Does APO epsilon4 correlate with MRI changes in Alzheimer's disease?
To assess the relation between APO E genotype and MRI white matter changes in Alzheimer's disease. The APO epsilon4 allele is correlated with amyloid angiopathy and other neuropathologies in Alzheimer's disease and could be associated with white matter changes. If so, there should be a dose effect. 104 patients with probable Alzheimer's disease (NINCDS-ADRDA criteria) in this Alzheimer's Disease Research Centre were studied. Patients received MRI and APO E genotyping by standardised protocols. Axial MRI was scored (modified Schelten's scale) for the presence and degree of white matter changes and atrophy in several regions by a neuroradiologist blinded to genotype. Total white matter and total atrophy scores were also generated. Data analysis included Pearson's correlation for regional and total imaging scores and analysis of variance (ANOVA) (or Kruskal-Wallis) and chi(2) for demographic and disease related variables. 30 patients had no epsilon4, 53 patients were heterozygous, and 21 patients were homozygous. The three groups did not differ in sex distribution, age of onset, age at MRI, MMSE, clinical dementia rating, or modified Hachinski ischaemia scores. There were no significant correlations between total or regional white matter scores and APO E genotype (Pearson correlation). No correlation between total or regional white matter scores and APO E genotype was found. The pathogenesis of white matter changes in Alzheimer's disease may be independent of APO E genotype.


Flexible metallic nanowires with self-adaptive contacts to semiconducting transition-metal dichalcogenide monolayers.
In the pursuit of ultrasmall electronic components, monolayer electronic devices have recently been fabricated using transition-metal dichalcogenides. Monolayers of these materials are semiconducting, but nanowires with stoichiometry MX (M = Mo or W, X = S or Se) have been predicted to be metallic. Such nanowires have been chemically synthesized. However, the controlled connection of individual nanowires to monolayers, an important step in creating a two-dimensional integrated circuit, has so far remained elusive. In this work, by steering a focused electron beam, we directly fabricate MX nanowires that are less than a nanometre in width and Y junctions that connect designated points within a transition-metal dichalcogenide monolayer. In situ electrical measurements demonstrate that these nanowires are metallic, so they may serve as interconnects in future flexible nanocircuits fabricated entirely from the same monolayer. Sequential atom-resolved Z-contrast images reveal that the nanowires rotate and flex continuously under momentum transfer from the electron beam, while maintaining their structural integrity. They therefore exhibit self-adaptive connections to the monolayer from which they are sculpted. We find that the nanowires remain conductive while undergoing severe mechanical deformations, thus showing promise for mechanically robust flexible electronics. Density functional theory calculations further confirm the metallicity of the nanowires and account for their beam-induced mechanical behaviour. These results show that direct patterning of one-dimensional conducting nanowires in two-dimensional semiconducting materials with nanometre precision is possible using electron-beam-based techniques.


MedLinac2: a GEANT4 based software package for radiotherapy.
Dose distribution evaluation in oncological radiotherapy treatments is an outstanding problem that requires sophisticated computing technologies to optimize the clinical results (i.e. increase the dose to the tumour and reduce the dose to the healthy tissues). Nowdays, dose calculation algorithms based on the Monte Carlo method are generally regarded as the most accurate tools for radiotherapy. The flexibility of the GEANT4 (GEometry ANd Tracking) Monte Carlo particle transport simulation code allows a wide range of applications, from high-energy to medical physics. In order to disseminate and encourage the use of Monte Carlo method in oncological radiotherapy, a software package based on the GEANT4 Monte Carlo toolkit has been developed. The developed package (MedLinac2) allows to simulate in an adequate flexible way a linear accelerator for radiotherapy and to evaluate the dose distributions.


Therapy of herpes zoster with oral acyclovir.
Oral acyclovir therapy for herpes zoster has been studied in double-blind, placebo-controlled trials of two dosages, 400 mg and 800 mg five times per day for 10 days. Compared with placebo recipients, recipients of the high-dosage acyclovir experienced a significantly shortened period of viral shedding, significantly accelerated time to 50 percent scabbing, significantly accelerated time to 50 percent healing, and after two days of therapy, significantly less frequent formation of new lesions. The duration and severity of acute pain were less in acyclovir recipients, with differences in pain severity achieving statistical significance (p = 0.03) between Days 3 and 10 and correlating with the treatment differences in new lesion formation. In studies of the 400 mg five times per day dose schedule, differences between acyclovir and placebo recipients were not significant. In a six-month follow-up of recipients in the higher dosage study, the acyclovir recipients experienced less post-zoster pain than placebo recipients; differences in the prevalence of pain were most significant for the presence of a persistent pain in the first three months of follow-up. Oral acyclovir at these dosages appears to be free of adverse reactions. In summary, oral acyclovir at a dosage of 800 mg five times per day for 10 days for treatment of acute herpes zoster is superior to 400 mg five times per day and favorably alters the course of the disease.


Reaction Dynamics of O((3)P) + Propyne: II. Primary Products, Branching Ratios, and Role of Intersystem Crossing from Ab Initio Coupled Triplet/Singlet Potential Energy Surfaces and Statistical Calculations.
The mechanism of the O((3)P) + CH3CCH reaction was investigated using a combined experimental/theoretical approach. Experimentally the reaction dynamics was studied using crossed molecular beams (CMB) with mass-spectrometric detection and time-of-flight analysis at 9.2 kcal/mol collision energy. Theoretically master equation (ME) simulations were performed on a potential energy surface (PES) determined using high-level ab initio electronic structure calculations. In this paper (II) the theoretical results are described and compared with experiments, while in paper (I) are reported and discussed the results of the experimental study. The PES was investigated by determining structures and vibrational frequencies of wells and transition states at the CASPT2/aug-cc-pVTZ level using a minimal active space. Energies were then determined at the CASPT2 level increasing systematically the active space and at the CCSD(T) level extrapolating to the complete basis set limit. Two separate portions of the triplet PES were investigated, as O((3)P) can add either on the terminal or the central carbon of the unsaturated propyne bond. Minimum energy crossing points (MECPs) between the triplet and singlet PESs were searched at the CASPT2 level. The calculated spin-orbit coupling constants between the T1 and S0 electronic surfaces were ∼25 cm(-1) for both PESs. The portions of the singlet PES that can be accessed from the MECPs were investigated at the same level of theory. The system reactivity was predicted integrating stochastically the one-dimensional ME using Rice-Ramsperger-Kassel-Marcus theory to determine rate constants on the full T1/S0 PESs, accounting explicitly for intersystem crossing (ISC) using the Landau-Zener model. The computational results are compared both with the branching ratios (BRs) determined experimentally in the companion paper (I) and with those estimated in a recent kinetic study at 298 K. The ME results allow to interpret the main system reactivity: CH3CCO + H and CH3 + HCCO are the major channels active on the triplet PES and are formed from the wells accessed after O addition to the terminal and central C, respectively; (1)CH3CH + CO and C2H3 + HCO are the major channels active on the singlet PES and are formed from the methylketene and acrolein wells after ISC. However, also a large number of minor channels (∼15) are active, so that the system reactivity is quite complicated. The comparison between computational and experimental BRs is quite good for the kinetic study, while some discrepancy with the CMB estimations suggests that dynamic non-ergodic effects may influence the system reactivity. Channel specific rate constants are calculated in the 300-2250 K and 1-30 bar temperature and pressure ranges. It is found that as the temperature increases the H abstraction reaction, whose contribution is negligible in the experimental conditions, increases in relevance, and the extent of ISC decreases from ∼80% at 300 K to less than 2% at 2250 K.


CCL2/CCR2 Axis Promotes the Progression of Salivary Adenoid Cystic Carcinoma via Recruiting and Reprogramming the Tumor-Associated Macrophages.
Objective: The present study investigated the roles and underlying mechanism of CCL2/CCR2 axis in the interactions between tumor cells and tumor-associated macrophages (TAMs) during the progression of salivary adenoid cystic carcinoma (SACC). Methods: Immunohistochemical staining and survival analysis were performed to study the correlation and clinical value of CD68, CD163, CCL2, and CCR2 expression in SACC cases. CCL2 silencing by RNA interference and CCR2 blocking by CCR2 specific antagonist (RS504393) were performed. ELISA, qRT-PCR, western blot, immunofluorescence, flow cytometry, CCK8, scratch wound healing, and transwell assays were used to explore the functional roles and possible mechanism of CCL2/CCR2 axis in the interactions between SACC cells and TAMs. The effects of targeting TAMs by blocking the CCL2/CCR2 axis were investigated in a xenograft mice model with SACC cells. Results: The high infiltration of TAMs marked by CD68 and high infiltration of M2 TAMs marked by CD163 were significantly correlated with the expression of CCL2 and CCR2 in SACC tissues. Notably, the high infiltration of TAMs and the overexpression of CCL2 were obviously associated with the clinical progression and poor prognosis of SACC. SACC cells derived CCL2 could activate its receptor CCR2 expression in TAMs in vitro. The in vitro results further indicated that the SACC cells derived CCL2 was involved in the recruitment, M2 polarization, and GDNF expression of TAMs through the CCL2/CCR2 axis. Meanwhile, TAMs derived GDNF promoted the proliferation, migration, and invasion of SACC cells through the GDNF/p-RET pathway. Treating immunodeficient mice with the CCR2 antagonist (RS504393) greatly inhibited the infiltration of TAMs and the tumorigenicity of SACC cells. Conclusion: These new findings indicated that the CCL2/CCR2 axis promoted the progression of SACC cells via recruiting and reprogramming TAMs. Targeting TAMs by blocking the CCL2/CCR2 axis might be a prospective strategy for SACC therapy.


Accelerating Precision Drug Development and Drug Repurposing by Leveraging Human Genetics.
The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples. To ensure these data are used to maximally benefit and accelerate both de novo drug discovery and drug repurposing efforts, we created the Accelerating Drug Development and Repurposing Incubator, a multidisciplinary think tank of experts in various therapeutic areas within both basic and clinical science as well as experts in legal, business, and other operational domains. The Incubator supports a diverse pipeline of drug indication finding projects, leveraging the natural experiment of human genetics.


