Oral-facial-digital syndrome with fibular aplasia: a new variant.
The oral-facial-digital (OFD) syndromes constitute a heterogeneous group of entities usually associated with certain features that permit a specific diagnosis. This report refers to a 10-month-old girl with cleft palate, mesomelic limb shortening, oligopolydactyly, and fibular aplasia. Since this combination has not been described previously, it is proposed as a distinct type of oral-facial-digital syndrome, and we suggest mutations of homeotic genes to explain some abnormalities present in the OFD syndromes.


Catheter ablation using advanced porous tip contact force-sensing radiofrequency catheter: Impact on health care utilization among patients with persistent atrial fibrillation.
Catheter ablation (CA) is an effective treatment for patients with persistent atrial fibrillation (PsAF); however, little is known about its impact on health care utilization for patients with PsAF. The ThermoCool SmartTouch SF (STSF) catheter (Biosense Webster) incorporates an advanced porous tip and contact force-sensing technology. The purpose of this study was to determine health care utilization among patients with PsAF who underwent ablation with the STSF catheter. A retrospective cohort study using the Premier Healthcare Database identified patients with PsAF undergoing CA with the STSF catheter in inpatient and outpatient settings. The proportion of patients experiencing AF-related inpatient admissions, outpatient admissions, emergency department (ED) visits, electrical cardioversion, and a composite outcome in the 12 months pre- vs postablation were compared using the McNemar test. Subanalyses were performed on study outcomes by race/ethnicity. The final sample included 3077 patients (mean age 65.9 years; 31.7% female). Among patients with PsAF undergoing ablation with the STSF catheter, relative reductions in health care utilization in the 12 months post- vs preablation included 55.3% in AF-related inpatient admissions (P <.0001), 38.9% in outpatient admissions (P <.0001), 52.4% in ED visits (P <.0001), and 61.2% in electrical cardioversions (P <.0001). Composite outcome utilization in the 12 months post- vs preablation declined by 40.2% (P <.0001) for the overall cohort, 40.0% for White patients (P <.0001), 52.2% for Black patients (P <.0001), and 50.1% for Asian patients (P = .032). Significant improvements in health care utilization were observed among PsAF patients who underwent ablation using the STSF catheter. Improvements were particularly marked in underrepresented racial and ethnic groups.


[Segmental monobloc osteotomy and bi-directional distraction for the treatment of Crouzon syndrome in an infant].
To discuss the segmental monobloc osteotomy and bi-directional distraction for the treatment of Crouzon syndrome in an infant. A 9-month-old female infant underwent monobloc osteotomy through combined intra- and extra-cranial way. The facial skull was divided into frontal, orbital and maxillary segments. The external distractor was used to move the frontal segment, orbital segment and midface forward. The internal distractor was used to move the maxilla downward. The consolidation lasted for 3 months after distraction. The osteotomy and distraction were successfully completed. The distraction distance reached 18 mm, showing by distractor. The real distraction distance of facial bone was 12 mm, documented by 3-D image. The skull deformity and severe depression of midface improved a lot. The exophthalmos and underbite were corrected. The obstructive sleep apnea also improved markedly. However, the downward movement of maxilla was limited. Monobloc osteotomy with external distractor, as well as maxillary distraction, could be used for Crouzon syndrome in infant. It is safe and effective method which can be performed in an early age for Crouzon syndrome with obstructive sleep apnea.


Evidence for the early reduction of the 24,25 double bond in the conversion of lanosterol to cholesterol in cerebrotendinous xanthomatosis.
The metabolism of lanosterol and 24,25-dihydrolanosterol (DL) was examined in a patient with cerebrotendinous xanthomatosis after intravenous pulse labeling with a mixture of DL-2-14C and 3S,4S,3R,4R-(4-3H)mevalonate. Sterols were isolated from the feces and purified by silver nitrate thin-layer chromatography, and their identities were confirmed by gas-liquid chromatography and mass spectrometry. Their specific activities were then determined and plotted as a function of time. These isotope ratio measurements and specific activity decay curves were consistent with 24,25-dihydrolanosterol and delta7-cholestenol being intermediates in the synthesis of cholesterol from mevalonate and lanosterol, and they suggested that reduction of the lanosterol side chain may occur as an early step in the synthesis of cholesterol. These results are in contrast to the results reported after the administration of triparanol, a delta24-reductase inhibitor.


Prokaryotic diversity in sediments beneath two polar glaciers with contrasting organic carbon substrates.
Microbial ecosystems beneath glaciers and ice sheets are thought to play an active role in regional and global carbon cycling. Subglacial sediments are assumed to be largely anoxic, and thus various pathways of organic carbon metabolism may occur here. We examine the abundance and diversity of prokaryotes in sediment beneath two glaciers (Lower Wright Glacier in Antarctica and Russell Glacier in Greenland) with different glaciation histories and thus with different organic carbon substrates. The total microbial abundance in the Lower Wright Glacier sediment, originating from young lacustrine sediment, was an order of magnitude higher (~8 × 10(6) cells per gram of wet sediment) than in Russell Glacier sediment (~9 × 10(5) cells g(-1)) that is of Holocene-aged soil origin. 4% of the microbes from the Russell Glacier sediment and 0.04-0.35% from Lower Wright Glacier were culturable at 10°C. The Lower Wright Glacier subglacial community was dominated by Proteobacteria, followed by Firmicutes. The Russell Glacier library was much less diverse and also dominated by Proteobacteria. Low numbers and diversity of both Euryarchaeota and Crenarchaeota were found in both sediments. The identified clones were related to bacteria with both aerobic and anaerobic metabolisms, indicating the presence of both oxic and anoxic conditions in the sediments.


PCA-based localization approach for segmentation of optic disc.
The optic disc is the origin of the optic nerve, where the axons of retinal ganglion cells join together. The size, shape and contour of optic disc are used for classification and identification of retinal diseases. Automatic detection of eye disease requires development of an efficient algorithm. This paper proposes an efficient method for optic disc segmentation and detection for the diagnosis of retinal diseases. The methodology involves optic disc localization, blood vessel inpainting and optic disc segmentation. Localization is based on principal component analysis, and segmentation is based on Markov random field segmentation. In order to get reasonable background images, blood vessel inpainting is done before segmentation. The proposed method tested with two standard databases MESSIDOR and DRIVE, and achieved an average overlapping score of 92.41, 92.17%, respectively; also validation experiments were done with one local database from Venu Eye Hospital, New Delhi, and obtained an average overlapping score of 91%. An efficient algorithm is developed for detecting optic disc using principal component analysis-based localization and Markov random field segmentation. The comparison with alternative method yielded results that demonstrate the superiority of the proposed algorithm for optic disc detection.


Towards liver segmentation in the wild via contrastive distillation.
Automatic liver segmentation is a key component for performing computer-assisted hepatic procedures. The task is challenging due to the high variability in organ appearance, numerous imaging modalities, and limited availability of labels. Moreover, strong generalization performance is required in real-world scenarios. However, existing supervised methods cannot be applied to data not seen during training (i.e. in the wild) because they generalize poorly. We propose to distill knowledge from a powerful model with our novel contrastive distillation scheme. We use a pre-trained large neural network to train our smaller model. A key novelty is to map neighboring slices close together in the latent representation, while mapping distant slices far away. Then, we use ground-truth labels to learn a U-Net style upsampling path and recover the segmentation map. The pipeline is proven to be robust enough to perform state-of-the-art inference on target unseen domains. We carried out an extensive experimental validation using six common abdominal datasets, covering multiple modalities, as well as 18 patient datasets from the Innsbruck University Hospital. A sub-second inference time and a data-efficient training pipeline make it possible to scale our method to real-world conditions. We propose a novel contrastive distillation scheme for automatic liver segmentation. A limited set of assumptions and superior performance to state-of-the-art techniques make our method a candidate for application to real-world scenarios.


Longitudinal and cross-sectional associations between the dietary inflammatory index and objectively and subjectively measured sleep among police officers.
Police officers experience exposures associated with increased inflammation, such as the stress associated with shiftwork and poor-quality diet, both of which have been shown to affect sleep duration and quality. This study examined the longitudinal and cross-sectional effects of the Energy-density Dietary Inflammatory Index (E-DII™) on objectively and subjectively measured sleep among police officers. Data were derived from the Buffalo Cardio-Metabolic Occupational Police Stress Cohort (n = 464 at baseline), with longitudinal data collected from 2004 to 2019. A food frequency questionnaire obtained estimated dietary intake from which E-DII scores were calculated. Dependent variables were objectively (Micro Motion Logger Sleep Watch™) and subjectively (Pittsburgh Sleep Quality Index) measured sleep quality and quantity. The analyses included a series of linear mixed-effects models used to examine cross-sectional and longitudinal associations between the E-DII and sleep quantity and quality. Cross-sectionally, more pro-inflammatory diets were associated with higher wake-after-sleep-onset but improved subjective sleep quality. In models accounting for both longitudinal and cross-sectional effects, for every 1-unit increase in the E-DII scores over time (representing a pro-inflammatory change), wake-after-sleep-onset increased by nearly 1.4 min (p = 0.07). This result was driven by officers who primarily worked day shifts (β = 3.33, p = 0.01). Conversely, for every 1-unit increase in E-DII score, the Pittsburgh Sleep Quality Index global score improved. More pro-inflammatory diets were associated with increased wake-after-sleep-onset, an objective measure of sleep quality. Intervention studies to reduce dietary inflammatory potential may provide greater magnitude of effect for changes in sleep quality.


A study of anaesthesia-related cardiac arrest from a Chinese tertiary hospital.
The present survey evaluated the incidence of perioperative cardiac arrests in a Chinese tertiary general teaching hospital over ten years. The incidence of cardiac arrest that occurred within 24 h of anaesthesia administration was retrospectively identified in the Third Affiliated Hospital of Sun Yat-Sen University between August 2007 and October 2017. Overall, 152,513 anaesthetics were included in the study period. Data collected included patient characteristics, American Society of Anaesthesiologists (ASA) physical status score, surgical specialty and anaesthesia technique. Cardiac arrests were assigned to one of three groups: "anaesthesia-related", "anaesthesia-contributing" or "anaesthesia-unrelated". In total, 104 cardiac arrests (6.8:10,000) and 34 deaths (2.2:10,000) were obtained. Among them, eleven cardiac arrests events were anaesthesia-related, resulting in an incidence of 0.7 per 10,000 anaesthetics. Sixteen cardiac arrests events were found to be anaesthesia-contributing, resulting in an incidence of 1.0 per 10,000 anaesthetics. Cardiovascular adverse events were the major events that contributed to anaesthesia-related cardiac arrest. Differences were found between events related and unrelated to anaesthesia with regard to ASA physical status and anaesthesia technique (P < 0.05). Anaesthesia-related cardiac arrest occurred in 11 of 104 cardiac arrests within 24 h of anaesthesia administration. Most cardiac arrests related to anaesthesia were due to cardiovascular events, including arrhythmia and hypotension after intravenous narcotic, as well as haemorrhage. ASA physical status of at least 3 and subarachnoid block appeared to be relevant risk factors for anaesthesia-related cardiac arrest.


