Efficacy of Cetuximab in Combination with FOLFIRI in a Patient with KRAS Wild-Type Metastatic Anal Cancer.
Anal canal cancer is a rare tumor without clear treatment evidence in the metastatic setting. In terms of the bad prognosis of patients with metastatic anal cancer, further therapeutic options are urgently needed. In this paper we present the case of a 64-year-old man suffering from undifferentiated squamous cell carcinoma with liver metastases. After progression on cisplatin and fluorouracil, tumor tissue was analyzed with respect to anti-EGFR therapy with cetuximab. There was no KRAS mutation and the EGFR expression level in the tumor tissue was 2+; ideal conditions for the immunotherapy. Encouraged by these results we started a therapy using FOLFIRI in combination with cetuximab. Fortunately the patient showed a partial response after 6 cycles. On patient's preference we did a therapy break of 6 weeks. Within this time period the disease was progressive indicating its aggressiveness. However, the same immunotherapy was able to stabilize the disease for a further 3 months. The patient died 21 months after diagnosis because of liver failure. Nevertheless, from our perspective the combination of FOLFIRI and cetuximab is quite a promising therapeutic option for patients with metastatic anal cancer. Potential predictive factors of the immunochemotherapy are discussed in this paper.


Successful treatment of cholesterol crystal embolism with anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody: a case report.
Background: We report a unique case of renal cholesterol crystal embolism (CCE) induced by carotid artery stenting that was successfully treated with evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9).Case presentation: A 77-year-old man with hypertension, hyperlipidemia, and chronic kidney disease was referred to our department for decreased estimated glomerular filtration rate (eGFR)-from 32.0 to 13.9 mL/min/1.73 m2-5 weeks after carotid artery stenting. Further examination revealed livedo reticularis in the bilateral toes and eosinophilia (723/μL). Skin biopsy from livedo reticularis tissue in the bilateral toes showed cholesterol clefts in the small arteries. The patient was therefore diagnosed with CCE. After 25 weeks' administration of evolocumab at a dose of 140 mg subcutaneously administered every 2 weeks, his eGFR had improved from 10.7 to 18.1 mL/min/1.73 m2.Conclusion: Evolocumab may have a beneficial effect on renal involvement in patients with CCE.


Long-Persistent Circularly Polarized Phosphorescence from Chiral Organic Ionic Crystals.
Long-persistent circularly polarized phosphorescence (LPCPP) is achieved for the first time in chiral organic ionic crystals at room temperature. The co-crystal composed of terephtalic acid (TPA) and chiral α-phenylethyamines (PEAs) gave rise to LPCPP with lifetimes up to 862 ms and large dissymmetric factor (glum ). The hybridization of TPA with chiral PEAs allows circular polarization of the generated long-persistent phosphorescence. The observed mirror-image twisted molecular structures in the rigid lattices were responsible for the chiroptical activation of the generated long-persistent phosphorescence.


[Clinical value of multislice spiral CT in caudal block].
To explore a new method for body surface orientation of the puncture site, determination of the direction of the needling and puncture depth for caudal block. Three-dimensional reconstruction of the pelvis was performed in 8 cases for measuring the distances between the sacral hiatus and the planned site of anesthetic delivery and the size of the sacral hiatus. After image processing with the technique of shaded surface display (SSD), the shapes of sacral hiatus and sacral tube were evaluated. Three-dimensional reconstruction of the pelvis in the 8 cases allowed clear view from any directions of the sacral hiatus and sacral tube and accurate measurement of the size of the sacral hiatus. After simulated cutting of half of the rumpbone, the distances between the sacral hiatus and the drug injection site were accurately measured. With these measurements, accurate preoperative localization of the puncture site on the skin was achieved and the anesthesia was successful in all the cases. This technique can provide accurate data for localization of the puncture site on the skin and determination of the direction of the needling and the puncture depth for caudal block to increase the successful rate of anesthesia, lower the operative risks and allow simulated operative training.


High glucose condition upregulated Txnip expression level in rat mesangial cells through ROS/MEK/MAPK pathway.
Thioredoxin interacting protein (Txnip) is one of the most abundantly up-regulated genes in response to hyperglycemia. The increased renal expression of Txnip was associated with type IV collagen accumulation in streptozotocin-induced diabetic mice. As the mechanism of action of high glucose is unknown, we undertook the investigation of the signaling pathway on the upregulation of Txnip expression induced by high glucose in rat mesangial cells. Rat mesangial cells were exposed to normal (5.5 mM) or high (25 mM) glucose at different time points. Txnip expression was determined using real-time RT-PCR and western-blotting at transcription and translation level, respectively. Intracellular reactive oxygen species (ROS) was detected by FACS Calibur flow cytometer using fluorescent probe (DCFH-DA).The treatment with high glucose resulted in an increase of Txnip mRNA from 4 h to 12 h and Txnip protein from 12 to 24 h in comparison with normal glucose condition. In addition, N-acetyl-cysteine (NAC) was found to decrease Txnip protein expression under high glucose condition. Furthermore, p38MAPK inhibitor SB203580 suppressed Txnip expression at transcription and protein level significantly to high glucose exposure. These results suggest that high glucose exposure improves Txnip mRNA and protein expression level by ROS/MEK/MAPK signaling pathway.


ROS Cocktails as an Adjuvant for Personalized Antitumor Vaccination?
Cancer is the second leading cause of death worldwide. Today, the critical role of the immune system in tumor control is undisputed. Checkpoint antibody immunotherapy augments existing antitumor T cell activity with durable clinical responses in many tumor entities. Despite the presence of tumor-associated antigens and neoantigens, many patients have an insufficient repertoires of antitumor T cells. Autologous tumor vaccinations aim at alleviating this defect, but clinical success is modest. Loading tumor material into autologous dendritic cells followed by their laboratory expansion and therapeutic vaccination is promising, both conceptually and clinically. However, this process is laborious, time-consuming, costly, and hence less likely to solve the global cancer crisis. Therefore, it is proposed to re-focus on personalized anticancer vaccinations to enhance the immunogenicity of autologous therapeutic tumor vaccines. Recent work re-established the idea of using the alarming agents of the immune system, oxidative modifications, as an intrinsic adjuvant to broaden the antitumor T cell receptor repertoire in cancer patients. The key novelty is the use of gas plasma, a multi-reactive oxygen and nitrogen species-generating technology, for diversifying oxidative protein modifications in a, so far, unparalleled manner. This significant innovation has been successfully used in proof-of-concept studies and awaits broader recognition and implementation to explore its chances and limitations of providing affordable personalized anticancer vaccines in the future. Such multidisciplinary advance is timely, as the current COVID-19 crisis is inexorably reflecting the utmost importance of innovative and effective vaccinations in modern times.


Current status of nucleoside antivirals in chronic hepatitis B.
Chronic hepatitis B is a serious disease both worldwide and in the United States. There are two types of drugs available to treat chronic hepatitis B virus (HBV) infection: interferons that boost the immune system, and antiviral or nucleoside analogues that are designed to interfere with HBV DNA to prevent its replication. This review focuses on nucleoside antivirals, namely lamivudine, entecavir and telbivudine, which are widely prescribed for patients with the disease, particularly lamivudine. Additionally, current Food and Drug Administration-approved nucleoside antivirals for hepatitis B will be briefly highlighted. Comparisons are performed based on previous clinical trials from primary sources. Treatments with entecavir and telbivudine are compared with lamivudine treatment in regard to pharmacotherapy, resistance and cost-effectiveness. Outcomes varied depending on each trial, but the main findings were more favorable for entecavir and telbivudine treatments than for lamivudine treatment. It was concluded that entecavir treatment is associated with better outcomes than lamivudine in the three aspects studied. Similarly, telbivudine showed more improvements than lamivudine in all three areas. Concomitant pharmacotherapy, especially in lamivudine-refractory patients, demonstrated significant improvement in the management of chronic hepatitis B. Furthermore, the availability of hepatitis B vaccines should enable us to prevent the occurrence of the disease.


Occlusal dysesthesia: a topical narrative review.
Occlusal dysesthesia (OD) is a disorder characterised by the sensation of uncomfortable bite with no obvious occlusal discrepancy. It is usually associated with emotional distress and is elicited by dental occlusal procedures. Multiple dental treatments are often provided to try to resolve the symptoms, but the outcome is usually dissatisfying for the dentist and disappointing for the patient. To summarise the specific features of OD, a PubMed search was carried out looking for all papers related to the topic. The references from the studies selected and from review articles were also examined for further relevant papers. A total of 138 articles were first identified, of which 18 of them were considered relevant to the topic. This article reviews the epidemiology, taxonomy and etio-pathophysiology, symptomatology, diagnosis and treatment of OD, with special relevance to issues of clinical importance and dental therapy. Any dental treatment must be avoided in patients with OD, because the results could be inadequate and it usually worsens the symptoms.


Complement activation in sickle cell disease: a liposome model.
Patients with sickle cell disease (SCD) have poorly defined abnormalities of their alternative complement pathway (ACP). We have previously shown chronic activation of the ACP in these patients. To determine the mechanism of this finding, we studied concentrations of the complement control proteins factors I and H in serum from patients with SCD and found no significant difference when they were compared with a control population. Because certain membrane surfaces promote ACP activation and changes occur in erythrocyte membrane phospholipid organization with sickling, we used a liposome model to determine whether ACP activation could be caused by abnormal phospholipid organization of sickle cells. Liposomes with the composition of the sickle cell outer leaflet, which is enriched in phosphatidylserine and phosphatidylethanolamine, activated the ACP significantly more than liposomes with normal outer leaflet phospholipid content. Similarly, liposomes with the composition of the erythrocyte inner membrane leaflet, containing large amounts of phosphatidylethanolamine and phosphatidylserine, activated the ACP more than liposomes with the phospholipid content of the outer leaflet. These findings suggest that phospholipid composition of membranes may play a role in their ability to promote ACP activation, and that changes in phospholipid organization in sickle cells may contribute to the chronic ACP activation observed in patients with SCD.


