot. However, when LPS was added simultaneously or up to 4 h after infection, a high TNF-alpha production was initiated. The virus-induced TNF-alpha mRNA accumulation appeared to be due to both transcriptional and post-transcriptional changes: an enhanced TNF-alpha gene transcription as determined by nuclear run-on transcription assay and a markedly prolonged half-life of TNF-alpha mRNA as shown in actinomycin D-treated macrophages. These findings imply that influenza A virus may 1) either directly or indirectly stimulate TNF-alpha gene transcription activators or may interfere with labile transcription repressor proteins and 2) may stabilize TNF-alpha mRNA by delaying its degradation. Both mechanisms, taken together, prime influenza A virus-infected macrophages for a high TNF-alpha release in response to LPS which, as clinical cases show, may adversely affect patients with combined influenza A virus and bacterial infections.


Alcohol use disorder and GABAB receptor gene polymorphisms in an Italian sample: haplotype frequencies, linkage disequilibrium and association studies.
Alcohol use disorder (AUD) is a complex trait with genetic and environmental influences. Several gene variants have been associated with the risk for AUD, including genes encoding the sub-units of the γ-aminobutyric acid (GABA) receptors. This study evaluated whether specific single nucleotide polymorphisms (SNPs) in genes encoding GABAB receptor sub-units can be considered as candidates for the risk of AUD. Seventy-four AUD subjects and 128 Italian controls were genotyped for 10 SNPs in genes encoding GABA-B1 and GABA-B2 sub-units (GABBR1 and GABBR2). Allele, genotype, and haplotype frequencies were tested for the association with the AUD trait. A significant difference between AUD individuals and controls was observed at genotype level for rs2900512 of GABBR2 gene. The homozygous T/T genotype was not found in the controls, whereas it was over-represented in the AUD individuals. Under the recessive model (T/T vs C/T + C/C) this result was statistically significant, as well as the Odds Ratio for the association with the AUD trait. The results provide preliminary data on the association between GABAB receptor gene variation and risk of AUD. To confirm this finding, studies with larger samples and additional characterisation of the phenotypic AUD trait are required.


DORSAL BRAINSTEM SYNDROME AND THE USE OF NEURALLY ADJUSTED VENTILATORY ASSIST (NAVA) IN AN INFANT.
To report a rare case of dorsal brainstem syndrome in an infant after hypoxic-ischemic episode due to severe sepsis and the use of neurally adjusted ventilatory assist (NAVA) to aid in diagnosis and in the removal of mechanical ventilation. A 2-month-old male infant, previously healthy, presented with severe sepsis that evolved to dorsal brainstem syndrome, which usually occurs after hypoxic-ischemic injury in neonates and infants, and is related to very specific magnetic resonance images. Due to neurological lesions, thei nfant remained in mechanical ventilation. A NAVA module was installed to keep track of phrenic nerve conduction to the diaphragm, having successfully showed neural conduction and helped removing mechanical ventilation. Dorsal brainstem syndrome is a rare condition that should be considered after hypoxic-ischemic episode in infants.


Reinforcement of the adrenergic overdrive in the metabolic syndrome complicated by obstructive sleep apnea.
Metabolic syndrome is characterized by a marked sympathetic overactivity. It is unknown, however, whether the neuroadrenergic activation can be ascribed to obstructive sleep apnoea (OSA), OSA exerts potentiating effects on the metabolic syndrome-related sympathetic activation and reflex/metabolic variables (insulin resistance) participate at the phenomenon. We conducted a cross-sectional study of healthy individuals and metabolic syndrome patients recruited in our outpatient clinic. Fifty-five middle-age men classified according to Adult Treatment Panel III criteria and apnea-hypopnea index (overnight polysomnographic evaluation) as healthy controls without OSA and metabolic syndrome patients without and with OSA were studied. Blood pressure (Finapres), heart rate (ECG) and muscle sympathetic nerve activity (MSNA; microneurography) were measured at rest and during baroreflex manipulation. Compared with controls, patients with metabolic syndrome with and without OSA displayed higher waist-hip ratio, blood pressure, triglycerides and homeostasis model assessment index values but lower high-density lipoprotein cholesterol. MSNA was significantly higher in patients with metabolic syndrome without OSA than in controls (61.9 +/- 3.9 vs. 37.7 +/- 4.1 bursts/100 heartbeats, respectively, P < 0.01), a further marked increase being detected in patients with metabolic syndrome with OSA (77.1 +/- 4.3 bursts/100 heart beats, P < 0.01). Compared with controls, baroreflex control of heart rate and MSNA was markedly impaired in patients with metabolic syndrome with OSA, a further impairment in baroreflex-heart rate modulation being detected in metabolic syndrome with OSA. In the metabolic syndrome group as a whole, at the multivariate analysis, MSNA was significantly related to the apnoea-hypopnoea index but not to other variables. Thus the sympathetic activation of metabolic syndrome occurs independently on OSA. OSA, however, markedly potentiates this neuroadrenergic abnormality via a hypoxic-dependent chemoreflex activation.


Comparing the simplified and international autoimmune hepatitis group criteria in primary sclerosing cholangitis.
Although highly sensitive and specific, the revised International Autoimmune Hepatitis Group (IAIHG) diagnostic criteria for autoimmune hepatitis (AIH) are cumbersome to use in clinical practice and rely upon a number of autoantibodies that are costly and are not widely available. The simplified scoring system for AIH attempts to rectify the complexity of the IAIHG criteria. To date, there have been few studies assessing the specificity of the simplified score for AIH when applied to patients with cholestatic liver diseases. The purpose of this study was to examine the specificity of the simplified scoring system for AIH as compared to the revised IAIHG criteria in a large cohort of patients with primary sclerosing cholangitis (PSC). The patient population consisted of 147 patients enrolled in two prospective trials at the Mayo Clinic examining the use of ursodeoxycholic acid in PSC. All of the patients underwent baseline blood work (including standard serologic testing to exclude other liver diseases), liver biopsy, and cholangiogram to confirm PSC. Demographic, laboratory, and histologic data were extracted for each subject. Simplified and revised IAIHG scores were calculated for each subject and compared. The simplified scoring system identified 2 patients with probable AIH and no patients with definite AIH. Comparatively, the revised IAIHG scoring system identified no patients with probable or definite AIH. As with the revised IAIHG criteria, the simplified scoring system for AIH has excellent specificity when applied to a PSC population.


Selective reduction of graft-versus-host disease-mediating human T cells by ex vivo treatment with soluble Fas ligand.
Previous work done in our laboratory, using mouse models, showed that soluble Fas ligand (sFasL) can efficiently delete donor anti-host T cells during their activation against irradiated host cells in MLCs. In the mouse models, this ex vivo sFasL treatment abrogated graft-vs-host disease (GVHD) while sparing donor T cells with antitumor reactivity. The present work was performed with human cells, to extend our work toward reduction of clinical GVHD. PBMC responders from a given individual (first party) were stimulated in vitro with irradiated PBMC stimulators from a second person (second party), in the presence of sFasL. In control MLCs without sFasL, alloreacting T cells began to up-regulate Fas (CD95) detectably and became sensitive to Fas-mediated apoptosis by as early as day 1-2. In MLCs containing sFasL, there were greatly reduced numbers of alloreacting CD3(+)CFSE(lo) cells, activation Ag-expressing CD4(hi) and CD8(hi) cells, IFN-gamma-producing CD4(+) and CD8(+) cells, and CD8(+)CD107a(+) CTLs. Furthermore, mice transplanted with the ex vivo sFasL/MLR-treated cells had prolonged time to fatal GVHD in an in vivo xenogeneic GVHD model. Responder cells harvested from primary MLCs containing sFasL had reduced proliferation in response to second party cells, but proliferated in response to CMV Ags, PHA, and third party cells. In addition, sFasL/MLR-treated cell populations contained influenza-specific T cells, CD4(+)FOXP3(+) T cells, and CD4(+)CD25(+) T cells. These data indicate that this ex vivo sFasL/MLR depletion of alloreacting human donor anti-host T cells was efficient and selective.


Workplace assessment in crisis? The way forward.
A recent Royal College of Physicians' study on assessment raises serious questions for workplace assessment. To address these, a system is recommended that bridges the gap from competence to performance and integrates supervised learning events (SLEs) that are formative in purpose with summative assessment of performance by entrustable professional activities (EPAs).