Absorption of magnesium chloride solution in small bowel disease.
The absorption of a magnesium chloride solution has been observed by balance studies in three patients with ileal resections and in one patient with idiopathic steatorrhoea and biliary cirrhosis. All patients were depleted of magnesium because of malabsorption. The mean net absorption of magnesium increased to 4.5, 4.9, 5.8 and 16.4 mmol magnesium per day, when a supply of 25 mmol magnesium was given. The result was encouraging with positive magnesium balances in all patients.


Effect of oral combination therapy with mexiletine and quinidine on left and right ventricular function.
Combination therapy with mexiletine (MEX) and quinidine (Q) may be more efficacious than monotherapy with either drug in suppressing ventricular arrhythmias, but its effects on ventricular performance are not known. Thus, right ventricular ejection fraction (RVEF) and left ventricular ejection fraction (LVEF) and wall motion score (WMS) were assessed in 14 patients with ventricular tachycardia before antiarrhythmic therapy, during MEX and Q monotherapies, and during combination therapy. During monotherapy, the daily doses and serum drug levels were: MEX, 621 mg/day and 3.4 microM/L; Q, 1573 mg/day and 8.3 microM/L, respectively. With combination therapy, the daily doses and serum drug levels were: MEX, 636 mg/day and 3.3 microM/L; Q, 1643 mg/day and 9.5 microM/L, respectively. Drug therapy did not affect group LVEF (drug free = 36 +/- 19%, MEX = 34 +/- 18%, Q = 36 +/- 19%, and combination MEX-Q = 35 +/- 19%), RVEF (drug free = 34 +/- 11%, MEX = 35 +/- 11%, Q = 36 +/- 13%, and combination MEX-Q = 36 +/- 12%), or WMS. Ventricular function reserve was assessed in five patients. Drug therapy did not affect group exercise LVEF (drug free = 44 +/- 14%, MEX = 42 +/- 12%, Q = 43 +/- 13%, and MEX-Q = 45 +/- 12%), RVEF (drug free = 38 +/- 10%, MEX = 40 +/- 11%, Q = 39 +/- 12%, and MEX-Q = 40 +/- 12%), WMS, or exercise duration. Combination MEX-Q therapy did not have a significant effect on exercise performance or ventricular function in seven additional patients in whom no exercise studies were done during monotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)


Alterations in retinal nerve fiber layer thickness following indirect traumatic optic neuropathy detected by nerve fiber analyzer, GDx-N.
To evaluate changes in the retinal nerve fiber layer following traumatic optic neuropathy. Observational case report. A patient presented with visual loss after an accident. Scanning laser polarimetry was performed. Thickness of the retinal nerve fiber layer increased immediately after the trauma but then progressively decreased. Severe loss was observed at day 90 and then ceased. Enlargement of the optic disk cup was also observed. This is the first report documenting early transient increase followed by progressive loss of the retinal nerve fiber layer in traumatic optic neuropathy.


Main branch stent deformation following difficult side branch rewiring and balloon dilatation. Rare complication of provisional T stenting.
Coronary artery bifurcations are one of the largest challenges in interventional cardiology. Presented is the case of a patient in whom restenosis of a drug-eluting stent (DES) occurred as a consequence of guide wire re-crossing between the main vessel stent struts and the vessel wall in the proximal part of DES, and consequential balloon crushing of the proximal portion of the DES. Initially, the complication was not recognized because of a good angiographic result and absence of intravascular ultrasound (IVUS) guidance during the procedure. During the second procedure, IVUS analysis explained the mechanism of the DES failure. The problem was solved with the implantation of a new DES.


Pickering emulsions stabilized by soybean protein isolate/chitosan hydrochloride complex and their applications in essential oil delivery.
In this work, fabrication of soybean protein isolate (SPI)/chitosan hydrochloride (CHC) composite particles stabilized O/W Pickering emulsions using soybean oil as an oil phase was optimized by examining the effects of pH, SPI/CHC mass ratio, SPI/CHC composite particle concentration and oil phase fraction on the stability of the emulsions. The results showed that under the conditions of SPI/CHC mass ratio 1:1, pH 4 and particle concentration 2 %, the SPI/CHC composite particles could stabilize the emulsions with oil phase fraction up to 80 %. At an oil phase fraction of 60 %, the emulsions had a minimum particle size. The microstructure, storage and oxidation stabilities and rheological properties of the emulsions were determined. Using this SPI/CHC composite particle-stabilized Pickering emulsion template, citrus essential oil (CEO) Pickering emulsion (CEOP) was prepared. CEOP was found to markedly inhibit two food-related microorganisms, Staphylococcus aureus and Escherichia coli. In addition, the CEOP emulsion dilution (containing 4500 μL CEO/L) not only improved the water solubility of CEO, but also effectively retarded the browning and bacterial growth of fresh-cut apple. The SPI/CHC-stabilized Pickering emulsion template constructed in this work provides a promising alternative for the delivery of antimicrobial essential oils in the food industry.


The ultrasound score and fetal heart-rate pattern as predictor of fetal outcome.
Over a period of one year 312 high-risk patients (HRP) were prospectively monitored using ultrasound score (USS), nonstress test (NST) and contraction stress test (CST). There were nine cases with low USS, seven of them had reactive NSTs, were delivered vaginally without any evidence of distress in labour and had normal Apgar scores with no perinatal morbidity. In the remaining two cases the NST was nonreactive and they were delivered by cesarean section because of fetal distress. The NST was not reactive in 18 patients, eight of them subsequently had abnormal CST and displayed fetal distress during labour. The USS was high in 16 cases. The results of this study seems to indicate that in cases with nonreactive NST, CST is a better predictor of fetal outcome than the ultrasound score.


Dexamethasone regulation of terminal differentiation in 3T3-F442A preadipocyte cell line.
The 3T3-F442A preadipocyte cell line was previously shown to possess specific glucocorticoid receptors whose number increased in the time course of differentiation. We have examined the effects of a three day dexamethasone treatment, added at confluence, on cells differentiated in the presence or absence of insulin. Triglyceride accumulation, polyamine content as well as glycerophosphate dehydrogenase and fatty acid synthetase activities were measured during the adipose conversion. We have also determined 2-deoxyglucose uptake in non-differentiated and differentiated cells. Dexamethasone was shown to decrease the adipose conversion by 3T3-F442A cells in the presence or absence of insulin. Intracellular spermidine content in differentiating cells was sensitive to dexamethasone and insulin in the same way as an enzymatic marker of terminal differentiation, glycerophosphate dehydrogenase. Dexamethasone decreases the 2 deoxyglucose uptake in non-differentiated and differentiated cells while insulin increases this uptake only in differentiated cells. This work shows that glucocorticoids inhibit adipocyte metabolism at distinct levels and suggests that these hormones might play an important role in the regulation of adipose tissue mass.


Preparation and characterization of a dihydromyricetin-sugar beet pectin covalent polymer.
A dihydromyricetin (DMY)-sugar beet pectin (SBP) covalent polymer was prepared using an alkaline method for the first time, and its structure and physicochemical properties were characterized. The results showed that the molecular weight, total phenol content, and ABTS radical scavenging ability of the polymer were positively correlated with DMY dosage. The polymer inhibited α-glucosidase in a mixed non-competitive and anti-competitive inhibition manner, and its inhibition performance depended on the total phenol content. Its maximum inhibitory activity was much higher than that of DMY, which was attributed to its strong protein binding capacity. The stability and β-carotene protective effects of the nano-emulsions stabilized with the DMY-SBP polymers were also positively correlated to the total phenol content and were superior to those stabilized by SBP. Therefore, the results obtained in this study may improve our functional understanding of natural polyphenol-polysaccharide polymers and promote the development of new nutraceuticals.


Adenocarcinoma of the esophagus: a survival study.
A 35 year review of adenocarcinomas of the esophagus was undertaken. We found the disease to be one of increasing incidence afflicting white males disproportionately. Risk factors remain to be clarified. Radiation therapy in curative doses and complete resection were competitively effective in terms of long-term survival. No survival advantage was found with palliative surgery compared with other means of therapy. Optimal combinations of treatment remain to be discovered.


Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma.
The authors reviewed a series of adult patients with extremity soft tissue sarcoma to determine the incidence of pulmonary metastases and outcome after treatment. Of 716 patients admitted between January 1983 and December 1990, 135 (19%) had isolated pulmonary metastases as the initial site of distant recurrence. Fifty-eight percent (78 of 135) of the patients were treated surgically, and 83% of them had their tumors completely resected. The median survival after complete resection was 19 months; incomplete resection, 10 months; and no operation, 8 months (p = 0.005). The 3-year survival rate after complete resection was 23%, compared with a 2% rate (1 of 57) in those treated nonsurgically (p < 0.001). Factors associated with an increased risk of pulmonary metastases included high tumor grade, tumor size greater than 5 cm, lower extremity site, and histologic type (spindle cell, tendosynovial, and extraskeletal osteosarcoma). Factors associated with complete resectability were the histologic types of spindle cell and extraskeletal osteosarcoma. Complete surgical resection remains the only possibility for cure from pulmonary metastases in soft tissue sarcoma; however, only 11% of the 19% of patients with an extremity sarcoma whose first distant recurrence is in the lung will be alive at 3 years, despite therapy. Complete resection and the development of more effective adjuvant treatments are imperative to improve outcome for this group of patients.


Endovascularly Treated Superficial Femoral Artery Aneurysm Rupture Secondary to Campylobacter fetus Bacteremia: A Case Report.
Degenerative aneurysms of the superficial femoral artery (SFA) are relatively rare and often recognized when they become symptomatic such as rupture. Infected SFA aneurysms are much rarer, especially those caused by Campylobacter fetus bacteremia. We report a case of a 67-year-old woman referred to our hospital owing to the presence of a painful reddish swelling on her left thigh. A huge SFA aneurysm rupture was diagnosed, and endovascular treatment with a covered stent was performed. C. fetus was detected in the blood culture thereafter, and antibacterial therapy was successfully performed without any additional surgical interventions. She remained well without any evidence of indolent infection 19 months after the endovascular treatment. The endovascular approach with appropriate prolonged antibacterial therapy would be a feasible alternative for managing selected infected aneurysm cases.