Cricopharyngeal Botox injection: indications and technique.
Botulinum injection is a widespread technique for treating oropharyngeal dysphagia although there are no standards or guidelines. Based on the literature review we try to make some recommendations. In the last 12 months molecular and pharmacological research has reported the working mechanism of the various botulinum toxin types which tries to explain former clinical observations such as variable response rate and therefore dosage, and toxin type specific resistance. Recent dose-ranging studies or comparisons of different toxin preparations or types rarely focus on oropharyngeal dysphagia. Injection of botulinum toxin A should be considered in cases of relative hypertonicity of the cricopharyngeal muscle and has an onset around day 7 and an offset of at least 4 months. The technique is simple and the complication rate is extremely low (7/100). There are some conditions for success: injection in the horizontal part of the cricopharyngeal muscle, and a high enough start dose. Botulinum injection may be preferred over surgical myotomy because of the low risk, low cost and effectiveness of the procedure. Only in cases of BoNT/A resistance should other toxin types be used.


Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models.
Glioblastoma (GBM) is a hypervascular primary brain tumor with poor prognosis. HET0016 is a selective CYP450 inhibitor, which has been shown to inhibit angiogenesis and tumor growth. Therefore, to explore novel treatments, we have generated an improved intravenous (IV) formulation of HET0016 with HPßCD and tested in animal models of human and syngeneic GBM. Administration of a single IV dose resulted in 7-fold higher levels of HET0016 in plasma and 3.6-fold higher levels in tumor at 60 min than that in IP route. IV treatment with HPßCD-HET0016 decreased tumor growth, and altered vascular kinetics in early and late treatment groups (p < 0.05). Similar growth inhibition was observed in syngeneic GL261 GBM (p < 0.05). Survival studies using patient derived xenografts of GBM811, showed prolonged survival to 26 weeks in animals treated with focal radiation, in combination with HET0016 and TMZ (p < 0.05). We observed reduced expression of markers of cell proliferation (Ki-67), decreased neovascularization (laminin and αSMA), in addition to inflammation and angiogenesis markers in the treatment group (p < 0.05). Our results indicate that HPßCD-HET0016 is effective in inhibiting tumor growth through decreasing proliferation, and neovascularization. Furthermore, HPßCD-HET0016 significantly prolonged survival in PDX GBM811 model.


Benefits of the thoracoscopic approach for short- or long-gap esophageal atresia.
To evaluate the feasibility and results of thoracoscopy in various types of esophageal atresia (EA). From April 2001 to August 2002, 5 patients with EA were treated by thoracoscopy. Their mean gestational age was 38 weeks and mean birth weight was 2700 g. Two patients had short-gap atresia with tracheo-esophageal fistula (type III according to Ladd's classification). Three had long-gap atresia: 2 with low fistula to the carina (type IV) and 1 without fistula (type I). Patients were placed in a prone position with the right side elevated at 80 degrees . Four intrapleural ports were necessary. The fistula when present was dissected and sutured with intrathoracic knots and esophageal anastomosis performed in the same manner. Positive airway pressure increased in all patients after insufflation but was kept in a safe range to prevent lung injury. An esophageal anastomosis was performed in 3 cases (2 short gaps and 1 long gap). Oral feeding started on day 6, and their mean length of hospital stay was 14 days. For one child with type IV EA, the anastomosis was impossible because of a long gap confirmed by an immediate thoracotomy. The ends were just approximated. A "spontaneous" fistula developed, and normal feeding was possible 2.5 months later. For the child with type I EA, the pouches could be only approximated at 2 months of age. A spontaneous fistula developed with a stenosis. A redo anastomosis by open surgery allowed for normal feeding. The thoracoscopic repair of an esophageal atresia is a reasonable choice for experienced surgeons treating patients, including those with long gaps.


Preparation and evaluation of 188 Re sulfide colloidal nanoparticles loaded biodegradable poly (L-lactic acid) microspheres for radioembolization therapy.
Radioembolization with radioactive microspheres has been an effective method for the treatment of liver lesions. The aim of this study was to prepare carrier-free 188 Re loaded poly (L-lactic acid) (PLLA) microspheres through 188 Re sulfide colloidal nanoparticles (188 Re-SC nanoparticles). The formation of 188 Re-SC nanoparticles was confirmed by ultraviolet-visible spectrophotometry. The labeling yield of 188 Re-SC nanoparticles was verified using the RTLC method. Effects of synthesis parameters on morphology and size of prepared 188 Re-sulfide colloidal-PLLA microspheres (188 Re-SC-PLLA microspheres) were studied by scanning electron microscopy. In vitro stability of 188 Re-SC-PLLA microspheres was investigated in normal saline at room temperature and in human serum at 37°C. In vivo distribution studies and gamma camera imaging were performed in healthy BALB/c mice. The microspheres could be prepared with sizes between 13 and 48 μm (modal value 29 μm) and radiolabeling efficiency >99%. After incubation, the microspheres were found stable in vitro up to 72 hours. The biodistribution after intravenous injection in healthy BALB/c mice showed high accumulation in lung as a first capture pathway organ for microsphere followed by great retention over 48 hours for these microspheres. These data show that 188 Re-SC-PLLA microspheres are suitable candidate for clinical studies.


Fuzzy-Based Microservice Resource Management Platform for Edge Computing in the Internet of Things.
Edge computing exhibits the advantages of real-time operation, low latency, and low network cost. It has become a key technology for realizing smart Internet of Things applications. Microservices are being used by an increasing number of edge computing networks because of their sufficiently small code, reduced program complexity, and flexible deployment. However, edge computing has more limited resources than cloud computing, and thus edge computing networks have higher requirements for the overall resource scheduling of running microservices. Accordingly, the resource management of microservice applications in edge computing networks is a crucial issue. In this study, we developed and implemented a microservice resource management platform for edge computing networks. We designed a fuzzy-based microservice computing resource scaling (FMCRS) algorithm that can dynamically control the resource expansion scale of microservices. We proposed and implemented two microservice resource expansion methods based on the resource usage of edge network computing nodes. We conducted the experimental analysis in six scenarios and the experimental results proved that the designed microservice resource management platform can reduce the response time for microservice resource adjustments and dynamically expand microservices horizontally and vertically. Compared with other state-of-the-art microservice resource management methods, FMCRS can reduce sudden surges in overall network resource allocation, and thus, it is more suitable for the edge computing microservice management environment.


An L₁-regularized logistic model for detecting short-term neuronal interactions.
Interactions among neurons are a key component of neural signal processing. Rich neural data sets potentially containing evidence of interactions can now be collected readily in the laboratory, but existing analysis methods are often not sufficiently sensitive and specific to reveal these interactions. Generalized linear models offer a platform for analyzing multi-electrode recordings of neuronal spike train data. Here we suggest an L(1)-regularized logistic regression model (L(1)L method) to detect short-term (order of 3 ms) neuronal interactions. We estimate the parameters in this model using a coordinate descent algorithm, and determine the optimal tuning parameter using a Bayesian Information Criterion. Simulation studies show that in general the L(1)L method has better sensitivities and specificities than those of the traditional shuffle-corrected cross-correlogram (covariogram) method. The L(1)L method is able to detect excitatory interactions with both high sensitivity and specificity with reasonably large recordings, even when the magnitude of the interactions is small; similar results hold for inhibition given sufficiently high baseline firing rates. Our study also suggests that the false positives can be further removed by thresholding, because their magnitudes are typically smaller than true interactions. Simulations also show that the L(1)L method is somewhat robust to partially observed networks. We apply the method to multi-electrode recordings collected in the monkey dorsal premotor cortex (PMd) while the animal prepares to make reaching arm movements. The results show that some neurons interact differently depending on task conditions. The stronger interactions detected with our L(1)L method were also visible using the covariogram method.


How to represent the decision process in a medication plan: the case of the Swiss cohort of inflammatory bowel diseases.
Inflammatory bowel diseases (IBD) belong to healthcare problems impacting the quality of life and inducing important costs for the healthcare system. There is still no magical cure against this kind of diseases, but many promising therapies are under investigation. In order to study the efficiency and side effects of the existing drugs and to evaluate new ones, large numbers of patients are followed in long term cohort studies. The particular constraints associated to the follow up of patients with IBD require the implementation of adapted and efficient tools. On the one hand, clinicians must be able to perform daily changes to the patient treatment in order to adapt it for its best efficiency and react to side effects. On the other hand, the tool must provide long term view on the data to allow large scale analyses regarding the efficiency of the investigated treatment. There are few solutions allowing a clear visualization of the treatment plan of the patients in the long term that indicates clearly the changes and the adverse events. In this work, we propose a new integrated tool that offers a clear temporal view over the patients' treatment.


Diesel exhaust (DE)-induced cytokine expression in human bronchial epithelial cells: a study with a new cell exposure system to freshly generated DE in vitro.
We devised a new in vitro cell exposure system to freshly generated diesel exhaust (DE), different from conventional in vitro culture systems, to examine the effects of DE on human epithelial cells. Using this system, we investigated the effects of DE on cytokine gene expressions in BET-1A human bronchial epithelial cells. DE significantly decreased [(3)H]thymidine incorporation into BET-1A cells. DE had a significant stimulatory effect on interleukin (IL)-8 release to a marked degree. IL-8 and transforming growth factor (TGF)-beta1 messenger RNA (mRNA) expression were induced by DE in a time-dependent manner. The gas obtained by filtration of DE alone did not show a sustained increase in IL-8 protein levels and showed no induction of IL-8 mRNA, suggesting that DE particles (DEPs) play an important role in the induction of IL-8 at both mRNA and protein levels. Antioxidants, pyrrolidine dithiocarbamate, and N-acetyl-L-cysteine significantly inhibited IL-8 mRNA and protein levels by BET-1A cells. These results indicate that freshly generated DEPs may be important in the induction of cytokines such as IL-8 and TGF-beta1 relevant to allergic airway inflammation.


Effect of urapidil on beta-adrenoceptors of rat atria.
The effects of the antihypertensive drug urapidil were studied on chronotropic responses to isoprenaline in rat isolated atria. Urapidil (1-30 microM) antagonized the responses to isoprenaline competitively, and the pA2 value was 6.05. Thus, in addition to its alpha 1-adrenoceptor blocking action for which the pA2 value is about 7, urapidil has beta-adrenoceptor blocking activity.