T Cells Control Chemokine Secretion by Keratinocytes.
The massive infiltration of lymphocytes into the skin is a hallmark of numerous human skin disorders. By co-culturing murine keratinocytes with splenic T cells we demonstrate here that T cells affect and control the synthesis and secretion of chemokines by keratinocytes. While pre-activated CD8+T cells induce the synthesis of CXCL9 and CXCL10 in keratinocytes and keep in check the synthesis of CXCL1, CXCL5, and CCL20, keratinocytes dampen the synthesis of CCL3 and CCL4 in pre-activated CD8+T cells. One key molecule is IFN-γ that is synthesized by CD8+T cells under the control of NFATc1 and NFATc2. CD8+T cells deficient for both NFAT factors are unable to induce CXCL9 and CXCL10 expression. In addition, CD8+T cells induced numerous type I IFN-inducible "defense genes" in keratinocytes encoding the PD1 and CD40 ligands, TNF-α and caspase-1. The enhanced expression of type I IFN-inducible genes resembles the gene expression pattern at the dermal/epidermal interface in lichen planus, an inflammatory T lymphocyte-driven skin disease, in which we detected the expression of CXCL10 in keratinocytes in close vicinity to the infiltration front of T cells. These data reflect the multifaceted interplay of lymphocytes with keratinocytes at the molecular level.


A case of chronic pancreatitis in which endoscopic ultrasonography was effective in the diagnosis of a pseudoaneurysm.
Endoscopic ultrasonography (EUS) was performed on a patient being treated for chronic pancreatitis because a submucosal tumor was observed in the stomach during gastrointestinal endoscopy. As internal pulsatile blood flow on Doppler was present, the diagnosis of an aneurysm was made. The pseudoaneurysm of the left gastric artery was embolized with histoacryl and lipiodol and the splenic artery was embolized with coils at the location of the pseudoaneurysm to prevent hemorrhage. Follow up EUS confirmed the cessation of blood flow from the pseudoaneurysm. Clinicians encountering a gastric submucosal tumor-like protrusion in a patient with chronic pancreatitis should use EUS to investigate the possibility of a pseudoaneurysm, which must be treated as quickly as possible once identified.


Effect of homocysteine on plaque formation and oxidative stress in patients with acute coronary syndromes.
Cardiovascular diseases, especially coronary artery disease (CAD), are major causes of death in industrialized countries. Elevated concentrations of plasma homocysteine (Hcy) have been associated with an increased risk of CAD. Increased plasma levels of chemokine, characterized by their ability to induce migration and activation of leukocytes, may contribute to the pathogenesis of CAD. This study was designed to investigate the changes of plasma Hcy, monocyte chemoattractant protein-1 (MCP-1) and oxidative stress markers in acute coronary syndrome patients. A total of 149 subjects were divided into four groups: 50 patients with unstable angina, 30 patients with acute myocardial infarction, 20 coronary restenosis patients after percutaneous coronary intervention and 49 healthy control subjects. Plasma levels of Hcy, MCP-1, malondialdehyde and superoxide dismutase were measured. Plasma levels of Hcy and MCP-1 showed significant increases in unstable angina, acute myocardial infarction and restenosis patients compared with control subjects (P < 0.05, respectively). Plasma levels of malondialdehyde were significantly increased in unstable angina and acute myocardial infarction patients when compared with control subjects (P < 0.05, respectively). Plasma superoxide dismutase levels were significantly reduced in acute myocardial infarction patients when compared with control group (P < 0.01). Hcy might act as an atherogenic factor through promoting chemokine, reactive oxygen species and oxidized low density lipoprotein production and thereby convert a stable plaque into an unstable potentially occlusive lesion.


Automatic day-2 intervention by a multidisciplinary antimicrobial stewardship-team leads to multiple positive effects.
Antimicrobial resistance rates are increasing. This is, among others, caused by incorrect or inappropriate use of antimicrobials. To target this, a multidisciplinary antimicrobial stewardship-team (A-Team) was implemented at the University Medical Center Groningen on a urology ward. Goal of this study is to evaluate the clinical effects of the case-audits done by this team, looking at length of stay (LOS) and antimicrobial use. Automatic e-mail alerts were sent after 48 h of consecutive antimicrobial use triggering the case-audits, consisting of an A-Team member visiting the ward, discussing the patient's therapy with the bed-side physician and together deciding on further treatment based on available diagnostics and guidelines. Clinical effects of the audits were evaluated through an Interrupted Time Series analysis and a retrospective historic cohort. A significant systemic reduction of antimicrobial consumption for all patients on the ward, both with and without case-audits was observed. Furthermore, LOS for patients with case-audits who were admitted primarily due to infections decreased to 6.20 days (95% CI: 5.59-6.81) compared to the historic cohort (7.57 days; 95% CI: 6.92-8.21; p = 0.012). Antimicrobial consumption decreased for these patients from 8.17 DDD/patient (95% CI: 7.10-9.24) to 5.93 DDD/patient (95% CI: 5.02-6.83; p = 0.008). For patients with severe underlying diseases (e.g., cancer) these outcome measures remained unchanged. The evaluation showed a considerable positive impact. Antibiotic use of the whole ward was reduced, transcending the intervened patients. Furthermore, LOS and mean antimicrobial consumption for a subgroup was reduced, thereby improving patient care and potentially lowering resistance rates.


Acetaminophen-induced differentiation of human breast cancer stem cells and inhibition of tumor xenograft growth in mice.
It is now believed that cancer stem cells (CSCs) that are resistant to chemotherapy due to their undifferentiated nature drive tumor growth, metastasis and relapse, so development of drugs that induce differentiation of CSCs should have a profound impact on cancer eradication. In this study, we screened medicines that are already in clinical use for drugs that induce differentiation of CSCs. We used MDA-MB-231, a human breast cancer cell line that contains cancer stem cell-like cells. We found that acetaminophen, an anti-inflammatory, antipyretic and analgesic drug, induces differentiation of MDA-MB-231 cells. Differentiation was assessed by observing alterations in cell shape and expression of differentiated and undifferentiated cell markers, a decrease in cell invasion activity and an increase in susceptibility to anti-tumor drugs. This increased susceptibility seems to involve suppression of expression of multidrug efflux pumps. We also suggest that this induction of differentiation is mediated by inhibition of a Wnt/β-catenin canonical signaling pathway. Treatment of MDA-MB-231 cells with acetaminophen in vitro resulted in the loss of their tumorigenic ability in nude mice. Furthermore, administration of acetaminophen inhibited the growth of tumor xenografts of MDA-MB-231 cells in both the presence and absence of simultaneous administration of doxorubicine, a typical anti-tumor drug for breast cancer. Analysis with various acetaminophen derivatives revealed that o-acetamidophenol has a similar differentiation-inducing activity and a similar inhibitory effect on tumor xenograft growth. These results suggest that acetaminophen may be beneficial for breast cancer chemotherapy by inducing the differentiation of CSCs.


[Evidence-based medicine: benefits, inconveniences and risks of a new dogma].
Progress in biostatistics and epidemiology during twentieth century contributed to clinical research development. Controversy about the real role of these disciplines in validating clinical activity isn't new: in history of medicine there are evidence since nineteenth century. Evidence-based medicine is a recent methodology to evaluate clinical investigation that begins to be considered gold standard in knowledge and medical practice evaluation. Its method is based mainly in systematized meta-analyses or revisions through which tries to offer answers to concrete clinical questions. These answers are, however, clearly of statistical nature. It is not useful in clinical practice but rather should be focused to teaching-learning process, as well as on the creation of work regulations. Its application implies certain benefits, but also several practical difficulties in cultural, academic and socio-economic fields, due to its use without discriminating. Thus, its correct use is a challenge to contemporary medicine.


Alterations in cognitive flexibility in a rat model of post-traumatic stress disorder.
Exposure to stressful or traumatic events is associated with increased vulnerability to post-traumatic stress disorder (PTSD). This vulnerability may be partly mediated by effects of stress on the prefrontal cortex (PFC) and associated circuitry. The PFC mediates critical cognitive functions, including cognitive flexibility, which reflects an organism's ability to adaptively alter behavior in light of changing contingencies. Prior work suggests that chronic or acute stress exerts complex effects on different forms of cognitive flexibility, via actions on the PFC. Similarly, PFC dysfunction is reported in PTSD, as are executive function deficits. Animal models that permit study of the effects of stress/trauma on cognitive flexibility may be useful in illuminating ways in which stress-linked cognitive changes contribute to PTSD. Here, we examined the behavioral effects of a rodent model of PTSD - single prolonged stress (SPS) - on performance of two forms of cognitive flexibility: reversal learning and strategy set-shifting. SPS did not impair acquisition of either a response or visual-cue discrimination but did cause slight impairments in the retrieval of the visual-cue rule. During response discrimination reversal, SPS rats made more perseverative errors. In comparison, during set-shifting from the visual-cue to response discrimination, SPS rats did not show enhanced perseveration, but did display increased never-reinforced errors, indicative of impairment in selecting a novel strategy. These data demonstrate that SPS leads to a complex and intriguing pattern of deficits in flexible responding and suggest that impairments in executive functioning associated with PTSD could, in part, be a neuro-cognitive consequence of trauma exposure.