The effect of ohmic return currents on biomagnetic fields.
To illustrate the calculation methods used for biomagnetic fields we present a detailed calculation of the B-field from a spherical cell in an infinite ohmic bath. The calculation is done from three approaches and the results are used to clarify some misinterpretations that may seem to be biophysical problems but are, in fact, creatures of the formalism used.


The stabilization of the C3b molecule in immune deposits by formalin.
Formalin-fixed tissue may be used as substrate for immunohistochemistry after enzymatic treatment with proteases. However, whether the antigenicity of C3b is restored is controversial owing to the protease sensitivity of the native molecule. The antigenicity and protease sensitivity of formalin-fixed and non-fixed C3b were tested by using C3b-opsonized yeast particles and the immunofluorescence technique. The results indicate that formalin, probably due to cross-linking, stabilizes C3b molecules and renders them less susceptible to protease treatment. Failures to detect C3b in immune deposits in fixed tissues may be due to factors other than protease treatment.


The frequency of live bacteria in gallstones.
Septic complications reported from stones and concretions lost in the peritoneal cavity following laparoscopic cholecystectomy reflect the infective potential of gallstones. Although bacteria have been demonstrated in the core of gallstones by scanning electron microscopy and molecular genetic techniques, gallstone culture is the only conclusive proof of whether such bacteria are viable and can cause infection. Gallstones retrieved from patients undergoing cholecystectomy were decontaminated after surface cleaning with alcohol, and each core was scooped for culture. In this study organisms were cultured from the cores of gallstones in 81% of cases of cholelithiasis and 77% of cases of gallbladder carcinoma, irrespective of stone type and size. Both enteric (57.5%) and non-enteric (20%) organisms were isolated in cholelithiasis, whereas only enteric bacteria could be cultured from cases of gallbladder carcinoma. Long thought to be a causative agent, Salmonella organisms were detected in none of the 14 cases of gallbladder carcinoma. Contrary to the popular belief that bacteria inside gallstones are dead, gallstones from most patients contain live bacteria with the potential to cause infective complications.


Atrophy of the tongue following complete versus partial hypoglossal nerve transection in a canine model.
The hypoglossal nerve (XII) has been used as a donor nerve in facial and laryngeal reinnervation. The purpose of this study was to investigate the neuromuscular changes that occur within the tongue following partial or complete transection of XII using a canine model. Histopathological comparison of tongue denervation following two types of XII resection in a canine model. Ten adult canines underwent complete unilateral resection of XII or resection of only the medial terminal branch of the hypoglossal nerve (mXII). After 6 months of recovery, tongue specimens were analyzed histopathologically using whole cross-sections. Routine histologic sections were assessed by two neuropathologists blinded to the type of denervation. The cross-sectional area was calculated of both sides of the tongue, and the amount of myosin was quantified morphometrically using immunohistochemistry for myosin (antimyosin heavy chain, fast isotype). Statistical comparison between partial and complete denervation was performed using the Student t test. Six months following XII transection, quantitative measures of the cross-sectional area of the tongue and content of myosin demonstrated severe muscle atrophy on the operated side of the tongue for both groups, compared to the nonoperated side. For partial transection involving only mXII, the degree of atrophy was less severe (P < .05). This study provides new histological information demonstrating that partial resection of the hypoglossal nerve, sacrificing only the proximal medial branch of the hypoglossal nerve (mXII), results in less severe atrophy of the tongue than complete transection of the entire hypoglossal nerve. NA Laryngoscope, 126:2689-2693, 2016.


HPV16 Impacts NHERF2 Expression in Oropharyngeal Cancers.
Infection with human papillomaviruses (HPVs), in particular with HPV type 16, is now considered to be a key risk factor for the development of a subset of oropharyngeal squamous cell carcinomas (OPSCC) that show different epidemiological, clinical, and prognostic characteristics from HPV-negative (HPV-) OPSCCs. So far, extensive research efforts aiming to distinguish these two distinct entities have not identified specific biomarkers, nor led to different therapies. Previous research has shown that HPV16 E6 oncoprotein binds NHERF2, inducing its proteasomal degradation, and consequently increasing cell proliferation; we therefore aimed to investigate how this might be reflected in human histological samples. We analyzed NHERF2 expression patterns in HPV16-positive (HPV16+) and HPV- OPSCC samples, to investigate any potential differences in NHERF2 pattern. Interestingly, we observed a statistically significant decrease in NHERF2 levels in HPV16+ and poorly differentiated HPV- OPSCCs, compared with healthy tissue. Furthermore, we observed a significant reduction in the percentage of NHERF2 immunoreactive cancer cells in HPV16+ tumors, compared with well and moderately differentiated HPV- OPSCCs, suggesting the importance of 16E6's targeting of NHERF2 in HPV-driven oncogenesis in the head and neck area.


An Overview of Anterior Skull Base Meningiomas and the Endoscopic Endonasal Approach.
Meningiomas represent 30% of all primary brain tumors. Anterior skull base meningiomas represent 8.8% of all meningiomas. Surgical resection is a main treatment option for tumors that are symptomatic and/or growing. Recurrence is directly related to the extent of resection of the tumor, the dural attachment, and pathologic bone. Endoscopic endonasal approaches represent an important addition to the treatment armamentarium for skull base meningiomas. This article provides an overview of meningiomas, with a focus on those of the anterior skull base and their management.


A possible improvement for structure-based drug design illustrated by the discovery of a Tat HIV-1 inhibitor.
The HIV-1 Tat protein is a promising target for AIDS therapy, due to its extra-cellular roles against the immune system. From the 2D-NMR structure of Tat, we have designed molecules, called TDS, able to bind to Tat and inhibit HIV-1 replication in vitro. This new family of antivirals is composed of a triphenylene aromatic ring substituted with at least one carbon chain bearing a succinimide group. These ligands are prepared from triphenylene or 2,6,10-trimethylphenylene in 3-6 steps depending on the target molecule.


The surgical risk in the treatment of Arnold Chiari malformations.
The authors describe a series of 26 patients (28 operations) with Arnold Chiari malformations who were admitted during a 4 year period. In 20 the malformation was treated by direct surgery on the posterior fossa. Seven were treated by ventriculoatrial shunting. An analysis of the surgical risks of each procedure is given. In addition a helpful guide in the choice of the proper surgical procedure is outlined.


Three novel SURF-1 mutations in Japanese patients with Leigh syndrome.
Leigh syndrome, a severe neurodegenerative disorder, commonly is associated with cytochrome c oxidase deficiency. Recent studies in white patients indicate that SURF-1 gene mutations can cause Leigh syndrome associated with cytochrome c oxidase deficiency. When we measured cytochrome c oxidase activity in cultured lymphoblastoid cells from our Japanese patients with typical Leigh syndrome, three patients demonstrated cytochrome c oxidase deficiency. Three novel mutations of the SURF-1 gene were identified in two of these three patients with cytochrome c oxidase deficiency. All mutations predicted loss of function of the SURF-1 protein; in both patients' cells, cytochrome c oxidase activity was decreased to less than 20% of the control mean. These results indicate that cultured lymphoblastoid cells are useful for elucidating the etiology of Leigh syndrome, and that loss of function of the SURF-1 gene product can be responsible for Leigh syndrome associated with severe cytochrome c oxidase deficiency in Japanese patients.


Characterizing brain oxygen metabolism in patients with multiple sclerosis with T2-relaxation-under-spin-tagging MRI.
In this study, venous oxygen saturation and oxygen metabolic changes in multiple sclerosis (MS) patients were assessed using a recently developed T2-relaxation-under-spin-tagging (TRUST) magnetic resonance imaging (MRI), which measures the superior sagittal venous sinus blood oxygenation (Yv) and cerebral metabolic rate of oxygen (CMRO(2)), an index of global oxygen consumption. Thirty patients with relapsing-remitting MS and 30 age-matched healthy controls were studied using TRUST at 3 T MR. The mean expanded disability status scale (EDSS) of the patients was 2.3 (range, 0 to 5.5). We found significantly increased Yv (P<0.0001) and decreased CMRO(2) (P=0.003) in MS patients (mean±s.d.: 65.9%±5.1% and 138.8±35.4 μmol per 100 g per minute) as compared with healthy control subjects (60.2%±4.0% and 180.2±24.8 μmol per 100 g per minute, respectively), implying decrease of oxygen consumption in MS. There was a significant positive correlation between Yv and EDSS and between Yv and lesion load in MS patients (n=30); on the contrary, there was a significant negative correlation between CMRO(2) and EDSS and between CMRO(2) and lesion load (n=12). There was no correlation between Yv and brain atrophy measures. This study showed preliminary evidence of the potential utility of TRUST in global oxygen metabolism. Our results of significant underutilization of oxygen in MS raise important questions regarding mitochondrial respiratory dysfunction and neurodegeneration of the disease.


Background and Update for S1602 "A Phase III Randomized Trial to Evaluate the Influence of BCG Strain Differences and T Cell Priming with Intradermal BCG Before Intravesical Therapy for BCG-naïve High-grade Non-muscle-invasive Bladder Cancer.
The S1602 Intergroup trial is a randomized phase III clinical trial that aims to test two important hypotheses: (1) priming with intradermal bacillus Calmette-Guérin (BCG) vaccine prior to standard intravesical BCG improves response to BCG in terms of recurrence-free survival and (2) Tokyo-172 BCG strain is non-inferior to TICE BCG in terms of time to high-grade recurrence. The study was approved by the Cancer Therapy Evaluation Program of the National Cancer Institute and activated in spring 2017. Here, we provide a synopsis of the study background, design, and update of the clinical trial.


Triple-functional albumin-based nanoparticles for combined chemotherapy and photodynamic therapy of pancreatic cancer with lymphatic metastases.
Lymphatic metastasis is the major metastatic pattern of pancreatic cancer and considered as an independent risk factor of survival. However, there is still no effective way for the diagnosis and treatment for lymphatic metastases of pancreatic cancer. In this study, using albumin as a carrier of gemcitabine (Gem), further modified by pyropheophorbide-a, we have designed and synthesized a nanoparticle (NP) compound named "pheophorbide-a (P@)-Gem-human serum albumin (HSA)-NPs". By utilization of its tracer ability of lymphatic metastases, which is triggered by near-infrared irradiation and its visible dying ability, the compound is used for drug delivery tracking, meanwhile as a treating drug, as well as the combined effect of photodynamic therapy and chemotherapy. By the nude mice model of lymphatic metastases of pancreatic cancer (BxPC-3-LN7), we aim to explore the feasibility, effectiveness, and biological safety of diagnosis and treatment for the lymphatic metastases of pancreatic cancer by P@-Gem-HSA-NP, thereby, providing new methods and strategies for the study of nanodrug carrier and research on lymphatic metastases of pancreatic cancer.