Response of Bovine Cumulus-Oocytes Complexes to Energy Pathway Inhibition during In Vitro Maturation.
Glucose or fatty acids (FAs) metabolisms may alter the ovarian follicle environment and thus determine oocyte and the nascent embryo quality. The aim of the experiment was to investigate the effect of selective inhibition of glucose (iodoacetate + DHEA) or FA (etomoxir) metabolism on in vitro maturation (IVM) of bovine COCs (cumulus-oocyte complexes) to investigate oocyte's development, quality, and energy metabolism. After in vitro fertilization, embryos were cultured to the blastocyst stage. Lipid droplets, metabolome, and lipidome were analyzed in oocytes and cumulus cells. mRNA expression of the selected genes was measured in the cumulus cells. ATP and glutathione relative levels were measured in oocytes. Changes in FA content in the maturation medium were evaluated by mass spectrometry. Our results indicate that only glucose metabolism is substantial to the oocyte during IVM since only glucose inhibition decreased embryo culture efficiency. The most noteworthy differences in the reaction to the applied inhibition systems were observed in cumulus cells. The upregulation of ketone body metabolism in the cumulus cells of the glucose inhibition group suggest possibly failed attempts of cells to switch into lipid consumption. On the contrary, etomoxir treatment of the oocytes did not affect embryo development, probably due to undisturbed metabolism in cumulus cells. Therefore, we suggest that the energy pathways analyzed in this experiment are not interchangeable alternatives in bovine COCs.


A Presidential Patent [Patents].
There is only one U.S. president who is also a patentee. One might guess that the president is Thomas Jefferson, who invented many things and considered himself to be an inventor. Or, we might guess George Washington whose work as a surveyor and planter, not to mention commander-in-chief of the army, brought him into contact with the latest technology of the 18th century.


Cellular inhibition of microtubule assembly by photoactivated sulphonated meso-tetraphenylporphines.
This work relates to studies on modes of phototoxicity by sulphonated mesotetraphenylporphines on cultured cells. Toxicity appears to be related to inhibition of microtubule function. Treatment of human cervix carcinoma cells of the line NHIK 3025 incubated for 18 h with meso-tetraphenylporphine sulphonates (TPPSn where n = 2a, 2o or 4) and exposed to light, inhibits multiplication for the first hours after light exposure, a significant fraction of the cells accumulating in mitosis. The maximal number of cells in mitosis after treatment (approximately 20%) is dependent on the fluence but is similar for all three photosensitizers. For the first hours after treatment the mitotic cells were always mainly in metaphase; mainly seen as c-metaphases and three-group metaphases. During this time anaphase and telophase cells were absent or greatly reduced in number. Indirect immunofluorescence staining of beta-tubulin showed that the spindle apparatus of mitotic cells was perturbed in all cases. Results are presented which indicate that photoactivation of TPPSn located on the plasma membrane destroys microtubules in interphase cells and leads to arrest of the cells in mitosis. The localization of the dye which sensitizes the photoinduced perturbation of microtubules is further discussed.


Comparative bioavailability of two losartan formulations in healthy human volunteers after a single dose administration.
To compare the bioavailability of two potassic losartan immediate release tablet (50 mg) formulations (Losartan from Laboratórios Cristália Ltd., Brazil, as a test formulation and Cozaar from Merck Sharp & Dohme Farmacêutica Ltd., Brazil, as a reference formulation) in 25 volunteers of both sexes. The study was conducted in an open, randomized, 2-period crossover design and a 1-week washout period. Plasma samples were obtained over a 24-hour interval. The concentrations of losartan and its active metabolite losartan acid were analyzed by combined reversed phase liquid chromatography and tandem mass spectrometry (LC-MS-MS) with negative ion electrospray ionization using a selected ion monitoring method. From the losartan and losartan acid plasma concentrations vs. time curves the following pharmacokinetic parameters were obtained: AUClast, AUC0-inf and Cmax. The geometric mean and respective 90% confidence interval (CI) of Losartan/Cozaar losartan percent ratios were 92.9% (82.2-105.0%) for Cmax, 99.0% (92.5-105.9%) for AUClast, and 99.1% (92.7-105.8%) for AUC0-inf. Furthermore, the geometric mean and respective 90% CI of Losartan/Cozaar losartan acid percent ratios were 98.5% (91.5-106.0%) for Cmax, 97.9% (93.3 102.7%) for AUClast, and 98.1% (93.6-102.9%) for AUC0-inf. Since the 90% CI for Cmax, AUClast and AUC0-inf were within the 80-125% interval proposed by the US Food and Drug Administration, it was concluded that the potassic losartan immediate release 50 mg tablet was bioequivalent to the Cozaar immediate release 50 mg tablet, according to both the rate and extent of absorption. While there were no significant differences in the bioequivalence assessed by either losartan or losartan acid, future bioequivalence studies on losartan may be performed by quantifying losartan alone as the parent compounds are more discriminative.


Carbon nanotube electron ionization source for portable mass spectrometry.
Cold cathode carbon nanotubes (CNTs) are used in a low-voltage quadrupole ion trap mass spectrometer and shown to be a viable low-power alternative to filament sources for portable mass spectrometry instrumentation. No heating is necessary, and the power consumption depends only on the switching characteristics of the electronics. The CNT electron sources are mounted directly in the ring electrode, and their performance is compared directly with a filament source also mounted in the ring electron. Up to a 5 × 10(-4) Torr CO(2) environment, reflecting conditions expected during operation in a Mars atmosphere, the CNT emitters may provide up to 1 μA of current over more than 200 h.


Genomewide linkage scan for nicotine dependence: identification of a chromosome 5 risk locus.
Nicotine dependence (ND) is costly to societies worldwide, moderately heritable, and genetically complex. Risk loci can be identified with genetic linkage analysis independent of prior physiological hypotheses. We completed a genomewide linkage scan to map loci increasing risk for DSM-IV ND and for a quantitative assessment of ND as measured by the Fagerstrom Test for Nicotine Dependence (FTND) in a set of 634 small nuclear families ascertained on the basis of multiple individuals affected with cocaine or opioid dependence. Of these, 507 had at least two subjects affected with ND. There are two distinct populations within this sample, European-Americans (EAs) and African-Americans (AAs). A region on chromosome 5 was identified as containing a gene that affects risk for ND on the basis of FTND score in the AA part of our sample (logarithm of the odds [lod] score 3.04; empirically determined to be genomewide-significant, p = .0374; point p = .0001). The highest lod score observed in the EA part of the sample was on chromosome 7 (lod score 2.73). Several other "possible" risk loci were identified in either AA or EA subjects, with many of these in proximity to previously suggested risk loci from other clinical samples. Three nominally significant single-nucleotide polymorphism associations were found at the peptidylglycine alpha-amidating monooxygenase (PAM) locus under the chromosome 5 linkage peak, also in the AA part of the sample. These data add to the growing evidence for locations for ND risk loci, add a novel statistically significant locus important in AAs, and suggest a gene that might be contributing to this linkage signal.


[Densitometric quantitation of platelet activating factor and other phospholipids in human saliva using enzyme reaction on a silica plate].
A sensitive quantitative analysis by thin layer chromatography was developed for the determination of platelet activating factor (PAF) and other phospholipids in human saliva. The saliva sample (0.6 ml) was pretreated by diatomite column extraction with chloroform-methanol (95:5, v/v). The extract (20 microliters) was spotted on a TLC plate. The mobile phase was chloroform-methanol-water (65:35:7, v/v). The development proceeded until the mobile phase front reached 8 cm from the spotted point, this process usually required 30 min. After development, phospholipase C and alkaline phosphatase solutions were sprayed on the TLC plate at 45 degrees C to hydrolyze phospholipids. By spraying a mixture of ammonium molybdate and Malachite Green, the produced phosphate was changed to molybdophosphate-Malachite Green aggregate, which gave a blue green spot. The colored spots were scanned at 620 nm by chromatoscanner. A linear relationship was obtained between peak area and PAF concentration in the range from 2 to 100 pmol/spot with a relative standard deviation of 2% (n = 7). By this procedure, lysophosphatidylcholine, phosphatidylcholine and phosphatidylethanolamine in human saliva were also determined sensitively. PAF levels in the range from 40 to 300 ng/ml were found in normal human salivas. Although differences in the total amounts of phospholipids in saliva were found for each healthy volunteer and sampling time, the composition of phospholipids was proved to be virtually constant.


[Spatial organization of the chicken alpha-globin gene domain in cells of different].
We have developed a technique for mapping the sites of DNA attachment to the nuclear matrix by hybridization of nuclear matrix DNA with an oligonucleotide array. The latter was made by immobilization of 60-mer oligonucleotides distributed within the area under study with a 2 Kb step on nylon filter. Using this approach we have analyzed the mode of interaction of a 100 Kb fragment of chicken chromosome 16 including the alpha-globin gene domain with the nuclear matrix. The 40 Kb DNA loop including all alpha-globin genes was detected in erythroid cells. One of the borders of this loop colocalized with the previously mapped MAR element and CTCF-dependent enhancer-blocking element. Also, a long transcribed area was found to be preferentially associated with the nuclear matrix. The spatial organization of the area under study in lymphoid cells was drastically different from this observed in erythroid cells.


Hydrogen peroxide exposure--325 exposures reported to a regional poison control center.
Isolated case reports have documented that hydrogen peroxide exposure can be associated with serious toxicity by various routes of exposure. The purpose of this study was to better delineate the epidemiology, medical outcome, and potential health hazards of hydrogen peroxide exposures to the general public. We performed a retrospective review of all exposures reported to a regional poison center over a 36 month period and found that of 95,052 exposures reported, 325 (.34%) were due to hydrogen peroxide. The pediatric population (< 18 years) accounted for 71% of hydrogen peroxide exposures and ingestion was the most common route of exposure (83%). Nausea and vomiting were the most common symptoms secondary to ingestion. Ocular and dermal exposures to dilute solutions resulted in transient symptoms without permanent sequelae. While most exposures by all routes resulted in a benign outcome (no effect or minor effect), there was a trend toward more severe outcomes in those who ingested a concentration greater than 10% (p = 0.011).


Metallisation of Textiles and Protection of Conductive Layers: An Overview of Application Techniques.
The rapid growth in wearable technology has recently stimulated the development of conductive textiles for broad application purposes, i.e., wearable electronics, heat generators, sensors, electromagnetic interference (EMI) shielding, optoelectronic and photonics. Textile material, which was always considered just as the interface between the wearer and the environment, now plays a more active role in different sectors, such as sport, healthcare, security, entertainment, military, and technical sectors, etc. This expansion in applied development of e-textiles is governed by a vast amount of research work conducted by increasingly interdisciplinary teams and presented systematic review highlights and assesses, in a comprehensive manner, recent research in the field of conductive textiles and their potential application for wearable electronics (so called e-textiles), as well as development of advanced application techniques to obtain conductivity, with emphasis on metal-containing coatings. Furthermore, an overview of protective compounds was provided, which are suitable for the protection of metallized textile surfaces against corrosion, mechanical forces, abrasion, and other external factors, influencing negatively on the adhesion and durability of the conductive layers during textiles' lifetime (wear and care). The challenges, drawbacks and further opportunities in these fields are also discussed critically.


