Hepatocyte-specific localization and copper-dependent trafficking of the Wilson's disease protein in the liver.
Wilson's disease is an inherited disorder of copper metabolism characterized by hepatic cirrhosis and neuronal degeneration. In this current study, a polyclonal antiserum specific for the Wilson's disease ATPase was used to examine the hepatic expression of this protein. Immunoblot analysis of lysates from human and rat liver detected a single 165-kDa protein, which by immunofluorescence was present only in hepatocytes and localized predominantly to the trans-Golgi network and exclusively in this compartment under low hepatic copper concentrations. Although hepatic copper concentration had no effect on the steady-state levels of the Wilson's disease protein, copper administration in vivo resulted in redistribution of this protein to a cytoplasmic vesicular compartment localized toward the hepatocyte canalicular membrane. The relative abundance of the Wilson's disease protein in the liver was found to be greatest in the fetus before the onset of biliary copper excretion. Taken together, these studies reveal a novel posttranslational mechanism of copper homeostasis in vivo consistent with the proposed function of the Wilson's disease protein in holoceruloplasmin biosynthesis and biliary copper excretion and of relevance to the broad clinical heterogeneity observed in this disease.


Childhood nutrition in predicting metabolic syndrome in adults: the cardiovascular risk in Young Finns Study.
Our aim was to study the associations of childhood lifestyle factors (the frequency of consumption of vegetables, fruit, fish, and meat, butter use on bread, and physical activity) with the metabolic syndrome (MetS) in adulthood. The study cohort consisted of 2,128 individuals, 3-18 years of age at the baseline, with a follow-up time of 27 years. We used the average of lifestyle factor measurements taken in 1980, 1983, and 1986 in the analyses. Childhood dietary factors and physical activity were assessed by self-reported questionnaires, and a harmonized definition of MetS was used as the adult outcome. Childhood vegetable consumption frequency was inversely associated with adult MetS (odds ratio [OR] 0.86 [95% CI 0.77-0.97], P = 0.02) in a multivariable analysis adjusted with age, sex, childhood metabolic risk factors (lipids, systolic blood pressure, insulin, BMI, and C-reactive protein), family history of type 2 diabetes and hypertension, and socioeconomic status. The association remained even after adjustment for adulthood vegetable consumption. Associations with the other childhood lifestyle factors were not found. Of the individual components of MetS, decreased frequency of childhood vegetable consumption predicted high blood pressure (0.88 [0.80-0.98], P = 0.01) and a high triglyceride value (0.88 [0.79-0.99], P = 0.03) after adjustment for the above-mentioned risk factors. Childhood vegetable consumption frequency is inversely associated with MetS in adulthood. Our findings suggest that a higher intake of vegetables in childhood may have a protective effect on MetS in adulthood.


Hemodynamic perturbations during robot-assisted laparoscopic radical prostatectomy in 45° Trendelenburg position.
Robot-assisted laparoscopic radical prostatectomy has gained widespread use. However, circulatory effects in patients subjected to an extreme Trendelenburg position (45°) are not well characterized. We studied 16 patients (ASA physical status I-II) with a mean age of 59 years scheduled for robot-assisted laparoscopic radical prostatectomy (45° head-down tilt, with an intraabdominal pressure of 11-12 mm Hg). Hemodynamics, echocardiography, gas exchange, and ventilation-perfusion distribution were investigated before and during pneumoperitoneum, in the Trendelenburg position and, in 8 of the patients, also after the conclusion of surgery. In the 45° Trendelenburg position, central venous pressure increased almost 3-fold compared with the initial value, with an associated 2-fold increase in mean pulmonary artery pressure and pulmonary capillary wedge pressure (P<0.01). Mean arterial blood pressure increased by 35%. Heart rate, stroke volume, cardiac output, and mixed venous oxygen saturation were unaffected during surgery, as were echocardiographic heart dimensions. After induction of anesthesia, isovolumic relaxation time was prolonged, with no further change during the study. Deceleration time was normal and stable. In the horizontal position after pneumoperitoneum exsufflation, filling pressures and mean arterial blood pressure returned to baseline levels. Pneumoperitoneum reduced lung compliance by 40% (P<0.01). Addition of the Trendelenburg position caused a further decrease (P<0.05). Arterial blood acid-base balance was normal. End-tidal carbon dioxide tension increased whereas arterial carbon dioxide was unaffected with unchanged ventilation settings. Pneumoperitoneum increased PaO2 (P<0.05). Ventilation-perfusion distribution, shunt, and dead space were unaltered during the study. Pneumoperitoneum and 45° Trendelenburg position caused 2- to 3-fold increases in filling pressures, without effects on cardiac performance. Filling pressures were normalized immediately after surgery. Lung compliance was halved. Gas exchange was unaffected. No perioperative cardiovascular complications occurred.


MIN1PIPE: A Miniscope 1-Photon-Based Calcium Imaging Signal Extraction Pipeline.
In vivo calcium imaging using a 1-photon-based miniscope and a microendoscopic lens enables studies of neural activities in freely behaving animals. However, the high and fluctuating background, the inevitable movements and distortions of imaging field, and the extensive spatial overlaps of fluorescent signals emitted from imaged neurons inherent in this 1-photon imaging method present major challenges for extracting neuronal signals reliably and automatically from the raw imaging data. Here, we develop a unifying algorithm called the miniscope 1-photon imaging pipeline (MIN1PIPE), which contains several stand-alone modules and can handle a wide range of imaging conditions and qualities with minimal parameter tuning and automatically and accurately isolate spatially localized neural signals. We have quantitatively compared MIN1PIPE with other existing partial methods using both synthetic and real datasets obtained from different animal models and show that MIN1PIPE has superior efficiency and precision in analyzing noisy miniscope calcium imaging data.


Evidence-based design and development of a VR-based treadmill system for gait research and rehabilitation of patients with Parkinson's disease.
Virtual reality (VR) in neurorehabilitation allows to reduce patient's risk and allows him to learn on a faster way. Up to now VR has been used in patients with Parkinson disease (PD) as a research tool and none of the developed systems are used in clinical practice. The goal of this project is to develop a VR-based system for gait therapy, and gait research of patients with PD designed based on published evidence. The developed system uses a digital camera to measure spatiotemporal gait parameters. The software was developed in C#, using Open-Source libraries that facilitates VR programming. The system has potential uses in clinical and research settings.


[Application of multinuclear in vivo magnetic resonance spectroscopy in oncology].
Cell metabolism and the metabolism of drugs can be monitored noninvasively and in vivo by magnetic resonance spectroscopy (MRS). At present, tumors cannot be differentiated by means of 31P MRS. This method can be used in tumor therapy follow-up for early detection of metabolic tumor response. 31P MRS is not helpful in determining whether patients respond to therapy or not. The first clinical results have been obtained using 1H MRS; however, no clinically relevant results have been obtained as yet. Preliminary experiments demonstrate that 19F MRS can be used to observe the metabolism of drugs.


Interventions to treat cutaneous leishmaniasis in children: A systematic review.
Case management in children with cutaneous leishmaniasis (CL) is mainly based on studies performed in adults. We aimed to determine the efficacy and harms of interventions to treat CL in children. We conducted a systematic review of clinical trials and cohort studies, assessing treatments of CL in children (≤12 years old). We performed structured searches in PubMed, CENTRAL, LILACS, SciELO, Scopus, the International Clinical Trials Registry Platform (ICTRP), clinicaltrials.gov and Google Scholar. No restrictions regarding ethnicity, country, sex or year of publication were applied. Languages were limited to English, Spanish and Portuguese. Two reviewers screened articles, completed the data extraction and assessment of risk of bias. A qualitative summary of the included studies was performed. We identified 1092 records, and included 8 manuscripts (6 Randomized Clinical Trials [RCT] and 2 non-randomized studies). Most of the articles excluded in full-text review did not report outcomes separately for children. In American CL (ACL), 5 studies evaluated miltefosine and/or meglumine antimoniate (MA). Their efficacy varied from 68-83% and 17-69%, respectively. In Old-World CL (OWCL), two studies evaluated systemic therapies: rifampicin and MA; and one study assessed efficacy of cryotherapy (42%, Per Protocol [PP]) vs intralesional MA (72%, PP). Few studies (4) provided information on adverse events (AEs) for children, and no serious AEs were reported in participants. Risk of bias was generally low to unclear in ACL studies, and unclear to high in OWCL studies. Information on efficacy of treatment for CL in children is scarce. There is an unmet need to develop specific formulations, surveillance of AEs, and guidelines both for the management of CL and clinical trials involving the pediatric population. The protocol of this review was registered in the PROSPERO International register of systematic reviews, number CRD42017062164.


Mechanism for singlet fission in pentacene and tetracene: from single exciton to two triplets.
Singlet fission (SF) could dramatically increase the efficiency of organic solar cells by producing two triplet excitons from each absorbed photon. While this process has been known for decades, most descriptions have assumed the necessity of a charge-transfer intermediate. This ab initio study characterizes the low-lying excited states in acene molecular crystals in order to describe how SF occurs in a realistic crystal environment. Intermolecular interactions are shown to localize the initially delocalized bright state onto a pair of monomers. From this localized state, nonadiabatic coupling mediated by intermolecular motion between the optically allowed exciton and a dark multi-exciton state facilitates SF without the need for a nearby low-lying charge-transfer intermediate. An estimate of the crossing rate shows that this direct quantum mechanical process occurs in well under 1 ps in pentacene. In tetracene, the dark multi-exciton state is uphill from the lowest singlet excited state, resulting in a dynamic interplay between SF and triplet-triplet annihilation.


Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart.
Heme oxygenase-1 (HO-1) is an inducible stress-response protein that imparts antioxidant and antiapoptotic effects. However, its pathophysiological role in cardiac remodeling and chronic heart failure (HF) is unknown. We hypothesized that induction of HO-1 in HF alleviates pathological remodeling. Adult male nontransgenic and myocyte-restricted HO-1 transgenic mice underwent either sham operation or coronary ligation to induce HF. Four weeks after ligation, nontransgenic HF mice exhibited postinfarction left ventricular (LV) remodeling and dysfunction, hypertrophy, fibrosis, oxidative stress, apoptosis, and reduced capillary density, associated with a 2-fold increase in HO-1 expression in noninfarcted myocardium. Compared with nontransgenic mice, HO-1 transgenic HF mice exhibited significantly (P<0.05) improved postinfarction survival (94% versus 57%) and less LV dilatation (end-diastolic volume, 46+/-8 versus 85+/-32 microL), mechanical dysfunction (ejection fraction, 65+/-9% versus 49+/-16%), hypertrophy (LV/tibia length 4.4+/-0.4 versus 5.2+/-0.6 mg/mm), interstitial fibrosis (11.2+/-3.1% versus 18.5+/-3.5%), and oxidative stress (3-fold reduction in tissue malondialdehyde). Moreover, myocyte-specific HO-1 overexpression in HF promoted tissue neovascularization and ameliorated myocardial p53 expression (2-fold reduction) and apoptosis. In isolated mitochondria, mitochondrial permeability transition was inhibited by HO-1 in a carbon monoxide (CO)-dependent manner and was recapitulated by the CO donor tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). HO-1-derived CO also prevented H2O2-induced cardiomyocyte apoptosis and cell death. Finally, in vivo treatment with CORM-3 alleviated postinfarction LV remodeling, p53 expression, and apoptosis. HO-1 induction in the failing heart is an important cardioprotective adaptation that opposes pathological LV remodeling, and this effect is mediated, at least in part, by CO-dependent inhibition of mitochondrial permeability transition and apoptosis. Augmentation of HO-1 or its product, CO, may represent a novel therapeutic strategy for ameliorating HF.


[Immune complex formation during the passive immunization of mice infected with the tick-borne encephalitis virus].
The results of investigations, indicating that the development of the infectious process in experimental encephalitis is accompanied by the formation of immune complexes circulating in the blood and localized in the brain tissue, are presented. The intravenous injections of a homologous serum preparation into intact animals induces the appearance of a rather low level of circulating immune complexes, which precedes the elimination of antibodies. The intravenous injection of a specific serum preparation two days after the infection of the animals with tick-borne encephalitis virus is accompanied by the formation of immune complexes; the course of infection is not aggravated.


Base-line and postthermal injury plasma histamine in rats.
Although plasma histamine concentration has been reported to increase after thermal injury in the rat to as much as 100-fold over normal human plasma levels, the pathophysiological significance and relevance to human disease is questionable. Lack of confidence in the rat as a model of histamine-mediated disease is based on reports that normal rat base-line plasma histamine concentration exceeds that of human plasma by 20- to 70-fold. The present study confirms that high concentrations of histamine (20-68.9 ng/ml) are found in rat plasma obtained in an uncontrolled manner; but concentrations are lower (1.17 +/- 0.49 ng/ml) or undetectable in a sensitive radioenzymatic assay when sampling technique and plasma isolation are controlled. The primary cause for falsely elevated values for plasma histamine concentration appeared to be due to manipulation of the rat. Plasma histamine concentration increased within 1 min after thermal injury and the increase was proportional to extent of surface area injured. In contrast to the finding of a single time-related peak of plasma histamine concentration after partial-thickness burn, a biphasic elevation was found after full-thickness injury. Thus the data indicate that normal rat plasma histamine concentration is similar to that of the human and below the reported threshold for modulation of a variety of immune responses. Furthermore, the data support a role for histamine and other mast-cell mediators in the local and systemic responses to injury.


A hydrophobic protein sequence can override a nuclear localization signal independently of protein context.
Simian virus 40 T antigen is specifically targeted to the nucleus by the signal Pro-Lys-Lys-128-Lys-Arg-Lys-Val. We have previously described the isolation of a simian virus 40 T-antigen mutant, 676FS, which retains a wild-type nuclear localization signal but fails to accumulate properly in the nucleus and interferes with the nuclear localization of heterologous proteins. Here we report that the hydrophobic carboxy-terminal sequence novel to 676FS T antigen overrides the nuclear localization signal if fused to other proteins, thereby anchoring the proteins in the cytoplasm. We discuss possible mechanisms by which missorting of such a fusion protein could interfere with the nuclear transport of heterologous proteins.


Direct transplantation of uncultured hair-follicle pluripotent stem (hfPS) cells promotes the recovery of peripheral nerve injury.
We previously showed that the stem cell marker nestin is expressed in hair follicle stem cells which suggested their pluripotency. We subsequently showed that the nestin-expressing hair-follicle pluripotent stem (hfPS) cells can differentiate in culture to neurons, glial cells, keratinocytes, and other cell types and can promote regeneration of peripheral nerve and spinal cord injuries upon injection to the injured nerve or spinal cord. The location of the hfPS cells has been termed the hfPS cell area (hfPSCA). Previously, hfPS cells were cultured for 1-2 months before transplantation to the injured nerve or spinal cord which would not be optimal for clinical application of these cells for nerve or spinal cord repair, since the patient should be treated soon after injury. In the present study, we addressed this issue by directly using the upper part of the hair follicle containing the hfPSCA, without culture, for injection into the severed sciatic nerve in mice. After injection of hfPSCA, the implanted hfPS cells grew and promoted joining of the severed nerve. The transplanted hfPS cells differentiated mostly to glial cells forming myelin sheaths, which promoted axonal growth and functional recovery of the severed nerve. These results suggest that the direct transplantation of the uncultured upper part of the hair follicle containing the hfPSA is an important method to promote the recovery of peripheral nerve injuries and has significant clinical potential.


Serious group B beta-hemolytic streptococcal infections in adults: report of two cases and review of the literature.
Adult infections with group B beta-hemolytic streptococci have been infrequently reported in the past. Two patients described herein, one with meningitis and the other with suppurative arthritis, emphasize that the organism is a potential pathogen and cause of serious infections in adults. The literature pertinent to these group B streptococcal infections is reviewed.


The Mediating Role of Diabetes Distress and Depressive Symptoms in Type 2 Diabetes Medication Adherence Gender Differences.
Background. Medication adherence is negatively related to both diabetes distress (DD) and depressive symptoms (DS). Past research suggests gender differences in adherence, DD, and DS. A gap exists in determining if gender differences in adherence are mediated by DD and DS, or if gender moderates differences in adherence by DD/DS. Aims. This study investigated the relationship between gender, DD, DS, and medication adherence and tested for mediating and moderating effects on medication adherence among American Indian adults with type 2 diabetes. Method. The Maawaji idi-oog mino-ayaawin (Gathering for Health) study was a community-based participatory research collaboration with five American Indian tribes. Participants, randomly recruited from clinic records, shared information during computer-assisted personal interviews. This study includes the 166 participants who reported using medications to treat their diabetes. The relationship between gender, DD, DS, and medication adherence are explored. Possible mediating and moderating effects on medication were tested using regression and path analysis. Results. Females had higher levels of DD and DS and lower levels of medication adherence. Higher levels of DD and DS were both associated with lower medication adherence. No evidence was found that gender moderates the relationship between DD or DS and medication adherence. Instead, DD and DS mediated the relationship between gender and medication adherence. Conclusions. Medication adherence differences in male and female patients may be attributable to DD and DS. The present research highlights both DD and DS as targets for clinicians and researchers alike.


Cancer mortality among local authority pest control officers in England and Wales.
To examine cancer mortality by tumour site among local authority pest control officers. Prospective mortality study, and follow up to the end of 1994, of 1485 male pest control officers aged between 17 and 69 and employed in 296 local authorities in England and Wales for at least six months between January 1980 and April 1984. Observed numbers of deaths were compared with those expected on the basis of the rates for relevant calendar year, cause, sex, and age specific groups for England and Wales. 200 deaths occurred during the follow up period of which 65 were certified as due to malignant neoplasms. No tumour type showed significantly more deaths than expected. Total all cause, lung cancer, and respiratory disease mortality were significantly lower than expected. 15 year follow up of a group of men handling a wide range of pesticides did not show any significant risk of cancer. This may be partially explained by the healthy worker effect and also the limited power of the study to detect significant increases in the less common tumours. Further long term follow up of this cohort will continue. Chemical control of pests that can cause human disease and can contaminate food and water has been, and will continue to be, a major public health measure. It is important to ensure that the health of those applying pesticides is not at excess risk. Negative results are important.


Parent and child mental health trajectories April 2020 to May 2021: Strict lockdown versus no lockdown in Australia.
To control a second-wave COVID-19 outbreak, the state of Victoria in Australia experienced one of the world's first long and strict lockdowns over July-October 2020, while the rest of Australia experienced 'COVID-normal' with minimal restrictions. We (1) investigate trajectories of parent/child mental health outcomes in Victoria vs non-Victoria and (2) identify baseline demographic, individual and COVID-19-related factors associated with mental health trajectories. Online community sample of 2004 Australian parents with rapid repeated assessment over 14 time-points over April 2020 to May 2021. Measures assessed parent mental health (Depression, Anxiety and Stress Scales-21), child depression symptoms (13-item Short Mood and Feelings Questionnaire) and child anxiety symptoms (four items from Brief Spence Children's Anxiety Scale). Mental health trajectories shadowed COVID-19 infection rates. Victorians reported a peak in mental health symptoms at the time of the second-wave lockdown compared to other states. Key baseline predictors, including parent and child loneliness (standardized regression coefficient [β] = 0.09-0.46), parent/child diagnoses (β = 0.07-0.21), couple conflict (β = 0.07-0.18) and COVID-19 stressors, such as worry/concern about COVID-19, illness and loss of job (β = 0.12-0.15), predicted elevated trajectories. Effects of predictors on parent and child mental health trajectories are illustrated in an online interactive app for readers (https://lingtax.shinyapps.io/CPAS_trend/). Our findings provide evidence of worse trajectories of parent and child mental health symptoms at a time coinciding with a second COVID-19 outbreak involving strict lockdown in Victoria, compared to non-locked states in Australia. We identified several baseline factors that may be useful in detecting high-risk families who are likely to require additional support early on in future lockdowns.