Pancreas Transplantation: Small-Center Experience in Type 1 Diabetes Mellitus in a High-Incidence Region.
Pancreas transplantation (PT) is the best option of care for patients with type I diabetes mellitus (T1DM). From July 2005 to September 2014, we performed 27 PT from deceased donors (24 simultaneous pancreas-kidney transplantations [SPKT] and 3 pancreas transplantations alone) in a region with a high incidence of T1DM. Enteric drainage and systemic venous derivation were accomplished for all PT. Cold and warm ischemia times were 291 ± 70 minutes and 32 ± 9 minutes, respectively. The rate of early re-operations was 33%, mainly because of bleeding occurrence. Mean donor age was 31 ± 11 years; all patients had ABO compatibility and negative cross-match. With a mean follow-up time of 2.3 years, no death was registered. Graft survival of PT was 96.7%, with 1 graft loss in the SPKT group (3.7%) after acute rejection. Nine patients were submitted successfully to re-operation for no life-threatening complications within 30 post-operative days. No early or late episode of vascular thrombosis, pancreatitis, or pancreatic fistula was observed. All patients with a functioning graft had excellent metabolic control, with mean glycosylated hemoglobin level at last follow-up of 5.5% and median fasting glucose level of 95 ± 13 mg/dL, comparable to that in the non-diabetic population. In our experience, PT is an excellent therapeutic solution for patients with T1DM. Despite fewer than 5 PT performed per year, graft and patient outcomes were similar to those in high-volume centers.


Impact of gender, maternal education, and birth order on the development of language comprehension: a longitudinal study from 18 to 36 months of age.
To investigate the impact of child gender, maternal education, and birth order on language comprehension (LC) status at 18 and 36 months of age and on the change in LC between these time points. Gender interactions and interactions between maternal education and birth order are also examined. This study is based on data from the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. Maternal report data on education, birth order, and child language in a sample of 44,921 children were used in linear regression analyses. At 18 and 36 months of age, first-born girls of mothers with high educational attainment had the highest level of LC. Between 18 and 36 months of age, first-born boys of mothers with high educational attainment had the highest increase in LC. Having a highly educated mother contributed more to the increase in LC in boys than in girls. The boys whose mothers had the highest education level had lower scores than the girls whose mothers had the lowest educational level, at both ages. Although significant, the considerable effect of high maternal education was not substantially dependent on birth-order status. Boys develop LC at a faster rate than girls between 18 and 36 months, but girls still remain superior in their level of LC at 36 months of age. Being firstborn or having a highly educated mother does not compensate for this lag.


Enhancement of Antinociception by Co-administrations of Nefopam, Morphine, and Nimesulide in a Rat Model of Neuropathic Pain.
Neuropathic pain is a chronic pain due to disorder in the peripheral or central nervous system with different pathophysiological mechanisms. Current treatments are not effective. Analgesic drugs combined can reduce pain intensity and side effects. Here, we studied the analgesic effect of nimesulide, nefopam, and morphine with different mechanisms of action alone and in combination with other drugs in chronic constriction injury (CCI) model of neuropathic pain. Male Wistar rats (n = 8) weighing 150-200 g were divided into 3 different groups: 1- Saline-treated CCI group, 2- Saline-treated sham group, and 3- Drug-treated CCI groups. Nimesulide (1.25, 2.5, and 5 mg/kg), nefopam (10, 20, and 30 mg/kg), and morphine (1, 3, and 5 mg/kg) were injected 30 minutes before surgery and continued daily to day 14 post-ligation. In the combination strategy, a nonanalgesic dose of drugs was used in combination such as nefopam + morphine, nefopam + nimesulide, and nimesulide + morphine. Von Frey filaments for mechanical allodynia and acetone test for cold allodynia were, respectively, used as pain behavioral tests. Experiments were performed on day 0 (before surgery) and days 1, 3, 5, 7, 10, and 14 post injury. Nefopam (30 mg/kg) and nimesulide (5 mg/kg) blocked mechanical and thermal allodynia; the analgesic effects of morphine (5 mg/kg) lasted for 7 days. Allodynia was completely inhibited in combination with nonanalgesic doses of nefopam (10 mg/kg), nimesulide (1.25 mg/kg), and morphine (3 mg/kg). It seems that analgesic drugs used in combination, could effectively reduce pain behavior with reduced adverse effects.


Early results of the modified Simmonds-Menelaus procedure for adolescent hallux valgus.
Adolescent hallux valgus is a common problem, and there is no agreement about the best surgical technique to use to correct this deformity. Excellent results have been reported with a distal soft tissue procedure and an associated osteotomy at the base of the first metatarsal. The current study reports the early results of using an incomplete osteotomy at the base of the first metatarsal. No hardware was used to fix the osteotomy, and the postoperative immobilization was shorter. The study included 20 feet in 11 female patients. All osteotomies healed primarily without complications. The average preoperative hallux valgus of 31.2 degrees was reduced to 17.8 degrees at a minimum of 2 years follow-up. The average intermetatarsal angle improved from 13.5 degrees in the preoperative period to 11.3 degrees. Using the duPont bunion rating score as an outcome assessment, the authors had 4 excellent and 16 good results.


Auditory outcomes after implantation and electrical stimulation of the lateral ampullar nerve in guinea pig.
To determine in a guinea pig model the factors of invasiveness of a bipolar electrode implanted in the horizontal semicircular canal (HSC) and to evaluate the consequences on hearing of electrical stimulation of the ampullary nerve. Sixteen guinea pigs divided into four groups underwent surgical opening of the HSC of one ear as follows: control (group 1), cyanoacrylate glue application on the HSC opening (group 2), electrode implantation with cyanoacrylate glue on the HSC opening (group 3), and electrode implantation with electrical stimulation (1 hr/day) for 9 days (group 4). Auditory brainstem responses were recorded before and after surgery and after electrical stimulation. The effectiveness of electrical stimulation in producing a horizontal vestibulo-ocular reflex was evaluated by recording eye movement with video-oculography. Group 1 animals showed hearing loss, and in group 2, sealing the HSC opening with cyanoacrylate glue preserved the hearing thresholds. After electrode implantation, seven of the eight animals showed hearing loss compared with preoperative values. Electrical stimulation did not induce additional hearing loss. Electrode implantation at the canal level entailed a risk of hearing loss in an animal model, but electrical stimulation of the horizontal ampullary nerve did not further alter hearing function.


Approaches to increasing analytical throughput of human samples with multi-isotope imaging mass spectrometry.
Multi-isotope imaging mass spectrometry (MIMS) combines stable isotope tracers with the quantitative imaging of NanoSIMS ion microscopy. With extensive safety precedent, use of stable isotopes in MIMS applications opens the possibility of studying a wide array of biological questions in humans[1]. Here we describe a series of approaches to increase the effective analytical throughput for detecting rare nuclear labeling events with MIMS. At the level of sample preparation, cells in suspension were either smeared at high density or pelleted cells were embedded and sectioned to reach nuclear depth. Presputtering conditions were optimized for each cell type to ensure the reproducible sampling of nuclei. Adipose tissue posed a different challenge as the large volume of adipocytes results in an obligatorily low density of nuclei in any given plane. Before introducing samples to the NanoSIMS instrument, all nuclei were fluorescently stained, imaged, and their coordinates recorded, allowing automated analysis of fields that contained at least one nucleus and therefore minimizing analysis of dead space. These data emphasize unique challenges posed by human studies, where both ethical and practical issues may limit the administration of stable isotope labels for prolonged periods of time as may be necessary to achieve high labeling frequencies in cells that divide infrequently.


Detection of small hypervascular hepatocellular carcinomas by EASL criteria: comparison with double-phase CT during hepatic arteriography.
To compare the detectability of small hypervascular hepatocellular carcinoma (HCC) between double-phase CT during hepatic arteriography (CTHA) criteria (hypervascular on the early-phase of CTHA and corona enhancement on the late-phase of CTHA) widely introduced in Japan and EASL criteria (hypervascular on the arterial dominant phase and wash out on the equilibrium phase of dynamic CT and/or MRI). 116 hypervascular HCC lesions (≤2 cm) of 38 patients were evaluated. CTHA was performed in every patient, both dynamic CT and dynamic MRI in 22 patients, only dynamic CT in 8, and only dynamic MRI in 8. Among them, the detectability of HCC lesions was statistically analyzed with χ2 test. Double-phase CTHA detected all HCCs. Dynamic CT revealed 38 (40%) of 95 small HCCs; during dynamic MRI 38 (40%) of 95 small HCCs were detected. The difference between dynamic CT or dynamic MRI and CTHA was statistically significant (p<0.05). The detectability of small hypervascular HCC on dynamic CT and dynamic MRI was almost the same and significantly lower as compared to that of CTHA. When comparing differences in the results of HCC treatment, differences in the diagnostic criteria applied should always be kept in mind.


Adaptations made to delivery of comprehensive medication management in the community pharmacy setting during COVID-19.
As a result of COVID-19, numerous adaptations were made to health care delivery, including comprehensive medication management (CMM) delivered in community pharmacies. Identify and describe the adaptations that have been made to the delivery of CMM among community pharmacies due to COVID-19. Community pharmacies participating in a CMM implementation and research initiative had regular coaching calls throughout COVID-19 and completed a survey of changes that occurred as a result of COVID-19. Coaching notes and survey results were summarized and mapped to the Framework for Reporting Adaptations and Modifications-Enhanced (FRAME) to systematically capture changes that occurred. A number of reactive adaptations were made to CMM delivery as a result of COVID-19, including increased virtual or remote delivery of CMM, delaying CMM visits to allow pharmacies to provide care directly related to the pandemic including COVID-19 testing and vaccines, wearing personal protective equipment (PPE) in visits, new ways of obtaining clinical patient information, and shifting CMM staffing models. Adaptations that occurred to CMM during COVID-19 allowed pharmacists to continue to serve their patients and meet public health needs.