Affective Empathy in Behavioral Variant Frontotemporal Dementia: A Meta-Analysis.
Background: Empathy deficits are a widely recognized symptom in the behavioral variant frontotemporal dementia (bvFTD), and although several reviews have examined cognitive empathy deficits, there are no meta-analytic studies on affective empathy deficits. Objective: Identify salience of affective empathy in bvFTD. Method: A thorough review of affective empathy found 139 possible studies, but only 10 studies included measures of affective empathy and met standardized criteria. Results: BvFTD patients demonstrated a modest impairment compared to controls across all tasks (d = 0.98). Empathic concern as measured by the interpersonal reactivity index was particularly effected (d = 1.12). Conclusions: This study provides evidence for an increased commitment to observing affective empathy in bvFTD and capturing its role in the disorder.


Identification of myelodysplastic syndrome-specific genes by DNA microarray analysis with purified hematopoietic stem cell fraction.
Myelodysplastic syndrome (MDS) is a slowly progressing hematologic malignancy associated with a poor outcome. Despite the relatively high incidence of MDS in the elderly, differentiation of MDS from de novo acute myeloid leukemia (AML) still remains problematic. Identification of genes expressed in an MDS-specific manner would allow the molecular diagnosis of MDS. Toward this goal, AC133 surface marker-positive hematopoietic stem cell (HSC)-like fractions have been collected from a variety of leukemias in a large-scale and long-term genomics project, referred to as "Blast Bank," and transcriptome of these purified blasts from the patients with MDS were then compared with those from AML through the use of oligonucleotide microarrays. A number of genes were shown to be expressed in a disease-specific manner either to MDS or AML. Among the former found was the gene encoding the protein Delta-like (Dlk) that is distantly related to the Delta-Notch family of signaling proteins. Because overexpression of Dlk may play a role in the pathogenesis of MDS, the disease specificity of Dlk expression was tested by a quantitative "real-time" polymerase chain reaction analysis. Examination of the Blast Bank samples from 22 patients with MDS, 31 with AML, and 8 with chronic myeloid leukemia confirmed the highly selective expression of the Dlk gene in the individuals with MDS. Dlk could be the first candidate molecule to differentiate MDS from AML. The proposal is made that microarray analysis with the Blast Bank samples is an efficient approach to extract transcriptome data of clinical relevance for a wide range of hematologic disorders.


Training high--living low: changes of aerobic performance and muscle structure with training at simulated altitude.
This study was undertaken to test the hypothesis that endurance training in hypoxia is superior to training of the same intensity in normoxia. To avoid adaptation to hypoxia, the subjects lived under normoxic conditions when not training. A secondary objective of this study was to compare the effect of high- vs. moderate-intensity training on aerobic performance variables. Thirty-three men without prior endurance training underwent a cycle ergometer training of 6 weeks, 5 d/week, 30 minutes/d. The subjects were assigned to 4 groups, N-high, N-low, H-high and H-low based on the training criteria normoxia (N; corresponding to a training altitude of 600 m), vs. hypoxia (H; training altitude 3850 m) and intensity (high; corresponding to 80% and low: corresponding to 67% of VO2max). VO2max measured in normoxia increased between 8.5 to 11.1%, independent of training altitude or intensity. VO2max measured in hypoxia increased between 2.9 and 7.2%. Hypoxia training resulted in significantly larger increases than normoxia training. Maximal power that subjects could maintain over a thirty-minute period (measured in normoxia or hypoxia) increased from 12.3 - 26.8% independent of training altitude. However, subjects training at high intensity increased performance more than subjects training at a low intensity. Muscle volume of the knee-extensors as measured by magnetic resonance imaging increased significantly in the H-high group only (+ 5.0%). Mitochondrial volume density measured by EM-morphometry in biopsy samples of m. vastus lat. increased significantly in all groups with the highest increase seen in the H-high group (+ 59%). Capillary length density increased significantly in the H-high group only (+ 17.2%). The main finding of this study is that in previously untrained people, training in hypoxia while living at low altitude increases performance in normoxia to the same extent as training in normoxia, but leads to larger increases of aerobic performance variables when measured under hypoxic conditions. Training intensity had no effect on the gain of VO2max. On the level of skeletal muscle tissue, the combination of hypoxia with high training intensity constitutes the most effective stimulus for increasing muscle oxidative capacity.


The disposition of theophylline in patients with lung and breast cancer.
The influence of extrahepatic neoplastic disease on the biotransformation of theophylline was assessed by comparing the pharmacokinetic and metabolic profile of the drug in six patients with advanced breast or bronchial carcinoma, without detectable liver metastases, and in six appropriately matched control subjects. Each subject was given a single dose of theophylline (5 mg/kg) in oral solution; blood and urinary samples were collected for up to 24 h after dosing. Theophylline was absorbed rapidly in all subjects and within 2 h reached comparable peak concentrations in both groups (cancer patients: 57.8 +/- 14.4 mumol/l; controls; 65.0 +/- 10.6 mumol/l; N.S., means +/- s.d.). No significant differences were observed between cancer patients and controls for theophylline apparent volume of distribution (0.44 +/- 0.07 vs 0.40 +/- 0.06 l/kg), total body clearance (40.8 +/- 12.8 vs 34.8 +/- 13.0 ml kg-1 h-1) and elimination half-life (8.0 +/- 1.6 vs 8.5 +/- 1.8 h). The excretion of the major metabolites 3-methyl-xanthine and 1,3-dimethyl-uric acid was also very similar in the two groups. These data do not provide any evidence for an altered rate or pattern of theophylline biotransformation in patients with advanced extrahepatic neoplastic disease.


Randomized trial of group therapy for repeated deliberate self-harm in adolescents.
To compare group therapy with routine care in adolescents who had deliberately harmed themselves on at least two occasions within a year. Single-blind pilot study with two randomized parallel groups that took place in Manchester, England. Sixty-three adolescents aged 12 through 16 years were randomly assigned to group therapy and routine care or routine care alone. Outcome data on suicide attempts were obtained without knowledge of treatment allocation on all randomized cases (62/63 by direct interview) on average 29 weeks later. The primary outcomes were depression and suicidal behavior. In intention-to-treat analyses, adolescents who had group therapy were less likely to be "repeaters" at the end of the study (i.e., to have repeated deliberate self-harm on two or more further occasions) than adolescents who had routine care (2/32 versus 10/31; odds ratio 6.3), but the confidence intervals for this ratio were wide (95% confidence interval 1.4 to 28.7). They were also less likely to use routine care, had better school attendance, and had a lower rate of behavioral disorder than adolescents given routine care alone. The interventions did not differ, however, in their effects on depression or global outcome. Group therapy shows promise as a treatment for adolescents who repeatedly harm themselves, but larger studies are required to assess more accurately the efficacy of this intervention.


The mental health of adults born of unwanted pregnancies, their siblings, and matched controls: a 35-year follow-up study from Prague, Czech Republic.
This study tested the hypothesis that being born of an unwanted pregnancy is a risk factor for poor mental health in adulthood. Self-report and objective data were collected at ages 28 to 31 and 32 to 35 years in a cohort of nearly 200 "unwanted" subjects born after their mothers had been twice denied an abortion for the same pregnancy. The same data were collected in a sociodemographically matched control cohort of "accepted" subjects whose mothers had not requested an abortion, and from siblings of both the unwanted subjects and the accepted control subjects. Logistic regression analyses conducted with several indicators of poor mental health in adulthood as dependent variables brought partial support for the hypothesis. Specifically, unwanted subjects became psychiatric patients (especially psychiatric inpatients) more frequently than their siblings and the accepted controls. Criminality, alcohol-related disorders, and heavy smoking were not associated with unwanted pregnancy.


Time course and reversibility of changes in the gizzards of red knots alternately eating hard and soft food.
The ability to change organ size reversibly can be advantageous to birds that perform long migrations. During winter, red knots (Calidris canutus) feed on shellfish and carry a muscular gizzard that weighs 10% of their body mass. Gizzard size decreases when these birds eat soft foods, e.g. while breeding in the tundra. We studied the reversibility and time course of such changes using ultrasonography. Two groups of shellfish-adapted knots (N=9 and N=10) were fed alternately a hard and a soft food type. Diet switches elicited rapid reversible changes. Switches from hard to soft food induced decreases to 60% of initial gizzard mass within 8.5 days, while switches to hard food induced increases in gizzard mass to 147% within 6.2 days. A third group of knots (N=11), adapted to soft food for more than 1 year, initially had very small gizzards (25% of the mass of shellfish-adapted gizzards), but showed a similar capacity to increase gizzard size when fed shellfish. This is the first non-invasive study showing rapid digestive organ adjustments in non-domesticated birds.


Accelerated diversification is related to life history and locomotion in a hyperdiverse lineage of microbial eukaryotes (Diatoms, Bacillariophyta).
Patterns of species richness are commonly linked to life history strategies. In diatoms, an exceptionally diverse lineage of photosynthetic heterokonts important for global photosynthesis and burial of atmospheric carbon, lineages with different locomotory and reproductive traits differ dramatically in species richness, but any potential association between life history strategy and diversification has not been tested in a phylogenetic framework. We constructed a time-calibrated, 11-gene, 1151-taxon phylogeny of diatoms - the most inclusive diatom species tree to date. We used this phylogeny, together with a comprehensive inventory of first-last occurrences of Cenozoic fossil diatoms, to estimate ranges of expected species richness, diversification and its variation through time and across lineages. Diversification rates varied with life history traits. Although anisogamous lineages diversified faster than oogamous ones, this increase was restricted to a nested clade with active motility in the vegetative cells. We propose that the evolution of motility in vegetative cells, following an earlier transition from oogamy to anisogamy, facilitated outcrossing and improved utilization of habitat complexity, ultimately leading to enhanced opportunity for adaptive divergence across a variety of novel habitats. Together, these contributed to a species radiation that gave rise to the majority of present-day diatom diversity.