Niacin-respondent subset of schizophrenia – a therapeutic review.
It is well known that niacin deficiency manifests with several psychiatric manifestations. Also historically evidence has accumulated that niacin augmentation can be used for treatment of schizophrenia. However, the etiopathological associations between niacin deficiency and schizophrenia as well as the mechanism of action of niacin in its treatment. More importantly, the subgroups of schizophrenia which will respond to niacin augmentation has never been highlighted in the literature. In this article, we review three of the mechanisms in which niacin deficiency could lead to schizophrenic symptoms: (1) Niacin deficiency neurodegeneration (2) Membrane phospholipid deficiency hypothesis and (3) Adrenochrome hypothesis. We will further move towards the clinical as well as treatment related associations as reviewed from the literature. Here, we propose a model that a subset of schizophrenia can respond to niacin augmentation therapy better than other subsets because these patients have contributions in their psychotic manifestations from the neural degeneration resulting from niacin deficiency. We present a short description of our case report which showed rapid improvement in schizophrenic psychotic symptoms subsequent to administration of niacin as an augmentation therapy. We, thus, propose that niacin deficiency is a contributory factor in schizophrenia development in some patients and symptom alleviation in these patients will benefit from niacin augmentation, especially in some particular psychotic features.


Interpretation of positive transcription-mediated amplification test results from polymerase chain reaction-negative samples obtained after treatment of chronic hepatitis C.
The Siemens VERSANT transcription-mediated amplification (TMA) assay is extremely sensitive for the detection of hepatitis C virus (HCV) RNA in serum. Eleven of 180 subjects in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial who achieved polymerase chain reaction (PCR)-defined sustained virological response (SVR) at week 72 also had TMA-positive results from the same blood draw; six were positive on repeat testing. We report the follow-up on these 11 patients, and the reproducibility of TMA test results from PCR-negative samples in relationship to antiviral treatment outcome. Peginterferon and ribavirin treatment was initiated in 1145 prior interferon nonresponders with advanced hepatic fibrosis. Treatment was continued for 48 weeks if patients had undetectable HCV RNA by PCR at treatment week 20. Frozen serum samples from weeks 12, 20, 24, 48, and 72 were subsequently tested by TMA. Nine of the 11 patients returned for testing (median, 30 months after the week 72 visit), and all had undetectable HCV RNA by TMA and PCR. Among 759 PCR-negative samples obtained during treatment that were tested twice by TMA, 17% overall exhibited consistently positive results, and 21% exhibited inconsistently positive results. SVR was more likely if TMA was consistently negative than if consistently or inconsistently positive. With continued treatment, patients with inconsistently positive TMA results were more likely to become TMA-negative than TMA-positive (P < 0.0001). In PCR-negative samples, positive TMA results may indicate the presence of low levels of HCV RNA. However, because patients with positive TMA results may achieve SVR, management decisions during therapy should not be based on a single positive TMA test result.


Anesthesiologist board certification and patient outcomes.
Board certification is often used as a surrogate indicator of provider competence, although few outcome studies have demonstrated its validity. The aim of this study was to compare the outcomes of patients who underwent surgical procedures under the care of an anesthesiologist with or without board certification. Medicare claims records for 144,883 patients in Pennsylvania who underwent general surgical or orthopedic procedures between 1991 and 1994 were used to determine provider-specific outcome rates adjusted to account for patient severity and case mix, and hospital characteristics. Outcomes of 8,894 cases involving midcareer anesthesiologists, 11-25 yr from medical school graduation, who lacked board certification were compared with all other cases. Midcareer anesthesiologist cases were studied because this group had sufficient time to become certified during an era when obtaining certification was already considered important, and consequently had the highest rate of board certification. Mortality within 30 days of admission and the failure-to-rescue rate (defined as the rate of death after an in-hospital complication) were the two primary outcome measures. Adjusted odds ratios for death and failure to rescue were greater when care was delivered by noncertified midcareer anesthesiologists (death = 1.13 [95% confidence interval, 1.00, 1.26], P < 0.04; failure to rescue = 1.13 [95% confidence interval, 1.01, 1.27], P < 0.04). Adjusting for international medical school graduates did not change these results. When anesthesiology board certification is very common, as in midcareer practitioners, the lack of board certification is associated with worse outcomes. However, the poor outcomes associated with noncertified providers may be a result of the hospitals at which they practice and not necessarily their manner of practice.


Utility of 99mTc-Sestamibi Heart/Liver Uptake Ratio in Screening Nonalcoholic Fatty Liver Disease During Myocardial Perfusion Imaging.
Purpose: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic hepatic disease worldwide, with functional impairment of the mitochondria occurring from early stages. Technetium-99m methoxy-isobutyl-isonitrile (99mTc-MIBI) is a lipophilic agent trapped in the mitochondria. This study aims to evaluate the utility of 99mTc-MIBI heart/liver uptake ratio in screening for NAFLD during myocardial perfusion imaging (MPI). Methods: Seventy eligible patients underwent a 2-d rest/stress 99mTc-MIBI scan with a 2-min planar image acquired in rest phase, at 30, 60, and 120 min postradiotracer administration. Heart/liver uptake ratio was calculated by placing identical regions of interest on the heart and liver dome. All patients underwent liver ultrasound and were allocated into groups A, having NAFLD; and B, healthy individuals without NAFLD. Results: Mean count per pixel heart/liver ratios gradually increased over time in either group; nonetheless the values were significantly higher in group A, regardless of acquisition timing; with the p-value equal to 0.007, 0.014, and 0.010 at 30, 60, and 120 min, respectively. Conclusion: Determining 99mTc-MIBI heart/liver uptake ratio during rest phase in patients undergoing MPI may be a useful, noninvasive screening method for NAFLD; with no additional cost, radiation burden, or adverse effects in these patients. Trial registration number: IR.SBMU.MSP.REC.1398.308.


The effect of recombinant activated factor VII on mortality in combat-related casualties with severe trauma and massive transfusion.
The majority of patients with potentially survivable combat-related injuries die from hemorrhage. Our objective was to determine whether the use of recombinant activated factor VII (rFVIIa) decreased mortality in combat casualties with severe trauma who received massive transfusions and if its use was associated with increased severe thrombotic events. We retrospectively reviewed a database of combat casualty patients with severe trauma (Injury Severity Score [ISS] >15) and massive transfusion (red blood cell [RBCs] >/=10 units/24 hours) admitted to one combat support hospital in Baghdad, Iraq, between December 2003 and October 2005. Admission vital signs and laboratory data, blood products, ISS, 24-hour and 30-day mortality, and severe thrombotic events were compared between patients who received rFVIIa (rFVIIa) and did not receive rFVIIa (rFVIIa). Of 124 patients in this study, 49 patients received rFVIIa and 75 did not. ISS, laboratory values, and admission vitals did not differ between rFVIIa and rFVIIa groups, except for systolic blood pressure (mm Hg) 105 +/- 33 and 92 +/- 28, p = 0.02 and temperature ( degrees F) 96.3 +/- 2.1 and 95.2 +/- 2.4, p = 0.03, respectively. Interactions between all vital signs and laboratory values measured upon admission, to include systolic blood pressure and temperature, were not significant when measured between rFVIIa use and 30-day mortality. Twenty-four-hour mortality was 7 of 49 (14%) in rFVIIa and 26 of 75 (35%) in rFVIIa, (p = 0.01); 30-day mortality was 15 of 49 (31%) and 38 of 75 (51%), (p = 0.03). Death from hemorrhage was 8 of 14 (57%) for rFVIIa patients compared with 29 of 37 (78%) for rFVIIa patients, (p = 0.12). The incidence of severe thrombotic events was similar in both groups. The early use of rFVIIa was associated with decreased 30-day mortality in severely injured combat casualties requiring massive transfusion, but was not associated with increased risk of severe thrombotic events.


Significance of the bacteriophage treatment schedule in reducing Salmonella colonization of poultry.
Salmonella remains the major cause of food-borne diseases worldwide, with chickens known to be the main reservoir for this zoonotic pathogen. Among the many approaches to reducing Salmonella colonization of broilers, bacteriophage offers several advantages. In this study, three bacteriophages (UAB_Phi20, UAB_Phi78, and UAB_Phi87) obtained from our collection that exhibited a broad host range against Salmonella enterica serovar Enteritidis and Salmonella enterica serovar Typhimurium were characterized with respect to morphology, genome size, and restriction patterns. A cocktail composed of the three bacteriophages was more effective in promoting the lysis of S. Enteritidis and S. Typhimurium cultures than any of the three bacteriophages alone. In addition, the cocktail was able to lyse the Salmonella enterica serovars Virchow, Hadar, and Infantis. The effectiveness of the bacteriophage cocktail in reducing the concentration of S. Typhimurium was tested in two animal models using different treatment schedules. In the mouse model, 50% survival was obtained when the cocktail was administered simultaneously with bacterial infection and again at 6, 24, and 30 h postinfection. Likewise, in the White Leghorn chicken specific-pathogen-free (SPF) model, the best results, defined as a reduction of Salmonella concentration in the chicken cecum, were obtained when the bacteriophage cocktail was administered 1 day before or just after bacterial infection and then again on different days postinfection. Our results show that frequent treatment of the chickens with bacteriophage, and especially prior to colonization of the intestinal tract by Salmonella, is required to achieve effective bacterial reduction over time.


[Guidelines for dental care in hemophilia patients].
Dentist usually lacking knowledge about congenital blood-clotting disorders. That leads to unreasonable limitations in use of modern dental care techniques. The following study result obtained in specialized center for blood-clotting disorders treatment should serve as guidelines for dental care in hemophilia patients.


[A comparative study among different therapeutic approaches to portal hypertension and bleeding esophageal varices].
Recurrence of haemorrhage in patients with portal hypertension is the most feared life-threatening complication and the one which most often conditions patient survival. The present study compares the results obtained in two groups of patients treated by surgery and endoscopic sclerotherapy, respectively, and a control group treated with traditional medical therapy during bleeding episodes and subsequently given no further treatment. The patients in each group were subdivided into three different risk classes on the basis of the Child classification. Patients treated surgically mainly belonged to Child classes A and B, whereas those treated by endoscopic sclerotherapy belonged to Child class C. The long-term survival results show no significant differences between the two groups. On the other hand, both groups show better survival data than the untreated patients. On the basis of the results obtained, the authors believe that surgical treatment appears to most indicated in patients belonging to the lower risk classes (Child A and B), whereas endoscopic sclerotherapy is better suited to patients belonging to the higher risk class (Child C).