Drug-Induced Liver Injury in the Setting of Chronic Liver Disease.
Drug-induced liver injury (DILI) is an uncommon but significant cause of liver injury and need for liver transplant. DILI in the setting of chronic liver disease (CLD) is poorly understood. Clinical features of patients presenting with DILI in the setting of CLD are similar to those without CLD with the exception of a higher incidence of diabetes among those with CLD and DILI. Diagnosis of DILI in CLD is difficult because there are no objective biomarkers and current causality assessments have not been studied in this population. Differentiating DILI from exacerbation of underlying liver disease is even more challenging.


Epithelioid hemangioendothelioma of the liver. Diagnostic features and role of liver transplantation.
Five cases of epithelioid hemangioendothelioma of the liver are reported. This unusual type of vascular tumor is often difficult to diagnose; its angiogenic nature is not overt at the radiologic level and may be overlooked by conventional histologic examination. At imaging procedures, epithelioid hemangioendothelioma of the liver presents as multiple focal hypovascular areas, disseminated in both lobes. The combination of these imaging abnormalities with a peculiar set of demographic and clinical features, including young age, good general condition, and progressive course, is suggestive. However, the final diagnosis can be established only by histologic examination of appropriate material collected by guided liver biopsies and may be helped by immunohistochemistry and ultrastructural examination. The accurate diagnosis of epithelioid hemangioendothelioma of the liver is of clinical and therapeutic relevance. In view of its favorable clinical course, orthotopic liver transplantation may be considered for the treatment of this tumor when intrahepatic dissemination contraindicates partial hepatectomy and extrahepatic extension, excluded by exploratory laparotomy, is absent.


Influence of cryopreservation methods of ex vivo rat and pig skin on the results of in vitro permeation test.
In vitro permeation test (IVPT) is a frequently used method for in vitro assessment of topical preparations and transdermal drug delivery systems. However, the storage of ex vivo skin for IVPT remains a challenge. Here, two cryopreservation media were chosen to preserve rat and pig skin at -20 °C and -80 °C for further IVPT, namely, 10 % DMSO and 10 % GLY. The skin viability test confirmed that the skin protective capacity of 10 % DMSO and 10 % GLY was almost equal. The results of skin viability and IVPT showed that the skin viability and permeability of rat skin in 10 %DMSO or 10 % GLY were maintained for at least 7 and 30 days at -20 °C and -80 °C compared to fresh skin, respectively; in contrast, those of porcine skin were just maintained for <7 days at -20 °C and -80 °C. These results indicated that ex vivo skin for IVPT preserved at -80 °C in 10 % DMSO or 10 % GLY was optimal. Furthermore, skin permeability was independent of skin barrier integrity. Our study provides reference conditions for preserving IVPT skin, and skin viability can be a potential indicator of IVPT skin.


CT-based attenuation correction of whole-body radiotherapy treatment positioning devices in PET/MRI hybrid imaging.
To implement computed tomography (CT)-based attenuation maps of radiotherapy (RT) positioning hardware and radiofrequency (RF) coils to enable hybrid positron emission tomography/magnetic resonance imaging (PET/MRI)-based RT treatment planning. The RT positioning hardware consisted of a flat RT table overlay, coil holders for abdominal scans, coil holders for head and neck scans and an MRI compatible hip and leg immobilization device. CT images of each hardware element were acquired on a CT scanner. Based on the CT images, attenuation maps of the devices were created. Validation measurements were performed on a PET/MR scanner using a 68Ge phantom (48 MBq, 10 min scan time). Scans with each device in treatment position were performed. Then, reference scans containing only the phantom were taken. The scans were reconstructed online (at the PET/MRI scanner) and offline (via e7tools on a PC) using identical reconstruction parameters. Average reconstructed activity concentrations of the device and reference scans were compared. The device attenuation maps were successfully implemented. The RT positioning devices caused an average decrease of reconstructed PET activity concentration in the range between -8.3 ± 2.1% (mean ± SD) (head and neck coil holder with coils) to -1.0 ± 0.5% (abdominal coil holder). With attenuation correction taking into account RT hardware, these values were reduced to -2.0 ± 1.2% and -0.6 ± 0.5%, respectively. The results of the offline and online reconstructions were nearly identical, with a difference of up to 0.2%. The decrease in reconstructed activity concentration caused by the RT positioning devices is clinically relevant and can successfully be corrected using CT-based attenuation maps. Both the offline and online reconstruction methods are viable options.


[The nitroblue tetrazolium reduction test in evaluating the function of the circulating leukocytes in mice with experimental malaria].
NBT-test for circulating neutrophils and monocytes in the blood of mice inoculated with Plasmodium berghei, strain N or LNK-65, have been performed. Within the first 24 h of the infection, before the onset of the recordable parasitemia or in the course of the subsequent six days (depending of the strain used for inoculation) a 50-100% reduction in NBT-positive cells was observed. This demonstrates the ability of malaria parasite to suppress the oxygen-dependent enzyme system in circulating phagocytes, neutrophils and monocytes of the host blood. The results of NBT-test could be utilized for the investigation of immunological disorders and also for the differential diagnosis of malarial infection.


The "Basket-in-Catheter" technique: facilitating transcystic bile duct exploration and optimising the management of suspected ductal stones.
The 'Basket-in-Catheter' (BIC) technique facilitates basket-only laparoscopic transcystic exploration (LTCE), increasing its success rate. Using the cholangiography catheter as a sheath is easier and safer than inserting the wire basket-alone. This study evaluates its benefits in confirmed and suspected ductal stones. Retrospective analysis of prospectively collected data on patients with pre-operative or operative suspicion of bile duct stones or with positive and equivocal intraoperative cholangiographies (IOC) who had LTCE attempted using blind basket trawling, without choledochoscopy, were reviewed. The incidence and outcomes of blind basket LTCEs attempted before and after introducing the BIC technique, whether or not stones were retrieved, were analysed. Blind basket LTCE was attempted in 732 patients. Of 377 (51.5%) patients undergoing successful stone retrieval, only 62% had pre-operative clinical and radiological risk factors for ductal stones, 25% had operative risk factors and 13% had silent stones discovered on IOC. Another 355 patients (48.5%) had negative trawling, although one half had pre-operative risk factors for ductal stones and 47.6% had operative risk factors, e.g. cystic duct stones or dilatation. This cohort had equivocal cholangiography in 25.9%. Following basket trawling, repeat IOC confirmed resolution of abnormalities. As no stones were retrieved, these were not considered duct explorations. The BIC technique facilitates safe and speedy bile duct clearance when stones are confirmed, avoiding choledochotomies, without significant complications. BIC duct trawling is also beneficial in patients with suspected ductal stones, helping to resolve equivocal IOCs. It helps surgeons to acquire and consolidate ductal exploration skills.


Pharmacokinetics and tissue diffusion of ganciclovir in mice and rats.
Congenital cytomegalovirus (CMV) infection is the leading infectious cause of birth defects, mental retardation and non-genetic sensorineural hearing loss. Murine models have been developed in order to understand the pathophysiological mechanisms underlying these lesions. These models are being proposed for the validation of therapeutic protocols for clinical use. The aim of this preclinical study was to assess the pharmacokinetics of the reference antiviral molecule, ganciclovir, in order to optimize these protocols and confirm the diffusion of the molecule to the appropriate target zones. Transplacental and intracochlear diffusion of ganciclovir was evaluated in mice and rats. Pharmacokinetics was assessed in adult mice and pups after 5 consecutive days of intraperitoneal injection of ganciclovir. The occurrence of hematological side effects of ganciclovir was evaluated in the different blood cell lineages. In adult rats, the intracochlear diffusion of ganciclovir was shown to achieve the same concentration as in blood. In gestating mice, transplacental diffusion was observed, with a fetal-to-maternal blood ratio of 0.5. In newborn mice, the plasma concentration profile of ganciclovir showed a peak at 2 h followed by a gradual decrease. In adult mice, the concentration peaked at 1 h, but became undetectable by 2 h after injection. Counts of white blood cells, red blood cells and platelets decreased significantly in ganciclovir-treated newborn mice. Our data provide evidence for the intracochlear diffusion of the molecule, which may be relevant for the treatment of sensorineural hearing loss in congenitally-infected children.


The pharmacology of airway hyperresponsiveness and inflammation.
Hyperresponsiveness is a key abnormality in asthma and deserves recognition both in the clinical presentation of asthma and its pathogenesis. Available evidence strongly suggests that inflammatory processes are important in producing this aspect of disordered airway physiology. Pharmacologic studies have greatly increased our knowledge of mechanisms involved in hyperresponsiveness but fall short of a complete explanation of the phenomenon. It is most likely that hyperresponsiveness, as measured in the laboratory, has many different components and that any single mechanism will be an insufficient explanation.


Plasma levels of aldosterone versus aldosterone precursors: a way to estimate the malignancy of asymptomatic and nonsecretory adrenal tumors: a French Retrospective Multicentric Study.
The aim of this study was to find out whether the dysfunction of aldosterone pathway, previously proposed as a marker of secretory adrenal carcinoma, is also found in nonsecretory adrenal carcinomas, which pose even more difficult diagnostic problems even for patients with hypertension accompanied or not by hypokalemia. The exploration consisted of using the same method (RIA preceded by a chromatographic step) to determine the plasma levels of the following steroids in the mineral corticosteroid pathway: deoxycorticosterone (DOC), 18-hydroxydeoxycorticosterone (18-OHDOC), corticosterone (B), 18 hydroxycorticosterone (18 OH B), and aldosterone. The subjects included 16 adults, each presenting with an endocrinologically asymptomatic adrenal mass associated for some patients with hypokalemia and hypertension (8 with adrenal carcinoma, 2 with adrenal metastasis from other forms of cancer, and 6 adenomas). These results show that even in nonsecretory adrenal carcinoma, there is a dysfunction of the aldosterone pathway, which can be evaluated from the ratio between aldosterone and the substrate of 11 beta hydroxylase (DOC) and its derivative (18-OH DOC). This study suggests that exploration of mineralocorticosteroid pathway can be used as a hormonal marker of adrenal carcinoma for both secretory and non-secretory malignant masses.


CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test.
To elucidate the roles of epidermal keratinocytes in the toxicological outcomes of chemically induced contact dermatitis, genome-scale transcriptional analyses were performed using normal human keratinocytes (NHKCs) treated with 10 μM sodium lauryl sulfate (SLS) or 5 μM urushiol. In Gene Ontology (GO) enrichment analyses, SLS- and urushiol-induced upregulated DEGs are commonly associated with the regulation of pro-inflammatory responses and epidermal differentiation processes in NHKCs whereas cellular protein metabolic process was also identified as a commonly downregulated DEG signature. Among the downregulated DEGs, CXCL14 was investigated as a potential biomarker for a new in vitro skin sensitization test using OECD TG429 reference chemicals. CXCL14 was significantly downregulated in NHKCs in response to 62.5% of the OECD TG429 sensitizers in a concentration-dependent manner. When the sensitizer-induced upregulation of chemokine CXCL8 was included in the analysis, 87.5% of the OECD TG429 reference sensitizing chemicals significantly induced either CXCL8 upregulation or CXCL14 downregulation in NHKCs. Only one OECD TG429 reference non-sensitizer changed the constitutive CXCL14 expression in NHKCs whereas five out of six non-sensitizers altered CXCL8 production. The reference irritating non-sensitizer SLS caused a false-positive outcome. The downregulation of constitutively expressed CXCL14 was regulated by both the MAPK/ERK and JAK3/STAT6 pathways in NHKCs. CXCL14 can be used as a mechanism-based biomarker in the development of in vitro skin sensitization tests and may help improve the distinction between allergenic sensitizers and non-sensitizers.


Biomechanical effect of ultraviolet-A-riboflavin cross-linking on simulated human corneal stroma model and its correlation with changes in corneal stromal microstructure.
In this study, we established an experimental human corneal stroma model of simulated cornea tissue composed of thin anterior cornea strips layers obtained from small incision lenticular extraction (SMILE) surgery. We investigated the biomechanical effect of ultraviolet-A- riboflavin cross-linking at different depths of corneal stroma model and correlated it with stromal microstructural changes examined by transmission electron microscopy (TEM). Corneal strips were harvested from fresh human corneal lenticules obtained after SMILE surgery. Experimental models (n = 34) were established by superimposing the corneal lenticule strips until their thickness reached close to 500 μm. Corneal cross-linking (CXL) was performed subsequently using standard or accelerated protocol. Elasticity and viscosity were quantified using stress-strain extensometer. TEM was used to visualize the collagen fiber diameter and interfibrillar spacing. The relative change in Young's modulus (rel. ΔE) decreased nonlinearly with increasing stromal depth both in the standard and accelerated groups. Compared to the sham controls, the rel. ΔE in standard and accelerated CXL groups increased significantly in the anterior 400 μm and 275 μm depth, respectively. Also, the relative change in stress (rel. ΔS) was significantly lower after standard and accelerated CXL compared to sham controls. Depth analysis showed similar results for the elastic effect. TEM images showed a small, non-significant increase in fibril diameter. The interfibrillar spacing decreased significantly after standard and accelerated CXL in the anterior-mid stromal region. We noted that the increase of corneal stiffness correlated with decrease in interfibrillar spacing after CXL. The stiffening effect was depth dependent. The effect of accelerated CXL was less in the deep corneal stromal regions compared to standard CXL.


Temperature and pH dependence of the association rate constant of elastase with alpha 2-macroglobulin.
Binding kinetics of porcine pancreatic elastase to human alpha 2-macroglobulin was monitored by measuring the enzymatic activity of alpha 2-macroglobulin-bound elastase on succinyltrialanine p-nitroanilide after inhibition of free elastase by alpha 1-proteinase inhibitor. The association of the two proteins follows second-order kinetics with a rate constant ka = 4.4 X 10(6) M-1 S-1 at pH 8.0 and 25 degrees C. The rate of association strongly increases between pH 5.0 and 8.0, suggesting that the rate-limiting step of binding is the proteolytic cleavage at the bait region of the macroglobulin. The study of the temperature dependence of ka shows that the binding of elastase to alpha 2-macroglobulin is characterized by a positive entropy of activation (delta S* = +35.3 e.u. at 25 degrees C).


Antioxidant Activity of Milk and Dairy Products.
The aim of the study was to present a review of literature data on the antioxidant potential of raw milk and dairy products (milk, fermented products, and cheese) and the possibility to modify its level at the milk production and processing stage. Based on the available reports, it can be concluded that the consumption of products that are a rich source of bioactive components improves the antioxidant status of the organism and reduces the risk of development of many civilization diseases. Milk and dairy products are undoubtedly rich sources of antioxidant compounds. Various methods, in particular, ABTS, FRAP, and DPPH assays, are used for the measurement of the overall antioxidant activity of milk and dairy products. Research indicates differences in the total antioxidant capacity of milk between animal species, which result from the differences in the chemical compositions of their milk. The content of antioxidant components in milk and the antioxidant potential can be modified through animal nutrition (e.g., supplementation of animal diets with various natural additives (herbal mixtures, waste from fruit and vegetable processing)). The antioxidant potential of dairy products is associated with the quality of the raw material as well as the bacterial cultures and natural plant additives used. Antioxidant peptides released during milk fermentation increase the antioxidant capacity of dairy products, and the use of probiotic strains contributes its enhancement. Investigations have shown that the antioxidant activity of dairy products can be enhanced by the addition of plant raw materials or their extracts in the production process. Natural plant additives should therefore be widely used in animal nutrition or as functional additives to dairy products.


Superconducting metamaterials for waveguide quantum electrodynamics.
Embedding tunable quantum emitters in a photonic bandgap structure enables control of dissipative and dispersive interactions between emitters and their photonic bath. Operation in the transmission band, outside the gap, allows for studying waveguide quantum electrodynamics in the slow-light regime. Alternatively, tuning the emitter into the bandgap results in finite-range emitter-emitter interactions via bound photonic states. Here, we couple a transmon qubit to a superconducting metamaterial with a deep sub-wavelength lattice constant (λ/60). The metamaterial is formed by periodically loading a transmission line with compact, low-loss, low-disorder lumped-element microwave resonators. Tuning the qubit frequency in the vicinity of a band-edge with a group index of ng = 450, we observe an anomalous Lamb shift of -28 MHz accompanied by a 24-fold enhancement in the qubit lifetime. In addition, we demonstrate selective enhancement and inhibition of spontaneous emission of different transmon transitions, which provide simultaneous access to short-lived radiatively damped and long-lived metastable qubit states.


A potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor.
SR 48968 is a potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor. SR 48968 selectively inhibited neurokinin A binding to its receptor and was a competitive antagonist of neurokinin A-mediated contraction of different isolated smooth muscle preparations from various species including human. In vivo, the compound inhibited the bronchoconstriction induced by neurokinin A in guinea pigs. SR 48968 can be used to study the physiological or pathological role of neurokinin A and may be useful in the treatment of neurokinin A-dependent pathology.


Julius Sachs (1832-1897) and the Unity of Life.
In 1865, the German botanist Julius Sachs published a seminal monograph entitled Experimental-Physiologie der Pflanzen (Experimental Physiology of Plants) and hence became the founder of a new scientific discipline that originated 150 y ago. Here, we outline the significance of the achievements of Sachs. In addition, we document, with reference to his Vorlesungen über Pflanzen-Physiologie (Lectures on the Physiology of Plants, 1882), that Sachs was one of the first experimentalists who proposed the functional unity of all organisms alive today (humans, animals, plants and other "vegetable" organisms, such as algae, cyanophyceae, fungi, myxomycetes, and bacteria).


Modification of experimental UV erythema by external steroids--a reflex photometric study.
A method for reflex photometric detection of the modification of a model of inflammation (UV erythema) by external corticoids is presented. The steroids which most effectively suppress erythema formation are those which have the strongest vasoconstrictor potency also on unchanged skin. A tachyphylaxis phenomenon can also be demonstrated after several applications of a synthetic steroid to the inflammation model.


Crossed Wires Versus 2 Lateral Wires in Management of Supracondylar Fracture of the Humerus in Children in the Hands of Junior Trainees.
The objective of this study was to evaluate and compare the outcome of the crossed and the lateral pin configurations in the management of supracondylar humeral fractures in children in the hands of junior trainees. Prospective randomized controlled trial. Level I Trauma Center. Sixty children with supracondylar humeral fractures. The mean age was 5.1 years (1.5-9 years). The minimum follow-up period was 6 months, with no patients lost to follow up. Thirty patients were managed by crossed and 30 by the lateral method. All surgeries were performed by junior trainees in their first 3 years of training. Postoperative stability, ulnar nerve injury, range of motions, and pin tract infection. The crossed configuration was stable in all the patients, whereas the lateral method was less stable in 20% of the cases because the distal fragment rotated in 5 patients and posteriorly displaced in 1 patient. The difference was statistically significant with a P value of 0.031. Ulnar nerve neurapraxia occurred in 1 patient from the lateral group and it recovered in the fourth month, whereas no ulnar nerve injury occurred in the crossed configuration group. Two patients in the lateral group lost approximately 100 of elbow flexion. This prospective randomized controlled trial showed that the crossed pin configuration method provided more stability than the lateral pin configuration, especially, in the hands of junior trainees in their first 3 years of training, and the difference was statistically significant. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.


COVID-19 among adults living with HIV: correlates of mortality among public sector healthcare users in Western Cape, South Africa.
While a large proportion of people with HIV (PWH) have experienced SARS-CoV-2 infections, there is uncertainty about the role of HIV disease severity on COVID-19 outcomes, especially in lower-income settings. We studied the association of mortality with characteristics of HIV severity and management, and vaccination, among adult PWH. We analysed observational cohort data on all PWH aged ≥15 years experiencing a diagnosed SARS-CoV-2 infection (until March 2022), who accessed public sector healthcare in the Western Cape province of South Africa. Logistic regression was used to study the association of mortality with evidence of antiretroviral therapy (ART) collection, time since first HIV evidence, CD4 cell count, viral load (among those with evidence of ART collection) and COVID-19 vaccination, adjusting for demographic characteristics, comorbidities, admission pressure, location and time period. Mortality occurred in 5.7% (95% CI: 5.3,6.0) of 17,831 first-diagnosed infections. Higher mortality was associated with lower recent CD4, no evidence of ART collection, high or unknown recent viral load and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis (especially more recent episodes of tuberculosis), chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults. Mortality was strongly associated with suboptimal HIV control, and the prevalence of these risk factors increased in later COVID-19 waves. It remains a public health priority to ensure PWH are on suppressive ART and vaccinated, and manage any disruptions in care that occurred during the pandemic. The diagnosis and management of comorbidities, including for tuberculosis, should be optimized.


De novo interstitial deletion of the long arm of chromosome 3: 46,XX,del(3)(q25.1q26.1).
A girl with an interstitial deletion of chromosome 3 is presented. The facial resemblance to an earlier reported patient with a shared breakpoint is addressed.