Metastatic tumours in the testis.
In a prospective autopsy study of male subjects with solic malignant neoplasms, six were shown to have metastatic deposits within the testis (2.5%). These were metastases from carcinoma of the prostate (two cases), melanoma (two cases), bronchial carcinoma (one case) and pleural mesothelioma (one case). In addition, four of 29 leukaemic patients and six of 28 with non-Hodgkin's lymphoma showed testicular involvement. The metastases from the solid tumours presented in solitary nodules, as multiple nodules or as a diffuse involvement. Microscopically, these were represented by tumour cells within the interstitial tissue without involvement of the seminiferous tubules; interstitial tissue and tubular involvement, and tumour confined to the seminiferous tubules respectively.


TCR beta chain influences but does not solely control autoreactivity of V alpha 14J281T cells.
CD1d-dependent accumulation of alphabeta T cells bearing a canonical Valpha14Jalpha281 alpha-chain (Valpha14+ T cells) is thought to model positive selection of lipid-specific T cells, based on their ability to recognize CD1d-presented self glycolipid(s). However, it has been difficult to demonstrate self ligand specificity in this system, as most Valpha14+ T cells do not exhibit significant autoreactivity despite high reactivity to alpha-galactosylceramide presented by CD1d (alpha-GalCer/CD1d). To assess the role of TCRbeta chain in determining the alpha-GalCer/CD1d vs autoreactive specificity of Valpha14+ T cells, we conducted TCRalpha or TCRbeta chain transduction experiments. In this study we demonstrate, by combining different TCRbeta chains with the Valpha14 alpha-chain in retrovirally transduced T cell lines, that the Valpha14 alpha-chain plays a primary role, necessary but not sufficient for imparting alpha-GalCer/CD1d recognition. beta-Chain usage alone is not the sole factor that controls the extent of autoreactivity in Valpha14+ T cells, since transduction of TCRalphabeta chains from a high CD1d autoreactive Valpha14+ T cell line conferred the alpha-GalCer/CD1d specificity without induction of autoreactivity. Thus, heterogeneity of Valpha14+ T cell reactivity is due to both beta-chain diversity and control mechanism(s) beyond primary TCR structure.


Mycobacterium kansasii.
The incidence of Mycobacterium kansasii varies widely over time and by region, but this organism remains one of the most clinically relevant isolated species of nontuberculous mycobacteria. In contrast to other common nontuberculous mycobacteria, M. kansasii is infrequently isolated from natural water sources or soil. The major reservoir appears to be tap water. Infection is likely acquired through the aerosol route, with low infectivity in regions of endemicity. Human-to-human transmission is thought not to occur. Clinical syndromes and radiological findings of M. kansasii infection are mostly indistinguishable from that of Mycobacterium tuberculosis, thus requiring microbiological confirmation. Disseminated disease is uncommon in HIV-negative patients and usually associated with severe immunosuppression. The majority of patients with M. kansasii pulmonary disease have underlying pulmonary comorbidities, such as smoking, chronic obstructive pulmonary disease, bronchiectasis, and prior or concurrent M. tuberculosis infection. Surveys in Great Britain, however, noted higher rates, with 8 to 9% of M. kansasii infections presenting with extrapulmonary disease. Common sites of extrapulmonary disease include the lymph nodes, skin, and musculoskeletal and genitourinary systems. The specificity of gamma interferon release assays (IGRAs) for M. tuberculosis may be reduced by M. kansasii infection, as M. kansasii encodes CFP-10 and ESAT-6, two antigens targeted by IGRAs. A study conducted to evaluate the therapy in rifampin-resistant disease found that patients with acquired rifampin resistance were treated with daily high-dose ethambutol, isoniazid, sulfamethoxazole, and pyridoxine combined with aminoglycoside therapy. Given the potential toxicities, particularly with aminoglycoside therapy, clarithromycin and/or moxifloxacin therapy could be considered as alternatives.


Plasticity of the differentiated state.
Heterokaryons provide a model system in which to examine how tissue-specific phenotypes arise and are maintained. When muscle cells are fused with nonmuscle cells, muscle gene expression is activated in the nonmuscle cell type. Gene expression was studied either at a single cell level with monoclonal antibodies or in mass cultures at a biochemical and molecular level. In all of the nonmuscle cell types tested, including representatives of different embryonic lineages, phenotypes, and developmental stages, muscle gene expression was induced. Differences among cell types in the kinetics, frequency, and gene dosage requirements for gene expression provide clues to the underlying regulatory mechanisms. These results show that the expression of genes in the nuclei of differentiated cells is remarkably plastic and susceptible to modulation by the cytoplasm. The isolation of the genes encoding the tissue-specific trans-acting regulators responsible for muscle gene activation should now be possible.


[CAPS: cryopyrin-associated periodic syndrome].
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by heterozygous mutations of NLRP3 gene. CAPS consists of three phenotypically similar but distinct syndromes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome and CINCA syndrome. Among them, FCAS shows the mildest phenotype while CINCA is the severest. Common symptoms include sporadic or cold-induced nonpruritic urticarial rash and fever. Severe cases suffers from deafness, meningitis, articular contracture and secondary amyloidosis. Gain-of-function mutations of NLRP3 causes excessive production of a potent proinflammatory cytokine IL-1β, thereby evokes autoinflammatory symptoms of CAPS. Recent advances of anti-IL-1 therapy dramatically improved the prognosis of CAPS. Currently three anti-IL-1 medicines are available, and all of them significantly improved clinical symptoms of CAPS patients. Although long-term observation is still needed, the molecular-targeted therapy has opened up a new opportunity for managing CAPS.


[Long-term observation and treatment of 30 cases of intrathoracic sarcoidosis].
The results of a long-term follow up for an average of 7.3 years (ranged from 6 months to 22 years) on 30 cases of intrathoracic sarcoidosis are reported. The course of the disease was more than 2 years in 90% (27/30), and less than 2 years in 10% (3/30). At the beginning of the observation, 53.3% (16/30) of the patients were in stage I, 36.7% (11/30) in stage II, and 10% (3/30) in stage III. But at the end of follow up, 6 cases had spontaneous remission, 9 had been cured, 6 were in stage II and 9 in stage III. Nor was in stage I or died. According to these results, the treatment of intrathoracic sarcoidosis is discussed.


Human Atopic Dermatitis Skin-derived T Cells can Induce a Reaction in Mouse Keratinocytes in vivo.
In atopic dermatitis (AD), the inflammatory response between skin-infiltrating T cells and keratinocytes is fundamental to the development of chronic lesional eczema. The aim of this study was to investigate whether skin-derived T cells from AD patients could induce an inflammatory response in mice through keratinocyte activation and consequently cause the development of eczematous lesions. Punch biopsies of the lesional skin from AD patients were used to establish skin-derived T cell cultures, which were transferred to NOD.Cg-Prkd(scid) Il2rg(tm1Sug) /JicTac (NOG) mice. We found that the subcutaneous injection of the human AD skin-derived T cells resulted in the migration of the human T cells from subcutis to the papillary dermis followed by the development of erythema and oedema in the mouse skin. Furthermore, the human T cells induced a transient proliferative response in the mouse keratinocytes shown as increased numbers of Ki-67(+) keratinocytes and increased epidermal thickness. Out of six established AD skin-derived T cell cultures, two were superior at inducing a skin reaction in the mice, and these cultures were found to contain >10% CCR10(+) T cells compared to <2% for the other cultures. In comparison, blood-derived in vitro-differentiated Th2 cells only induced a weak response in a few of the mice. Thus, we conclude that human AD skin-derived T cells can induce a reaction in the mouse skin through the induction of a proliferative response in the mouse keratinocytes.


IgG4-infiltrate in post-intubation tracheal stenosis: a call to interventional pulmonologist and thoracic surgeons.
Since December 2019, Sars-CoV2 infection has become a pandemic health emergency. The most severe manifestation of COVID-19 is acute respiratory distress syndrome requiring intensive care unit admission and mechanical ventilation. The most serious, although rare, complication of prolonged MV is post-intubation tracheal stenosis. We hypothesized that, in addition to recognized risk factors in COVID-19 patients, additional factors may promote airways injury. We analyzed data from 13 patients with PITS referred to our Thoracic Surgery Department from 2020 to 2022 divided in two groups: 8 ex-COVID-19 patients (in MV for ARDS during Sars-Cov2 positivity) and 5 non-COVID-19 patients (in MV for other reasons). Computer-tomography and bronchoscopy were performed to confirm diagnosis of PITS. Surgical treatment including tracheal resection and end-to-end anastomosis was performed in all patients. Tracheal samples were histologically analyzed to define the existence of any difference between the two groups. The presence of total immunoglobulin G (IgG) and immunoglobulin G4 (IgG4) were tested. IgG infiltrate was present in both groups. IgG4-infiltrate was significantly represented in the tracheal sample of ex-COVID-19 patients and absent in the non-COVID-19 cohort of patients. It is suggested that COVID-19 patients have almost double the risk of developing tracheal injuries. This work supports the idea of a major predisposition for such injuries in COVID-19 patients due to a possible immune-mediated mechanism leading to aberrant and fibrotic wound healing following a trigger insult (in this case MV with oro-tracheal tube). In the near future an increasing incidence of PITS is expected. Interventional pulmonologist and thoracic surgeons might be called to deal with this possibility. Clarification of the physiopathology of PITS is needed to prevent excessive tracheal scarring following prolonged endotracheal intubation and recurrence after endoscopic and/or surgical treatment. Careful prevention, early detection and effective management of this life-threatening condition are warranted.


Reactivity to nickel sulfate at sodium lauryl sulfate pretreated skin sites is higher in atopics: an echographic evaluation by means of image analysis performed on 20 MHz B-scan recordings.
The aim of this study was to establish an objectively assessable procedure simulating simultaneous exposure to irritants and allergens in domestic and occupational environments, in order to evaluate differences in the reactivity to the combination of these substances in atopic and non-atopic nickel-sensitized subjects. Thirty-four nickel-sensitive patients, 20 of whom were affected by atopic dermatitis, underwent four patch tests with NiSO4 0.05% aq. on two adjacent sites of both volar forearms, with a 24-h application time. Two of the test sites were treated with sodium lauryl sulfate (SLS) 5% for 30 min, before application of the nickel sulfate preparation. Echographic recordings were performed by a 20-MHz B-scanner and processed by an image analysis program, providing a numerical representation of the picture data, based on the attribution of fictional values to the amplitudes of the echoes. The dermal inflammatory reaction was quantified by an amplitude band, marking the hypo-reflecting part of the dermis, whereas epidermal damage was assessed by a band highlighting the entrance echo. Pre-treatment with SLS of the skin area where nickel sulfate was subsequently applied greatly enhanced the allergic response at 24 and 72 h, both in subjects with atopic dermatitis and in subjects with allergic contact dermatitis. However, in atopics, the increase in the allergic reactivity after irritation of the skin was more pronounced both by clinical and by echographic evaluation. These observations stress the importance of the concurrent action of irritants and allergens in maintaining the dermatitis in atopics.