Copper, zinc, cadmium and lead biosorption by Gymnogongrus torulosus. Thermodynamics and kinetics studies.
Gymnogongrus torulosus adsorption efficiency for cadmium(II), copper(II), lead(II) and zinc(II) were studied in batch mode in different acidic conditions. The adsorbent removal efficiency was determined as a function of contact time, initial metal ions concentration, pH and temperature. G. torulosus was characterized by SEM, water adsorption surface area and EDS. The Langmuir, Freundlich, Dubinin-Radushkevich and Temkin models have been applied and results showed that the biosorption process was better described by the Langmuir model. Kinetic experiments demonstrated that fast metal uptakes follow a pseudo-second-order kinetic model and that intra-particle diffusion and/or chemisorption were the rate-limiting steps. Experimental results show that G. torulosus isotherm followed the biosorption series, Cu>Cd∼Zn∼Pb. Biosorption capacities were affected by solution parameters. The maximum metal uptake (qmax) increased with increasing pH. The affinity constant, qmax, and the pseudo-second-order kinetic constants were calculated for the adsorption of all studied metals onto G. torulosus. The Gibbs free energy of the adsorption process as well as the process enthalpy and entropy were calculated from experimental results.


Human lung carcinoma cells engineered to release IL2, IL7, GM-CSF and TNF alpha.
A human lung adenocarcinoma cell line (LC89) was transduced with the IL2, IL7, GM-CSF and TNF alpha genes by retroviral vector mediated infection. This induced the constitutive and stable release of all cytokines. No difference or modulation was found in the parental and gene transduced LC89 cells with regard to cytokine receptor expression, in vitro cell growth and proliferation, nor in cell surface expression of different adhesion molecules. Following injection into immunosuppressed nu/nu mice, IL2 gene transduced LC89 cells lost their tumorigenic potential. LC89 cells engineered to release IL7 and TNF alpha grew in nu/nu mice, but in 40% of the animals tumor regression was observed. GM-CSF gene transduced LC89 cells showed a tumorigenic capacity identical to that of the parental clone. The levels of TGF beta(1) released by IL2, IL7 and GM-CSF gene transduced LC89 cells were markedly reduced compared to those of the parental and TNF alpha gene transduced cells. The results of this study support the concept that human lung cancer cells engineered with different cytokine genes maintain their intrinsic morphologic and proliferative features, while their tumorigenic and immunosuppressive capacities can be profoundly down-modulated. Both these effects are optimally achieved following insertion of the IL2 gene, suggesting that vaccination protocols with IL2 gene transduced tumor cells may be considered for the management of human lung cancer.


Regulation of persistent activity by background inhibition in an in vitro model of a cortical microcircuit.
We combined in vitro intracellular recording from prefrontal cortical neurons with simulated synaptic activity of a layer 5 prefrontal microcircuit using a dynamic clamp. During simulated in vivo background conditions, the cell responded to a brief depolarization with a sequence of spikes that outlasted the depolarization, mimicking the activity of a cell recorded during the delay period of a working memory task in the behaving monkey. The onset of sustained activity depended on the number of action potentials elicited by the cue-like depolarization. Too few spikes failed to provide enough NMDA drive to elicit sustained reverberations; too many spikes activated a slow intrinsic hyperpolarization current that prevented spiking; an intermediate number of spikes produced sustained activity. When high dopamine levels were simulated by depolarizing the cell and by increasing the amount of NMDA current, the cell exhibited spontaneous 'up-states' that terminated by the activation of a slow intrinsic hyperpolarizing current. The firing rate during the delay period could be effectively modulated by the standard deviation of the inhibitory background synaptic noise without significant changes in the background firing rate before cue onset. These results suggest that the balance between fast feedback inhibition and slower AMPA and NMDA feedback excitation is critical in initiating persistent activity and that the maintenance of persistent activity may be regulated by the amount of correlated background inhibition.


Structural aspects of the inactive X chromosome.
A striking difference between male and female nuclei was recognized early on by the presence of a condensed chromatin body only in female cells. Mary Lyon proposed that X inactivation or silencing of one X chromosome at random in females caused this structural difference. Subsequent studies have shown that the inactive X chromosome (Xi) does indeed have a very distinctive structure compared to its active counterpart and all autosomes in female mammals. In this review, we will recap the discovery of this fascinating biological phenomenon and seminal studies in the field. We will summarize imaging studies using traditional microscopy and super-resolution technology, which revealed uneven compaction of the Xi. We will then discuss recent findings based on high-throughput sequencing techniques, which uncovered the distinct three-dimensional bipartite configuration of the Xi and the role of specific long non-coding RNAs in eliciting and maintaining this structure. The relative position of specific genomic elements, including genes that escape X inactivation, repeat elements and chromatin features, will be reviewed. Finally, we will discuss the position of the Xi, either near the nuclear periphery or the nucleolus, and the elements implicated in this positioning.This article is part of the themed issue 'X-chromosome inactivation: a tribute to Mary Lyon'.


Fibrinopeptide A and platelet factor levels in unstable angina pectoris.
Fibrinopeptide A, platelet factor 4, beta-thromboglobulin, thromboxane B2, and 6-keto-prostaglandin F1 alpha were estimated by radioimmunoassay on venous plasma samples taken within 48 hr of admission from 16 consecutive patients with unstable angina and 15 patients with stable angina matched for clinical variables. The ratio of circulating platelet aggregates, platelet aggregation to increasing concentrations of ADP (0.455 to 1.82 micrograms/ml), and platelet thromboxane B2 production in vitro were also tested. The two groups of patients were statistically similar in terms of sex distribution, age, presence of risk factors, use of medication, extent of coronary artery disease and history of previous myocardial infarction. Mean plasma levels of fibrinopeptide A were 2.7 +/- 0.4 ng/ml (geometric means +/- SEM, range 1.5 to 5.5) in patients with stable angina vs 5.5 +/- 1.8 ng/ml (range 2.4 to 32; p less than .001) in those with unstable angina. In the latter group, after 6 to 8 days, fibrinopeptide A levels decreased to 3.6 +/- 0.5 ng/ml (range 1.5 to 9.3; p less than .04 vs admission). All other variables measured were statistically identical in the two groups. We conclude that plasma fibrinopeptide A levels, as opposed to platelet factors, discriminate between patients with unstable and stable angina, indicating an activation of the coagulation system in unstable angina.


[Doppler sonographic characterization of vessels of the posterior cranial fossa using a suboccipital paramedian approach].
By means of transcranial Doppler sonography we examined the posterior cranial fossa from the suboccipital paramedian region. This enabled us to identify the basilar artery in its entire course, as well as the posterior inferior cerebellar artery. The advantages of this approach are, in particular, the possibilities of examining postoperatively by Doppler sonography after medial surgical approach, as well as the future utilisation the technique within the overall framework of stereometric transcranial Doppler sonography.


Repetitive exercise dystonia: A difficult to treat hazard of runner and non-runner athletes.
Runner's dystonia has previously been described in small series or case reports as a lower limb, task-specific dystonia. We have occasionally encountered this disorder and recognized the same phenomenon in non-runners regularly engaging in lower limb exercise. We wished to characterize the syndrome further, including outcomes, treatment, and the diagnostic usefulness of electrophysiology. We conducted a retrospective review and follow-up survey of adults seen at Mayo Clinic (1996-2015) with task-specific dystonia arising after prolonged repetitive lower limb exercise. The findings were compared to all 21 previously reported cases of runner's dystonia. We identified 20 patients with this condition, 13 runners and seven non-runner athletes. Median age at dystonia onset was in mid-adulthood. Correct diagnosis was delayed by a median of 3.5 years in runners and 1.6 years in non-runners, by which time more than one-third of patients had undergone unsuccessful invasive procedures. Most patients had dystonia onset in the distal lower limb. Dystonia was task-specific with exercise at onset but progressed to affect walking in most. Sensory tricks were reported in some. Surface EMG was consistent with task-specific dystonia in nine patients. Botulinum toxin, levodopa, clonazepam, trihexyphenidyl, and physical therapy provided modest benefit to some, but all patients remained substantially symptomatic at last follow up. Repetitive exercise dystonia is task-specific, confined to the lower limb and occasionally trunk musculature. It tends to be treatment-refractory and limits ability to exercise. Diagnosis is typically delayed, and unnecessary surgical procedures are common. Surface EMG may aid the diagnosis.