Increased expression of pendrin in eosinophilic chronic rhinosinusitis with nasal polyps.
Chronic rhinosinusitis with nasal polyps is a heterogeneous disease and appropriate diagnostic algorithms in individual cases are necessary for effective medical treatment. The purpose of this study was to clarify the relationship between the pendrin expression of nasal polyps and clinical and pathological characteristic features of eosinophilic chronic rhinosinusitis. A total of 68 patients were classified into eosinophilic chronic rhinosinusitis or non-eosinophilic chronic rhinosinusitis groups according to the degree of eosinophilic infiltration into the nasal polyps. Clinical, hematological, and immunohistochemical analyses were performed and statistically compared between both groups. Thirty-eight were classified into eosinophilic chronic rhinosinusitis and 30 into non-eosinophilic chronic rhinosinusitis groups. There were no significant differences in age distribution, sex ratio, prevalence of asthma, or any other complications between the groups. The mean Lund-Mackay score and the number of serum eosinophils was significantly higher in the eosinophilic chronic rhinosinusitis than in the non-eosinophilic chronic rhinosinusitis groups. The pendrin expression was more frequently detected in the epithelial surface layer of nasal polyps in the eosinophilic chronic rhinosinusitis than in the non-eosinophilic chronic rhinosinusitis groups. In addition, mucin 5AC was more widely expressed in the eosinophilic chronic rhinosinusitis than in the non-eosinophilic chronic rhinosinusitis. Increased expression of pendrin and mucin 5AC in the nasal polyps would be associated with development of eosinophilic chronic rhinosinusitis. This finding could allow the development of a novel therapeutic agent targeted specifically to patients with eosinophilic chronic rhinosinusitis.


Analysis of the dimensions of the labial bone wall in the anterior maxilla: a cone-beam computed tomography study.
Immediate implant placement in extraction socket does not appear to prevent the resorption of the labial wall. It has been recommended that a minimal thickness of 1-2 mm of buccal bone should be available to preclude the resorption of the facial vertical dimension of the socket wall. The aim was to determine the dimension of the facial buccal plate of bone in the anterior esthetic zone at different levels and relate it to immediate implant placement. Seventy-three patients' cone-beam tomographic scans were included in the study (42 female and 31 male, mean age 39.6 years). The images were acquired using OnDemand software. The measurements taken included: 1. Distance between the CEJ and the alveolar crest. 2. The labial bone thickness at different levels in relation to alveolar crest: at 1, 2, and 4 mm. The measurements demonstrated that the distance between the CEJ and the crest was 2.10 ± 0.85 for the central and 2.09 ± 0.72 for the lateral incisor. The measurement taken at M0 (crestal level) revealed that only 1% of the incisors showed a thick labial bone (1-2 mm) and 73% showed a thin bony wall (0.5-1 mm) and 25% showed very thin wall <0.5 mm. At the M1, 7% showed very thin bony wall and 86% showed a thin bony wall while only 6% exhibited a thick bony wall. The M2 showed only 1% of very thin bony wall, and about 85% showed a thin bony wall and 14% exhibited a thick bony level. The M4 demonstrated very thin bony wall and about 75% thin bony wall and 23% showed thick bony wall. Males showed statistically significantly higher mean distance between cemento-enamel junction and alveolar crest (CEJ-AC) than females at the central as well as lateral incisors. To obtain good results, meticulous preoperative analysis is recommended. Thus, to chose an adequate treatment approach, the utilization of CBCT is recommended.


Simultaneous determination of toxic metabolites by linear combination derivative spectrophotometry.
A linear combination derivative spectrophotometric method is described. The method overcomes the problem of overlapping in derivative spectrophotometry and allows the maximum use of quantitative information. In addition, the method can be used to increase the selectivity, sensitivity and accuracy of the simultaneous analysis of multicomponent mixtures. The application of the method to the simultaneous determination of bongkrekic acid and toxoflavin, the toxic metabolites produced by Pseudomonas farinofermentans, is described.


Morphogenesis of extra-embryonic tissues directs the remodelling of the mouse embryo at implantation.
Mammalian embryos change shape dramatically upon implantation. The cellular and molecular mechanism underlying this transition are largely unknown. Here, we show that this transition is directed by cross talk between the embryonic epiblast and the first extra-embryonic tissue, the trophectoderm. Specifically, we show via visualisation of a Cdx2-GFP reporter line and pharmacologically mediated loss and gain of function experiments that the epiblast provides FGF signal that results in differential fate acquisition in the multipotent trophectoderm leading to the formation of a tissue boundary within this tissue. The trophectoderm boundary becomes essential for expansion of the tissue into a multi-layered epithelium. Folding of this multi-layered trophectoderm induces spreading of the second extra-embryonic tissue, the primitive endoderm. Together, these events remodel the pre-implantation embryo into its post-implantation cylindrical shape. Our findings uncover how communication between embryonic and extra-embryonic tissues provides positional cues to drive shape changes in mammalian development during implantation.


TP73 DNA methylation and upregulation of ΔNp73 are associated with an adverse prognosis in breast cancer.
Accumulated evidence suggests that aberrant methylation of the TP73 gene and increased levels of ΔNp73 in primary tumours correlate with poor prognosis. However, little is known regarding the transcriptional and functional regulation of the TP73 gene in breast cancer. The aim of the present study was to determine the expression of the ΔNp73 isoform, its relationship with DNA methylation of TP73 and their clinical prognostic significance in breast cancer patients. TP73 gene methylation was studied in TCGA datasets and in 70 invasive ductal breast carcinomas (IDCs). The expression of p73 isoforms was evaluated by immunohistochemistry (IHC) and Western blot and correlated with clinicopathological variables and clinical outcome. We observed that the methylation of diverse CpG islands of TP73 differed significantly between molecular subtypes. An inverse correlation was found between p73 protein expression and the methylation status of the TP73 gene. The expression of exon 3' of p73 (only expressed in ΔNp73) was significantly higher in patients with wild-type p53. Immunohistochemical analysis revealed that all p73 isoforms were localised in both the nuclear and cytoplasmic compartments. We confirmed a positive association between the expression of ∆Np73 and high histological grade. Our findings suggest that high expression of ΔNp73 could be used to determine the aggressiveness of IDCs and could be incorporated in the pathologist's report.


Serum concentrations of insulin-like growth factor and insulin-like growth factor binding protein 3 and recurrent colorectal adenomas.
Insulin-like growth factor I (IGF-I) and its primary binding protein, IGFBP-3, have been associated with colorectal cancer incidence in prior epidemiologic studies. High concentrations of IGF-I generally result in increasing risk and high concentrations of IGFBP-3 in decreasing risk. Only one prior study of IGF-I and IGFBP-3 and adenoma recurrence has been reported. We assayed fasting serum from 375 subjects with and 375 subjects without a recurrent adenoma during the course of the Polyp Prevention Trial to determine baseline concentrations of IGF-I and IGFBP-3. To estimate relative risk of adenoma recurrence over the course of 4 years of follow-up for each of these serum measures, we calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable logistic regression models adjusting for age, gender, body mass index, intervention group, aspirin, smoking, ethnicity, and education. For both IGF-I and IGFBP-3, we found trends indicating decreased risk for subjects in the high compared with the low quartile (for IGF-I: OR, 0.65; 95% CI 0.41-1.01; for IGFBP-3: OR, 0.66; 95% CI, 0.42-1.05). The associations were even greater for advanced adenomas (for IGF-I: OR, 0.51; 95% CI, 0.21-1.29; for IGFBP-3: OR, 0.32; 95% CI, 0.13-0.82). These results showed an unexpected null association, or even the suggestion of a reduction in risk for recurrent adenoma, with not just high IGFBP-3 concentration but also with high levels of IGF-I. Why IGF-I would decrease risk of recurrent adenoma (as distinct from incident adenoma or colorectal cancer) is not clear.


Upper extremity wound management: intermediate infections.
A careful history and physical examination, including information regarding position of the hand at the time of injury, presence of other disease, handedness, age, and occupation, are all essential to evaluate hand infection. If surgery is anticipated, antibiotics should generally be withheld until operative cultures are obtained. Infections secondary to human bite injuries are common and are usually caused by a blow of the fist to the mouth. These injuries can produce crippling sequelae, must be managed promptly and aggressively, and often require surgery. Flexor tenosynovitis, often caused by a penetrating injury, may be treated nonoperatively if the patient presents within 24 to 48 hours of onset. Older injuries always require incision and drainage of the flexor tendon sheath. Most authors agree that surgical management of dog bite wounds to the hand is essential. Cat and arthropod bites may also require surgery.


A single-atom quantum memory.
The faithful storage of a quantum bit (qubit) of light is essential for long-distance quantum communication, quantum networking and distributed quantum computing. The required optical quantum memory must be able to receive and recreate the photonic qubit; additionally, it must store an unknown quantum state of light better than any classical device. So far, these two requirements have been met only by ensembles of material particles that store the information in collective excitations. Recent developments, however, have paved the way for an approach in which the information exchange occurs between single quanta of light and matter. This single-particle approach allows the material qubit to be addressed, which has fundamental advantages for realistic implementations. First, it enables a heralding mechanism that signals the successful storage of a photon by means of state detection; this can be used to combat inevitable losses and finite efficiencies. Second, it allows for individual qubit manipulations, opening up avenues for in situ processing of the stored quantum information. Here we demonstrate the most fundamental implementation of such a quantum memory, by mapping arbitrary polarization states of light into and out of a single atom trapped inside an optical cavity. The memory performance is tested with weak coherent pulses and analysed using full quantum process tomography. The average fidelity is measured to be 93%, and low decoherence rates result in qubit coherence times exceeding 180 microseconds. This makes our system a versatile quantum node with excellent prospects for applications in optical quantum gates and quantum repeaters.