Obesity and functional decline: epidemiology and geriatric consequences.
Obesity is growing in prevalence among older Americans and is accompanied by an unfortunate burden of chronic disease, functional decline, and poor quality of life. Elevated past or current body mass index (BMI) is strongly associated with increased self-reported functional limitations. Supportive findings have also related decreased physical performance test scores with elevated BMI. Body composition analyses have explored which body compartment is most strongly associated with obesity-related functional impairments. Studies have suggested possible contributions of decreased muscle mass and increased fat mass. Weight reduction intervention studies that have examined functional outcomes among older persons are limited.


Fetus in fetu.
A 2-month-old boy was found to have an abdominal mass in the left upper quadrant. Surgical removal revealed the mass to be a fetus in fetu. Dissection and roentgenologic examination unequivocally demonstrated the presence of vertebral column and organs arranged appropriately to the vertebral axis.


Protein Structural Studies by Traveling Wave Ion Mobility Spectrometry: A Critical Look at Electrospray Sources and Calibration Issues.
The question whether electrosprayed protein ions retain solution-like conformations continues to be a matter of debate. One way to address this issue involves comparisons of collision cross sections (Ω) measured by ion mobility spectrometry (IMS) with Ω values calculated for candidate structures. Many investigations in this area employ traveling wave IMS (TWIMS). It is often implied that nanoESI is more conducive for the retention of solution structure than regular ESI. Focusing on ubiquitin, cytochrome c, myoglobin, and hemoglobin, we demonstrate that Ω values and collisional unfolding profiles are virtually indistinguishable under both conditions. These findings suggest that gas-phase structures and ion internal energies are independent of the type of electrospray source. We also note that TWIMS calibration can be challenging because differences in the extent of collisional activation relative to drift tube reference data may lead to ambiguous peak assignments. It is demonstrated that this problem can be circumvented by employing collisionally heated calibrant ions. Overall, our data are consistent with the view that exposure of native proteins to electrospray conditions can generate kinetically trapped ions that retain solution-like structures on the millisecond time scale of TWIMS experiments.


Taxonomic status and redescription of the genus Brasicystis Thatcher, 1979 (Digenea: Didymozoidae).
Brasicystis bennetti Thatcher, 1979 was first described from specimens obtained from the subcutaneous tissues of the mouth and operculum of Plagioscyion squamosissimus from the Amazon River in Brazil, however since 2008, Brasicystis has been considered a genus inquirendum. This study reviews some of the diagnostic characters from the original description of B. bennetti from the Amazon Delta, and redescribes the genus and species with a discussion of their taxonomic status. Ultrastructural and molecular approaches complement the data presented on this monotypic genus. The diagnosis of the tribe Didymozoini Monticelli, 1888 is amended to incorporate the genus Brasicystis, which is redescribed and revalidated here, with the proposal of an amended key.


Postnatal growth of the dog's bronchial tree.
Polyester resin casts of the bronchial tree were made from the lungs of four Labrador dogs which weighed 0.5, 3.4, 7.5 and 30.0 kg, respectively. The branching trees were ordered by the method of Strahler and plots made of number, mean diameter and mean length of branches in each order. The four length plots were found to lie parallel to each other, as did three of the four diameter plots. When data are divided by the cube root of body weight the length plots almost coincide, as do the diameter plots. This indicates that the bronchial tree grows in constant proportion to the cube root of body weight.


Risk and protective factors for atrial fibrillation after cardiac surgery and valvular interventions: an umbrella review of meta-analyses.
Postoperative atrial fibrillation (POAF) is a common complication affecting approximately one-third of patients after cardiac surgery and valvular interventions. This umbrella review systematically appraises the epidemiological credibility of published meta-analyses of both observational and randomised controlled trials (RCT) to assess the risk and protective factors of POAF. Three databases were searched up to June 2021. According to established criteria, evidence of association was rated as convincing, highly suggestive, suggestive, weak or not significant concerning observational studies and as high, moderate, low or very low regarding RCTs. We identified 47 studies (reporting 61 associations), 13 referring to observational studies and 34 to RCTs. Only the transfemoral transcatheter aortic valve replacement (TAVR) approach was associated with the prevention of POAF and was supported by convincing evidence from meta-analyses of observational data. Two other associations provided highly suggestive evidence, including preoperative hypertension and neutrophil/lymphocyte ratio. Three associations between protective factors and POAF presented a high level of evidence in meta-analyses, including RCTs. These associations included atrial and biatrial pacing and performing a posterior pericardiotomy. Nineteen associations were supported by moderate evidence, including use of drugs such as amiodarone, b-blockers, glucocorticoids and statins and the performance of TAVR compared with surgical aortic valve replacement. Our study provides evidence confirming the protective role of amiodarone, b-blockers, atrial pacing and posterior pericardiotomy against POAF as well as highlights the risk of untreated hypertension. Further research is needed to assess the potential role of statins, glucocorticoids and colchicine in the prevention of POAF. CRD42021268268.


The Spanish tourist sector facing extreme climate events: a case study of domestic tourism in the heat wave of 2003.
This research explores, by means of a questionnaire-based survey, public knowledge and perception as well as the behaviour of young Spanish tourists before, during and after the summer holiday period affected by an episode of extreme heat in 2003. The survey was administered between November and December 2004. The extraordinary heat wave of the summer of 2003 can be seen as an example of a normal episode in terms of the predicted intensity and duration of European summers towards the end of the twenty-first century. It can therefore be used as the laboratory setting for this study. In this context, the use of the climate analogue approach allows us to obtain novel perspectives regarding the future impact that this type of event could have on tourist demand, based on a real experience. Likewise, such an approach allows the strategies of adaptation implemented by the different elements in the tourist system in order to cope with the atmospheric episode to be evaluated. Such strategies could prove useful in reducing vulnerability when faced with similar episodes in the future. The main results indicate that Spanish tourists (young segment market) are flexible in adapting to episodes of extremely high temperatures. Their personal perception of the phenomenon, their behaviour and the adaptation measures implemented to a greater or lesser extent before that time, reduce the vulnerability of the sector when faced with this type of event, at least from the point of view of this young segment of the internal national market. In Spain, the episode of extreme heat of 2003 has led to the implementation or improvement of some adaptive measures after the event, especially in the fields of management, policy and education.


Aortic anatomic severity grade correlates with resource utilization.
Potential cost effectiveness of endovascular aneurysm repair (EVAR) compared with open aortic repair (OAR) is offset by the use of intraoperative adjuncts (components) or late reinterventions. Anatomic severity grade (ASG) can be used preoperatively to assess abdominal aortic aneurysms, and provide a quantitative measure of anatomic complexity. The hypothesis of this study is that ASG is directly related to the use of intraoperative adjuncts and cost of aortic repair. Patients who undergo elective OAR and EVAR for abdominal aortic aneurysms were identified over a consecutive 3-year period. ASG scores were calculated manually using three-dimensional reconstruction software by two blinded reviewers. Statistical analysis of cost data was performed using a log transformation. Regression analyses, with a continuous or dichotomous outcome, used a generalized estimating equations approach with the sandwich estimator, being robust with respect to deviations from model assumptions. One hundred forty patients were identified for analysis, n = 33 OAR and n = 107 EVAR. The mean total cost (± standard deviation) for OAR was per thousand (k) $38.3 ± 49.3, length of stay (LOS) 13.5 ± 14.2 days, ASG score 18.13 ± 3.78; for EVAR, mean total cost was k $24.7 ± 13.0 (P = .016), LOS 3.0 ± 4.4 days (P = .012), ASG score 15.9 ± 4.13 (P = .010). In patients who underwent EVAR, 25.2% required intraoperative adjuncts, and analysis of this group revealed a mean total cost of k $31.5 ± 15.9, ASG score 18.48 ± 3.72, and LOS 3.9 ± 4.5, which were significantly greater compared with cases without adjunctive procedures. An ASG score of ≥15 correlated with an increased propensity for requirement of intraoperative adjuncts; odds ratio, 5.75 (95% confidence interval, 1.82-18.19). ASG >15 was also associated with chronic kidney disease, end stage renal disease, hypertension, female sex, increased cost, and use of adjunctive procedures. Complex aneurysm anatomy correlates with increased total cost and need for adjunctive procedures during EVAR. Preoperative assessment with ASG scores can delineate patients at greater risk for increased resource use. Patient comorbid factors are associated with anatomic complexity defined according to ASG. A critical examination of the relationship between anatomic complexity and finances is required within the context of aggressive endovascular treatment strategies and shifts toward value-based reimbursement.


Cardiac output measurement: lack of agreement between thermodilution and thoracic electric bioimpedance in two clinical settings.
To determine the agreement between thermodilution (TD) and thoracic electric bioimpedance (TEB) techniques in cardiac output (CO) measurements in hyperdynamic kidney recipients and normodynamic patients subjected to radical cystectomy. The main objective was to determine the reliability of TEB in CO measurement. Open two-group study. University hospital. 19 kidney recipients and 5 radical cystectomy patients. Radial artery cannula and pulmonary artery floating catheter were inserted. The eight ECG spot electrodes of the TEB device were situated on the body surface. Simultaneous CO measurements with TD and TEB were recorded at strategic points during the dynamic state of anesthesia and surgery. The mean difference (bias, TD-TEB) was higher in KRs (1.36 L/min) than radical cystectomy patients (-0.69 L/min). The corresponding 95% confidences of the bias were 1.10 to 1.54 L/min and -0.83 to -0.55 L/min. The precisions (SDs of bias) in kidney recipients and radical cystectomy patients were 1.08 L/min and 0.66 L/min, respectively. The limits of agreement were -0.97 to 3.51 L/min in kidney recipients and -1.99 to 0.61 L/min in radical cystectomy patients. The 95% confidences of the limits of agreement in kidney recipients were -1.09 to -0.49 for the lower limit and 3.21 to 3.81 for the upper limit. The corresponding values in radical cystectomy patients were -2.23 to -1.75 L/min and 0.37 to 0.85 L/min. These findings demonstrate lack of agreement between TEB and TD in CO measurements in a hyperdynamic and a normodynamic clinical setting. It is concluded that the TEB device is unreliable in CO measurement and cannot replace or be interchanged with TD.