Blocking the class I histone deacetylase ameliorates renal fibrosis and inhibits renal fibroblast activation via modulating TGF-beta and EGFR signaling.
Histone deacetylase (HDAC) inhibitors are promising anti-fibrosis drugs; however, nonselective inhibition of class I and class II HDACs does not allow a detailed elucidation of the individual HDAC functions in renal fibrosis. In this study, we investigated the effect of MS-275, a selective class I HDAC inhibitor, on the development of renal fibrosis in a murine model of unilateral ureteral obstruction (UUO) and activation of cultured renal interstitial fibroblasts. The UUO model was established by ligation of the left ureter and the contralateral kidney was used as a control. At seven days after UUO injury, kidney developed fibrosis as indicated by deposition of collagen fibrils and increased expression of collagen I, fibronectin and alpha-smooth muscle actin (alpha-SMA). Administration of MS-275 inhibited all these fibrotic responses and suppressed UUO-induced production of transforming growth factor-beta1 (TGF-beta), increased expression of TGF-beta receptor I, and phosphorylation of Smad-3. MS-275 was also effective in suppressing phosphorylation and expression of epidermal growth factor receptor (EGFR) and its downstream signaling molecule, signal transducer and activator of transcription-3. Moreover, class I HDAC inhibition reduced the number of renal tubular cells arrested in the G2/M phase of the cell cycle, a cellular event associated with TGF-beta1overproduction. In cultured renal interstitial fibroblasts, MS-275 treatment inhibited TGF-beta induced phosphorylation of Smad-3, differentiation of renal fibroblasts to myofibroblasts and proliferation of myofibroblasts. These results demonstrate that class I HDACs are critically involved in renal fibrogenesis and renal fibroblast activation through modulating TGF-beta and EGFR signaling and suggest that blockade of class I HDAC may be a useful treatment for renal fibrosis.


Adenylate cyclase toxin subverts phagocyte function by RhoA inhibition and unproductive ruffling.
Adenylate cyclase toxin (CyaA or ACT) is a key virulence factor of pathogenic Bordetellae. It penetrates phagocytes expressing the alpha(M)beta(2) integrin (CD11b/CD18, Mac-1 or CR3) and paralyzes their bactericidal capacities by uncontrolled conversion of ATP into a key signaling molecule, cAMP. Using pull-down activity assays and transfections with mutant Rho family GTPases, we show that cAMP signaling of CyaA causes transient and selective inactivation of RhoA in mouse macrophages in the absence of detectable activation of Rac1, Rac2, or RhoG. This CyaA/cAMP-induced drop of RhoA activity yielded dephosphorylation of the actin filament severing protein cofilin and massive actin cytoskeleton rearrangements, which were paralleled by rapidly manifested macrophage ruffling and a rapid and unexpected loss of macropinocytic fluid phase uptake. As shown in this study for the first time, CyaA/cAMP signaling further caused a rapid and near-complete block of complement-mediated phagocytosis. Induction of unproductive membrane ruffling, hence, represents a novel sophisticated mechanism of down-modulation of bactericidal activities of macrophages and a new paradigm for action of bacterial toxins that hijack host cell signaling by manipulating cellular cAMP levels.


Dynamic tongue area measurements in ultrasound images for adults with obstructive sleep apnea.
Obstructive sleep apnea is a chronic breathing disorder where the recursive collapse of the upper airway causes cessation of airflow during sleep. Quantitative assessments of dynamic tongue motion may provide a better understanding of the mechanism of obstructive sleep apnea. Tongue area changes, in submental ultrasound images recorded during wakefulness from normal breathing by the Müller manoeuvre, were tracked using the modified optical flow-based method. The results demonstrated that patients with obstructive sleep apnea had a larger mid-sagittal tongue area compared to the control group (during normal breathing, p = .004, during the Müller manoeuvre p = .005, and differences between normal breathing and the Müller manoeuvre, p = .01). Tongue area measurements were significantly different in patients with varying severity of OSA during normal breathing and during the Müller manoeuvre, and had differences between normal breathing and the Müller manoeuvre (p = .005, p = .008 and p = .03, respectively). Patients with moderate or severe obstructive sleep apnea exhibited minimal movement of the tongue. In contrast, normal controls and patients with mild obstructive sleep apnea demonstrated bidirectional tongue motions during a transition from normal breathing to the Müller manoeuvre in wakefulness. Identifying different patterns of deformation and displacement of the tongue may have potential in evaluating the presence and the pathogenesis of OSA.


Failure to develop multiple sclerosis in patients with neurologic symptoms without objective evidence.
Many patients referred to multiple sclerosis (MS) centers with symptoms suggestive of MS are found to have normal neurologic examinations, normal or non-specific brain magnetic resonance imaging (MRI) scan findings, and normal cerebrospinal fluid (CSF). Persistent symptoms often lead to multiple consultations and repeated diagnostic investigations. We performed a study to evaluate the diagnostic utility of repeated evaluations in patients with normal initial assessments and persistent neurologic symptoms. 143 patients were evaluated initially and 109 returned for a second evaluation after a mean interval of 4.4 years. All 143 patients had normal initial examinations, brain MRI scans, screening blood tests, and CSF studies. Spinal cord imaging was normal in all patients tested (cervical cord, n = 126; 88.1%; thoracic cord, n = 58; 40.6%). Evoked potential studies were abnormal in a small percentage of patients: visual evoked potentials, VEP (8.1%), somatosensory evoked potentials, SSEP (4.9%), and brainstem auditory evoked potentials, BAEP (2.8%). All follow-up patients (n = 109) had normal examinations and MRI scans. Repeat CSF studies (n = 35; 32.1%) and spinal cord imaging (cervical cord n = 57; 52.3%; thoracic cord n = 32; 29.4%) were normal in all follow-up patients tested. No patients at initial presentation or at follow-up fulfilled diagnostic criteria for MS. and clinicians may be reassured that persistent neurologic symptoms in the absence of objective clinical evidence do not lead to the development of MS. Costly serial investigations should be carefully considered, particularly in the presence of normal neurologic examination at follow-up.


Quantification of the content of cannabinol in commercially available e-liquids and studies on their thermal and photo-stability.
Cannabidiol (CBD) has become a buzzword in many products that have bloomed on the market. The scientific community and some authorities have recently raised concerns on the quality of these products. In particular, the discrepancy between the labelled and the real content of cannabidiol in liquids for e-cigarettes seems to be emerging as a major issue. Furthermore, to-date no studies have been carried out on the chemical stability upon storage of these type of products. The aim of this work was to investigate the accuracy in labelling of thirteen commercially e-liquids containing CBD and the effects of different storage conditions on their quality. The results showed that only 38% of samples were labelled within a ±10% variance from their labels. Stability tests showed a maximum degradation of CBD when samples were stored at 37 °C for 30 days with average values up to 20%. The effect of light was lower but still significant with averages values up to 15% degradation after 30 days. In conclusion, we believe that health authorities should regulate and control this market more stringently to protect customers and their health. Furthermore, our stability tests have shown that if clear indications are provided on the best storage conditions, the quality of these products can be mostly preserved.


Gene expression study on peripheral blood identifies progranulin mutations.
Peripheral blood is a readily available tissue source allowing relatively noninvasive screening for a host of medical conditions. We screened total-blood progranulin (PGRN) levels in 107 patients with neurodegenerative dementias and related conditions, and 36 control subjects, and report the following findings: (1) confirmation of high progranulin expression levels in peripheral blood; (2) two subjects with reduced progranulin levels and mutations in the PGRN gene confirmed by direct sequencing; and (3) greater PGRN messenger RNA levels in patients with clinical diagnosis of Alzheimer's disease. This proof-of-principle report supports the use of gene quantification as diagnostic screen for PGRN mutations and suggests a potential role for progranulin in Alzheimer's disease.