Continental diatom biodiversity discovery and description in China: 1848 through 2019.
In this paper we inventory the continental diatom taxa described from inland waters in China, from the first species descriptions dating back to 1848 through 2019. China's geography and hydrography are complex, including the world's highest mountains, many large rivers, salty lakes, and large karst regions. From this area, a total of 1128 taxa have been described from China over this time period. We examine the number of taxa described in ca. 20-year intervals and note the periods of time of no to few descriptions, versus time intervals with many taxon descriptions. Early on, taxon descriptions of freshwater diatoms from China were done by mostly by Europeans working alone, and the time frame of 1948 to 1967 had few descriptions, as a devasting famine and the cultural revolution impacted scientific work and productivity. B.V. Skvortzov produced a large number of taxon descriptions, during his time in residence in Harbin, later while in Sao Paulo, Brazil, and even posthumously. More recently, a wide range of labs and collaborations across China, and with a diverse array of international partners, is ushering in a new, robust era of research on the biodiversity of continental diatoms. A few areas of research and work for the future are discussed.


Bilateral contact ground reaction forces and contact times during plyometric drop jumping.
Drop jumping (DJ) is used in training programs aimed to improve lower extremity explosive power. When performing double-leg drop jumps, it is important to provide an equal stimulus to both legs to ensure balanced development of the lower legs. The aim of this study was to bilaterally analyze the ground reactions forces and temporal components of drop jumping from 3 heights. Ten recreationally active male subjects completed 3 bounce-drop jumps from 3 starting heights (0.2, 0.4, and 0.6 m). Two linked force platforms were used to record left- and right-leg peak vertical force, time to peak force, average force, ground contact time, impulse and time differential. Between-height and between-leg comparisons for each variable were made using a multivariate analysis of variance with post hoc Wilcoxon tests (p < 0.05). Results indicated that force and time variables increased as drop jump height increased (p < 0.0001). Post hoc analyses showed that at 0.2- and 0.4-m bilateral differences were present in the time to peak force, average force, and impulse. No bilateral differences for any variables were shown at 0.6-m starting height. The contact time for all jumps was <0.26 seconds. At 0.2 m, only 63% of the subjects had a starting time differential of <0.01 seconds, rising to 96.3% at 0.6 m. The results indicated that 0.6 m is the suggested drop jump height to ensure that no bilateral differences in vertical forces and temporal components occur; however, shorter contact times were found at the lower heights.


The DUX4 homeodomains mediate inhibition of myogenesis and are functionally exchangeable with the Pax7 homeodomain.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by inappropriate expression of the double homeodomain protein DUX4. DUX4 has bimodal effects, inhibiting myogenic differentiation and blocking MyoD at low levels of expression, and killing myoblasts at high levels. Pax3 and Pax7, which contain related homeodomains, antagonize the cell death phenotype of DUX4 in C2C12 cells, suggesting some type of competitive interaction. Here, we show that the effects of DUX4 on differentiation and MyoD expression require the homeodomains but do not require the C-terminal activation domain of DUX4. We tested the set of equally related homeodomain proteins (Pax6, Pitx2c, OTX1, Rax, Hesx1, MIXL1 and Tbx1) and found that only Pax3 and Pax7 display phenotypic competition. Domain analysis on Pax3 revealed that the Pax3 homeodomain is necessary for phenotypic competition, but is not sufficient, as competition also requires the paired and transcriptional activation domains of Pax3. Remarkably, substitution mutants in which DUX4 homeodomains are replaced by Pax7 homeodomains retain the ability to inhibit differentiation and to induce cytotoxicity.


Acrokeratoelastoidosis.
A 45-year-old white woman presented with several years' history of firm, shiny papules on the lateral hands with slight extension to the dorsal fingers. The lesions first appeared between the index fingers and thumbs on both hands. They gradually increased in number, coalescing into plaques and affecting the junction between the palmar and dorsal skin. The patient did not have involvement of her feet. She had been diagnosed previously with chronic eczema that had failed to respond to multiple topical medications. In addition, the patient's sister had similar lesions on both hands. The patient denied any symptoms of hyperhidrosis, excessive sun exposure, or trauma. The plaques were asymptomatic, but were cosmetically unappealing to the patient. On physical examination, small, firm, skin-colored, hyperkeratotic papules, coalescing into plaques, were located on the junction between the palmar and dorsal skin on both lateral margins of the thumb and on the radial side of the index finger (Fig. 1). There were no lesions on the feet. A biopsy taken from a papule on the patient's left hand was consistent histologically with acrokeratoelastoidosis. The biopsy showed marked degeneration of collagen in the dermis with solar elastosis and some smudging of the papillary dermal collagen (Fig. 2). She was treated with clobetasone cream to the affected areas on the hands. After 6 weeks of treatment, she reported no significant improvement.


Ureteric obstruction in renal allograft recipients.
In 50 consecutive renal allograft recipients, operated upon between September 1975 and March 1977, we have encountered 10 cases of ureteric obstruction. The patients fell into two groups: those with ureteric obstruction of early onset due to intraluminal blood clot, oedema of the distal end of the ureter, ureteric tip necrosis or extrinsic compression by the spermatic cord, and those with obstruction of late onset due to ureteric fibrosis. Two cases of ureteric obstruction due to oedema and 1 due to intraluminal blood clot resolved spontaneously. Transurethral ureteric meatotomy, a recommended procedure for the relief of ureteric obstruction in suitable cases, was successful in 1 of our patients. The remaining 6 patients required open surgical procedures for relief of obstruction. In no instance did ureteric obstruction result in death or graft failure.


[Activity registration in intensive care units].
Intensive care treatment is expensive and its capacity is limited. The population of elderly patients with greater need for intensive care increases. It has become more important to evaluate the use of intensive care resources and to compare it with the results of treatment. Diagnoses do not provide a satisfactory description of the stay in the intensive care unit. Scoring systems for severity of illness and for resource needs are therefore of great value. The Norwegian Board of Health has requested all intensive care units in Norway to describe their activities by scoring systems for severity of illness, SAPS II (Simplified Acute Physiology Score II) and for use of resources NEMS (Nine Equivalents of Nursing Manpower Use Score). The systems are generally well recognised, easy to learn and not time-consuming. Through SAPS II and NEMS it is possible to compare results of treatment and use of resources across intensive care units or against a standard.


Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia.
Imatinib-insensitive leukemia stem cells (LSCs) are believed to be responsible for resistance to BCR-ABL tyrosine kinase inhibitors and relapse of chronic myelogenous leukemia (CML). Identifying therapeutic targets to eradicate CML LSCs may be a strategy to cure CML. In the present study, we discovered a positive feedback loop between BCR-ABL and protein arginine methyltransferase 5 (PRMT5) in CML cells. Overexpression of PRMT5 was observed in human CML LSCs. Silencing PRMT5 with shRNA or blocking PRMT5 methyltransferase activity with the small-molecule inhibitor PJ-68 reduced survival, serial replating capacity, and long-term culture-initiating cells (LTC-ICs) in LSCs from CML patients. Further, PRMT5 knockdown or PJ-68 treatment dramatically prolonged survival in a murine model of retroviral BCR-ABL-driven CML and impaired the in vivo self-renewal capacity of transplanted CML LSCs. PJ-68 also inhibited long-term engraftment of human CML CD34+ cells in immunodeficient mice. Moreover, inhibition of PRMT5 abrogated the Wnt/β-catenin pathway in CML CD34+ cells by depleting dishevelled homolog 3 (DVL3). This study suggests that epigenetic methylation modification on histone protein arginine residues is a regulatory mechanism to control self-renewal of LSCs and indicates that PRMT5 may represent a potential therapeutic target against LSCs.


Parasitology yesterday--following the trends.
The 1980s were a period of great activity in the field of parasitology that generated a vast amount of research published in approximately 20 specialist and several other learned journals. There was, however, no vehicle for disseminating the exciting discoveries that were being made in an immediate, easily readable and accessible form suitable for teachers, students and others interested in aspects of the subject that were broader than their own particular specialty. To fill this perceived gap, Elsevier decided in 1985 that it would be worthwhile publishing Parasitology Today to complement its other successful Trends journals. In this article, I review the breadth of coverage of topics published during the first year of Parasitology Today, most of which continue to be of interest today.


Switching behaviour of individual Ag-TCNQ nanowires: an in situ transmission electron microscopy study.
The organic semiconductor silver-tetracyanoquinodimethane (Ag-TCNQ) exhibits electrical switching and memory characteristics. Employing a scanning tunnelling microscopy setup inside a transmission electron microscope, the switching behaviour of individual Ag-TCNQ nanowires (NWs) is investigated in detail. For a large number of NWs, the switching between a high (OFF) and a low (ON) resistance state was successfully stimulated by negative bias sweeps. Fitting the experimental I-V curves with a Schottky emission function makes the switching features prominent and thus enables a direct evaluation of the switching process. A memory cycle including writing, reading and erasing features is demonstrated at an individual NW. Moreover, electronic failure mechanisms due to Joule heating are discussed. These findings have a significant impact on our understanding of the switching behaviour of Ag-TCNQ.


Advances in umbilical cord blood cell therapy: the present and the future.
Umbilical cord blood (UCB), previously seen as medical waste, is increasingly recognized as a valuable source of cells for therapeutic use. The best-known application is in hematopoietic stem cell transplantation (HSCT), where UCB has become an increasingly important graft source in the 28 years since the first umbilical cord blood transplantation (UCBT) was performed. Recently, UCB has been increasingly investigated as a putative source for adoptive cell therapy. Areas covered: This review covers the advances in umbilical cord blood transplantation (UCBT) to overcome the limitation regarding cellular dose, immunological naivety and additional cell doses such as DLI. It also provides an overview regarding the progress in adoptive cellular therapy using UCB. Expert opinion: UCB has been established as an important source of stem cells for HSCT. Successful strategies to overcome the limitations of UCBT, such as the limited cell numbers and naivety of the cells, are being developed, including novel methods to perform in vitro expansion of progenitor cells, and to improve their homing to the bone marrow. Promising early clinical trials of adoptive therapies with UCB cells, including non-immunological cells, are currently performed for viral infections, malignant diseases and in regenerative medicine.