The Biomechanical and Histological Processes of Rerouting Biceps to Treat Chronic Irreparable Rotator Cuff Tears in a Rabbit Model.
Recently, the biceps was rerouted into a newly fabricated bicipital groove for in situ superior capsular reconstruction (SCR), resulting in promising time-zero cadaveric and clinical outcomes. However, no studies have determined the in vivo biomechanical and histological processes after the biceps is transposed to a nonanatomic position. To explore the in vivo biomechanical and histological processes of the rerouting biceps tendon to treat chronic irreparable rotator cuff tears (IRCTs) in a rabbit model. Controlled laboratory study. A total of 94 skeletally mature male rabbits were used to create a chronic IRCT model in the supraspinatus tendon. Then, the biceps rerouting procedures were performed in rabbits with chronic IRCT. Eighteen rabbits were sacrificed at 1, 3, 6, 9, and 12 weeks postoperatively for biomechanical testing, micro-computed tomography scanning, and histological analysis. The biomechanical and histological changes of intra- and extra-articular portions of the rerouting biceps were evaluated at each time point, with the contralateral native superior capsule (NSC) and the native biceps (NB) as controls, respectively. The morphology and bone formation of the fabricated bicipital grooves were evaluated, with native grooves as controls. The intra-articular rerouting biceps tendon was progressively remodeled over time, displaying denser fibers and more mature collagen than those of the NSC, with gradual improvements in the tendon-to-bone healing interface from 6 to 12 weeks. Consequently, the failure load and stiffness of the intra-articular rerouting biceps portion increased with time and were significantly higher than those of the NSC from 9 weeks. Similarly, the extra-articular portion of the rerouting biceps progressively healed into a new bicipital groove, as demonstrated by a smaller tendon-to-bone interface from 6 to 12 weeks, resulting in greater failure load and stiffness at 9 and 12 weeks than those of the NB attachment. The newly fabricated bicipital groove showed similar morphology to that of the native groove with sufficient trabecular bone formed underneath. The rerouting biceps could progressively remodel and heal into the newly fabricated bicipital groove over time, resulting in greater biomechanical performances in intra- and extra-articular portions than the NSC and the NB attachment. The biceps rerouting technique may be a feasible procedure to perform in situ SCR to treat IRCT in the future clinical practice; however, more clinical evidence is required.


Haemoglobin SC disease presenting with a compartment syndrome secondary to a deep vein thrombosis.
A patient presented with a deep vein thrombosis (DVT), which resulted in a compartment syndrome of both the thigh and the calf. Subsequently, the patient was found to have haemoglobin SC disease. Prompt fasciotomies were performed; however, some muscle and nerve damage was later clinically apparent. This case highlights the value of prompt diagnosis of compartment syndrome and the need for urgent formal fasciotomies. The case also demonstrates the value of seeking an underlying cause for a DVT when none is apparent.


Accuracy and Predictors of Success of EUS-B-FNA in the Diagnosis of Pulmonary Malignant Lesions: A Prospective Multicenter Italian Study.
The role of endoscopic ultrasound with bronchoscope fine-needle aspiration (EUS-B-FNA) in the diagnosis of suspected malignant pulmonary lesions adjacent to the esophagus has been poorly investigated. The aim of the present study was to assess the accuracy of EUS-B-FNA for the diagnosis and molecular profiling of paraesophageal pulmonary lesions, as well as its predictors of success. Patients who underwent EUS-B-FNA for the diagnosis of paraesophageal lesions were consecutively enrolled in four Italian centers. Demographic, clinical, procedural, pathological, and molecular characteristics of the malignant samples were collected. The primary outcome was the diagnostic accuracy for pulmonary malignancies. Secondary outcomes were diagnostic yield and predictors of success for diagnosis and molecular profiling. 107 adult patients (60 [56.1%] males; median (interquartile range) age: 69 [60-70] years) were enrolled. The diagnostic accuracy of EUS-B-FNA was 95.3% in the overall cohort and 95.2% in the 99 patients with a final diagnosis of malignancy. Neither clinical nor procedural variables significantly affected the diagnostic accuracy, whereas rapid on-site evaluation (ROSE), performed by pathologists or trained pulmonologists, was a strong predictor for a complete molecular profiling (OR [95% CI]: 12.9 [1.2-137.4]; p value: 0.03). EUS-B-FNA is a safe and accurate method for the diagnosis of paraesophageal pulmonary lesions. The presence of ROSE is relevant for a complete molecular profiling in this selected cohort of patients with advanced lung cancer.


Early growth retardation in diabetic pregnancy.
Thirty-five insulin-dependent diabetic women with reliable menstrual histories were examined by ultrasonic scanning in the 7th-14th weeks of pregnancy. Judged from crown-to-rump length the fetuses were on average 5.4 days smaller than those in a local normal series. Ten of the fetuses were nine days or more smaller than normal and had a lower mean birth weight than the others, though the mean gestational age was similar. Maternal diabetes was not more severe in this group, but only two of the mothers had attended a special hospital for control of their disease as compared with 19 of the remainder. Although babies of diabetic mothers are often overweight, there appears to be a subgroup of cases in which fetal growth is retarded early in pregnancy, leading to low birth weight and possibly a higher incidence of congenital malformations.


Transplanted spleen stromal cells with osteogenic potential support ectopic myelopoiesis.
Spleen stromal lines which support in vitro hematopoiesis are investigated for their lineage origin and hematopoietic support function in vivo. Marker expression and gene profiling identify a lineage relationship with mesenchymal stem cells and perivascular reticular cells described recently in bone marrow. Stromal lines commonly express Cxcl12, Pdgfra and Pdgfr typical of bone marrow derived perivascular reticular cells but reflect a unique cell type in terms of other gene and marker expression. Their classification as osteoprogenitors is confirmed through ability to undergo osteogenic, but not adipogenic or chondrogenic differentiation. Some stromal lines were shown to form ectopic niches for HSCs following engraftment under the kidney capsule of NOD/SCID mice. The presence of myeloid cells and a higher representation of a specific dendritic-like cell type over other myeloid cells within grafts was consistent with previous in vitro evidence of hematopoietic support capacity. These studies reinforce the role of perivascular/perisinusoidal reticular cells in hematopoiesis and implicate such cells as niches for hematopoiesis in spleen.


Bacterial urinary tract infections in diabetes.
Diabetes mellitus has a number of long-term effects on the genitourinary system. These effects predispose to bacterial urinary tract infections in the patient with diabetes mellitus. Bacteriuria is more common in diabetic women than in nondiabetic women because of a combination of host and local risk factors. Upper tract infection complications are also more common in this group. Diabetic patients are at higher risk for intrarenal abscess, with a spectrum of disease ranging from acute focal bacterial pyelonephritis to renal corticomedullary abscess, to the renal carbuncle. A number of uncommon complicated urinary tract infection complications occur more frequently in diabetics, such as emphysematous pyelonephritis and emphysematous pyelitis. Because of the frequency and severity of urinary tract infection in diabetic patients, prompt diagnosis and early therapy is warranted. A plain abdominal radiograph is recommended as a minimum radiographic screening tool in the patient with diabetes presenting with systemic signs of urinary tract infection. Ultrasonography or further radiographic studies such as CT scanning may also be warranted, depending on the clinical picture, to identify upper urinary tract complications early for appropriate intervention.


Acute undifferentiated leukemia: implications for cellular origin and clonality suggested by analysis of surface markers and immunoglobulin gene rearrangement.
Although B cell leukemias and, recently, T cell leukemias can be identified both by surface marker and molecular analysis, there remains a population of acute undifferentiated leukemias (AUL) that cannot be allocated definitively to a single cell lineage. AUL was diagnosed in nine patients according to stringent criteria. We combined both immunologic and molecular approaches to analyze further the ambiguous origin of AUL cells. Southern blot analysis revealed rearranged Ig heavy-chain genes in seven patients and indicated a biclonal or oligoclonal leukemic cell population in three of them, including one case of AUL with translocation (4;11). Analysis of cell surface markers showed expression of at least one early B cell-associated antigen (BA-1, BA-2, B4, UL-38) in six of these seven patients, with coexpression of a myeloid antigen (VIM-2) in three patients. Leukemic cells of two other patients neither exhibited Ig chain gene rearrangements nor expressed B cell-associated antigens. T cell receptor beta-chain genes showed germline configuration in all nine cases. Our results demonstrate heterogeneity among AUL patients based on molecular and surface marker analyses and suggest that most AUL blast cells are derived from a precursor cell that shares phenotypic and genotypic characteristics of early B cells with certain surface antigens of myeloid cells, in some cases of AUL more than one abnormal cell clone or subclone may exist, and the cellular origin, at least of some AULs exhibiting t(4;11), may be truly B cell lineage committed.


Climate and air-quality benefits of a realistic phase-out of fossil fuels.
The combustion of fossil fuels produces emissions of the long-lived greenhouse gas carbon dioxide and of short-lived pollutants, including sulfur dioxide, that contribute to the formation of atmospheric aerosols1. Atmospheric aerosols can cool the climate, masking some of the warming effect that results from the emission of greenhouse gases1. However, aerosol particulates are highly toxic when inhaled, leading to millions of premature deaths per year2,3. The phasing out of unabated fossil-fuel combustion will therefore provide health benefits, but will also reduce the extent to which the warming induced by greenhouse gases is masked by aerosols. Because aerosol levels respond much more rapidly to changes in emissions relative to carbon dioxide, large near-term increases in the magnitude and rate of climate warming are predicted in many idealized studies that typically assume an instantaneous removal of all anthropogenic or fossil-fuel-related emissions1,4-9. Here we show that more realistic modelling scenarios do not produce a substantial near-term increase in either the magnitude or the rate of warming, and in fact can lead to a decrease in warming rates within two decades of the start of the fossil-fuel phase-out. Accounting for the time required to transform power generation, industry and transportation leads to gradually increasing and largely offsetting climate impacts of carbon dioxide and sulfur dioxide, with the rate of warming further slowed by reductions in fossil-methane emissions. Our results indicate that even the most aggressive plausible transition to a clean-energy society provides benefits for climate change mitigation and air quality at essentially all decadal to centennial timescales.


Hereditary premature sensescence of the rabbit. I. Chronic form; general features.
The occurrence of hereditary premature senescence in a family of pure bred Belgian hares belonging to a rabbit-breeding colony organized for the investigation of constitutional problems, has been described. Representatives of 20 generations of the complex have been studied. The condition was a degeneration of variable degrees of severity and two principal forms were recognized, the acute and the chronic, the chronic being the more frequent. The chronic form has now been described in terms of the principal local or external manifestations; that is, degeneration of the coat and skin, lesions of the eyes and feet, and reproductive abnormalities, and of the general deterioration which in severe cases pursued a progressive course characterized by muscle wasting, fat reduction, emaciation, weakness, and death. The acute form will be described in the next paper (2).