Decreasing Risk of First and Subsequent Surgeries in Patients With Crohn's Disease in England From 1994 through 2013.
Gastrointestinal (GI) surgery is an important part of the treatment algorithm for patients with Crohn's disease (CD) that is complicated or does not respond to medical therapy. Cohort studies from Denmark and Canada have shown that the risk of primary surgery is decreasing but there is a lack of contemporary data on subsequent resections. We examined trends in first and second GI resections in patients with CD. We performed a retrospective cohort study using the United Kingdom primary care database ResearchOne, collecting data from patients with Crohn's disease from 1994 through 2013. We compared rates of first and second GI resections with etiological factors. Among 3059 incident cases of CD, 13%, 21%, and 26% of the patients underwent surgical resections after 1, 5, and 10 years, respectively. Of patients with an initial resection, 20% required an additional operation when followed for 10 years after the initial resection. We found a significant reduction in first surgery, from 44% to 21% after 10 years of disease, from 1994 to 2003 (χ2 for trend, P < .05). There was a significant reduction in second resections, in a 10-year follow-up period, from 40% in 1994 to 17% in 2003 (χ2 for trend, P < .05). Duration of disease, younger age at diagnosis, smoking, and immunomodulator use were positively associated with first surgeries. Duration of disease was significantly associated with the risk of undergoing a second resection. In a retrospective analysis of a United Kingdom primary care database, we observed a significant reduction in first and subsequent GI surgeries among patients with CD over the past 20 years in England.


Choice of gDNA isolation method has a significant impact on average murine Telomere Length estimates.
Telomere Length (TL) and integrity is significantly associated with age-related disease, multiple genetic and environmental factors. We observe mouse genomic DNA (gDNA) isolation methods to have a significant impact on average TL estimates. The canonical qPCR method does not measure TL directly but via the ratio of telomere repeats to a single copy gene (SCG) generating a T/S ratio. We use a monochromatic-multiplex-qPCR (mmqPCR) method which multiplexes the PCR and enables quantification of the target and the single copy gene within the same qPCR reaction. We demonstrate that TL measurements, from murine gDNA, isolated via Spin Columns (SC) and Magnetic Beads (MB), generate significantly smaller T/S ratios compared to gDNA isolated via traditional phenol/chloroform methods. The former methods may impede correct TL estimation by producing non representative fragment sets and reducing qPCR efficacy. This work highlights discrepancies in TL measurements due to different extraction techniques. We recommend the use of gDNA isolation methods that are shown to preserve DNA length and integrity, such as phenol/chloroform isolation. We propose that widely used high throughput DNA isolation methodologies can create spurious associations within a sample set, thus creating misleading data. We suggest that published TL associations should be revisited in the light of these data.


Parameters of technological growth.
The key parameters to technological growth have been identified as societal resources and societal expectations. Both of these are evident functions of technology, and their combined effects can be expected to continue technology's historical exponential growth. This growth pattern would be substantially altered only if we assume that knowledge is bounded or if society makes a conscious decision to stop the flow of resources into the production of new technological options. Although such conscious selection among individual technical fields is to be expected, it is very unlikely to apply to the totality of technology since, as society grows more complex it continuously creates new needs (priority factor), which in turn provide new opportunities for the application of technological options (payoff factor). The analysis also clearly emphasizes the important role which awareness of new technologies plays in forming societal expectations. These considerations indicate that the technological component of the world simulation model proposed by Meadows et al. (1) and Forrester (2) is best represented by an exponential growth function. The importance of this has been shown by Boyd (3) (Fig. 1), whose "technological optimist" curve has slightly less than exponential growth. Private comnmunication with Boyd indicates that an exponential assumption would reduce the time for equilibrium by several decades. Boyd also indicated that in his modification of the world dynamics model, an exponential technological growth would eventually dominate all other parameters in determining the long-term approach to a steady state. It is evident that the behavior of any world system model is very sensitive to the growth and interaction assumptions for its principal parameters. Thus, model studies should not be easily presumed to represent reality. The one conclusion that appears to be valid regardless of approach is the evident merit of reducing population growth. The parameter for quality of life shown in Fig. 1, parts 2 and 5, is the product of material levels, overcrowding, food, and pollution. The one factor that a "technological optimist" cannot expect to substantially alter in this model is the effect of overcrowding (Fig. 1, parts 3 and 6). Certainly, the many clear values of reducing population growth and improving the environment do not appear to require the justification of a world system analysis. In like manner, it seems appropriate to encourage the "technological optimist" to provide future options for societal choice, even though there may be present philosophical uncertainties as to their eventual merits. Unlike resources found in nature, technology is a manmade resource whose abundance can be continuously increased, and whose importance in determining the world's future is also increasing.


Cutaneous surgeons cannot predict blood-thinner status by intraoperative visual inspection.
Cutaneous surgeons cannot predict blood-thinner status by intraoperative visual inspection. Many surgeons believe they can discern whether a patient is taking an anticoagulant or a platelet inhibitor (blood thinner) by visual inspection of intraoperative oozing. However, there is little objective evidence to support this strongly held belief. The authors' objective was to determine whether visual inspection of intraoperative oozing during cutaneous surgery is accurate in identifying use of blood thinners. Blinded physician evaluators observed intraoperative oozing in 110 patients having cutaneous excisional surgery, rated the amount of oozing, and judged the likelihood that the patient was taking a blood-thinning agent. On the basis of the impressions of the most senior evaluator, 43 patients having used aspirin in the past 14 days or warfarin or vitamin E in the past 2 days, seven were judged as definitely or probably taking blood-thinning agents (sensitivity, 16.3 percent; 95 percent confidence interval, 6.8 to 30.7 percent). Of 67 patients who did not report recent use of a blood-thinning agent, just 11 were judged as definitely or probably taking blood-thinning agents (false-positive rate, 16.4 percent; 95 percent confidence interval, 8.5 to 27.5 percent). The level of training of the physicians doing the judging did not affect diagnostic sensitivity. Only 10 of the 110 patients (9.1 percent) were assessed as exhibiting excessive oozing, and of those, only four (40 percent) were actually taking a blood thinner. Results were similar when only patients who were taking aspirin or warfarin were analyzed. Thus, contrary to a commonly and strongly held belief, visual inspection of intraoperative oozing during cutaneous excisional surgery correlates poorly with blood-thinner use by patients. The data add further evidence that use of blood thinners does not have an objectively measurable adverse effect during cutaneous surgery.


Evolution and topology in the yeast protein interaction network.
The integrity of the yeast protein-protein interaction network is maintained by a few highly connected proteins, or hubs, which hold the numerous less-connected proteins together. The structural importance and the increased essentiality of these proteins suggest that they are likely to be conserved in evolution, implying a strong relationship between the number of interactions and their evolutionary distance to its orthologs in other organisms. The existence of this coherence was recently reported to strongly depend on the quality of the protein interaction and orthologs data. Here, we introduce a novel method, the evolutionary excess retention (ER), allowing us to uncover a robust and strong correlation between the conservation, essentiality, and connectivity of a yeast protein. We conclude that the relevance of the hubs for the network integrity is simultaneously reflected by a considerable probability of simultaneously being evolutionarily conserved and essential, an observation that does not have an equivalent for nonessential proteins. Providing a thorough assessment of the impact noisy and incomplete data have on our findings, we conclude that our results are largely insensitive to the quality of the utilized data.


[Cooperative neuronal activity of the n. accumbens and the frontal cortex in cats trained to choose stimuli of various value].
It was shown that the two-way interaction between neurons of the frontal cortex and n. accumbens progressively increases, whereas their regularity simultaneously decreases with the rise in impulsiveness and drop in self-control in behavior. In case of the long-latency instrumental reactions, a control of the frontal cortex neurons by neurons of the n. accumbens weakens during presentation of conditioned stimuli only in "impulsive" animals, which is correlated with low network activity of the n. accumbens. Comparison of patterns of fronto-accumbal interactions during performance of the same type of activity revealed similar correlations in the neuronal pairs before and during presentation of conditioned stimuli, whereas different patterns corresponded to different types of activity.


Mono-specific algal diets shape microbial networking in the gut of the sea urchin Tripneustes gratilla elatensis.
Algivorous sea urchins can obtain energy from a diet of a single algal species, which may result in consequent changes in their gut microbe assemblies and association networks. To ascertain whether such changes are led by specific microbes or limited to a specific region in the gut, we compared the microbial assembly in the three major gut regions of the sea urchin Tripneustes gratilla elatensis when fed a mono-specific algal diet of either Ulva fasciata or Gracilaria conferta, or an algal-free diet. DNA extracts from 5 to 7 individuals from each diet treatment were used for Illumina MiSeq based 16S rRNA gene sequencing (V3-V4 region). Niche breadth of each microbe in the assembly was calculated for identification of core, generalist, specialist, or unique microbes. Network analyzers were used to measure the connectivity of the entire assembly and of each of the microbes within it and whether it altered with a given diet or gut region. Lastly, the predicted metabolic functions of key microbes in the gut were analyzed to evaluate their potential contribution to decomposition of dietary algal polysaccharides. Sea urchins fed with U. fasciata grew faster and their gut microbiome network was rich in bacterial associations (edges) and networking clusters. Bacteroidetes was the keystone microbe phylum in the gut, with core, generalist, and specialist representatives. A few microbes of this phylum were central hub nodes that maintained community connectivity, while others were driver microbes that led the rewiring of the assembly network based on diet type through changes in their associations and centrality. Niche breadth agreed with microbes' richness in genes for carbohydrate active enzymes and correlated Bacteroidetes specialists to decomposition of specific polysaccharides in the algal diets. The dense and well-connected microbial network in the gut of Ulva-fed sea urchins, together with animal's rapid growth, may suggest that this alga was most nutritious among the experimental diets. Our findings expand the knowledge on the gut microbial assembly in T. gratilla elatensis and strengthen the correlation between microbes' generalism or specialism in terms of occurrence in different niches and their metabolic arsenal which may aid host nutrition.