Electrophysiological effects of melanocortin receptor ligands on neuronal activities of monoaminergic neurons in rats.
The melanocortin-4 (MC4) receptor may possibly be involved in stress and stress-related behavior. In the present study, we examined effects of an intracerebroventricular injection of the MC4 receptor agonist, Ac-[Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH 4-10-NH2 (MT II), and the MC4 receptor inverse agonist, Agouti-related protein (AGRP), on dorsal raphe nucleus (DRN) serotonergic neurons and the locus coeruleus (LC) noradrenergic neurons, both of which are brain neuronal systems related to responses to stress. The firing rate of DRN serotonergic neurons was increased by MTII, while AGRP had a lack of effect on the firing rate of DRN serotonergic neurons. In comparison with the DRN, MTII significantly reduced the firing rate of LC noradrenergic neurons, while AGRP increased LC neuronal activity. These findings suggest that MC4 receptor ligands differently regulate serotonergic and noradrenergic neuronal systems. The MC4 receptor mediating multiple regulation on the monoaminergic neuronal system may, in part, relate to stress responses (anxiety and/or depressive behavior).


Effects of long term vigabatrin on somatosensory evoked potentials in epileptic patients.
1. Vigabatrin has proved to be a very effective antiepileptic in clinical trials, with excellent long term tolerability. 2. The purpose of this study was to test the central nervous system (CNS) safety of the drug during long term clinical use, due to the existence of species-dependent intramyelinic oedema in animal toxicology studies. 3. Somatosensory evoked potentials were recorded repeatedly over a mean period of 11 months, in 54 adult patients with refractory epilepsy who received vigabatrin as add-on therapy to their current antiepileptic regime. 4. There was no suggestion throughout the study that vigabatrin could lead to a prolongation of neuronal conduction times within the CNS pathways. 5. The results are consistent with previous studies of somatosensory, visual and brainstem auditory evoked potentials in patients. In view of the results observed in the dog, where increases in central latencies of somatosensory evoked potentials were clearly apparent, these data provide strong reassurance about the neurological safety of vigabatrin in the treatment of epileptic patients.


β cell regeneration and novel strategies for treatment of diabetes (Review).
The etiology of diabetes is primarily attributed to the lack of functioning β cells, which in-turn leads to insulin deficiency or insulin resistance, and this ultimately leads to β cell dysfunction. Restoring the number and function of β cells is an effective means of improving or even curing diabetes. β cell regeneration is a potential method for increasing the number of functioning β cells. In addition to self-duplication of pancreatic β cells, β cells can be regenerated from embryonic stem cells, human induced pluripotent stem cells and pancreatic stem cells. Based on these mechanisms, proliferation and differentiation into functional β cells in vitro is one of the most promising strategies for treatment of diabetes. Although β cell regeneration has significant potential in the treatment of insulin-deficient diabetes, and significant progress has been made in this regard, there remains challenges which prevent its use in the clinic.


Medication administration: are you up to date?
Pharmacists working in long-term care facilities are often called upon to educate nurses and other care staff on proper medication-administration technique. New medications, as well as new drug-delivery methods for older medications, require all health care practitioners to learn about the specific manufacturers' recommendations for each product. In addition, keeping abreast of current infection-control standards is imperative for all staff administering medications.


Exaggerated activity of HPA axis in obese rats fed normocaloric liquid nutrition.
Experimental and clinical studies have shown alterations in activity of systems responsible for neuroendocrine stress response in obese individuals. Therefore we investigated the effect of palatable normocaloric liquid nutrition (Fresubin) on alterations in activity of the hypothalamic-pituitary-adrenal (HPA) axis in male Wistar rats of different developmental stages. Control rats (CON) received standard pellet chow all the time from weaning (21st day of age) to 150 days. Fresubin was administered throughout the experiment (LN), only in juvenility (from 21st to 90th day of age; LNJ) or only in adulthood (from 90th to 150th day of age; LNA). Body weight and energy intake were periodically monitored. Adrenal gland and fat tissue weight and plasma corticosterone levels (CORT) was determined after sacrification. Fresubin intake induced obesity in LN and LNA rats. In LN and LNA rats were observed elevated serum CORT levels, but only in LN rats with significant twofold increase compared to LNJ rats. However, the weight of adrenal glands did not differ between LN, LNJ and LNA experimental groups. Based on our results, we suggest, that obesity induced by Fresubin in LN and LNA rats is accompanied by increased HPA activity represented by elevated plasma CORT levels in these rats.


Infection Staging and Incidence Surveillance Applications of High Dynamic Range Diagnostic Immuno-Assay Platforms.
Custom HIV staging assays, including the Sedia HIV-1 Limiting Antigen (LAg) Avidity EIA and avidity modifications of the Ortho VITROS anti-HIV-1+2 and Abbott ARCHITECT HIV Ag/Ab Combo assays, are used to identify "recent" infections in clinical settings and for cross-sectional HIV incidence estimation. However, the high dynamic range of chemiluminescent platforms allows differentiating recent and long-standing infection on signal intensity, and this raises the prospect of using unmodified diagnostic assays for infection timing and surveillance applications. We tested a panel of 2500 well-characterized specimens with estimable duration of HIV infection with the 3 assays and the unmodified ARCHITECT. Regression models were used to estimate mean durations of recent infection (MDRIs), context-specific false-recent rates (FRRs) and correlation between diagnostic signal intensity and LAg measurements. Hypothetical epidemiological scenarios were constructed to evaluate utility in surveillance applications. Over a range of MDRIs (reflecting recency discrimination thresholds), a diluted ARCHITECT-based RITA produced lower FRRs than the VITROS platform (FRR ≈ 0.5% and 1.5%, respectively at MDRI ≈ 200 days), and the unmodified diagnostic ARCHITECT produces incidence estimates with comparable precision to LAg (relative SE ≈ 17.5% and 15%, respectively at MDRI ≈ 200 days). ARCHITECT S/CO measurements were highly correlated with LAg optical density measurements (r = 0.80), and values below 200 are strongly predictive of LAg recency and duration of infection less than 1 year. Low quantitative measurements from the unmodified ARCHITECT obviate the need for additional recency testing, and its use is feasible in clinical staging and incidence surveillance applications.


Effects of continuous conjugated estrogen and micronized progesterone therapy upon lipoprotein metabolism in postmenopausal women.
The effects of continuously administering both conjugated equine estrogens (CEE) and micronized progesterone (MP) on the concentration, composition, production and catabolism of very low density (VLDL) and low density lipoproteins (LDL) have not previously been reported. The mechanism of the hormonally induced reductions of plasma LDL cholesterol of S(f) 0;-20 (mean 16%, P < 0.005) and LDL apoB (mean 6%, P < 0.025) were investigated by studying the kinetics of VLDL and LDL apolipoprotein (apo) B turnover after injecting autologous (131)I-labeled VLDL and (125)I-labeled LDL into each of the 6 moderately hypercholesterolemic postmenopausal subjects under control conditions and again in the fourth week of a 7-week course of therapy (0.625 mg/d of CEE + 200 mg/d of MP). The combined hormones significantly lowered plasma LDL apoB by increasing the mean fractional catabolic rate of LDL apoB by 20% (0. 32 vs. 0.27 pools/d, P < 0.03). Treatment also induced a significant increase in IDL production (6.3 vs. 3.7 mg/kg/d, P = 0.028). However, this did not result in an increase in LDL production because of an increase in IDL apoB direct catabolism (mean 102%, P = 0.033). VLDL kinetic parameters were unchanged and the concentrations of plasma total triglycerides (TG), VLDL-TG, VLDL-apoB did not rise as often seen with estrogen alone. Plasma HDL-cholesterol rose significantly (P < 0.02). Our major conclusion is that increased fractional catabolism of LDL underlies the LDL-lowering effect of the combined hormones.


Bipartite regulation of different components of the MHC class I antigen-processing machinery during dendritic cell maturation.
Dendritic cells (DC) are professional antigen-presenting cells (APC) which proceed from immature to a mature stage during their final differentiation. Immature DC are highly effective in terms of antigen uptake and processing, whereas mature DC become potent immunostimulatory cells. Until now, the expression profiles of the major components of the MHC class I antigen-processing machinery (APM) during DC development have not been well characterized. In this study, the mRNA and protein expression levels of the IFN-gamma inducible proteasome subunits, of the proteasome activators PA28, and of key components required for peptide transport and MHC class I-peptide complex assembly have been evaluated in immature and mature stages of human monocyte-derived DC using semiquantitative RT-PCR and Western blot analyses. The IFN-gamma-responsive immunoproteasome subunits LMP2, LMP7 and MECL1 are up-regulated in immature DC, whereas the other components of the MHC class I presentation machinery, such as PA28, TAP, tapasin, and HLA heavy and light chains, were found to be more abundant in mature DC. These findings support the hypothesis that immature DC produced by the differentiation of monocytes in response to IL-4 and granulocyte macrophage colony stimulating factor first increase their capacity to capture antigens and process them into peptides, thereby switching from housekeeping to immunoproteasomes, while mature DC rather up-regulate the components required for peptide translocation and MHC class I-peptide complex formation, and thus specialize in antigen presentation. Our results establish that MHC class I, like MHC class II surface expression, is markedly regulated during DC development and maturation.


Monitoring of a Highly Flexible Aircraft Model Wing Using Time-Expanded Phase-Sensitive OTDR.
In recent years, the use of highly flexible wings in aerial vehicles (e.g., aircraft or drones) has been attracting increasing interest, as they are lightweight, which can improve fuel-efficiency and distinct flight performances. Continuous wing monitoring can provide valuable information to prevent fatal failures and optimize aircraft control. In this paper, we demonstrate the capabilities of a distributed optical fiber sensor based on time-expanded phase-sensitive optical time-domain reflectometry (TE-ΦOTDR) technology for structural health monitoring of highly flexible wings, including static (i.e., bend and torsion), and dynamic (e.g., vibration) structural deformation. This distributed sensing technology provides a remarkable spatial resolution of 2 cm, with detection and processing bandwidths well under the MHz, arising as a novel, highly efficient monitoring methodology for this kind of structure. Conventional optical fibers were embedded in two highly flexible specimens that represented an aircraft wing, and different bending and twisting movements were detected and quantified with high sensitivity and minimal intrusiveness.