Biosensing Technologies for Therapeutic Drug Monitoring.
Therapeutic drug monitoring (TDM) is the clinical practice of measuring pharmaceutical drug concentrations in patients' biofluids at designated intervals to allow a close and timely control of their dosage. This practice allows for rapid medical intervention in case of toxicity-related issues and/or adjustment of dosage to better fit the therapeutic demand. Currently, TDM is performed in centralized laboratories employing instruments, such as immunoassay analyzers and mass spectrometers that can be run only by trained personnel. However, the time required for the preparation, samples analysis, and data processing, together with the related financial cost, severely affects the application of TDM in medical practices. Therefore, a new generation of analytical tools is necessary to respond to the timely need of drug administration or reduction aiming at effectively treating oncologic patients. State-of-the-Art Technologies for TDM: Technological advances in the field of nanosciences and biosensors offer the unique opportunity to address such issues. The interest for the so-called nanobiosensors is considerably increasing, particularly in drug discovery and clinical chemistry, even though there are only few examples reporting their use for TDM. The techniques employing nanobiosensors are mainly based on electrochemical, optical, and mass detection systems. In this review, we described the most promising methodologies that, in our opinion, will bring TDM towards the next stage of clinical practice in the future.


Left Ventricular Mechanics Assessed by 2-dimensional Speckle Tracking Echocardiography in Children and Adolescents With Idiopathic Scoliosis.
A retrospective review of data collected prospectively. The study aimed to assess the possible effects of idiopathic scoliosis on left ventricular (LV) myocardial performance in children and adolescent patients. Spine anomaly may impair cardiorespiratory function. It has been confirmed that respiratory function decreased in patients with scoliosis. However, limited study of the effect of scoliosis on heart function has been published, and no assessment of myocardial deformation of these patients has been reported to our knowledge. Forty-one patients with a median age of 16 years and a median Cobb's angle of 75 degrees were studied. LV myocardial deformation was evaluated using 2-dimensional speckle-tracking echocardiography. The results were compared with those of 33 controls. The correlations between Cobb's angle and echocardiographic parameters in patients were also explored. Compared with controls, patients had significantly lower global LV longitudinal systolic strain in all 3 views (4 chamber, 2 chamber, and 3 chamber views), lower global radial and circumferential strains in mitral valve (MV) level and papillary muscle (PM) level; reduced LV longitudinal early diastolic strain rate (SRe) in all 3 longitudinal views and reduced radial SRe in MV level and reduced circumferential SRe in apical (AP) level; decreased LV longitudinal late diastolic strain rate in 4-chamber view and decreased radial ones in all 3 short-axis levels. Among patients, Cobb's angle correlated negatively with LV global radial strain of MV level (r=-0.37, P=0.02), global circumferential strain of MV level (r=-0.35, P=0.03), and global circumferential strain of PM level (r=-0.49, P=0.001), whereas positively with LV longitudinal SRa of 4-chamber view (r=0.46, P=0.003), longitudinal SRa of 2-chamber view (r=0.49, P=0.001), and circumferential SRa of AP level (r=0.35, P=0.02). LV mechanics are impaired in patients with idiopathic scoliosis, which correlate with the severity of scoliosis. Our findings suggest the need and provide a mechanical basis for further studies in these patients.


Acute hepatic failure: a Western perspective.
Acute hepatic failure (AHF) is an uncommon, devastating syndrome, which results in death or the need for liver transplantation in more than 50% of cases. While AHF has numerous causes, most cases are due to viral hepatitis and drug toxicity or idiosyncratic reactions. A significant group with indeterminate causation remains, despite careful investigation. In many of these cases a viral aetiology is suspected, although yet not proven. Major differences exist in the aetiology of AHF between the West and Eastern countries. A wider range of aetiologies exists in the West. Common causes include acetaminophen toxicity and idiosyncratic drug reactions, while viral hepatitis is less frequent. Hepatitis E infection is rarely seen in Western countries in contrast to its high prevalence in the East. The mainstay of AHF management is supportive care in an intensive care unit. Liver transplantation is now the standard of care in many Western liver units for individuals who have a less than 20% probability of survival. Lack of availability of donor livers at short notice remains a significant problem. Methods of liver support used while waiting for a donor liver or for the native liver to regenerate include bioartificial livers, extracorporeal liver-assist devices, extracorporeal whole organ perfusion (human and transgenic pig) and hepatocyte transplantation. The effectiveness of these methods remains unproven and awaits controlled clinical trials. Both transplantation and liver-support methods require specialized units and expensive and complicated equipment. Further research is necessary to identify modalities of therapy that would be effective as well as widely accessible.


Forgetting Memories and Their Attractiveness.
We study numerically the memory that forgets, introduced in 1986 by Parisi by bounding the synaptic strength, with a mechanism that avoids confusion; allows remembering the pattern learned more recently; and has a physiologically very well-defined meaning. We analyze a number of features of this learning for a finite number of neurons and finite number of patterns. We discuss how the system behaves in the large but finite N limit. We analyze the basin of attraction of the patterns that have been learned, and we show that it is exponentially small in the age of the pattern.


Frequency of incidental findings on computed tomography of trauma patients.
To determine the incidence and frequency of follow-up instructions for incidental findings on computed tomography (CT) scanning of the abdomen and pelvis in trauma patients. We performed a retrospective chart review of all adult patients triaged to the trauma service at a Level I trauma center between July 1, 2003 and June 30, 2004. Included patients were 16 years of age and older who underwent abdomen and pelvic CT scans as part of their primary evaluation. We excluded patients under the age of 16 years, patients unable to complete radiographic studies due to deterioration in condition, patients with missing CT scan reports, and transferred patients who had CT scans done at outside facilities. A total of 1,633 patients presented to the trauma service during the study period; 922 patients met inclusion criteria. Of these, 392 had incidental findings noted on the formal radiology report. Twenty patients with incidental findings either received additional workup during their hospital admission for their trauma injuries or were notified of the findings on discharge. Nine died prior to discharge. One hundred twenty-two patients with incidental findings had those findings noted in the history and physical or discharge summary with no documentation of follow-up. There was no documentation of any incidental findings in the electronic record for the majority of patients (242) with incidental findings. The majority of incidental findings discovered on abdomen and pelvic CT scanning of trauma patients are not documented; therefore, many patients may not receive the appropriate recommended follow up.


Prevalence of Workplace Violence and Effects of De-escalation Training Among Hospitalists: A Pilot Study.
Workplace violence (WPV) is increasing in healthcare and negatively impacts healthcare worker outcomes. De-escalation training for healthcare workers is recommended to reduce WPV from patients and visitors. Hospitalists may be at high risk for WPV, but the magnitude of WPV and the impact of de-escalation training among hospitalists is not known. We investigated the baseline prevalence of WPV experienced by 37 hospitalists at a single center. After an in-person de-escalation training, we measured hospitalists' self-reported "Confidence in Coping with Patient Aggression" using a validated scale (score range 10-110). In the 12 months before de-escalation training, 86.5% of participants reported at least one form of WPV: 83.8% verbal abuse, 29.7% racial abuse, 18.9% physical violence, and 16.2% sexual abuse. The mean confidence score increased significantly from pre-training (43.2) to immediately after training (68.5) and remained significantly elevated at three months (57.2), six months (60.2), and after 12 months (59.9) (all P < 0.05; Ptrend <0.05). Hospitalists are at high risk for WPV. Structured in-person de-escalation training may provide the sustained ability for hospitalists to cope with WPV.


Relation of clinical, echocardiographic and electrocardiographic features of cardiac amyloidosis to the presence of the transthyretin V122I allele in older African-American men.
Previous studies have shown that 3% to 4% of African Americans carry an amyloidogenic allele of the human serum protein transthyretin (TTR V122I). The allele appears to have an absolute anatomic risk for cardiac amyloid deposition after 65 years of age. In this study, a case-control comparison was performed of clinical, echocardiographic, and electrocardiographic characteristics of 23 age at risk carriers of the amyloidogenic allele and 46 age-, gender-, and ethnically matched noncarriers being evaluated for cardiac disease using standard clinical testing. The 2 groups were matched for blood pressure and the cardiac ejection fraction. None of the subjects had a prestudy diagnosis of cardiac amyloidosis. Carriers of the amyloidogenic allele were found to have statistically significant increases in the occurrence of many of the echocardiographic features of cardiac amyloidosis relative to the noncarriers and a higher frequency of congestive heart failure and atrial fibrillation. The observations suggest that TTR V122I represents a substantial risk for clinically significant cardiac amyloidosis in elderly African American men, behaving as an age-dependent autosomal dominant disease-associated allele. The diagnosis is difficult to make but can be suspected in African Americans aged >60 years on the basis of age, echocardiographic evidence of diastolic dysfunction, and interventricular septal thickening, even in the absence of more recently available sophisticated echocardiographic techniques for evaluating long-axis function and cardiac magnetic resonance imaging. Positive results for the amyloidogenic TTR V122I allele support the diagnosis and define the origin of the disease, which can be confirmed by endomyocardial biopsy.


Increased expression of ornithine decarboxylase by gamma-ray in mouse epidermal cells: relationship with protein kinase C signaling pathway.
The correlation between ornithine decarboxylase (ODC) protein induction and specific protein kinase C (PKC) isozyme expression by gamma-ray in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated normal and v-rasHa transformed mouse keratinocytes was examined. TPA at 100 nM was treated in primary mouse keratinocytes immediately after 4 Gy, 8 Gy and 16 Gy gamma-ray irradiation. After 4 hrs, cells were harvested and the protein expression levels of PKC isozymes (PKC alpha, -delta, -epsilon, -eta and -zeta) and ODC were examined. For v-rasHa infection, primary keratinocytes were infected with a defected retrovirus containing the v-rasHa gene. After 3 hrs of irradiation, each PKC isozyme and ODC protein expression were tested. Gamma-ray increases ODC protein expression in both TPA-treated normal and v-rasHa transformed mouse keratinocytes and this phenomenon correlated to the increased induction of PKC alpha without altering other PKC isozymes. Tyrosine phosphorylation of epidermal growth factor receptor protein was also stimulated during gamma-ray induced cellular changes in TPA-treated normal mouse keratinocytes. These results indicate that PKC alpha as an important regulator of mouse epidermal changes by gamma-radiation, contributes to the ODC expression occurring during exposure to tumor promoter, such as TPA, and epidermal neoplasia induced by ras activation.