Surgical management of cysts of the head of the pancreas.
Thirty patients with cysts of the cephalic portion of the pancreas treated by operation between 1966 and 1980 were reviewed to determine whether any variation existed from the usual treatment of cysts of the body and tail of the gland. Sixteen patients had chronic pancreatitis, six had acute pancreatitis, four had cysts of indeterminate causes, three had adenocarcinoma of the pancreas, and in one patient a cyst developed after external trauma. External drainage was used in 14 patients, internal drainage in ten patients, and combinations of cyst drainage and anastomosis of Wirsung's duct or resection were performed in six patients. No operative deaths occurred, and the rate of cyst recurrence was minimal. Diabetes mellitus developed in 40% of patients with chronic pancreatitis despite conservative management. Recurrent pain in 13 patients and the discovery of associated carcinoma in one patient at initial treatment and later in two others cast doubt on the usefulness of simple internal or external drainage of cysts for pain except in a setting of acute pancreatitis. Resection of the pancreatic head or drainage of dilated pancreatic ducts should more often be carried out in the primary treatment of cephalic cysts with pain due to chronic pancreatitis.


The actin cross-linker Filamin/Cheerio mediates tumor malignancy downstream of JNK signaling.
Cell shape dynamics, motility, and cell proliferation all depend on the actin cytoskeleton. Malignant cancer cells hijack the actin network to grow and migrate to secondary sites. Understanding the function of actin regulators is therefore of major interest. In the present study, we identify the actin cross-linking protein Filamin/Cheerio (Cher) as a mediator of malignancy in genetically defined Drosophila tumors. We show that in invasive tumors, resulting from cooperation of activated Ras with disrupted epithelial cell polarity, Cher is upregulated in a Jun N-terminal kinase (JNK)-dependent manner. Although dispensable in normal epithelium, Cher becomes required in the tumor cells for their growth and invasiveness. When deprived of Cher, these tumor clones lose their full potential to proliferate and breach tissue boundaries. Instead, the Cher-deficient clones remain confined within the limits of their source epithelium, permitting survival of the host animal. Through interaction with the myosin II heavy chain subunit, Cher is likely to strengthen the cortical actomyosin network and reinforce mechanical tension within the invasive tumors. Accordingly, Cher is required for aberrant expression of genes downstream of the Hippo/Yorkie signaling in the tumor tissue. Our study identifies Cher as a new target of JNK signaling that links cytoskeleton dynamics to tumor progression.


An Eye on the Wnt Inhibitory Factor Wif1.
The coordinated interplay between extrinsic activating and repressing cell signaling molecules is pivotal for embryonic development and subsequent tissue homeostasis. This is well exemplified by studies on the evolutionarily conserved Wnt signaling pathways. Tight temporal and spatial regulation of Wnt signaling activity is required throughout lifetime, from maternal stages before gastrulation until and throughout adulthood. Outside cells, the action of numerous Wnt ligands is counteracted and fine-tuned by only a handful of well characterized secreted inhibitors, such as for instance Dickkopf, secreted Frizzled Related Proteins and Cerberus. Here, we give an overview of our current understanding of another secreted Wnt signaling antagonist, the Wnt inhibitory factor Wif1. Wif1 can directly interact with various Wnt ligands and inhibits their binding to membrane bound receptors. Epigenetic promoter methylation of Wif1, leading to silencing of its transcription and concomitant up-regulation of Wnt signaling, is a common feature during cancer progression. Furthermore, an increasing number of reports describe Wif1 involvement in regulating processes during embryonic development, which so far has not received as much attention. We will summarize our knowledge on Wif1 function and its mode of action with a particular focus on the zebrafish (Danio rerio). In addition, we highlight the potential of Wif1 research to understand and possibly influence mechanisms underlying eye diseases and regeneration.


Hormonal and reproductive factors and risk of postmenopausal thyroid cancer in the NIH-AARP Diet and Health Study.
Worldwide, thyroid cancer incidence rates are higher among women than men. While this suggests a possible etiologic role of female sex hormones, clear associations between hormonal and reproductive factors and thyroid cancer have not been observed. However, few large prospective studies have been conducted. Hazard ratios (HRs) and 95% confidence intervals (CIs) for hormonal and reproductive factors and incident thyroid cancer were estimated using Cox regression methods in the prospective US NIH-AARP Diet and Health Study. Between 1995 and 2006, 312 first primary incident thyroid cancers were diagnosed among 187,865 postmenopausal women ages 50-71 at baseline. Thyroid cancer was not associated with ages at menarche or menopause, menopause type, or parity. Oral contraceptive use for ≥10 years (vs. never use) was inversely associated with thyroid cancer risk (HR, 0.48; 95%CI, 0.28-0.84; P(trend)=0.01). Women who reported current menopausal hormone therapy at baseline had an increased thyroid cancer risk vs. never users (HR 1.38; 95% CI: 1.07-1.79) but there was no trend with increasing duration of use. Women with benign breast disease (BBD) had a significantly higher thyroid cancer risk vs. women without BBD (HR, 1.47; 95% CI, 1.09-1.99). Our results do not support a strong role for female hormonal and reproductive factors including ages at menarche and menopause, type of menopause or parity, in thyroid cancer etiology among postmenopausal women. Compared with previous studies, no clear patterns emerge for exogenous hormone use but further analysis in large, prospective populations may be informative. The HR for BBD is consistent with the one previous prospective analysis that examined this association.


Varied Role of Ubiquitylation in Generating MHC Class I Peptide Ligands.
CD8+ T cell immunosurveillance is based on recognizing oligopeptides presented by MHC class I molecules. Despite decades of study, the importance of protein ubiquitylation to peptide generation remains uncertain. In this study, we examined the ability of MLN7243, a recently described ubiquitin-activating enzyme E1 inhibitor, to block overall cytosolic peptide generation and generation of specific peptides from vaccinia- and influenza A virus-encoded proteins. We show that MLN7243 rapidly inhibits ubiquitylation in a variety of cell lines and can profoundly reduce the generation of cytosolic peptides. Kinetic analysis of specific peptide generation reveals that ubiquitylation of defective ribosomal products is rate limiting in generating class I peptide complexes. More generally, our findings demonstrate that the requirement for ubiquitylation in MHC class I-restricted Ag processing varies with class I allomorph, cell type, source protein, and peptide context. Thus, ubiquitin-dependent and -independent pathways robustly contribute to MHC class I-based immunosurveillance.


Corticosteroid requirements in polymyalgia rheumatica.
Polymyalgia rheumatica (PMR) is a systemic inflammatory disease of unknown cause that affects older individuals. Clinical symptoms respond promptly to corticosteroids, but treatment is often required for several years, frequently resulting in adverse drug effects. Guidelines for the optimal use of corticosteroids that maximize relief of symptoms but minimize adverse effects of the therapy are needed. To determine whether clinical or laboratory parameters in PMR could be identified that allow for stratifying patients into subsets with differences in corticosteroid requirements. We studied 27 patients with PMR treated with a standardized schedule of prednisone. Patients were reevaluated at monthly intervals for pain scores and physician and patient assessments. Plasma interleukin 6 level and the erythrocyte sedimentation rate were measured at each visit. The duration of steroid therapy and the cumulative steroid dose were calculated. Based on the initial response to therapy and the duration of disease, the 27 patients could be subdivided into 3 distinct groups. Eight with low erythrocyte sedimentation rates responded rapidly and required corticosteroids for less than 1 year with rare disease flares on tapering of prednisone. Twelve others responded well initially but did not tolerate reduction to lower doses and had remitting disease of more than 1 year. Seven patients had only a partial response to the initial steroid regimen. After 4 weeks of therapy, the erythrocyte sedimentation rates improved, but levels of interleukin 6 remained elevated. Pretreatment pain scores were also higher in these partial responder patients (P = .05). Polymyalgia rheumatica is a heterogeneous disease with variations in the treatment duration and dose of corticosteroids required for suppression of symptoms. Pretreatment erythrocyte sedimentation rate and nonresponsiveness of interleukin 6 to steroid therapy are helpful in dividing patients into subsets with different treatment requirements.