Polymerase chain reaction for detection of Mycobacterium tuberculosis in epiretinal membrane in Eales' disease.
Tuberculous etiology has been suggested in Eales' disease. Because epiretinal membrane (ERM) is formed on the inner surface of the retina in Eales' disease, it could be the most appropriate intraocular specimen for investigation. Therefore, a nested polymerase chain reaction (nPCR), which detects MPB64 gene of Mycobacterium tuberculosis on the archival specimens of ERM of well-documented Eales' and non-Eales' patients, was applied and the results compared. nPCR technique was standardized, and the sensitivity and specificity of the primers were determined. nPCR technique was applied to tissue sections obtained from formalin-fixed and paraffin-embedded tissues of ERM from 23 patients with Eales' disease and 27 noninfective and non-Eales' disease patients as controls. nPCR technique was specific for M. tuberculosis genome and sensitive enough to detect 0.25 fg (corresponding to the presence of a single bacillus). Eleven (47.8%) ERM of 23 Eales' disease and 3 (11.1%) of 27 controls were positive for M. tuberculosis genome. The difference between the two groups was statistically significant (P = 0.001), indicating association of this bacterium with Eales' disease. The demonstration of the presence of M. tuberculosis DNA by nPCR technique in significant number of ERM of Eales' disease compared with the controls further emphasizes the probable role of this bacterium in the pathogenesis of this enigmatic clinical condition.


Factors influencing the separation of glu-plasminogen affinity forms I and II by affinity chromatography.
Native human plasminogen, the proenzyme of plasmin (E.C. 22.214.171.124) occurs in blood in two well defined forms, affinity forms I and II. In this paper, the feasibility of separating these forms of human native plasminogen by affinity chromatography, is shown to be dependent on two factors: 1) the ionic composition of the buffer containing the displacing agent: buffers of varying contents of sodium, Tris, phosphate and chloride ions were compared, and 2) the type of adsorbent. Two adsorbents were compared: Sepharose-lysine and Sepharose-bisoxirane-lysine. Only in the phosphate containing buffers, irrespective of the type of adsorbent, the affinity forms can be separated. The influence of the adsorbent can be accounted for by a large difference in dissociation constants of the complex between plasminogen and the immobilized lysine.


Expert Clinical Management of Severe Immune-Related Adverse Events: Results from a Multicenter Survey on Hot Topics for Management.
There are differences in recommendations for the management of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs). To assess the real-world management of irAEs, three surveys regarding ICI-induced hepatitis (IIH), renal irAEs, and myositis were developed and sent to experts in each area. Fifty-six surveys were completed (17 IIH, 20 renal irAEs, and 19 myositis). All experts agreed on performing imaging in every suspected case of severe IIH. Sixty-five percent agreed on performing a liver biopsy in patients not responding to corticosteroids. The most common indication for corticosteroid use (59%) was for severe IIH not improving after discontinuation of ICIs. Additionally, 60% of the experts agreed on performing a biopsy for stage 2/3 acute kidney injury (AKI), and 70% recommended imaging for any stage of AKI. Thirty-five percent favored corticosteroids in AKI patients with creatinine levels 2-3-fold above baseline. For myositis, 58% would recommend a muscle biopsy in a patient with weakness and creatine kinase levels of 5000 U/L; 47% would also opt for an endomyocardial biopsy when the troponin levels are increased. Fifty-eight percent recommended oral corticosteroids for myositis, and 37% recommended additional therapy, mainly immunoglobulins. These results show substantial differences in expert practice patterns for the management of severe liver, kidney, and muscular irAEs.


Perceived Fatigability: Utility of a Three-Dimensional Dynamical Systems Framework to Better Understand the Psychophysiological Regulation of Goal-Directed Exercise Behaviour.
A three-dimensional framework of perceived fatigability emphasises the need to differentiate between the qualitatively distinct inputs of sensory-discriminatory, affective-motivational and cognitive-evaluative processes that shape the perceptual milieu during prolonged endurance exercise. This article reviews the framework's utility to better understand how cause-effect relationships come to be and how perception-action coupling underpins pacing behaviour and performance fatigability. Preliminary evidence supports the hypotheses that perceived strain plays a primary role in trajectory regulation of pacing behaviour, core affect plays a primary and mediatory role in behavioural performance regulation, and the mindset shift associated with an action crisis plays a primary role in the intensity dependent volitional self-regulatory control of conflicting motivational drives. The constructs hypothesised to underpin perceived fatigability are systematically linked, context-dependent, constraint-based, distinguishable and show proportional continuous interdependency. They are further interrelated with dynamic changes in pacing behaviour, performance fatigability and physiological disturbance. Appropriate measurement selections for the subordinate constructs perceived physical strain, perceived mental strain, valence, arousal, action crisis and flow state are discussed. To better understand the non-proportional discontinuous effects of fatigue on discrete shifts in thought states and mindsets, non-linear dynamical systems theory is introduced as an unbiased overarching theory of governing principles in the temporal evolution of complex systems. This provides the opportunity to discuss the bio-psycho-social fatigue phenomenon from a dynamical and holistic perspective. The proposed framework offers a sophisticated alternative to the Gestalt concept of perceived exertion and comprehensively accounts for the psychophysiological processes that determine pacing behaviour and performance. It has the potential to enrich theory development and facilitate a deeper understanding of the psychophysiological regulation of goal-directed exercise behaviour.


Nitric oxide synthase mRNA levels correlate with gene expression of angiotensin II type-1 but not type-2 receptors, renin or angiotensin converting enzyme in selected brain areas.
Recent data suggest that there is interaction between peripheral angiotensin II and nitric oxide. However, sparse information is available on the mutual interaction of these two compounds in the brain. The potential intercourse of nitric oxide with brain neuropeptides needs to be substantiated by assessing its local production and gene expression of the synthesizing enzymes involved. The aim of the present study was to evaluate whether the gene expression of brain nitric oxide synthase (bNOS) is related to the sites of gene expression of different components of the rat brain renin angiotensin system (renin, angiotensin converting enzyme (ACE) or angiotensin receptors of AT1 and AT2 subtypes). The levels of corresponding mRNAs were measured and correlated in nine structures of adult rat brain (hippocampus, amygdala, septum, thalamus, hypothalamus, cortex, pons, medulla and cerebellum). As was expected, positive correlation was observed between renin and angiotensin-converting enzyme mRNAs. Moreover, a significant correlation was found between brain NO synthase and AT1 receptor mRNAs, but not with mRNA of the AT2 receptor, ACE and renin. Parallel distribution of mRNAs coding for bNOS and AT1 receptors in several rat brain structures suggests a possible interaction between brain angiotensin 11 and nitric oxide, which remains to be definitely demonstrated by other approaches.


Deference to Expertise: Making Care Safer.
Since the seminal report by the Institute of Medicine, To Err Is Human, was issued in 1999, significant efforts across the health care industry have been launched to improve the safety and quality of patient care. Recent advances in the safety of health care delivery have included commitment to creating high-reliability organizations (HROs) to enhance existing quality improvement activities. This article will explore key elements of the HRO concept of deference to expertise, describe the structural elements that support nurses and other personnel in speaking up, and provide examples of practical, evidence-based tools to help organizations support and encourage all members of the health care team to speak up.


[Association between obesity and risk for colorectal advanced adenoma].
Objectives: To understand the association between obesity and the risk for colorectal advanced adenoma. Methods: Community residents aged 45 to 74 who had participated in the Shanghai community-based colorectal cancer (CRC) screening project in 2008 were included in our study. Anthropometries information including body weight, height and risk factors for colorectal advanced adenoma were collected. Results on colonoscopic diagnosis and personal health records were used for supplementary outcome information retrieval. Multivariate Cox proportional hazard regression models were used to evaluate the hazard ratio (HR) and 95%CI of obesity on the risk for colorectal advanced adenoma. Results: 20 811 residents were followed up for 122 739.36 person-years, with a median follow-up time of 5.87 years. A total of 657 cases of advanced adenomas were identified. After adjusting for potential confounding risk factors such as age, sex, family history of CRC, level of education, marriage, cigarette smoking, alcohol drinking, foods intake including fat, fried or pickled, vegetables and fruits etc., the HR was 1.25 (95%CI: 1.04-1.51) for obese people when compared with the normal weight persons. Further stratified analysis by age, gender and family history of CRC, results showed that obese people had a much higher risk of colorectal advanced adenoma than those with normal weight (male: HR=1.57, 95%CI: 1.20-2.04; more than 60- year-old: HR=1.63, 95%CI: 1.23-2.16). Conclusion: Data from this large scale population-based study revealed that obesity might be an independent risk factor for colorectal advanced adenoma and the risk increases along with the increase of BMI in China.


Distribution of mannose receptor in blunt snout bream (Megalobrama amblycephala) during the embryonic development and its immune response to the challenge of Aeromonas hydrophila.
The mannose receptor (MR) is a type I transmembrane protein. Its ectodomain has eight C-type lectin-like domains, which are able to recognize and mediate the phagocytosis of a wide range of pathogens. Comprehensive studies have revealed that mammalian MR is widely distributed in the mononuclear phagocyte system (MPS, previously known as the reticuloendothelial system) and play a key role both in the physiological clearance and cell activation. Hitherto, neither the MR distribution, nor the function of clearance and cell activation has been investigated in fish. In the previous study, we have reported the full-length cDNA of blunt snout bream MR, analyzed its structure and relative mRNA expression during embryogenesis and in the liver, head kidney, spleen and intestine of fish after stimulation with killed Aeromonas hydrophila. In the present study, we developed a rabbit polyclonal antibody against MR and undertook a systematic survey of the expression of MR at the protein level by immunohistochemistry. To get more information about MR function, the mRNA expression of MR, pro-inflammatory factor TNF-α and anti-inflammatory factor ARG2 genes was measured by qRT-PCR in the liver, head kidney, and spleen after A. hydrophila challenge. We first observed MR expression in the yolk sac at the fertilized egg stage and possibly MR was expressed by early macrophages. We also showed the MR distribution in head kidney, body kidney, spleen, liver, intestine, muscle, brain, heart, and gills. Following A. hydrophila challenge the MR immunoreactive cells became more widespread in head kidney and spleen, which are the major reticuloendothelial systems of fish. The quantitative studies at mRNA levels showed that there exists a high correlation between MR expression and immune cytokine expressions after bacteria challenge.