Serial magnetic resonance imaging for monitoring medical therapy effects in Crohn's disease.
Tumor necrosis factor (TNF) antagonists can induce mucosal healing in patients with Crohn's disease (CD), but the effects on transmural inflammation and stenotic lesions are largely unknown. We performed a retrospective study in 50 patients (54% female, median age 37 yr) with CD who had undergone serial magnetic resonance imaging (MRI) examinations while receiving infliximab or adalimumab. Patients were grouped as clinical responders or nonresponders based on physician's assessment, laboratory, and endoscopic appearance. MRI scoring was performed by 2 radiologists in consensus blinded to clinical data using a validated MRI scoring system. In total, 64 lesions on MRI were identified for analysis. Analyses were performed using paired t test and Wilcoxon rank test. During anti-TNF treatment, MRI inflammation scores improved in 29 of 64 lesions (45.3%), remained unchanged in 18 of 64 lesions (28.1%), or deteriorated in 17 of 64 lesions (26.6%) over time. In the anti-TNF responder group, the mean intestinal inflammation score of all lesions improved from 5.19 to 3.12 (P < 0.0001). The mean inflammation scores in stenotic lesions in anti-TNF responders also improved significantly, from 6.33 to 4.58 (P = 0.01). In contrast, the mean inflammation scores did not change significantly (5.55-5.92, P = 0.49) in nonresponders. Diagnostic accuracy of anti-TNF response on MRI was 68%. Improved inflammatory activity on serial MRI scans was observed in patients with clinical response to medical therapy with anti-TNF agents in luminal CD. MRI can be used as a complementary approach to measure transmural inflammation in patients with CD and guide the optimal use of TNF antagonists in daily clinical practice.


Vector engineering to improve a staphylococcal surface display system.
A previously developed expression system for surface display of heterologous proteins on the surface of Staphylococcus carnosus employs the secretion signals from a Staphylococcus hyicus lipase and the cell wall anchoring part of Staphylococcus aureus protein A (SpA) to achieve surface display of expressed recombinant proteins. The system has been successfully used in various applications but the vector has not been considered genetically stable enough to allow protein library display applications, which would be of obvious interest. A new set of vectors, differing in size and devoid of a phage f1 origin of replication, were constructed and evaluated in terms of bacterial growth characteristics and vector stability. Furthermore, surface expression of a model surface protein was monitored by an enzymatic whole-cell assay and flow cytometry. The engineered expression vectors demonstrated dramatically improved stability and growth properties and two of the novel vectors demonstrated retained high surface density of the displayed model protein. The flow cytometry was found to be a powerful tool for observing the surface density of displayed heterologous proteins, and would thus be a rational strategy for monitoring the optimisation of any surface display system. The implications of these improved display vectors for future protein library applications are discussed.


Activation of the CD95 system increases with disease progression in human immunodeficiency virus type 1-infected children and adolescents.
Increased apoptosis in infected as well as noninfected cells has been invoked in CD4+ T helper cell depletion during HIV-1 infection. A strong increase in the expression of CD95 (APO-1/Fas) and CD95 ligand, key regulators of apoptosis in normal T cells, has previously been described in freshly isolated T cells from HIV-1-positive children when compared with healthy age-matched controls. We also found an increase in spontaneous as well as specific CD95-mediated apoptosis in CD4+ and CD8+ T cells from these patients. However, the relationship of these findings to disease progression in children with HIV infection is not known. MEASUREMENTS AND SUBJECTS: We studied expression of CD95 and CD95 ligand as well as sensitivity towards spontaneous and anti-CD95-triggered apoptosis of T cells in 33 HIV-1-positive children and adolescents in different disease stages. Loss of CD4+ T cells in vivo was paralleled by an increase in the percentage of CD95 high T cells and an increase in anti-CD95-induced apoptosis of CD4+ T cells. CD95L mRNA was constantly up-regulated in T cells from patients in intermediate disease stages whereas patients with normal CD4 counts and patients with advanced T cell loss showed CD95 ligand-mRNA levels in or slightly above the range of normal controls. Disturbed regulation of the CD95 system may play an important role in the development of immunodeficiency during the course of HIV infection in children.


Catastrophizing Maladaptive Coping Affects the Association Between Viral Anxiety and Fear of Progression in Cancer Patients During COVID-19 Pandemic.
The aim of the present study was to explore whether or not cancer patients' viral anxiety and depression during the coronavirus-2019 (COVID-19) pandemic were associated with a fear of cancer progression. We also assessed whether coping strategies affected the relationship. The present cross-sectional survey included cancer patients who visited Ulsan University Hospital in Ulsan, Korea. The participants' demographic information and responses to the following symptoms rating scales were collected: Stress and Anxiety to Viral Epidemic- 6; Patient Health Questionnaire-9; Cognitive Emotion Regulation Questionnaire-short version; or Fear of Progression Questionnaire-short version. Of the 558 cancer patients surveyed, 25 (4.5%) reported that their treatment schedule was delayed during the COVID-19 pandemic. The patients' fear of progression was found to be related to age (β=-0.08; p=0.011), viral anxiety (β=0.40; p<0.001), depression (β= 0.26; p<0.001), and catastrophizing coping strategies (β=0.15; p=0.004), for an overall adjusted R2 of 0.46 (F=66.8; p<0.001). Mediation analysis showed that viral anxiety and depression were directly associated with fear of progression, while catastrophizing mediated this relationship. Fear of progression in cancer patients was associated with viral anxiety, depression, and maladaptive coping techniques, such as catastrophizing, during the COVID-19 pandemic.


Enhanced tumour uptake of radiolabelled antibodies by hyperthermia. Part II: Application of the thermal equivalency equation.
Clinical application of local hyperthermia as a means for modulating drug and macro-molecular tumour uptake have been slow to develop, due in part to the difficulty in designing and comparing heating protocols. The thermal isodose formula developed by Sapareto and Dewey is used in cytotoxicity and radiosensitization hyperthermia protocols to compare different time/temperature combinations; however, its relevance to other end-points has not been evaluated. The current study was undertaken to determine whether heating protocols of different time and temperature, but predicted to be thermally equivalent by this formula, had similar effects on the tumour and normal tissue distribution of radiolabelled tumour-specific (anti-tenascin 81C6) and non-specific (anti-dansyl TPS3.2) monoclonal antibodies (mAbs). Two thermally equivalent heating protocols, 4 h at 41.8 degrees C and 45 min at 43 degrees C, were compared in mice with subcutaneous D54 MG human glioma xenografts. A 4-fold increase in xenograft localization of 81C6 mAb was achieved relative to that in non-heated control groups with both heating protocols. Both hyperthermia protocols also resulted in improved tumour:normal tissue ratios. However, differences in absolute tumour and normal tissue uptake were seen, suggesting that the thermal isodose formula has limited usefulness in the design and comparison of hyperthermia protocols for enhancing the tumour uptake of radiolabelled mAbs.


Brief Report: Markers of Spontaneous Preterm Delivery in Women Living With HIV: Relationship With Protease Inhibitors and Vitamin D.
Women living with HIV (WLHIV) have increased risk of spontaneous preterm delivery (SPTD). We sought to identify plasma predictors of SPTD and their correlations with factors that increase the risk of SPTD, such as vitamin D deficiency and use of protease inhibitors. Plasma was obtained from 103 WLHIV with SPTD (≤35 weeks gestation) and 205 controls with term deliveries (TDs; ≥37 weeds) matched to cases 2:1 by race and gestational age at blood draw. TNFα, IFNγ, IL6, IL8, IL1β, IL18, IL17, granulocyte colony stimulating factor (GCSF), MCP1, IP10, sIL2Rα, sCD14, vascular endothelial factor a, monocyte colony stimulation factor, GROα, MMP9, IL10, TGFβ, sCTLA4, and eicosanoids were compared between cases adjusting for known SPTD risk factors. Participants had similar demographic characteristics, but cases had higher plasma HIV RNA, lower CD4 cells, and more advanced HIV disease compared with controls. High sIL2Rα was associated with increased risk of SPTD. High sCD14, GCSF, PGF2α, and 5-HEPE were marginally associated with increased risk of SPTD. Women who initiated protease inhibitors-containing antiretroviral treatment before or during the first trimester had higher levels of GCSF and 5-HEPE compared with women without such exposure before plasma collection. Vitamin D insufficiency was associated with higher inflammatory sCD14 and PGF2α, and lower anti-inflammatory 5-HEPE. The best plasma predictor of SPTD in WLHIV was sIL2Rα, a marker of T-cell activation. Markers of monocyte activation and eicosanoids were marginally increased in WLHIV and SPTD, suggesting that they may also play a role in the pathogenesis of this disorder.


Multiple marker mapping of quantitative trait loci in a cross between outbred wild boar and large white pigs.
A quantitative trait locus (QTL) analysis of growth and fatness data from a three generation pig experiment is presented. The population of 199 F2 animals was derived from a cross between wild boar and Large White pigs. Animals were typed for 240 markers spanning 23 Morgans of 18 autosomes and the X chromosome. A series of analyses are presented within a least squares framework. First, these identify chromosomes containing loci controlling trait variation and subsequently attempt to map QTLs to locations within chromosomes. This population gives evidence for a large QTL affecting back fat and another for abdominal fat segregating on chromosome 4. The best locations for these QTLs are within 4 cM of each other and, hence, this is likely to be a single QTL affecting both traits. The allele inherited from the wild boar causes an increase in fat deposition. A QTL for intestinal length was also located in the same region on chromosome 4 and could be the same QTL with pleiotropic effects. Significant effects, owing to multiple QTLs, for intestinal length were identified on chromosomes 3 and 5. A single QTL affecting growth rate to 30 kg was located on chromosome 13 such that the Large White allele increased early growth rate, another QTL on chromosome 10 affected growth rate from 30 to 70 kg and another on chromosome 4 affected growth rate to 70 kg.


[The pacifism of Henry Dunant].
From various writings of the founder of the International Red Cross and above all from his late work L'avenir sanglant it is deduced as the Dunant anticipating and prophetically interpreting the curse of the war is an internationalist (for some aspects a romantic anarchist) and a convinced pacifist. We show therefore how much has been false and backbiters the defamations that followed to the attribution of the first Nobel prize for the peace.


Correction: Specialty detection in the context of telemedicine in a highly imbalanced multi-class distribution.
[This corrects the article DOI: 10.1371/journal.pone.0290581.].