Modeling early stages of endoderm development in epiblast stem cell aggregates with supply of extracellular matrices.
Endoderm precursors expressing FoxA2 and Sox17 develop from the epiblast through the gastrulation process. In this study, we developed an experimental system to model the endoderm-generating gastrulation process using epiblast stem cells (EpiSCs). To this end, we established an EpiSC line i22, in which enhanced green fluorescent protein is coexpressed with Foxa2. Culturing i22 EpiSCs as aggregates for a few days was sufficient to initiate Foxa2 expression, and further culturing of the aggregates in Matrigel promoted the sequential activation of transcription factor genes involved in endoderm precursor development, e.g., Eomes, Gsc, and Sox17. In aggregation culture of i22 cells for 3 days, all cells expressed POU5F1, SOX2, and E-cadherin, a signature of the epiblast, whereas expression of GATA4 and SOX17 was also activated moderately in dispersed cells, suggesting priming of these cells to endodermal development. Embedding the aggregates in Matrigel for further 3 days elicited migration of the cells into the lumen of laminin-rich matrices covering the aggregates, in which FOXA2 and SOX17 were expressed at a high level with the concomitant loss of E-cadherin, indicating the migratory phase of endodermal precursors. Prolonged culturing of the aggregates generated three segregating cell populations found in post-gastrulation stage embryos: (1) definitive endoderm co-expressing high SOX17, GATA4, and E-cadherin, (2) mesodermal cells expressing a low level of GATA4 and lacking E-cadherin, and (3) primed epiblast cells expressing POU5F1, SOX2 without E-cadherin. Thus, aggregation of EpiSCs followed by embedding of aggregates in the laminin-rich matrix models the gastrulation-dependent endoderm precursor development.


[Assessment of left ventricular ejection fraction and wall motion in patients after myocardial infarction with and without persistent electrocardiographic ST-segment elevation--using gated radionuclide angiography].
In everyday practice two-dimensional echocardiography is a routine method used to diagnose left ventricular (LV) wall motion abnormalities and determine ejection fraction (EF). However, in some patients, for technical reasons, it is possible to apply only apical projections and EF and LV wall motion abnormalities cannot be therefore obtained. The aim of the study was to measure LV EF and wall motion abnormalities in the patients healed from MI, with and without persistent electrocardiographic ST segment elevation, in whom echocardiographic diagnosis was difficult. LV wall motion abnormalities and EF were determined using non-invasive method--gated radionuclide angiography. Gated radionuclide angiography was performed in 45 patients, 3 months after previous anterior MI. The study was acquired after technetium 99mTc red cell labeling in vivo. The data were collected using a Toshiba scintillation gamma camera with a MODUMED computer system coupled with a gating device. Patients were divided into two groups. Group I consisted of 24 patients with persistent electrocardiographic ST segment elevation and group II--of 21 patients without persistent elevation of this segment. In the group I, left ventricular ejection fraction ranged between 10 and 36% (mean: 24%). In 9/24 patients (38%) diffuse hypokinesis, in 7/24 patients (29%) regional akinesis and in the last 8/24 patients (33%) regional dyskinesis with impaired dilated left ventricular systolic and diastolic function were observed. In the group II, left ventricular ejection fraction ranged from 19 to 47%. Mean value of this parameter equaled 32% and was statistically significantly higher than in patients from group II. In 9/21 patients (42%) diffuse hypokinesis, in 2/21 patients (10%) regional anterior wall hypokinesis with the normal function of other walls, and in the last 10/21 patients (48%) regional anterior wall akinesis with the diffuse hypokinesis of other walls were localized. In the patients without persistent electrocardiographic ST segment elevation, diffuse hypokinesis was observed in majority of cases. In none of those patients ventricular aneurysm was diagnosed. In the patients with persistent electrocardiographic ST segment elevation, three types of decreased left ventricular function (diffuse hypokinesis, regional akinesis and ventricular aneurysm) were observed. It should be noted that in 1/3 of those patients ventricular aneurysm was diagnosed. Presence of diskinetic wall motion abnormalities in group I (in 8/24 patients) was statistically significantly more frequent (p < 0.01) than in group II (in 0/21 patients). 1. Presence of persistent electrocardiographic ST segment elevation in a patient with post infarction myocardial failure is a prerequisite for suspicion of post myocardial infarction left-ventricular aneurysm. 2. In patients without persistent electrocardiographic ST segment elevation and post infarction myocardial failure diffuse hipokinesis (sometimes with regional akinesis) is predominantly observed.


People with cancer and their family caregivers' personal experience of using supportive eHealth technology: A narrative review.
To synthesise existing qualitative evidence regarding the experiences of people living with cancer and their family caregivers using eHealth technology in their home setting. A narrative review using a systematic approach was utilised. Five databases (PubMed, CINAHL, EMBASE, PsycINFO and the Cochrane Library) were searched using a tailored search strategy to identify primary research articles published between January 2005 and May 2021. Studies were quality appraised using the Critical Appraisal Skills Programme's Qualitative Studies Checklist and the Mixed Method Appraisal Tool, where relevant. Identified studies were appraised by three reviewers and data were extracted for analysis. Key themes were identified and agreed upon by the authors. 28 empirical studies were included in the review. Five major themes emerged: (i) understanding of cancer and its care (ii) alignment and integration of eHealth technology into daily life (iii) connection and collaboration with healthcare professionals, family and peers (iii) reassurance and sense of safety (iv) and the psychosocial impact on the self during the cancer experience. eHealth technology can have positive role in the lives of people with cancer and their family caregivers, beyond the intended health outcomes of the intervention. Individual preferences amongst people with cancer and their family caregivers using eHealth technology must be considered, especially regarding cancer information delivery, content and support methods. This review underlines a critical need for further in-depth evidence on the personal meaning and relationships people with cancer and their family caregivers develop with eHealth technology in an ambulatory care setting.


Long-term functional and mobility outcomes for individuals with arthrogryposis multiplex congenita.
Arthrogryposis multiplex congenita (AMC) is a birth defect that involves congenital joint contractures in two or more joints including the limbs, spine, and jaw. The purpose of our study was to identify long-term outcomes of adults with AMC. We recruited 177 participants from over 15 countries, making this the largest international study of adults with AMC. Participants provided demographic information including living situation and mobility and completed two standardized outcome measures, of quality of life and physical activity, using an online survey format. The data were compiled and descriptive analyses were performed. The study group consisted of 72% females and a mean age of 39 years. Over 90% of participants had upper and lower limb involvement, 35% had scoliosis or lordosis while 16% had jaw problems. Participants had an average of nine (0-70) surgeries at the time of the study. The majority (75%) of respondents lived independently of family members (on their own or with a partner). Participants were nearly three times more likely to have a graduate degree than the general US population. Participants reported lower physical function scores than the general US population; however, they reported similar or higher scores for the other quality of life domains of the SF-36. They were considerably less physically active than able-bodied individuals. Half of participants experienced chronic back pain and 60% reported joint pain. Additionally, almost half of the participants took regular pain medications.


[Use of antibioticograms for individual programs of antibacterial therapy].
The increasing role of antibiotic-resistant microorganisms in etiology of bacterial infections and the increased number of the antibiotics used for the treatment of patients with purulent infections require a rational approach to the choice of the optimal drug. Antibiotic sensitivity of the causative agents of bacterial infections is considered at present as one of the main indices determining the efficacy of antibacterial therapy. Determination of antibiotic sensitivity by the disk diffusion method with quantitative and semi-quantitative interpretation of the results provides information for choosing the most effective drug and calculating its optimal dose in control therapy. Equations for calculating the MICs antibiotics by the inhibition growth zones and the drug levels in blood and urine attained with the use of different doses and administration routes are presented.


Implementation of a conservative checklist-based protocol for oxytocin administration: maternal and newborn outcomes.
The purpose of this study was to examine the effects of a conservative and specific checklist-based protocol for oxytocin administration on maternal and newborn outcome. The protocol was based on maternal and fetal response to oxytocin rather than infusion rate. This was a retrospective chart review and data extraction of the last 100 patients receiving oxytocin before implementation of the protocol and the first 100 patients receiving oxytocin after protocol implementation. The 2 groups were demographically similar. For the pre- and postprotocol groups, the mean time of infusion to delivery was 8.5 +/- 5.3 hours versus 8.2 +/- 4.5 hours (NS), the maximum oxytocin infusion rate was 13.8 +/- 6.3 mU/min versus 11.4 +/- 6.1 mU/min (P = .003) and the cesarean delivery rate was 15% versus 13% (NS). Every index of newborn outcome was improved in the post-protocol group, but these differences did not individually reach statistical significance. However, newborns with any index of adverse outcome were significantly fewer in the post protocol group (31 vs 18, P = .049). System wide implementation of this program was associated with a decline in the rate of primary cesarean delivery from 23.6% in 2005 to 21.0% in 2006. Implementation of a specific and conservative checklist-based protocol for oxytocin infusion based on maternal and fetal response results in a significant reduction in maximum infusion rates of oxytocin without lengthening labor or increasing operative intervention. Cesarean delivery rate declined system-wide following implementation of this protocol. Newborn outcome also appears to be improved.


Characterization of class 1 integrons in metallo-β-lactamase-producing Acinetobacter baumannii isolates from hospital environment.
The emergence and widespread dissemination of antibiotic resistance in A. baumannii, has become a globally challenge. The increasing hospital outbreaks by multi-drug resistant (MDR) A. baumannii strains, shows the necessity of continuous monitoring to find sources of resistant strains in hospitals. This study aimed to identify the presence of class 1 integrons and metallo-β-lactamase (MBL) related genes in A. baumannii isolates from hospital environment. In order to identify A. baumannii isolates, a total of 297 environmental samples were collected from burn wards and intensive care units (ICUs) of two university hospitals. Resistance to common antibiotics was studied by disk diffusion method and microbroth dilution assay was used to determine the minimum inhibitory concentrations (MICs) of imipenem, colistin and tigecycline. The A. baumannii isolates were studied by polymerase chain reaction (PCR) for the presence of class 1 integrons (intI1, intl CS) and metallo-β-lactamases (MBLs) (blaIMP, blaVIM, blaNDM) genes. A. baumannii was identified in 68/297 (22.9%) of hospital environment. All A. baumannii strains were multidrug-resistant (MDR), but none of them were resistant to colistin, tigecycline and ampicillin-sulbactam. All (100%) and 38 (95.0%) of A. baumannii isolates from ICUs and burn wards were imipenem resistant respectively. Class 1 integrons was identified in 30/40 (75.0%) and 23/28 (82.1%) isolates from burn wards and ICUs respectively. Two different types of gene cassettes were identified, which included: arr-2, ereC, aadA1, cmlA5 and arr2, cmlA5. MBL genes including blaVIM and blaIMP were detected in 26/28 (92.8%), 27/28(96.4%) and 39/40 (97.5%) and 31/40 (77.5%) of the isolates from the ICUs and the burn wards respectively. None of the isolates contained the blaNDM-1 gene. The findings of the present study showed that the isolation rate of MBL producing carbapenem-resistant A. baumannii (CRAB) was relatively high in the environmental surface of burn wards and ICUs, which can be considered as a potential source of outbreaks in hospitalized patients.