Genome-Wide Identification and Expression Analysis of the Zinc Finger Protein Gene Subfamilies under Drought Stress in Triticum aestivum.
The zinc finger protein (ZFP) family is one of plants' most diverse family of transcription factors. These proteins with finger-like structural domains have been shown to play a critical role in plant responses to abiotic stresses such as drought. This study aimed to systematically characterize Triticum aestivum ZFPs (TaZFPs) and understand their roles under drought stress. A total of 9 TaC2H2, 38 TaC3HC4, 79 TaCCCH, and 143 TaPHD were identified, which were divided into 4, 7, 12, and 14 distinct subgroups based on their phylogenetic relationships, respectively. Segmental duplication dominated the evolution of four subfamilies and made important contributions to the large-scale amplification of gene families. Syntenic relationships, gene duplications, and Ka/Ks result consistently indicate a potential strong purifying selection on TaZFPs. Additionally, TaZFPs have various abiotic stress-associated cis-acting regulatory elements and have tissue-specific expression patterns showing different responses to drought and heat stress. Therefore, these genes may play multiple functions in plant growth and stress resistance responses. This is the first comprehensive genome-wide analysis of ZFP gene families in T. aestivum to elucidate the basis of their function and resistance mechanisms, providing a reference for precise manipulation of genetic engineering for drought resistance in T. aestivum.


Mitochondrial-targeted Signal transducer and activator of transcription 3 (STAT3) protects against ischemia-induced changes in the electron transport chain and the generation of reactive oxygen species.
Expression of the STAT3 transcription factor in the heart is cardioprotective and decreases the levels of reactive oxygen species. Recent studies indicate that a pool of STAT3 resides in the mitochondria where it is necessary for the maximal activity of complexes I and II of the electron transport chain. However, it has not been explored whether mitochondrial STAT3 modulates cardiac function under conditions of stress. Transgenic mice with cardiomyocyte-specific overexpression of mitochondria-targeted STAT3 with a mutation in the DNA-binding domain (MLS-STAT3E) were generated. We evaluated the role of mitochondrial STAT3 in the preservation of mitochondrial function during ischemia. Under conditions of ischemia heart mitochondria expressing MLS-STAT3E exhibited modest decreases in basal activities of complexes I and II of the electron transport chain. In contrast to WT hearts, complex I-dependent respiratory rates were protected against ischemic damage in MLS-STAT3E hearts. MLS-STAT3E prevented the release of cytochrome c into the cytosol during ischemia. In contrast to WT mitochondria, ischemia did not augment reactive oxygen species production in MLS-STAT3E mitochondria likely due to an MLS-STAT3E-mediated partial blockade of electron transport through complex I. Given the caveat of STAT3 overexpression, these results suggest a novel protective mechanism mediated by mitochondrial STAT3 that is independent of its canonical activity as a nuclear transcription factor.


Primary osteosarcoma of the uterus: a report of two cases.
Primary extraskeletal osteosarcoma is an uncommon disease and has been reported to affect the uterus only rarely. Less than 20 cases have so far been reported in the English literature. The common clinical presentation is heavy bleeding per vaginam, and in virtually all cases, the diagnosis has been made at an advanced stage of the disease. Various authors have recommended adjuvant chemotherapy, but outcomes have so far been uniformly poor, with survival extended by months rather than years. We present two cases of this rare condition, which were diagnosed four months apart within our histopathology laboratory andconfirmed the very late presentation of the disease in one and the poor survival of both patients. None declared.


Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication.
To investigate the role of Delta-like ligand 4 (DLL4) on tumour growth in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) in vivo. We suppressed DLL4 expression in an HBV expressing HCC cell line, HepG2.2.15 and analysed the growth ability of cells as subcutaneous tumours in nude mice. The expression of tumour angiogenesis regulators, VEGF-A and VEGF-R2 in tumour xenografts were examined by western blotting. The tumour proliferation and neovasculature were examined by immunohistochemistry. The viral replication and viral protein expression were measured by quantitative PCR and western blotting, respectively. Eighteen days after implantation, tumour volume in mice implanted with shDLL4 HepG2.2.15 was significantly smaller than in mice implanted with control HepG2.2.15 (P < 0.0001). The levels of angiogenesis regulators, VEGF-A and VEGF-R2 were significantly decreased in implanted tumours with suppressed DLL4 compared with the control group (P < 0.001 and P < 0.05, respectively). Furthermore, the suppression of DLL4 expression in tumour cells reduced cell proliferation and the formation of new blood vessels in tumours. Unexpectedly, increased viral replication was observed after suppression of DLL4 in the tumours. This study demonstrates that DLL4 is important in regulating the tumour growth of HBV-associated HCC as well as the neovascularization and suppression of HBV replication.


Increased patient information does not reduce patient anxiety regarding urodynamic studies.
To establish if patient anxiety pre-urodynamic investigation can be reduced by providing more information within the patient information sheet (PIS). Two prospective cohorts of consecutive patients (round 1, n = 98 and round 2, n = 94) were asked to complete a visual analogue scale (VAS) quantifying their anxiety prior to urodynamics (UDS) and again after UDS quantifying their anxiety of potentially repeating UDS. Patients in round 1 received the standard hospital PIS. Concurrently with round 1, a parallel group of patients (n = 95) completed a questionnaire regarding their experience of UDS and their post-UDS complications. This information was incorporated into a revised PIS used in round 2. In both rounds, the VAS reduced post-UDS (Wilcoxon matched-pairs test p < 0.001). In females, pre-UDS VAS was significantly higher in round 2 than round 1 (Mann-Whitney U test p = 0.037). In males, pre-UDS VAS was lower in round 2 than round 1, but this difference was not statistically significant (Mann-Whitney U test p = 0.112). Post-UDS VAS was remarkably similar between round 1 and 2. Patients are less anxious about having repeat UDS regardless of the depth of information provided. However, more detailed information before UDS failed to significantly reduce patient anxiety.


[Segmental resection of the liver by Glissonean pedicle transection for primary liver cancer].
To study the clinical effect of segmental resection of the liver using Glissonean pedicle transection for primary liver cancer. The clinical data of 55 primary liver cancer patients admitted from January 2006 to October 2008 were analyzed retrospectively. Twenty-five of the patients underwent segmental resection of the liver by Glissonean pedicle transection (group A), and 30 underwent routine hepatectomy (group B). The positivity rate of the resection margin, micrometastasis in the hepatic parenchyma surrounding the lesions and postoperative recurrence rates were investigated. The positivity rate of the resection margin was 4.0% in group A, significantly lower than that of group B. The number of histological micrometastasis was significantly higher in group A than in group B (16 vs 8). The median distance of histological micrometastasis was 6.8 mm (2.7-25.6 mm) in group A and 4.2 mm (2.4-9.0 mm) in group B. The one-year recurrence rate was significantly lower in group A than in group B (16% vs 26.7%). Glissonean pedicle transection for segmental liver resection is a simpler procedure than routine hepatectomy for primary liver cancer and can reduce the number of histological micrometastasis and recurrence rate.


Corticotropin-releasing factor receptors in human pituitary gland: autoradiographic localization.
Corticotropin-releasing factor (CRF) receptors were localized in the human pituitary gland by an in vitro labeling light microscopic autoradiographic technique using an 125I-labeled analog of ovine CRF substituted with norleucine and tyrosine at amino acid residues 21 and 32, respectively. Specific binding sites for CRF were observed in the anterior lobe while no specific binding sites for CRF were present in the posterior pituitary lobe. The CRF binding sites in the anterior lobe occurred in clusters which predominated in the anteromedial portion of the lobe. This pattern of localization of CRF binding sites resembles previously reported distributions of corticotrophs in anterior pituitary. These data support the physiological role of endogenous CRF in regulating hormone secretion from the anterior lobe of the human pituitary.


Structure and properties of major largomycin FII chromophore components.
Largomycin FII, a protein antitumor antibiotic of molecular weight 29,300 daltons, contains a chromophore that is separable under mild denaturing conditions. The chromophore complex was found to be considerably less stable than the holoprotein towards light and heat, suggesting a protective effect of the protein on the chromophore. Separation of the chromophore into several components was achieved using high performance liquid chromatography, and the biological activity of the isolated components was determined. Data gathered from UV, IR, proton and carbon NMR, and fast atom bombardment mass spectrometry indicated that all the chromophore components belong to the pluramycin class of antitumor agents. Pluramycin A and deacetylpluramycin A were found to be the two major components.


Nutritional status of the elderly. III. Vitamin nutriture of elderly pensioners in Perugia.
The thiamin, riboflavin, vitamin C, vitamin A, folacin, and vitamin B12 nutriture was assessed in a longitudinal study in 206 aged pensioners of the city of Perugia. The prevalence of thiamin and riboflavin malnutrition, particularly in men, was rather high. Unexpectedly low values of plasma vitamin C were not uncommon among men. For folacin there were a large number of individuals with low plasma levels, while the plasma levels of vitamin A and B12 is in general satisfactory. As in other studies, no significant correlation between vitamin nutriture and intake was found.


Evaluating Birth Frequencies and Embryonic Lethality in Transgenesis Following Pronuclear Injection of HIV DNA.
The likelihood that expression of a foreign gene in a mammalian cell is deleterious to viability is confronted whenever novel transgenic animals are made. A pathological response to transgene expression is even desired in transgenic mouse models of human disease. The derivation of HIV-transgenic mice in our laboratory using multiple recombinant forms of an HIV provirus has resulted in mixed success best explained by the variable toxicity of the different transgenes. Employing a standardized approach to pronuclear injections, experimental variation amongst recombinant HIV transgenes was documented in terms of the percentage of pregnancies following embryo transfer into pseudopregnant mice and the percentage of transplanted embryos leading to term births in these pregnant females (giving rise to an index of birth success, SI). Results compiled over 5 years suggested that the SI reflected transgene toxicity, in this case of HIV gene products early in embryogenesis. These observations have guided the design of productive transgenes for mouse models of HIV-related diseases and may be generally applicable in transgenesis. Copyright 1995 S. Karger AG, Basel