Implementation of full/half bowtie filter models in a commercial treatment planning system for kilovoltage cone-beam CT dose estimations.
The purpose of this study was to implement full/half bowtie filter models in a com-mercial treatment planning system (TPS) to calculate kilovoltage (kV) cone-beam CT (CBCT) doses of Varian On-Board Imager (OBI) kV X-ray imaging system. The full/half bowtie filter models were created as compensators in Pinnacle TPS using MATLAB software. The physical profiles of both bowtie filters were imported and hard-coded in the MATLAB system. Pinnacle scripts were written to import bowtie filter models into Pinnacle treatment plans. Bowtie filter-free kV X-ray beam models were commissioned and the bowtie filter models were validated by analyzing the lateral and percent-depth-dose (PDD) profiles of anterior/posterior X-ray beams in water phantoms. A CT dose index (CTDI) phantom was employed to calculate CTDI and weighted CTDI values for pelvis and pelvis-spotlight CBCT protocols. A five-year-old pediatric anthropomorphic phantom was utilized to evaluate absorbed and effective doses (ED) for standard and low-dose head CBCT protocols. The CBCT dose calculation results were compared to ion chamber (IC) and Monte Carlo (MC) data for the CTDI phantom and MOSFET and MC results for the pediatric phantom, respectively. The differences of lateral and PDD profiles between TPS calculations and IC measurements were within 6%. The CTDI and weighted CTDI values of the TPS were respectively within 0.25 cGy and 0.08 cGy compared to IC measurements. The absorbed doses ranged from 0 to 7.22 cGy for the standard dose CBCT and 0 to 1.56 cGy for the low-dose CBCT. The ED values were found to be 36-38 mSv and 7-8 mSv for the standard and low-dose CBCT protocols, respectively. This study demonstrated that the established full/half bowtie filter beam models can produce reasonable dose calculation results. Further study is to be performed to evaluate the models in clinical situations.


Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate.
Antigen-presenting cells (APCs) internalize antigens and present antigen-derived peptides to T cells. Although APCs have been thought to exhibit a well-developed capacity for lysosomal proteolysis, here we found that they can exhibit two distinct strategies upon antigen encounter. Whereas macrophages contained high levels of lysosomal proteases and rapidly degraded internalized proteins, dendritic cells (DCs) and B lymphocytes were protease-poor, resulting in a limited capacity for lysosomal degradation. Consistent with these findings, DCs in vivo degraded internalized antigens slowly and thus retained antigen in lymphoid organs for extended periods. Limited lysosomal proteolysis also favored antigen presentation. These results help explain why DCs are able to efficiently accumulate, process, and disseminate antigens and microbes systemically for purposes of tolerance and immunity.


[Characteristics of the antihypoxic properties of 3-hydroxypyridine-class antioxidants].
It was found during experiments using three models of hypoxia (hypobaric, normobaric, hemic) in mice that derivatives of 3-hydroxypyridine possess an antihypoxic effect. They are as active as sodium hydroxybutyrate but less active than gutimine. A clear-cut dependence of the antihypoxic activity on the radical character in the 2nd position of 3 hydroxypyridine was revealed. The presence of a hydroxy group in the 3rd position of pyridine ring was shown to be very important for the antihypoxic properties. The data suggesting different degrees of involvement of GABA and benzodiazepine receptors in realization of the antihypoxic effect were obtained.


[Commentary on the symposium "Projection of Molecular Epidemiology Medicine"].
Molecular epidemiology represents an association between molecular biology and traditional epidemiologic research. Molecular epidemiology focuses on genetic and environmental risk factors at the molecular level that influences etiology and distribution of diseases oriented to early diagnosis and treatment. Since 1993 Mexico has been participating at the International Molecular Epidemiology Task Force (IMETAF) supported by the World Health Organization and Pan American Health Organization. Mexico was the first country in Latin American that established projects in molecular epidemiology. Presentations in the Symposium Projection of molecular epidemiology in medicine, expressed the future potential of genetic knowledge in identification of genes that contribute to susceptibility or resistance to diseases.


[The use of depakene and depakene-chrono in idiopathic generalized epilepsy].
During 5 years, 104 patients with different types of idiopathic generalized epilepsy were treated with depakine and depakine-chrono in monotherapy and polytherapy schedule. Thirty-three patients had childhood absence epilepsy, 34--juvenile absence epilepsy, 33--juvenile myoclonic epilepsy and 3--generalized convulsive seizures in wake up periods. Mean medication dose was 1200 mg daily. Significant improvement of the patient's state was revealed in 50% of the cases, being most efficient in patients with juvenile myoclonic epilepsy (60.6%) and in children absence epilepsy (57.5%). Indices of remission formation and quality changed in the same direction--complete remissions were more frequent in juvenile absence epilepsy. Depakine is concluded to be an effective medication for the treatment of idiopathic generalized epilepsy.


The role of the posterior cerebellum in saccadic adaptation: a transcranial direct current stimulation study.
The posterior vermis of the cerebellum is considered to be critically involved in saccadic adaptation. However, recent evidence suggests that the adaptive decrease (backward adaptation) and the adaptive increase (forward adaptation) of saccade amplitude rely on partially separate neural substrates. We investigated whether the posterior cerebellum could be differentially involved in backward and forward adaptation by using transcranial direct current stimulation (TDCS). To do so, participants' saccades were adapted backward or forward while they received anodal, cathodal, or sham TDCS. In two extra groups, subjects underwent a nonadaptation session while receiving anodal or cathodal TDCS to control for the direct effects of TDCS on saccadic execution. Surprisingly, cathodal stimulation tended to increase the extent of both forward and backward adaptations, while anodal TDCS strongly impaired forward adaptation and, to a smaller extent, backward adaptation. Forward adaptation was accompanied by a greater increase in velocity with cathodal stimulation, and reduced duration of change for anodal stimulation. In contrast, the expected velocity decrease in backward adaptation was noticeably weaker with anodal stimulation. Stimulation applied during nonadaptation sessions did not affect saccadic gain, velocity, or duration, demonstrating that the reported effects are not due to direct effects of the stimulation on the generation of eye movements. Our results demonstrate that cerebellar excitability is critical for saccadic adaptation. Based on our results and the growing evidence from studies of vestibulo-ocular reflex and saccadic adaptation, we conclude that the plasticity at the level of the oculomotor vermis is more fundamentally important for forward adaptation than for backward adaptation.


The distribution of alpha 2 beta 1, alpha 3 beta 1 and alpha 6 beta 4 integrins identifies distinct subpopulations of basal keratinocytes in the outer root sheath of the human anagen hair follicle.
The human hair follicle is composed of different concentric compartments, which reflect different programmes of differentiation. Using monoclonal antibodies against alpha 2 beta 1 and alpha 3 beta 1 integrins we demonstrated a shift in their expression, from a basolateral distribution in the basal cells of the lower outer root sheath, to an apicolateral expression in the upper outer root sheath, as in epidermis. This shift takes place in a transition zone, localized to the midpart of the follicle. The distinct basolateral distribution of alpha 2 beta 1 and alpha 3 beta 1 integrins in the lower portion of the outer root sheath coincides with the presence of basal cell protrusions and is probably linked to the presence of the vitreous membrane which surrounds the bottom part of the anagen human hair follicle. Moreover, we showed that the expression of alpha 6 beta 4 integrin is discontinuous along the hair follicle and coincides with that of laminin 5. Together these results establish that within a given compartment-namely the outer root sheath-several domains can be clearly identified, which probably reflect the onset of successive differentiation pathways along the hair follicle.


Involvement of ST1B subfamily of cytosolic sulfotransferase in kynurenine metabolism to form natriuretic xanthurenic acid sulfate.
Natriuretic substances are a group of molecules affecting sodium homeostasis in the body. Recently, two new molecules having natriuresis effects, xanthurenic acid 8-O-beta-d-glucoside and xanthurenic acid 8-O-sulfate (XA sulfate), have been isolated from human urine. In the present study, we have investigated the sulfation of xanthurenic acid (XA) in mouse tissues to assess the contribution of specific sulfotransferases (STs) to the reaction. Cytosols from tissues of both sexes of C57BL/6N mice (liver, stomach, jejunum, colon, and kidney) were capable of forming XA sulfate, with various K(m) values. Jejunum cytosol showed the lowest K(m) value, and its V(max)/K(m) value was much greater than those of other tissues. The kinetic analyses with recombinant mouse (m) STs (Sult1a1, Sult1b1, Sult1c2, and Sult1d1) showed the lowest K(m) value for mSult1b1, and the value was comparable with that for jejunum cytosol. The highest expression of mSult1b1 in small intestine was confirmed at the mRNA and protein levels. mSult1b1 is thus suggested as a major enzyme responsible for XA sulfation in jejunum. Similar to mSult1b1, human SULT1B1 and rat Sult1b1 mediated XA sulfation efficiently. Thus, XA is likely to be an endogenous substrate for ST1B members. In contrast to XA, an XA-related compound, kynurenic acid strongly inhibited mSult1b1-mediated sulfations, with IC(50) values at a micromolar range. These results indicate the functional role of ST1B subfamily of ST in XA sulfate formation in the body.


Age related changes in hyaluronan expression leads to Meibomian gland dysfunction.
The prevalence of dry eye disease (DED) ranges from ∼5 to 50 % and its associated symptoms decrease productivity and reduce the quality of life. Approximately 85 % of all DED cases are caused by Meibomian gland dysfunction (MGD). As humans and mice age, their Meibomian glands (MGs) undergo age-related changes resulting in age related-MGD (ARMGD). The precise cause of ARMGD remains elusive, which makes developing therapies extremely challenging. We previously demonstrated that a hyaluronan (HA)-rich matrix exists surrounding the MG, regulating MG morphogenesis and homeostasis. Herein, we investigated whether changes to the HA matrix in the MG throughout life contributes towards ARMGD, and whether altering this HA matrix can prevent ARMGD. For such, HA synthase (Has) knockout mice were aged and compared to age matched wild type (wt) mice. MG morphology, lipid production, PPARγ expression, basal cell proliferation, stem cells, presence of atrophic glands and MG dropout were analyzed at 8 weeks, 6 months, 1 year and 2 years of age and correlated with the composition of the HA matrix. We found that as mice age, there is a loss of HA expression in and surrounding the MGs of wt mice, while, in contrast, Has1-/-Has3-/- mice present a significant increase in HA expression through Has2 upregulation. At 1 year, Has1-/-Has3-/- mice present significantly enlarged MGs, compared to age-matched wt mice and compared to all adult mice. Thus, Has1-/-Has3-/- mice continue to develop new glandular tissue as they age, instead of suffering MG atrophy. At 2 years, Has1-/-Has3-/- mice continue to present significantly larger MGs compared to age-matched wt mice. Has1-/-Has3-/- mice present increased lipid production, increased PPARγ expression and an increase in the number of proliferating cells when compared to wt mice at all-time points analyzed. Taken together, our data shows that a loss of the HA matrix surrounding the MG as mice age contributes towards ARMGD, and increasing Has2 expression, and consequently HA levels, prevents ARMGD in mice.