Townes-Brocks syndrome. A neonate with extended spectrum and thrombocytopenia.
Townes-Brocks syndrome is a rare malformation syndrome characterized by thumb, auricular, renal, and anal anomalies. Both familial and isolated cases with clinical heterogeneity were reported in the medical literature. We present a sporadic case with typical clinical features and extended spectrum, that has previously not been described. Left sided facial palsy, external auditory canal atresia, club hand with radius aplasia, bilateral clubfoot, and sacral skin tag were the additional findings. Isolated patent ductus arteriosus was the associated congenital heart defect. Thrombocytopenia was another documented hematological abnormality.


Tailoring buckybowls for fullerene recognition. A dispersion-corrected DFT study.
A series of buckybowls with different sizes and structures have been tested as potential receptors of fullerenes C60, C70 and C40. Among these bowls are corannulene (C20H10), sumanene (C21H12), pinakene (C28H14), hemifullerene (C30H12), circumtrindene (C36H12), pentaindenocorannulene (C50H20) and bowl-shaped hexabenzocoronene derivatives. An exhaustive study, taking into account different orientations of fullerenes, was performed in order to obtain the most favourable arrangement for interacting with the bowls. Complexes were optimised at the SCC-DFTB-D level and interaction energies were obtained at the B97-D2/TZVP level including BSSE corrections. Comparison with the full B97-D2/TZVP results (optimisation plus interaction energies) suggests that the B97-D2/TZVP//SCC-DFTB-D approach may be a useful screening tool for designing fullerene receptors. Regarding the "catching" ability of the different buckybowls, it can be concluded that the shape of a buckybowl plays a crucial role in its success. Thus, it seems that the addition of flaps at the bowl rim by benzannelation is an effective strategy for enhancing the interaction with fullerenes, providing enough flexibility to extend the contact surface with the fullerene moiety. Accordingly, a bowl-shaped hexabenzocoronene derivative (C72H24) showed the best ability among the buckybowls evaluated for catching the fullerenes C60, C70 and C40; it is noteworthy that, when interacting with C60, the interaction energy is three times that corresponding to the prototypical buckybowl, corannulene. On the contrary, the more rigid and compact is the structure of a buckybowl, the smaller its ability to interact with fullerenes.


Ultraviolet-A1 (340-400 nm) irradiation therapy in systemic lupus erythematosus.
Ultraviolet-A1 (UV-A1) wavelengths have been found effective in mitigating signs and symptoms of disease activity in systemic lupus erythematosus (SLE) but studies have been uncontrolled. To rigorously assess the effectiveness and safety of daily low-dose UV-A1 irradiation as a therapeutic agent in this disorder we enrolled 26 women with SLE in an 18-week two-phase study. During the initial six-week prospective, double-blind, placebo-controlled phase, the patients were divided into two groups; Group A was exposed to 60kJ/m2 of UV-A1 (340-400 nm) irradiation within a sunbed five days a week for three weeks and Group B was exposed for an equal amount of time to visible light of greater than > 430 nm (placebo). Each group was then crossed over for exposure to the other source for three weeks. During the second phase-2 weeks-patients and physicians were unblinded and patients were irradiated with progressively decreasing levels of UV-A1 only. Twenty-five patients completed the six-week placebo-controlled phase of the study and eighteen patients participated for the entire 18 weeks. In Group A the systemic lupus activity measure (SLAM) score improved significantly after three weeks of five-day-a-week UV-A1 irradiation (P < 0.05), regressing to baseline during the three weeks of placebo irradiation. Improvement recurred and progressed with six weeks of three-day-a-week UV-A1 irradiation (P < 0.05). Group B patients responded negligibly to the three weeks of visible light, more sharply to UV-A1, and as with Group A, maximally to the six weeks of three-day-a-week UV-A1 (P < 0.01). With twice- and then once-weekly UV-A1 irradiation the SLAM scores worsened slightly. All patients decreased their drug use. Anti-double-stranded DNA antibodies (anti-dsDNA) decreased significantly (P < 0.05) and anti-nuclear antibodies non-significantly. Side effects were negligible. Visible light had no significant effect. In conclusion, low-dose UV-A1 irradiation effectively, comfortably, and without apparent toxicity diminished signs and symptoms of disease activity in SLE.


Biomechanical configurations of mandibular transport distraction osteogenesis devices.
Mandibular bone transport (MBT) distraction osteogenesis devices are used for achieving reconstruction of mandibular defects in a predictable way, with few complications, less complexity than other alternative surgical procedures, and minimal tissue morbidity. However, selection of appropriate MBT device characteristics is critical for ensuring both their mechanical soundness and their optimal distraction function for each patient's condition. This article assesses six characteristics of currently available MBT devices to characterize their design and function and to classify them in a way that assists the selection of the best device option for each clinical case. In addition, the present work provides a framework for both the biomechanical conception of new devices and the modification of existing ones.


Genome-wide analysis uncovers high frequency, strong differential chromosomal interactions and their associated epigenetic patterns in E2-mediated gene regulation.
An emerging Hi-C protocol has the ability to probe three-dimensional (3D) architecture and capture chromatin interactions in a genome-wide scale. It provides informative results to address how chromatin organization changes contribute to disease/tumor occurrence and progression in response to stimulation of environmental chemicals or hormones. In this study, using MCF7 cells as a model system, we found estrogen stimulation significantly impact chromatin interactions, leading to alteration of gene regulation and the associated histone modification states. Many chromosomal interaction regions at different levels of interaction frequency were identified. In particular, the top 10 hot regions with the highest interaction frequency are enriched with breast cancer specific genes. Furthermore, four types of E2-mediated strong differential (gain- or loss-) chromosomal (intra- or inter-) interactions were classified, in which the number of gain-chromosomal interactions is less than the number of loss-chromosomal interactions upon E2 stimulation. Finally, by integrating with eight histone modification marks, DNA methylation, regulatory elements regions, ERα and Pol-II binding activities, associations between epigenetic patterns and high chromosomal interaction frequency were revealed in E2-mediated gene regulation. The work provides insight into the effect of chromatin interaction on E2/ERα regulated downstream genes in breast cancer cells.


The chemical production of mutations. The effect of chemical mutagens on cells and their genetic material is discussed.
Since the discovery of the first potent mutagens over 20 years ago, progress in mutation research has been rapid. Many new mutagens, belonging to a variety of chemical classes, have been discovered, and for some of them the reaction with DNA in vitro has been established. It seems that the findings of these chemical investigations usually also apply to viruses which are treated outside the cell. This has made chemical mutagens into an important tool for the analysis of the genetic code. When DNA is treated inside the cell, its reactions would not be expected to be always identical with those observed in vitro; in one case they have, indeed, been found to be different.


Antioxidant supplementation for lung disease in cystic fibrosis.
Airway infection leads to progressive damage of the lungs in cystic fibrosis (CF) and oxidative stress has been implicated in the etiology. Supplementation of antioxidant micronutrients (vitamin E, vitamin C, beta-carotene and selenium) or N-acetylcysteine (NAC) as a source of glutathione, may therefore potentially help maintain an oxidant-antioxidant balance. Glutathione or NAC can also be inhaled and if administered in this way can also have a mucolytic effect besides the antioxidant effect. Current literature suggests a relationship between oxidative status and lung function. This is an update of a previously published review. To synthesise existing knowledge on the effect of antioxidants such as vitamin C, vitamin E, beta-carotene, selenium and glutathione (or NAC as precursor of glutathione) on lung function through inflammatory and oxidative stress markers in people with CF. The Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register and PubMed were searched using detailed search strategies. We contacted authors of included studies and checked reference lists of these studies for additional, potentially relevant studies. We also searched online trials registries.Last search of Cystic Fibrosis Trials Register: 08 January 2019. Randomised and quasi-randomised controlled studies comparing antioxidants as listed above (individually or in combination) in more than a single administration to placebo or standard care in people with CF. Two authors independently selected studies, extracted data and assessed the risk of bias in the included studies. We contacted study investigators to obtain missing information. If meta-analysed, studies were subgrouped according to supplement, method of administration and the duration of supplementation. We assessed the quality of the evidence using GRADE. One quasi-randomised and 19 randomised controlled studies (924 children and adults) were included; 16 studies (n = 639) analysed oral antioxidant supplementation and four analysed inhaled supplements (n = 285). Only one of the 20 included studies was judged to be free of bias.Oral supplements versus controlThe change from baseline in forced expiratory volume in one second (FEV1) % predicted at three months and six months was only reported for the comparison of NAC to control. Four studies (125 participants) reported at three months; we are uncertain whether NAC improved FEV1 % predicted as the quality of the evidence was very low, mean difference (MD) 2.83% (95% confidence interval (CI) -2.16 to 7.83). However, at six months two studies (109 participants) showed that NAC probably increased FEV1 % predicted from baseline (moderate-quality evidence), MD 4.38% (95% CI 0.89 to 7.87). A study of a combined vitamin and selenium supplement (46 participants) reported a greater change from baseline in FEV1 % predicted in the control group at two months, MD -4.30% (95% CI -5.64 to -2.96). One study (61 participants) found that NAC probably makes little or no difference in the change from baseline in quality of life (QoL) at six months (moderate-quality evidence), standardised mean difference (SMD) -0.03 (95% CI -0.53 to 0.47), but the two-month combined vitamin and selenium study reported a small difference in QoL in favour of the control group, SMD -0.66 (95% CI -1.26 to -0.07). The NAC study reported on the change from baseline in body mass index (BMI) (62 participants) and similarly found that NAC probably made no difference between groups (moderate-quality evidence). One study (69 participants) found that a mixed vitamin and mineral supplement may lead to a slightly lower risk of pulmonary exacerbation at six months than a multivitamin supplement (low-quality evidence). Nine studies (366 participants) provided information on adverse events, but did not find any clear and consistent evidence of differences between treatment or control groups with the quality of the evidence ranging from low to moderate. Studies of β-carotene and vitamin E consistently reported greater plasma levels of the respective antioxidants.Inhaled supplements versus controlTwo studies (258 participants) showed inhaled glutathione probably improves FEV1 % predicted at three months, MD 3.50% (95% CI 1.38 to 5.62), but not at six months compared to placebo, MD 2.30% (95% CI -0.12 to 4.71) (moderate-quality evidence). The same studies additionally reported an improvement in FEV1 L in the treated group compared to placebo at both three and six months. One study (153 participants) reported inhaled glutathione probably made little or no difference to the change in QoL from baseline, MD 0.80 (95% CI -1.63 to 3.23) (moderate-quality evidence). No study reported on the change from baseline in BMI at six months, but one study (16 participants) reported at two months and a further study (105 participants) at 12 months; neither study found any difference at either time point. One study (153 participants) reported no difference in the time to the first pulmonary exacerbation at six months. Two studies (223 participants) reported treatment may make little or no difference in adverse events (low-quality evidence), a further study (153 participants) reported that the number of serious adverse events were similar across groups. With regards to micronutrients, there does not appear to be a positive treatment effect of antioxidant micronutrients on clinical end-points; however, oral supplementation with glutathione showed some benefit to lung function and nutritional status. Based on the available evidence, inhaled and oral glutathione appear to improve lung function, while oral administration decreases oxidative stress; however, due to the very intensive antibiotic treatment and other concurrent treatments that people with CF take, the beneficial effect of antioxidants remains difficult to assess in those with chronic infection without a very large population sample and a long-term study period. Further studies, especially in very young children, using outcome measures such as lung clearance index and the bronchiectasis scores derived from chest scans, with improved focus on study design variables (such as dose levels and timing), and elucidating clear biological pathways by which oxidative stress is involved in CF, are necessary before a firm conclusion regarding effects of antioxidants supplementation can be drawn. The benefit of antioxidants in people with CF who receive CFTR modulators therapies should also be assessed in the future.