Taking language science to zoom school: Virtual outreach to elementary school students.
We describe guest speaker presentations that we developed to bring language science to elementary school students via videoconference. By using virtual backgrounds and guided discovery learning, we effectively engage children as young as 7 years in in-depth explorations of language science concepts. We share the core principles that guide our presentations and describe two of our outreach activities, Speech Detectives and Bilingual Barnyard. We report brief survey data from 157 elementary school students showing that they find our presentations interesting and educational. While our pivot to virtual outreach was motivated by the Covid-19 pandemic, it allows us to reach geographically diverse audiences, and we suggest that virtual guest speaker presentations will remain a viable and effective method of public outreach.


The effect of antagonistic salt on a confined near-critical mixture.
We consider a near-critical binary mixture with addition of antagonistic salt (hydrophilic cations and hydrophobic anions) confined between weakly charged and selective surfaces. A mesoscopic functional for this system is developed from a microscopic description by a systematic coarse-graining procedure. The functional reduces to the Landau-Brazovskii functional for amphiphilic systems for a sufficiently large ratio between the correlation length in the critical binary mixture and the screening length. Our theoretical result agrees with the experimental observation [Sadakane et al., J. Chem. Phys., 2013, 139, 234905] that the antagonistic salt and the surfactant both lead to a similar mesoscopic structure. For very low salt concentration ρion the Casimir potential is the same as in the presence of inorganic salt. For larger ρion the Casimir potential takes a minimum followed by a maximum for separations of order of tens of nanometers, and exhibits an oscillatory decay very close to the critical point. For separations of tens of nanometers the potential between surfaces with a linear size of hundreds of nanometers can be of order of kBT. We have verified that in the experimentally studied samples [Sadakane et al., J. Chem. Phys., 2013, 139, 234905, Leys et al., Soft Matter, 2013, 9, 9326] the decay length is too small compared to the period of oscillations of the Casimir potential, but the oscillatory force could be observed closer to the critical point.


Prediction of pharmacokinetic drug-drug interactions causing atorvastatin-induced rhabdomyolysis using physiologically based pharmacokinetic modelling.
Atorvastatin and its lactone form metabolite are reported to be associated with statin-induced myopathy (SIM) such as myalgia and life-threatening rhabdomyolysis. Though the statin-induced rhabdomyolysis is not common during statin therapy, its incidence will significantly increase due to pharmacokinetic drug-drug interactions (DDIs) with inhibitor drugs which inhibit atorvastatin's and its lactone's metabolism and hepatic uptake. Thus, the quantitative analysis of DDIs of atorvastatin and its lactone with cytochrome P450 3A4 (CYP3A4) and organic anion-transporting polypeptide (OATP) inhibitors is of great importance. This study aimed to predict pharmacokinetic DDIs possibly causing atorvastatin-induced rhabdomyolysis using Physiologically Based Pharmacokinetic (PBPK) Modelling. Firstly, we refined the PBPK models of atorvastatin and atorvastatin lactone for predicting the DDIs with CYP3A4 and OATP inhibitors. Thereafter, we predicted the exposure changes of atorvastatin and atorvastatin lactone originating from the case reports of atorvastatin-induced rhabdomyolysis using the refined models. The simulation results show that pharmacokinetic DDIs of atorvastatin and its lactone with fluconazole, palbociclib diltiazem and cyclosporine are significant. Consequently, clinicians should be aware of necessary dose adjustment of atorvastatin being used with these four inhibitor drugs.


Factors Associated With the Mechanism of ACL Tears in the National Football League: A Video-Based Analysis.
The factors associated with anterior cruciate ligament (ACL) injury mechanism in professional American football players are not well-understood. It was hypothesized that football-related and player-specific factors, such as position and body mass index (BMI), are associated with ACL injury mechanism in these athletes. Descriptive epidemiology study. Videos of ACL tears occurring in National Football League (NFL) games over 6 consecutive seasons from 2014 to 2019 were reviewed by 2 orthopaedic surgeons who specialize in sports medicine. For each injury, the role of contact (direct contact [contact to the injured knee/lower extremity], indirect contact [contact not involving the injured knee/lower extremity], or no contact) as well as playing situation and lower extremity position were recorded. Additional player characteristics, timing of injury, and surface information were obtained from NFL game-day and injury database statistics. Of the 140 ACL tears, a minority occurred via direct contact to the injured lower extremity (30%), although this varied by position. Just over two-thirds (70%) of ACL tears in offensive linemen occurred via direct contact to the injured lower extremity, while wide receivers had no direct contact ACL tears. Elevated BMI was associated with a greater likelihood of ACL tears occurring via direct contact (53% in players with BMI ≥35 kg/m2 vs 24% in players with BMI <35 kg/m2; P = <.01). Rookies had the lowest percentage of direct contact ACL tears (18%; P = .22). ACL tears that occurred during the middle 8 weeks of the regular season resulted more often from direct contact (38%; P = .06). ACL tears that occurred in the third quarter were the most likely to occur via direct contact (44%), while those that occurred in the fourth quarter were the least likely to occur via direct contact (13%; P < .01). Although most NFL players sustained ACL tears via a noncontact mechanism (ie, through indirect or no contact), players with an elevated BMI, especially on the offensive line, were more likely to injure their ACL through direct contact. Position-dependent variance in injury mechanism may help guide injury prevention efforts in these athletes.


Cosmetic surgery training in plastic surgery residency programs in the United States: how have we progressed in the last three years?
In 2006, a survey performed by Morrison et al analyzed the experience of aesthetic surgery training from the perspective of residents and their program directors in plastic surgery programs across the United States. The authors conducted a survey to follow-up on the Morrison results three years after publication, to assess the changes in plastic surgery residency programs. In December 2009, a 17-question survey was sent to program directors, and a 19-question survey was sent to senior residents in all Accreditation Council for Graduate Medical Education-approved plastic surgery residency programs in the United States. The questions were posed in a five-point ranking format. The two additional questions included in the senior resident survey related to career aspirations and desirable areas of additional training. Ninety-two program directors and 397 senior residents received the survey. Forty-four program director surveys (47.8%) and 117 (29.5%) senior resident surveys were returned. Two-thirds of programs offered a residents' clinic, which was considered the preferred method of cosmetic surgery education by residents. Residents reported increased exposure to nonsurgical procedures such as lasers and injectables. Abdominoplasty, breast augmentation, and breast reduction remained the procedures most frequently performed by residents with confidence, as in the 2006 survey. Facial aesthetic procedures, including rhinoplasty and facelift, remained challenging to residents. Many residents (55.7%) felt confident integrating cosmetic surgery into their practice. One-third of residents reported that they would apply for a cosmetic fellowship. This survey shows an improvement in cosmetic surgery training for plastic surgery residents in the United States, particularly in that noninvasive cosmetic treatments are being increasingly taught. Since 2006, steps have been taken to provide more comprehensive cosmetic surgery education to residents, encouraging the delivery of the safe, high-quality care expected of a board-certified plastic surgeon.


Cu-bearing steel reduce inflammation after stent implantation.
Copper (Cu)-bearing stainless steel with release of Cu2+ ions is a novel material for coronary stents that could reduce the in-stent restenosis after the stent implantation. The inflammation has been recently recognized as an important factor to smooth muscle cells proliferation, thrombosis, and hence the restenosis post-angioplasty. The objective of this study is to further investigate the effect and relevant mechanism of Cu-bearing stainless steel (316L-Cu SS) on the inflammation reaction after stent implantation. The results demonstrated that, compared with commercial coronary stent material (316L SS), 316L-Cu SS could inhibit the inflammation caused by endothelial dysfunction through blockading the inflammatory factors (TNF-α, IL-1β, 6, 8), which would then reduce the recruitment and infiltration of leukocytes, rather than have direct effect on leukocytes. This finding further explained the reduction effect of 316L-Cu SS on in-stent restenosis from a novel view.


Interleukin-22 in kidney injury and regeneration.
Interleukins have become well-known regulators of innate and adaptive immunity-related tissue inflammation. Recently, IL-22 has gained a lot of interest for its unique functions in maintaining and regaining epithelial integrity. IL-22 is exclusively secreted by different immune cell subsets, while IL-22 receptors are mainly expressed by epithelial cells. As the kidney is largely an epithelial organ, the functional role of IL-22 in the kidney deserves to be explored in detail. Here, we briefly summarize the key features of IL-22 biology and review the available data on its expression and functional roles in kidney injury and kidney regeneration. Furthermore, we provide suggestions on how to explore this evolving field in the future.