Simultaneous autoradiographic and immunohistochemical localization of estrogen and gonadotropin in the rat pituitary.
A combined autoradiographic and immunohistochemical technique is introduced which is suitable to simultaneously localize hypophyseal sites of nuclear (3-H)-estradiol uptake and anti-hCG-characterized "gonadotropes". Most, but not all, "gonadotropes" show significant nuclear concentration of radioactivity. A large percentage of non-"gonadotropes" also show nuclear uptake of label.


Surfactant-induced assembly of enzymatically-stable peptide hydrogels.
The secondary structure of peptides in the presence of interacting additives is an important topic of study, having implications in the application of peptide science to a broad range of modern technologies. Surfactants constitute a class of biologically relevant compounds that are known to influence both peptide conformation and aggregation or assembly. We have characterized the secondary structure of a linear nonapeptide composed of a hydrophobic alanine/phenylalanine core flanked by hydrophilic acid/amine units. We show that the anionic surfactant sodium dodecyl sulfate (SDS) induces the formation of β-sheets and macroscopic gelation in this otherwise unstructured peptide. Through comparison to related additives, we propose that SDS-induced secondary structure formation is the result of amphiphilicity created by electrostatic binding of SDS to the peptide. In addition, we demonstrate a novel utility of surfactants in manipulating and stabilizing peptide nanostructures. SDS is used to simultaneously induce secondary structure in a peptide and to inhibit the activity of a model enzyme, resulting in a peptide hydrogel that is impervious to enzymatic degradation. These results complement our understanding of the behavior of peptides in the presence of interacting secondary molecules and provide new potential pathways for programmable organization of peptides by the addition of such components.


Akt2, a novel functional link between p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in myogenesis.
Activation of either the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt or the p38 mitogen-activated protein kinase (MAPK) signaling pathways accelerates myogenesis but only when the reciprocal pathway is functional. We therefore examined the hypothesis that cross-activation between these signaling cascades occurs to orchestrate myogenesis. We reveal a novel and reciprocal cross-talk and activation between the PI 3-kinase/Akt and p38 MAPK pathways that is essential for efficient myoblast differentiation. During myoblast differentiation, Akt kinase activity correlated with S473 but not T308 phosphorylation and occurred 24 h after p38 activation. Inhibition or activation of p38 with SB203580, dominant-negative p38, or MKK6EE regulated Akt kinase activity. Analysis of Akt isoforms revealed a specific increase in Akt2 protein levels that coincided with AktS473 phosphorylation during myogenesis and an enrichment of S473-phosphorylated Akt2. Akt2 promoter activity and protein levels were regulated by p38 activation, thus providing a mechanism for communication. Subsequent Akt activation by S473 phosphorylation was PI 3-kinase dependent and specific for Akt2 rather than Akt1. Complementary to p38-mediated transactivation of Akt, activation or inhibition of PI 3-kinase regulated p38 activity upstream of MKK6, demonstrating reciprocal communication and positive feedback characteristic of myogenic regulation. Our findings have identified novel communication between p38 MAPK and PI 3-kinase/Akt via Akt2.


Interferon lambda-3 polymorphism and response to pegylated interferon in patients with hepatitis D.
Specific single nucleotide polymorphisms (SNPs) near the interferon lambda-3 (IFNλ3) gene (formerly interleukin 28B) influence the response to treatment with interferon in hepatitis C patients. We aimed to investigate such an influence in hepatitis D patients. The study population consisted of hepatitis D patients who were previously treated with pegylated interferon for one year and who were spontaneous clearers of the virus post recent superinfection. The SNP of IFNλ3, rs12979860, was determined by polymerase chain reaction-restriction fragment length polymorphism protocol. The total number of patients was 64; median age was 30.5 years and 53 were male. The number of patients with sustained virological response 1 year post-treatment was 17, non-responders 29, relapsers 11 and spontaneous clearers post superinfection 7. Cirrhosis was present in 28 (44%). IFNλ3, rs12979860 genotype CC, was present in 41 (64.1%), CT in 21 (32.8%) and TT in 2 (3.1%). There was no difference in the body mass index, baseline alanine aminotransferase, hepatitis B e antigen and HBV DNA status among patients with sustained response and response failure (no response or relapse). The median age of response failures was 33.5 years compared to 26 in responders (P=0.024). They had higher gamma glutamyl transferase levels (P=0.030) and cirrhosis (P=0.003). Genotype CC was present in 29/40 of response failures compared to 9/17 of the responders (P=0.152). Logistic regression analysis showed that cirrhosis was the independent risk factor for failure to have a response (P=0.001). 4/7 patients with spontaneous clearance had genotype CC. IFNλ3 rs12979860 SNP does not have any significant influence on long-term hepatitis D clearance. Presence of cirrhosis may influence the response.


Restoration of bioactive lantibiotic suicin from a remnant lan locus of pathogenic Streptococcus suis serotype 2.
Lantibiotics are ribosomally synthesized, posttranslationally modified antimicrobial peptides. Their biosynthesis genes are usually organized in gene clusters, which are mainly found in Gram-positive bacteria, including pathogenic streptococci. Three highly virulent Streptococcus suis serotype 2 strains (98HAH33, 05ZYH33, and SC84) have been shown to contain an 89K pathogenicity island. Here, on these islands, we unveiled and reannotated a putative lantibiotic locus designated sui which contains a virulence-associated two-component regulator, suiK-suiR. In silico analysis revealed that the putative lantibiotic modification gene suiM was interrupted by a 7.9-kb integron and that other biosynthesis-related genes contained various frameshift mutations. By reconstituting the intact suiM in Escherichia coli together with a semi-in vitro biosynthesis system, a putative lantibiotic named suicin was produced with bactericidal activities against a variety of Gram-positive strains, including pathogenic streptococci and vancomycin-resistant enterococci. Ring topology dissection indicated that the 34-amino-acid lantibiotic contained two methyllanthionine residues and one disulfide bridge, which render suicin in an N-terminal linear and C-terminal globular shape. To confirm the function of suiK-suiR, SuiR was overexpressed and purified. In vitro analysis showed that SuiR could specifically bind to the suiA gene promoter. Its coexpression with suiK could activate suiA gene promoter in Lactococcus lactis NZ9000. Conclusively, we obtained a novel lantibiotic suicin by restoring its production from the remnant sui locus and demonstrated that virulence-associated SuiK-SuiR regulates its production.


Mutational analysis of the ATP-binding site in HslU, the ATPase component of HslVU protease in Escherichia coli.
HslU is the ATPase component of the ATP-dependent HslVU protease in Escherichia coli. To gain an insight into the structure and function of HslU, site-directed mutagenesis was performed to generate a mutation in the ATP-binding site of the ATPase (i.e., to replace the Lys63 with Thr). Unlike the wild-type HslU, the mutant form (referred to as HslU/K63T) could not hydrolyze ATP or support the ATP-dependent hydrolysis of N-carbobenzoxy-Gly-Gly-Leu-7-amido-4-methyl coumarin by HslV. The wild-type HslU (a mixture of monomer and dimer) formed a multimer containing 6-8 subunits in the presence of either ATP or ADP, indicating that ATP-binding, but not its hydrolysis, is required for oligomerization of HslU. However, HslU/K63T remained as a monomer whether or not the adenine nucleotides were present. Furthermore, ATP or ADP could protect HslU, but not HslU/K63T, from degradation by trypsin. These results suggest that the mutation in the ATP-binding site results in prevention of the binding of the adenine nucleotides to HslU and hence in impairment of both oligomerization and ATPase function of HslU.


Cost-benefit analysis of newer versus older antidepressants--pharmacoeconomic studies comparing SSRIs/SNRIs with tricyclic antidepressants.
Changes in the social and health services over the last years have forced doctors to concern themselves with cost benefit calculations and budget forecasting. Cost considerations are a (co-) determinant in the choice of antidepressants as well as neuroleptics and/or antipsychotics. In recent years, pharmacoeconomic studies have been performed to answer the question as to what extent treatment with new antidepressants, in particular SSRIs, is actually less expensive than treatment with (generic) tricyclic antidepressants due to better safety profiles and higher compliance in spite of the considerably higher retail price. Following descriptions of the methodological principles, the currently available studies are presented and discussed critically in this report. It can be stated that the economic value of different antidepressants can not be decided definitively at the present time. The available data do not allow the conclusion that SSRIs should be preferred over tricyclic antidepressants with the argument that the treatment as a whole is more cost effective in spite of the higher costs.


The complex role of SIRT6 in carcinogenesis.
SIRT6, a member of the mammalian sirtuins family, functions as a mono-ADP-ribosyl transferase and NAD(+)-dependent deacylase of both acetyl groups and long-chain fatty acyl groups. SIRT6 regulates diverse cellular functions such as transcription, genome stability, telomere integrity, DNA repair, inflammation and metabolic related diseases such as diabetes, obesity and cancer. In this review, we will discuss the implication of SIRT6 in the biology of cancer and the relevance to organism homeostasis and lifespan.


Implementing early goal-directed therapy in the emergency setting: the challenges and experiences of translating research innovations into clinical reality in academic and community settings.
Research knowledge translation into clinical practice pathways is a complex process that is often time-consuming and resource-intensive. Recent evidence suggests that the use of early goal-directed therapy (EGDT) in the emergency department care of patients with severe sepsis and septic shock results in a substantial mortality benefit; however, EGDT is a time- and resource-intensive intervention. The feasibility with which institutions may translate EGDT from a research protocol into routine clinical care, among settings with varying resources, staff, and training, is largely unknown. The authors report the individual experiences of EGDT protocol development, as well as preimplementation and postimplementation experiences, at three institutions with different emergency department, intensive care unit, and hospital organization schemes.