Sui generis: gene therapy and delivery systems for the treatment of glioblastoma.
Gene therapy offers a multidimensional set of approaches intended to treat and cure glioblastoma (GBM), in combination with the existing standard-of-care treatment (surgery and chemoradiotherapy), by capitalizing on the ability to deliver genes directly to the site of neoplasia to yield antitumoral effects. Four types of gene therapy are currently being investigated for their potential use in treating GBM: (i) suicide gene therapy, which induces the localized generation of cytotoxic compounds; (ii) immunomodulatory gene therapy, which induces or augments an enhanced antitumoral immune response; (iii) tumor-suppressor gene therapy, which induces apoptosis in cancer cells; and (iv) oncolytic virotherapy, which causes the lysis of tumor cells. The delivery of genes to the tumor site is made possible by means of viral and nonviral vectors for direct delivery of therapeutic gene(s), tumor-tropic cell carriers expressing therapeutic gene(s), and "intelligent" carriers designed to increase delivery, specificity, and tumoral toxicity against GBM. These vehicles are used to carry genetic material to the site of pathology, with the expectation that they can provide specific tropism to the desired site while limiting interaction with noncancerous tissue. Encouraging preclinical results using gene therapies for GBM have led to a series of human clinical trials. Although there is limited evidence of a therapeutic benefit to date, a number of clinical trials have convincingly established that different types of gene therapies delivered by various methods appear to be safe. Due to the flexibility of specialized carriers and genetic material, the technology for generating new and more effective therapies already exists.


Changes in gastrointestinal hormones and leptin after Roux-en-Y gastric bypass surgery.
Roux-en-Y gastric bypass (RYGB) imparts long-term weight loss, the mechanisms for which are not well understood. Changes in leptin and gastrointestinal (GI) hormones, including glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin, may contribute to the relative success of RYGB compared with conventional weight loss methods. This study evaluated changes in GI hormones and leptin post-RYGB. The study also evaluated whether GI hormones differed after a short-term dose of protein or fat. GLP-1, PYY, ghrelin, and leptin were assessed in 16 women before RYGB and up to 1 year after RYGB. Plasma was collected before and at several times after a short-term equicaloric dose of protein or fat. GLP-1 area under the curve (AUC) increased at week 6 and 1 year in the fat beverage (FAT-BEV) group compared with baseline. PYY AUC remained elevated at 1 year in the FAT-BEV group. Ghrelin AUC decreased at week 2, week 6, and 1 year in the protein beverage (PRO-BEV) group compared with baseline. Ghrelin AUC was lower in the PRO-BEV group compared with the FAT-BEV group at week 6. Fasted leptin decreased at all visits in both groups and was lower in the FAT-BEV group compared with the PRO-BEV group at 1 year. Changes from baseline were evident for all GI hormones and leptin; some differences were evident soon after surgery (ghrelin, leptin), whereas others were maintained long term (GLP-1, PYY, ghrelin, leptin). In response to a short-term stimulus, protein suppressed ghrelin and fat potently stimulated GLP-1 and PYY. Future work in this area is warranted.


Outdoor passive air monitoring of semi volatile organic compounds (SVOCs): a critical evaluation of performance and limitations of polyurethane foam (PUF) disks.
The most commonly used passive air sampler (PAS) (i.e. polyurethane foam (PUF) disk) is cheap, versatile, and capable of accumulating compounds present both in gas and particle phases. Its performance for particle associated compounds is however disputable. In this study, twelve sets of triplicate PUF-PAS were deployed outdoors for exposure periods of 1-12 weeks together with continuously operated active samplers, to characterize sampling efficiency and derive sampling rates (RS) for compounds belonging to 7 SVOC classes (including particle associated compounds). PUF-PAS efficiently and consistently sampled polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polycyclic aromatic hydrocarbons (PAHs), and eight novel brominated flame retardant (nBFR) compounds. Low accuracy and lack of sensitivity was observed for most polychlorinated dibenzo-p-dioxins/furans PCDD/Fs and polybrominated diphenyl ethers (PBDEs) (under the conditions of this study), with the exception of some congeners which may be used as qualitative markers for their respective classes. Application of compound specific RS was found crucial for all compounds except PCBs. Sampling efficiency of the particle associated compounds was often low.


Antigenic and functional characterization of a rat central nervous system-derived cell line immortalized by a retroviral vector.
We have immortalized rat central nervous system (CNS) cells of primary cultures of rat optic nerve with murine leukemia virus psi-2,SV-40-6, which is defective in assembly and contains the SV-40 large T antigen and neomycin resistance genes, to produce a cell line that we named A7. After drug selection, greater than 90% of the growing cells expressed nuclear SV-40 large T cells and a fraction of these contained the astrocyte-specific marker, glial fibrillary acidic protein. The majority of these cells also expressed surface marker A4 (specific for neural tube derivatives), Ran 2, p185 (the 185-kD phosphoprotein product of the neu oncogene), and fibronectin, but did not express the astrocyte enzymes glutamine synthetase and monoamine oxidase B. Surface markers characteristic of glial progenitors (A2B5) and oligodendrocytes (galactocerebroside) were not detected. After two rounds of cell cloning, subclone A7.6-3 expressed Ran 2, fibronectin, and the neural cell adhesion molecule (N-CAM) but not glial fibrillary acidic protein and A4. The A7 cell line and subclones also displayed certain functions of type 1 astrocytes: the conditioned medium of these cells had a potent mitogenic activity for glial progenitor cells which could be neutralized by anti-platelet-derived growth factor antibodies and monolayers of these cells supported the growth of embryonic hypothalamic neurons. We conclude that a retrovirus containing SV-40 large T antigen can immortalize rat CNS cells and that such immortalized glial cells retain at least two important functions of type 1 astrocytes: the ability to secrete platelet-derived growth factor and to support the growth of embryonic CNS neurons. Moreover, such stable immortalized clonal cell lines can be used to study gene regulation in glial cells.


US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja®).
In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure. Preliminary data from a randomized, double-blind trial (APEKS-NP) in patients with nosocomial pneumonia due to carbapenem-susceptible gram-negative bacteria showed a similar rate of mortality as compared to meropenem. We describe the uncertainties and challenges in the interpretation of the CREDIBLE-CR trial and some benefit-risk considerations for the use of cefiderocol in clinical practice. Clinical Trials Registration: NCT02321800.


Trypsin and activation of circulating trypsinogen contribute to pancreatitis-associated lung injury.
Pancreatic proteases are secreted in acute pancreatitis, but their contribution to associated lung injury is unclear. Applying models of mild edematous (intravenous caerulein) and severe necrotizing (intraductal glycodeoxycholic acid) pancreatitis in rats, we showed that both trypsinogen and trypsin concentrations in peripheral blood, as well as lung injury, correlate with the severity of the disease. To isolate the potential contribution of proteases to lung injury, trypsin or trypsinogen was injected into healthy rats or trypsinogen secreted in caerulein pancreatitis was activated by intravenous enterokinase. Pulmonary injury induced by protease infusions was dose dependent and was ameliorated by neutrophil depletion. Trypsinogen activation worsened lung injury in mild pancreatitis. In vitro incubation of leukocytes with trypsinogen showed that stimulated leukocytes can convert trypsinogen to trypsin. In conclusion, this study demonstrates that the occurrence and severity of pancreatitis-associated lung injury (PALI) corresponds to the levels of circulating trypsinogen and its activation to trypsin. Neutrophils are involved in both protease activation and development of pulmonary injury.


Simple and accurate expressions for diffuse reflectance of semi-infinite and two-layer absorbing and scattering media: erratum.
A previous paper [Appl. Opt.48, 6670 (2009)] presented analytical expressions for the diffuse reflectance of semi-infinite homogeneous and two-layer refracting, absorbing, and anisotropically scattering media exposed to normal and collimated light. It also reported various regression coefficients associated with the analytical expressions obtained by fitting the diffuse reflectance predicted from Monte Carlo (MC) simulations. Although the formulation and the MC simulation results were correct, the values of some regression coefficients were erroneously reported. This erratum points out the error in the original paper and reports the correct values. It also presents alternative expressions for when the medium has an index of refraction of 1.44, corresponding to the human skin in the visible portion of the spectrum.