Drug-Disease Interaction: Effect of Inflammation and Nonsteroidal Anti-Inflammatory Drugs on Cytochrome P450 Metabolites of Arachidonic Acid.
Inflammatory conditions increase cardiovascular (CV) risk. Some nonsteroidal anti-inflammatory drugs (NSAIDs) that are used to treat pain and inflammation are also associated with CV complications. Inflammation, but not NSAIDs, disrupts the balance of vasodilator and vasoconstrictor components of the renin-angiotensin system within the heart. Herein, we report the effect of both inflammation and NSAIDs (rofecoxib, celecoxib, and meloxicam) on the physiologically active cytochrome P450 metabolites of arachidonic acid (ArA) in the rat with adjuvant arthritis. After oral administration of 7 daily therapeutically equivalent doses of NSAIDs or vehicle, the anti-inflammatory response, as well as the ArA metabolites and drug concentrations in plasma, heart and kidneys were assessed. Inflammation in the form of adjuvant arthritis caused a significant tissue-dependent imbalance of ArA metabolites by elevating the ratio of cardiotoxic 20-hydroxyeicosatetraenoic acid over cardioprotective epoxyeicosatrienoic acids in the heart, and reducing the ratio in the kidney. The observed imbalance was augmented by cardiotoxic rofecoxib but not by other examined NSAIDs with known milder cardiotoxicity. The cardio-renal toxicity of NSAIDs with known severe CV side effects may be due to altered cytochrome P450-mediated ArA acid metabolism. The ArA metabolism profile may be a marker of NSAIDs safety and toxicity.


Radiotherapy alone and chemoradiation for nonmetastatic esophageal carcinoma. A critical review of chemoradiation.
Sixty-five patients with nonmetastatic (Stages I, II, and III) esophageal cancer (EC) were treated with radiotherapy (RT) alone (56.00 to 61.00 Gy in 6 to 7 weeks) or synchronous combinations of radiotherapy and chemotherapy (RT-CT). RT-CT consisted of 41.40 to 50.40 Gy in 4.5 to 8 weeks with continuous infusion 5-fluorouracil 5-FU (1000 mg/m2/d for 4 days in weeks 1, 4, and 8), mitomycin C (10 mg/m2 intravenously [IV] in weeks 1 and 8), cisplatin (75 mg/m2 IV in week 4). Maintenance CT consisted of methotrexate (200 mg/m2 IV), leucovorin (10 mg/m2 orally every 6 hours for 5 doses), and 5-FU (600 mg/m2 IV) in weeks 10, 12, and 14. Thirty-five patients treated by RT alone (Group A) were comparable in terms of age, sex, AJC staging, histologic condition, and location of primary with 30 patients treated by RT-CT (Group B). In Group A (range, 2- to 144+ months), two patients (42 and 144 months) are alive and well. In Group B (range, 2- to 59+ months), 12 patients (7 to 59 months) are alive and well. Median survival in Group A is 8 months, compared with 15 months for patients achieving a complete response (CR) in Group B. Patients in Group B achieved a 77% CR rate by endoscopy-biopsy, whereas 30% of the patients in Group A achieved a CR (P = 0.0001). The recurrence rates at the primary site/regional nodes were 77% and 27% in Groups A and B, respectively (P = 0.0001). The incidences of distant metastases were 29% and 20%, respectively (P = 0.423). In Group A, the 1-year and 2-year cumulative survival rates were 27% and 13%, respectively. In Group B, the cumulative survival rates were 53% at 1 year and 29% at 2 years (P = 0.023). Aside from reversible myelotoxicity, the incidences of pulmonary fibrosis, esophagitis, and fistulae formation were less frequent in the combined technique treatment group. A compilation of reported chemoradiation protocols for EC indicates consistently improved 1-year and 2-year survival rates, compared with surgical and RT series. The key to further improvement in the treatment of EC appears to lie in increasing the biologic response (RT fractionation and endocavitary RT) and optimal use of multiple effective CT agents with nonadditive toxicities.


Single dose and cross tolerance studies of beta-phenethylamine, d-amphetamine and LSD in the chronic spinal dog.
The effects of beta-phenethylamine (PEA), d-amphetamine and LSD were studied on spinal reflexes, autonomic signs, and behavior in the non-tolerant and LSD tolerant (30 microgram/kg/day) chronic spinal dog. LSD (10 microgram/kg) facilitated the flexor reflex, produced the stepping reflex, increased respiration, pulse rate and temperature, slightly dilated pupils and produced whining, tracking and restlessness. Direct tolerance developed to all of these effects except temperature. PEA (0.8 mg/kg/min infused for 12 min) and amphetamine (3.2 mg/kg) facilitated the flexor reflex, increased respiration, temperature and the skin twitch reflex latency, caused a marked mydriasis, retracted the nictitating membrane and produced restlessness and stereotypic head movements. PEA but not amphetamine elicited stepping, and only amphetamine consistently slowed heart rate. No cross tolerance to the physiologic or behavioral effects of amphetamine was observed. Partial tolerance developed only to the actions of PEA on the stepping reflex and the nictitating membrane. The single dose effects and the lack of cross tolerance to amphetamine and PEA suggest modes of action different from LSD. PEA has some actions which differ from those of amphetamine.


Optimal dose for stroke thrombolysis in Asians: low dose may have similar safety and efficacy as standard dose.
Although intravenous tissue-type plasminogen activator (t-PA) at a standard dose of 0.9 mg kg(-1) is effective for patients with acute ischemic stroke, concerns have been raised regarding Asians. To compare the safety and efficacy between low and standard doses for stroke thrombolysis. Consecutive patients receiving t-PA treatment were recruited according to the prespecified dosing policy from two medical centers in Taiwan: low dose (0.7 mg kg(-1) ) at National Cheng Kung University Hospital (NCKUH) from August 2006 to June 2009, or standard dose (0.9 mg kg(-1) ) at NCKUH from July 2009 to December 2010 and at Changhua Christian Hospital from May 2008 to December 2010. The primary safety outcome was the occurrence of symptomatic intracerebral hemorrhage (SICH). The secondary efficacy outcome was the proportion of patients with a modified Rankin Scale (mRS) grade of ≤ 1 at 3 months. From August 2006 to December 2010, 261 patients were recruited, of whom 105 and 156 received low and standard doses, respectively. The occurrence of SICH was non-significantly lower in the standard-dose group than in the low-dose group (2.6% vs. 4.8%, respectively; P = 0.34). The favorable outcome of mRS grade of ≤ 1 at 3 months was similar (38.4% and 41.1%, respectively; P = 0.676). A review of other case series of low vs. standard doses in Asians also showed similar safety and efficacy. Our study, as well as other case series on Asians, revealed that standard-dose thrombolysis for acute ischemic stroke in an Asian population carries no increased risk of symptomatic intracerebral hemorrhage when compared with the low dose.


In vitro controlled release of extracellular vesicles for cardiac repair from poly(glycerol sebacate) acrylate-based polymers.
Cell therapy to restore cardiac function in chronic heart failure has been extensively studied. However, its therapeutic value is limited due to poor cell engraftment and survival and the therapeutic outcomes have been attributed to paracrine secretions such as extracellular vesicles (EV). The direct use of EV is an attractive therapeutic strategy and it has been shown that the kinetics of delivery of the EV to the targeted tissue may impact the outcomes. However, there are currently no technologies to deliver EV to the heart in a controlled and tunable manner. The objective of this study was to design a controlled release system, based on a photocurable adhesive polymer, to locally deliver EV to the cardiac tissue. We have first demonstrated that the adhesive polymer, PGSA-g-EG, did not impact the EV bioactivity in vitro and was biocompatible in vivo when tested in a rat model. Importantly, the polymer remained attached to the heart surface for at least 1 month. We have then evaluated and optimized the in vitro release kinetics of the EV from the PGSA-g-EG polymer. Freeze-dried EV formulations were developed to tune the release kinetics and maximize the loading in the polymeric material. Moreover, despite the instability of the EV in aqueous medium at 37°C, the PGSA-g-EG polymer was able to release bioactive EV for at least 14 days. Overall, these results suggest that the PGSA-g-EG is a suitable material to promote the controlled delivery of bioactive EV over an extended period of time. STATEMENT OF SIGNIFICANCE: Extracellular vesicles (EV) are an investigational class of therapeutics that has shown promise to restore cardiac function following an ischemic event. Furthermore, its translation to the clinics is expected to pose less regulatory challenges than cell-based therapies. However, EV therapeutic outcomes are likely to be impacted by the route of administration and the kinetics of delivery to the target tissue. Therefore, there is a need for biomaterial-based technologies to deliver, in a controlled and tunable manner, EV to the heart. The present study describes the use of PGSA-g-EG polymer as an adhesive cardiac patch with potential to enable the controlled delivery of bioactive EV over an extended period of time to the cardiac tissue.


[High level expression of foreign gene via multiple joined operons and a new concept on the restricted constant of total amount of plasmid DNA per cell of Escherichia coli].
To examine the feasibility of linking operons in tandem to enhance expression of heterologous genes in Escherichia coli and to clarify the potential control mechanism of the total plasmid DNA amount in each host cell. Two series of expression plasmids, CW11 and CW12, containing 1 to 4 and 1 to 3 heterologous gene operon(s), respectively, were constructed. The molecular size of the CW11 series varied from 5.47 kb to 12.26 kb in 2.25 kb increments. The CW12 series varied from 5.40 kb to 9.72 kb in 2.16 kb increments. Protein expression was analyzed via SDS-PAGE and laser scanning. Plasmid copy number was determined by incorporation with 3H-TdR([3H]-thymidine). No influence of the tandem-joined operons on host growth and plasmid stability was observed. Upon induction, the desired protein accumulated in the CW11 series were 46.0%, 54.8%, 56.1%, and 60.1% of total cell protein. In the CW12 series, the yields were 33.5%, 44.0%, and 47.1% of total cell protein. With increasing size, however, plasmid copy number decreased. Further calculation showed that the total amount of plasmid DNA per cell is restricted to some extent. There seems exists a mechanism to control the maximum level of total plasmid DNA amount in each host cell. Increasing the target gene dosage by tandem linking of operons enhanced the expression level of a desired protein. Although the size (kb) and the copy number of each plasmid are negatively interrelated, it seems that as for certain plasmids, their total DNA amount per cell is a restricted constant for a specific E. coli strain under identical incubation condition.


Toxicity prediction from toxicogenomic data based on class association rule mining.
While the recent advent of new technologies in biology such as DNA microarray and next-generation sequencer has given researchers a large volume of data representing genome-wide biological responses, it is not necessarily easy to derive knowledge that is accurate and understandable at the same time. In this study, we applied the Classification Based on Association (CBA) algorithm, one of the class association rule mining techniques, to the TG-GATEs database, where both toxicogenomic and toxicological data of more than 150 compounds in rat and human are stored. We compared the generated classifiers between CBA and linear discriminant analysis (LDA) and showed that CBA is superior to LDA in terms of both predictive performances (accuracy: 83% for CBA vs. 75% for LDA, sensitivity: 82% for CBA vs. 72% for LDA, specificity: 85% for CBA vs. 75% for LDA) and interpretability.