Quality of Life of Pediatric Patients With Long QT Syndrome.
Children with long QT syndrome (LQTS) live with the risk of sudden death, activity restrictions, and the need for daily medications. We sought to evaluate the quality of life (QOL), self-perception, and behavior of patients with LQTS as perceived by both patients and their parents and identify predictors of lower QOL. QOL (Pediatric QOL Inventory [PedsQL] and Pediatric Cardiac Quality of Life Inventory [PCQLI]), self-perception, and behavioral inventories were completed by patients with LQTS and their parents. Comparison of PedsQL scores was made to published data for healthy children using t tests, and PCQLI scores were compared with those of patients with differing complexity of congenital heart disease. Mixed modeling was used for multivariable analysis. Sixty-one patients with LQTS were evaluated (age 13.6 ± 3.0 years; male 49%). Compared with healthy children, the PedsQL Total, Psychosocial, and Physical Health Summary scores were significantly lower for patients with LQTS and parent proxy reports (p ≤0.001). In general, PCQLI scores of patients with LQTS and parents were similar to those of patients with tetralogy of Fallot (p ≥0.2), lower than those of patients with bicuspid aortic valve (p ≤0.02), and higher than those of patients with single ventricle (p ≤0.03). Lower patient and parent PCQLI scores were associated with internalizing problems. For parents, the presence of a cardiac device and medication side effects were additionally associated with lower PCQLI scores. In conclusion, patients with LQTS and their parents report lower QOL than normal children secondary to physical and psychosocial factors. Increasing focus on the psychological well-being of these patients is needed in an effort to improve their QOL.


Application of watershed modeling system (WMS) for integrated management of a watershed in Turkey.
Watershed models, that enable the quantification of current and future pollution loading impacts, are essential tools to address the functions and conflicts faced in watershed planning and management. In this study, the Watershed Modeling System (WMS) version 7.1 was used for the delineation of boundaries of Koycegiz Lake-Dalyan Lagoon watershed located in the southwest of Turkey at the Mediterranean Sea coast. A Digital Elevation Model (DEM) was created for one of the major streams of the watershed, namely, Kargicak Creek by using WMS, and DEM data were further used to extract stream networks and delineate the watershed boundaries. Typical properties like drainage areas, characteristic length and slope of sub-drainage areas have also been determined to be used as model inputs in hydrological and diffuse pollution modeling. Besides, run-off hydrographs for the sub-drainages have been calculated using the Rational Method, which produces valuable data for calculating the time variable inflow and input pollution loads to be further utilized in the future water quality models of the Creek. Application of WMS in the study has shown that, it is capable to visualize the results in establishing watershed management strategies.


Hippocampal volume change following ECT is mediated by rs699947 in the promotor region of VEGF.
Several studies have shown that electroconvulsive therapy (ECT) results in increased hippocampal volume. It is likely that a multitude of mechanisms including neurogenesis, gliogenesis, synaptogenesis, angiogenesis, and vasculogenesis contribute to this volume increase. Neurotrophins, like vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) seem to play a crucial mediating role in several of these mechanisms. We hypothesized that two regulatory SNPs in the VEGF and BDNF gene influence the changes in hippocampal volume following ECT. We combined genotyping and brain MRI assessment in a sample of older adults suffering from major depressive disorder to test this hypothesis. Our results show an effect of rs699947 (in the promotor region of VEGF) on hippocampal volume changes following ECT. However, we did not find a clear effect of rs6265 (in BDNF). To the best of our knowledge, this is the first study investigating possible genetic mechanisms involved in hippocampal volume change during ECT treatment.


Sleep polygraphic effects of trimipramine in depressed patients. Preliminary report.
Preliminary results are presented from an ongoing study in hospitalised depressed patients. Changes in sleep parameters were assessed on days 1 to 3 and 12 to 14 of a 4-week study in which patients received trimipramine 150 mg on day 1 and 100 mg thereafter. On days 1 to 3 and 12 to 14, 7 depressed patients had a significantly increased total sleep time and sleep efficiency index and a significantly decreased total wake time and number of intrasleep wake episodes per hour of sleep. Trimipramine treatment had no significant effect on REM sleep, percentage of REM sleep, REM duration and REM sleep stability index. However, a significant increase in REM latency was noted on days 1 to 3 but not on days 12 to 14. These polygraphic data suggest that trimipramine effects a very rapid and maintained sleep improvement in these depressed patients without significant alterations to the parameters of REM sleep.


A Prototype System for High Frame Rate Ultrasound Imaging based Prosthetic Arm Control.
The creation of unique control methods for a hand prosthesis is still a problem that has to be addressed. The best choice of a human-machine interface (HMI) that should be used to enable natural control is still a challenge. Surface electromyography (sEMG), the most popular option, has a variety of difficult-to-fix issues (electrode displacement, sweat, fatigue). The ultrasound imaging-based methodology offers a means of recognising complex muscle activity and configuration with a greater SNR and less hardware requirements as compared to sEMG. In this study, a prototype system for high frame rate ultrasound imaging for prosthetic arm control is proposed. Using the proposed framework, a virtual robotic hand simulation is developed that can mimic a human hand as illustrated in the link: https://youtu.be/LBcwQ0xzQK0. The proposed classification model simulating four hand gestures has a classification accuracy of more than 90%.Clinical relevance-The proposed system enables an ultrasound imaging based human machine interface that can be a research and development platform for novel control strategies of a hand prosthesis.


Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.
Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients' clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.


[Effects of a hypoxic stimulus on the dependence of tissue respiration on oxygen pressure in vitro].
Experimental studies of the dynamics of energy exchange in tissues of the rats' visceral organs (brain, heart, liver, and kidney) shortly after hypoxic stimulation displayed substantial variations in the respiratory activity of visceral tissues, and Km for oxygen at the start of the follow-on reaction (24 h, 72 h, and 120 h) which subsided later on (240 h and 360 h). These were in concert with a gross decline in the intensity of visceral tissue breathing at the initial oxygen pressure in vitro and a rise at critical pO2, a decrease in the affinity of cardiac, hepatic and renal tissues for oxygen at the onset of the follow-on reaction and an increase in the affinity at subsequent time points. Throughout the period of observation, high affinity for oxygen was observed in cerebral tissues. Combination of alpha-tocopherol and the hypoxic stimulus substantially suppressed the respiratory activity in all the visceral tissues of rats at the initial oxygen pressure and in the liver and kidney, at critical pO2. Increased utilization of the low pressure oxygen was observed in the brain and the heart. More pronounced changes in tissue affinity for oxygen were revealed in the heart and the liver, and least pronounced, in the brain and the kidney. A conclusion is drawn that alpha-tocopherol can strongly influence moderation of the stressful factor on the level of tissue homogenates.


Early surgery-related complications after aneurysm clip placement: an analysis of causes and patient outcomes.
Most reports of series on ruptured intracranial aneurysms contain information on select intraoperative complications. An understanding of all surgical complications, however, may guide us toward improved surgical procedures and enrich discussions concerning alternative management strategies, such as endovascular treatment, which are not exempt from complications and aneurysm recurrence. The study consists of a retrospective review of the charts, images, and notes from follow-up visits of 143 consecutive patients with subarachnoid hemorrhage (SAH) who were surgically treated during a 3-year period by one neurosurgeon. A surgical complication was determined based on findings of a clinical and/or radiological study in the absence of confounding factors such as the initial SAH ictus, vasospasm, hydrocephalus, and septic status. Functional outcome was assessed between 2 and 3 months post-SAH by using the Glasgow Outcome Scale (GOS). A procedure-related surgical complication was diagnosed in 29 (20.3%) of 143 patients studied. A brain tissue injury, including cerebral edema and hemorrhagic contusions, was diagnosed in 6.3% of patients, an unpredicted residual aneurysm neck in 5.3% of patients, and a cranial nerve deficit in 2.8% of patients. Functional outcome was good in 22 (75.9%) of the 29 patients with surgical complications. Death due to a surgical complication occurred in one (0.7%) of 143 patients. Surgical complications are more prevalent than previously thought. They may have been overlooked previously because of the high percentage of good functional outcomes and low mortality rates in this group. The identification of surgical complications may encourage the search for solutions to improve surgical treatment of aneurysmal SAH.


Diffusion modeling of percutaneous absorption kinetics. 1. Effects of flow rate, receptor sampling rate, and viable epidermal resistance for a constant donor concentration.
A diffusion model for the percutaneous absorption of a solute through the skin is developed for the specific case of a constant donor concentration with a finite removal rate from the receptor due to either perfusion rate or sampling. The model has been developed to include a viable epidermal resistance and a donor-stratum corneum interfacial resistance. Numerical inversion of the Laplace domain solutions were used for simulations of solute flux and cumulative amount absorbed and to model specific examples of percutaneous absorption. Limits of the Laplace domain solutions were used to define the steady-state flux, lag time, and receptor concentration. Steady-state approximations obtained from the solutions were used to relate the steady-state flux and the effective permeability coefficient to the viable epidermis resistance, a donor-stratum corneum interfacial resistance, receptor removal rate, and partitioning between the receptor and donor phases. The lag time was shown to be dependent on these parameters and on the volume of the receptor phase. It is concluded that curvilinear cumulative amount and flux-time profiles are dependent on the processes affecting percutaneous absorption, the shapes of the profiles reflecting the processes most determining transport.


Chronic myelomonocytic leukaemia in a child with constitutional partial trisomy 8 mosaicism.
We present a 3-year-old boy with constitutional partial trisomy 8 mosaicism (karyotype 47,XY, + del(8)(p12)/46,XY) who developed chronic myelomonocytic leukaemia and we review the few reported cases of constitutional trisomy 8 mosaicism (CT8M) associated with malignancy. This case highlights the association between CT8M and the development of malignancies, haematological malignancies in particular.