γ-Cyclodextrin as a Catalyst for the Synthesis of 2-Methyl-3,5-diarylisoxazolidines in Water.
A green and efficient 1,3-dipolar cycloaddition of nitrones with different styrenes and cinnamates using a catalytic amount of γ-cyclodextrin (γ-CD) in water has been developed to give substituted isoxazolidines. γ-CD was found to be highly efficacious in carrying out this reaction under an eco-friendly environment, affording moderate to excellent yields and, in some cases, excellent diastereomeric excess (up to >95%) at 100 °C in 8-12 h. The catalyst can be easily recuperated and recycled for several times without loss of activity. Water, an eco-friendly reaction medium, has been utilized for the first time, to the best of our knowledge, in this reaction. The credit of the presented protocol includes high yields and catalyst reusability, and precludes the use of organic solvents. The use of in silico calculations allowed us to rationalize the obtained results and to improve the stereoselectivity.


Localization of group II and III metabotropic glutamate receptors at pre- and postsynaptic sites of inner hair cell ribbon synapses.
Glutamate is the major excitatory neurotransmitter in the CNS binding to a variety of glutamate receptors. Metabotropic glutamate receptors (mGluR1 to mGluR8) can act excitatory or inhibitory, depending on associated signal cascades. Expression and localization of inhibitory acting mGluRs at inner hair cells (IHCs) in the cochlea are largely unknown. Here, we analyzed expression of mGluR2, mGluR3, mGluR4, mGluR6, mGluR7, and mGluR8 and investigated their localization with respect to the presynaptic ribbon of IHC synapses. We detected transcripts for mGluR2, mGluR3, and mGluR4 as well as for mGluR7a, mGluR7b, mGluR8a, and mGluR8b splice variants. Using receptor-specific antibodies in cochlear wholemounts, we found expression of mGluR2, mGluR4, and mGluR8b close to presynaptic ribbons. Super resolution and confocal microscopy in combination with 3-dimensional reconstructions indicated a postsynaptic localization of mGluR2 that overlaps with postsynaptic density protein 95 on dendrites of afferent type I spiral ganglion neurons. In contrast, mGluR4 and mGluR8b were expressed at the presynapse close to IHC ribbons. In summary, we localized in detail 3 mGluR types at IHC ribbon synapses, providing a fundament for new therapeutical strategies that could protect the cochlea against noxious stimuli and excitotoxicity.-Klotz, L., Wendler, O., Frischknecht, R., Shigemoto, R., Schulze, H., Enz, R. Localization of group II and III metabotropic glutamate receptors at pre- and postsynaptic sites of inner hair cell ribbon synapses.


The AIDS dementia complex: II. Neuropathology.
In order to define the histopathological substrate of the dementia that frequently complicates the acquired immune deficiency syndrome (AIDS), we analyzed the neuropathological findings in 70 autopsied adult AIDS patients, 46 of whom had suffered clinically overt dementia. Less than 10% of the brains were histologically normal. Abnormalities were found predominantly in the white matter and in subcortical structures, with relative sparing of the cortex. Their frequency and severity generally correlated well with the degree and duration of clinical dementia. Most commonly noted was diffuse pallor in the white matter, which in the pathologically milder cases was accompanied by scanty perivascular infiltrates of lymphocytes and brown-pigmented macrophages, and in the most advanced cases by clusters of foamy macrophages and multinucleated cells associated with multifocal rarefaction of the white matter. However, in nearly one third of the demented cases the histopathological findings were remarkably bland in relation to the severity of clinical dysfunction. In addition, similar mild changes were noted in over one half of the nondemented patients, consistent with subclinical involvement. Vacuolar myelopathy was found in 23 patients and was generally more common and severe in patients with advanced brain pathology. Evidence of cytomegalovirus (CMV) infection was noted in nearly one quarter of the brains and was associated with a relative abundance of microglial nodules, but correlated neither with the major subcortical neuropathology nor with the clinical dementia, indicating that CMV infection likely represented a second, superimposed process. This study establishes the AIDS dementia complex as a distinct clinical and pathological entity and, together with accumulating virological evidence, suggests that it is caused by direct LAV/HTLV-III brain infection.


Tin/Tin Oxide Nanostructures: Formation, Application, and Atomic and Electronic Structure Peculiarities.
For a very long period, tin was considered one of the most important metals for humans due to its easy access in nature and abundance of sources. In the past, tin was mainly used to make various utensils and weapons. Today, nanostructured tin and especially its oxide materials have been found to possess many characteristic physical and chemical properties that allow their use as functional materials in various fields such as energy storage, photocatalytic process, gas sensors, and solar cells. This review discusses current methods for the synthesis of Sn/SnO2 composite materials in form of powder or thin film, as well as the application of the most advanced characterization tools based on large-scale synchrotron radiation facilities to study their chemical composition and electronic features. In addition, the applications of Sn/SnO2 composites in various fields are presented in detail.


Evaluation of digital image enhancement techniques for liver scintigrams.
Digital image enhancement techniques were employed in an effort to improve the resolution of Anger camera liver images. The premise employed was that methods which improve lesion detectability in liver phantoms should also do so in actual liver scintigrams. The types of image processing evaluated were: contrast enhancement, finite and infinite impulse response, modulation transfer function correction, homomorphic and median filtering. Observers were used to evaluate each method for its ability to improve lesion detectability using a five category rating system. The Localization Receiver Operating Characteristic (LROC) curve was used as the primary rank ordering method. A point system and analysis of variance were used as corroborative methods, incorporating measures of accuracy and consistency of the observers' answers.


Identification and characterization of an Xp22.33;Yp11.2 translocation causing a triplication of several genes of the pseudoautosomal region 1 in an XX male patient with severe systemic lupus erythematosus.
The X;Y translocation break point sequence in an XX male patient with prepubertal systemic lupus erythematosus (SLE) was characterized with the intention of identifying a predisposing gene(s) for SLE. Spectral karyotyping of the patient's metaphase chromosomes showed normal autosomes and 2 X chromosomes, one of which displayed a small portion of the Y chromosome. Using a Y chromosome polymerase chain reaction (PCR) walking strategy and inverse PCR, we found that the abnormal recombination occurred between retroviral long terminal repeats located at Xp22.33 (position 0.95 Mb; inside the pseudoautosomal regions) and Yp11.2 (4.20 Mb) downstream of the sex-determining region Y (SRY) gene. The complete DNA sequence of the break point was determined, revealing a partial duplication of the pseudoautosomal region 1 (PAR1) in the derivative X chromosome and causing a partial trisomy of the 12 known genes located between the interleukin-3 receptor alpha (IL3RA; position 1.1 Mb on the X and Y chromosomes) and CD99 (position 2.2 Mb) genes inclusively. All other X chromosome genes were present as 2 copies. Real-time quantitative PCR confirmed the presence of 3 copies of each of the 12 genes in the patient's genomic DNA. We also found that RNA for 1 of the candidate genes was indeed overexpressed in the patient's blood as compared with normal subjects. Taken together, the uniqueness of the translocation, the rarity of severe prepubertal SLE in males, and the presence of SLE in some patients with Klinefelter's syndrome (who have a triplication of the 2 PAR regions) point to a possible relationship between the partial triplication of the PAR1 region and the development of SLE.


Kinetics of superoxide formation by respiratory chain NADH- dehydrogenase of bovine heart mitochondria.
Formation of superoxide anions (O2-) by bovine heart NADH-dehydrogenase preparation (Complex I) supported by an NADH- or NADPH-generating system was studied kinetically. Both NADH- and NADPH-dependent superoxide-forming activities of Complex I were biphasic in double reciprocal plots. The NADH-dependent reaction had two sets of kinetic parameters: One Km value for NADH was 10 times higher than the other one, and the Vmax of the reaction with high Km was about 4 times higher than that of the reaction with low Km. Similar Vmax values were obtained for the NADPH-dependent reactions but the Km values were a thousand times higher than those of the NADH-dependent reactions. The plots of the NADH-dependent activity of rotenone-treated submitochondrial particles were also biphasic. The double reciprocal plots of NADH- and NADPH-dependent 2,6-dichlorophenolindophenol (DCIP) reductase activities of Complex I were linear and the plots of the superoxide-forming activities against the DCIP reductase activities were biphasic. These results indicate that the biphasic double reciprocal plots of the superoxide-forming activities against reduced coenzymes are not caused by interaction between reduced coenzymes and the NADH-dehydrogenase but are due to the presence of at least two superoxide-forming sites in the respiratory chain NADH-dehydrogenase.