Adrenomedullin is increased in the portal circulation during chronic sepsis in rats.
A clinical hallmark of sepsis is an early, hyperdynamic cardiac phase (increased cardiac output) that degrades to a hypodynamic phase, which results in poor gut perfusion and subsequent gastrointestinal (GI) hypoxemia, tissue ischemia, necrosis and loss of gut barrier function. Studies in rat cecal-ligation and puncture suggest that the potent vasodilator adrenomedullin (AM) might initiate or maintain the hypodynamic phase. We hypothesize that AM expression is increased in acute Escherichia coli bacteremia and chronic E coli-Bacteroides fragilis sepsis. Acute bacteremia: male Sprague-Dawley rats were anesthetized (urethane/alpha-chloralose), tracheotomized, and cannulated for monitoring blood pressure (MABP) and heart rate (HR) and for infusion of E coli (10(9) colony-forming units [CFU] E coli per 1 mL normal saline) and blood sampling. Arterial blood was withdrawn for arterial blood gas (ABG) measurements every 60 minutes. After 6 hours, we harvested lung, liver, kidney, spleen, and small intestine tissue samples and drew arterial and portal blood for AM enzyme-linked immunosorbent assay (ELISA). Chronic sepsis: a sterile gauze pad was implanted and animals recovered for 5 days. Twenty-four hours (10(9) CFU E coli and 10(9) CFU B fragilis per 1 mL normal saline; 1 injection) or 72 hours (2 injections) after the inoculation of the back sponge, rats were anesthetized, intubated, and cannulated as above. MABP, HR, and ABG were measured for 1 hour before tissue and serum harvest for AM ELISA. Sepsis increased HR and MABP in all groups. Acute sepsis caused a respiratory alkalosis and pH was also elevated in chronic sepsis. Serum AM levels were increased in all groups compared with baseline and remained elevated at every time point, but were not different between saline controls and septic animals at any time point, except for the portal serum from the 72-hour chronic sepsis, which was elevated. These data suggest that surgical manipulation alone is sufficient to stimulate AM secretion, most probably from endothelial cells. While the AM levels were decreasing at 72 hours compared with 6 hours or 24 hours in the arterial blood and the saline control portal blood, it remained elevated in the septic portal samples, suggesting that the sepsis-induced increase of AM was derived from the gut by a different mechanism than that which elevated arterial serum levels.


Correlation between foveal cone outer segment tips line and visual recovery after epiretinal membrane surgery.
To determine whether there is a significant correlation between the integrity of the foveal microstructures and the best-corrected visual acuity (BCVA) after pars plana vitrectomy for epiretinal membrane (ERM) removal. This was a retrospective, interventional case series. Forty-six eyes of 45 patients with an ERM underwent vitrectomy. The foveal area was examined by spectral-domain-optical coherence tomography (SD-OCT) preoperatively and postoperatively. The correlation between the length of the photoreceptor cone outer segment tips (COST) line defect, the inner segment/outer segment junction (IS/OS) line defect, the external limiting membrane (ELM) line defect, and the BCVA was determined. The length of the COST line defect was significantly correlated with the BCVA at postoperative 1, 3, 6, 9, and 12 months (P < 0.001 for all). Forward stepwise regression analyses showed that the postoperative BCVA was significantly correlated with the length of COST line defect (P < 0.001) but not with the IS/OS line and ELM line defects for up to 6 months. The preoperative length of the COST line defect was significantly correlated with the postoperative BCVA at 12 months (P = 0.005), but the lengths of the IS/OS line defect and ELM line defect were not. The factor that best predicted the postoperative BCVA was the length of the preoperative COST line defect (P = 0.04) but not the preoperative BCVA (P = 0.69). The recovery of the foveal COST line defect is correlated with the BCVA after ERM surgery. The length of the preoperative COST line defect can predict the potential foveal function. (ClinicalTrials.gov number, NCT01549249.).


Laparoscopic Cholecystectomy Is Safe in Emergency General Surgery Patients with Cirrhosis.
Cirrhosis is associated with adverse outcomes after emergency general surgery (EGS). The objective of this study was to determine the safety of laparoscopic cholecystectomy (LC) in EGS patients with cirrhosis. We performed a two-year retrospective cohort analysis of adult patients who underwent LC for symptomatic gallstones. The primary outcome was the incidence of intraoperative complications. Of 796 patients, 59 (7.4%) were cirrhotic, with a median model for end-stage liver disease (MELD) score of 15 (IQR, 7). On unadjusted analysis, patients with cirrhosis were older, more likely to be male (both P < 0.01), diabetic (P < 0.001), had a higher incidence of preadmission antithrombotic therapy use (P < 0.02), and experienced a longer time to surgery (3.2 vs 1.8 days, P < 0.001). Coarsened exact matching revealed no difference in intra- or postoperative complications between groups (P = 0.67). Operative duration was longer in patients with cirrhosis (162 vs 114 minutes, P = 0.001), who also had a nonsignificant increase in the rate of conversion to an open cholecystectomy (14% vs 4%, P = 0.07). The results of this study indicate that LC may be safely performed in EGS patients with cirrhosis.


Mechanisms of deleterious effects of some pesticide exposure on pigs.
The increase in the size of the global population increases the food and energy demand, making the use of pesticides in agricultural and livestock industries unavoidable. Exposure to pesticides can be toxic to the non-target species, such as humans, wildlife, and livestock, in addition to the target organisms. Various chemicals are used in the livestock industry to control harmful organisms, such as insects, weeds, and parasites. Pigs are one of the most important food sources for humans. In addition, pigs can be used as promising models for assessing the risk of absorption of environmental pollutants through the skin and oral exposure since they are physiologically similar to humans. Exposure to numerous environmental pollutants, such as mycotoxins, persistent organic pollutants, and heavy metals, has been reported to adversely affect growth, fertility, and endocrine homeostasis in pigs. Various pesticides have been observed in porcine tissues, blood, urine, and processed foods; however, there is a lack of comprehensive understanding of their effects on porcine health. This review provides a comprehensive description of the characteristics of pesticides that pigs can be exposed to and how their exposure affects porcine reproductive function, intestinal health, and endocrine homeostasis in vivo and in vitro.


Diagnostic value of EBUS-TBNA for lung cancer with non-enlarged lymph nodes: a study in a tuberculosis-endemic country.
In tuberculosis (TB)-endemic areas, contrast-enhanced computed tomography (CT) and positron emission tomography (PET) findings of lung cancer patients with non-enlarged lymph nodes are frequently discrepant. Endobronchial ultrasound-guided transbronchial aspiration (EBUS-TBNA) enables real-time nodal sampling, and thereby improves nodal diagnosis accuracy. This study aimed to compare the accuracy of nodal diagnosis by using EBUS-TBNA, and PET. We studied 43 lung cancer patients with CT-defined non-enlarged mediastinal and hilar lymph nodes and examined 78 lymph nodes using EBUS-TBNA. The sensitivity, specificity, positive predictive value, and negative predictive value of EBUS-TBNA were 80.6%, 100%, 100%, and 85.7%, respectively. PET had low specificity (18.9%) and a low positive predictive value (44.4%). The diagnostic accuracy of EBUS-TBNA was higher than that of PET (91% vs. 47.4%; p<0.001). Compared to CT-based nodal assessment, PET yielded a positive diagnostic impact in 36.9% nodes, a negative diagnostic impact in 46.2% nodes, and no diagnostic impact in 16.9% nodes. Patients with lymph nodes showing negative PET diagnostic impact had a high incidence of previous pulmonary TB. Multivariate analysis indicated that detection of hilar nodes on PET was an independent predictor of negative diagnostic impact of PET. In a TB-endemic area with a condition of CT-defined non-enlarged lymph node, the negative diagnostic impact of PET limits its clinical usefulness for nodal staging; therefore, EBUS-TBNA, which facilitates direct diagnosis, is preferred.


Evaluation of the PaCER Algorithm for Postoperative Subthalamic Nucleus Deep Brain Stimulation Electrode Localization.
Deep Brain Stimulation (DBS) is an established therapy for many movement disorders. DBS entails electrical stimulation of precise brain structures using permanently implanted electrodes. Following implantation, locating the electrodes relative to the target brain structure assists patient outcome optimization. Here we evaluated an open-source automatic algorithm (PaCER) to localize individual electrodes on Computed Tomography imaging (co-registered to Magnetic Resonance Imaging). In a dataset of 111 participants, we found a modified version of the algorithm matched manual-markups with median error less than 0.191 mm (interquartile range 0.698 mm). Given the error is less than the voxel resolution (1 mm3) of the images, we conclude that the automatic algorithm is suitable for DBS electrode localizations.Clinical Relevance- Automated DBS electrode localization identifies the closest electrode to the target brain structure; allowing the neurologist to direct electrical stimulation to maximize patient outcomes. Further, if none of the electrodes are deemed suitable, localization will guide re-implantation.


Visible light-hardened glass-ionomer cement base/liner as an interim restorative material.
A visible light-hardening, glass-ionomer cement, dentinal base/liner has been used as a dentinal and enamel replacement restorative material for certain lesions in primary teeth. The material has all the advantages of glass-ionomer cements and the additional advantage of rapid hardening by light curing. The procedure for using the material as a restorative material in primary teeth is described, and several cases are documented.


Analysis of CAG repeats in five SCA loci in Mexican population: epidemiological evidence of a SCA7 founder effect.
Spinocerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders. CAG (cytosine-adenine-guanine) trinucleotide repeat expansions in the causative genes have been identified as the cause of different SCA. In this study, we simultaneously genotyped SCA1, SCA2, SCA3, SCA6, and SCA7 applying a fluorescent multiplex polymerase chain reaction assay. We analyzed 10 families with SCA (64 patients) from five different communities of Veracruz, a Mexican southeastern state, and identified 55 patients for SCA7 and 9 for SCA2, but none for SCA1, SCA3, or SCA6. To our knowledge, this sample represents one of the largest series of SCA7 cases reported worldwide. Genotyping of 300 healthy individuals from Mexican population and compiled data from different ethnicities showed discordant results concerning the hypothesis that SCA disease alleles arise by expansion of large normal alleles.


Towards safer neonatal transfer: the importance of critical incident review.
Critical incidents are common during the inter-hospital transfer of sick patients, and infants are an especially vulnerable group. To examine the effect of critical incident review on the number of adverse events during inter-hospital transfer of sick infants. Critical incidents over an eight year period are reported from a single neonatal transfer service before and after major service changes were made. The changes were instigated as part of ongoing critical incident reviews. Changes made as a result of critical incident review significantly reduced the number of incidents contributed to by poor preparation, transport equipment or clinical problems, ambulance delays, and ambulance equipment failure. The continuous process of critical incident reporting and review can reduce the number of adverse events during the transfer of critically ill infants.