Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer.
Thirty-three adult and pediatric patients with refractory malignancies were treated with escalating doses of melphalan (120-225 mg/m2 IV over 3 days) followed by reinfusion of previously harvested and cryopreserved autologous marrow. The hematological and nonhematological toxicities and the therapeutic effects of this regimen were evaluated. Increasing doses of melphalan did not alter the rate of decline nor the recovery of peripheral blood counts. Granulocyte (greater than 500/microL) and platelet count (greater than 20,000/microL) recovery occurred in a median of 19 (range 12-54) and 24 (range: 12-54) days after bone marrow transplantation, respectively. Five patients experienced severe infection, three of which were fatal, and one patient died due to thrombocytopenic hemorrhage. Toxicity to the gastrointestinal system was dose limiting. The maximum tolerated dose of melphalan was 180 mg/m2; only three of 24 patients experienced severe stomatitis, esophagitis, and diarrhea at this level or less, while eight of nine patients at 225 mg/m2 were affected (p less than 0.005). Administration of cyclophosphamide (300 mg/m2 IV) 1 week before melphalan therapy did not reduce the incidence of severe gastrointestinal toxicity. Plasma melphalan concentration peaked 30-60 min after infusion (4.8-11.5 micrograms/mL) but declined rapidly. Cerebrospinal fluid concentration was 10% of the corresponding plasma concentration and was undetectable at 3 hours. Antitumor responses occurred in nine of 13 patients with malignant melanoma (five complete and four partial remissions), and ranged 2-12+ months with a median of 5 months. Four of six neuroblastomas demonstrated responses (three complete and one partial remission( lasting a median of 7.5 (range: 5-10) months. Other tumors in which this regimen had activity included breast cancer and Ewing's sarcoma. The overall response rate for the 33 patients was 30% complete remissions (10 patients) and 21% partial remissions (seven patients). High dose melphalan and autologous bone marrow transplantation is a promising therapy for patients with malignancies for which no effective treatment is known or for patients whose cancer is refractory to conventional therapeutic agents.


Relationship between blood glucose on admission and prognosis in patients with acute myocardial infarction treated with percutaneous coronary intervention.
Diabetes mellitus in patients with myocardial infarction affects in-hospital and late mortality. It has been shown that the glucose level on admission can also affect prognosis. This conclusion was based on an analysis performed on a heterogeneous group of patients, treated not only with percutaneous coronary intervention (PCI) but also with fibrinolysis. Moreover, the threshold values hyperglycaemia for the diagnosis of were also variable. To assess whether glucose level on admission affects in-hospital and one-year prognosis in patients with ST-segment elevation myocardial infarction (STEMI) treated with PCI. Consecutive patients with STEMI treated with PCI were included in the analysis. Patients with STEMI complicated by cardiogenic shock were also included. Three groups according to the glucose level on admission were analysed: group I - <7.8 mmol/l (140 mg/dl), group II - 7.8-11.1 mmol/l (140-200 mg/dl), and group III - > or = 11.1 mmol/l (200 mg/dl). The incidence of diabetes mellitus in the total group (1027 patients) was 26.1%, and of cardiogenic shock - 9.2%. Group I consisted of 472 patients, group II - 307 patients, and group III - 248 patients. Compared with normoglycaemic patients, those with elevated glucose level were older, more often female, had more often hypertension, diabetes mellitus, cardiogenic shock, were more often treated with fibrinolysis before PCI but were less often smokers. Multivessel disease and initial patency of the infarct-related artery (TIMI 0-1) were more often observed in patients with higher glucose level. A trend towards a higher incidence of reocclusion was also more often present in patients with increased glucose level. Moreover, mean creatine kinase concentration was the highest and the left ventricular ejection fraction was the lowest in group III. During the in-hospital stay, the complication rate was as follows: stroke (1.1% vs. 1.3% vs. 4.4%), and mortality (2.8 vs. 4.9 vs. 13.3%) in groups I, II, and III, respectively. The same tendency was observed during the one-year follow-up period: stroke (1.3 vs. 2.9 vs. 6.9%), mortality (6.4 vs. 9.1 vs. 22.6%). The 1 mmol/l (18 mg/dl) increase of the baseline glucose level among various risk factors was an independent prognostic factor of higher -year mortality (HR=1.06; 95% CI 1.02-1.09). Diabetes mellitus did not affect prognosis among patients included in the analysis. Elevated glucose level on admission is associated with adverse prognosis in patients with STEMI treated with PCI.


Three-dimensional evaluation of morphology and position of impacted supernumerary teeth in cases of cleidocranial dysplasia.
Cleidocranial dysplasia (CCD) is a congenital anomaly characterized by the presence of impacted supernumerary teeth and delayed eruption of permanent teeth. However, there has been no detailed investigation on supernumerary teeth in patients with CCD using three-dimensional (3D) imaging techniques. The purpose of this study was to elucidate the morphology and position of supernumerary teeth using 3D images reconstructed from cone-beam computed tomography (CBCT) data in a group of five Japanese subjects (male, 3; female, 2; age, 15.0-25.4 years) with CCD. All five subjects exhibited supernumerary teeth (39 in total; average, 7.8; range, 1-15). All supernumerary teeth were impacted and existed as pairs with adjacent permanent teeth. Comparison of the size (the crown and dental-root lengths, the crown mesiodistal and buccolingual diameters), the number of cusps and dental roots, the position, and direction of supernumerary teeth in relation to the adjacent permanent teeth was analyzed. The results of relationship analyses revealed that, at sites other than the molar region, supernumerary teeth were positioned on the lingual and distal sides and supernumerary teeth resembled the morphology of their adjacent permanent teeth in terms of the number of cusps but were smaller than the adjacent permanent teeth. In the molar region, supernumerary teeth were microdontia, which were apparently small and obscure morphologically. In addition, while all adjacent permanent teeth exhibited normal direction, five supernumerary teeth exhibited inverse direction. The findings of this study will improve our understanding of the characteristics of CCD and provide important information for the pathophysiology and clinical treatment.


Regulation of Mutant p53 Protein Expression.
For several decades, p53 has been detected in cancer biopsies by virtue of its high protein expression level which is considered indicative of mutation. Surprisingly, however, mouse genetic studies revealed that mutant p53 is inherently labile, similar to its wild type (wt) counterpart. Consistently, in response to stress conditions, both wt and mutant p53 accumulate in cells. While wt p53 returns to basal level following recovery from stress, mutant p53 remains stable. In part, this can be explained in mutant p53-expressing cells by the lack of an auto-regulatory loop with Mdm2 and other negative regulators, which are pivotal for wt p53 regulation. Further, additional protective mechanisms are acquired by mutant p53, largely mediated by the co-chaperones and their paralogs, the stress-induced heat shock proteins. Consequently, mutant p53 is accumulated in cancer cells in response to chronic stress and this accumulation is critical for its oncogenic gain of functions (GOF). Building on the extensive knowledge regarding wt p53, the regulation of mutant p53 is unraveling. In this review, we describe the current understanding on the major levels at which mutant p53 is regulated. These include the regulation of p53 protein levels by microRNA and by enzymes controlling p53 proteasomal degradation.


The spectrum of irritant-induced asthma: sudden and not-so-sudden onset and the role of allergy.
A retrospective investigation of 86 asthmatic subjects defined clinical features of irritant-induced asthma and assessed the contributory role of an allergic predisposition. Three categories of asthma were evaluated: (1) occupational asthma due to a sensitizer (11 subjects, 13%); (2) irritant-induced asthma (54 persons, 63%); and (3) not occupational/environmental exposure-related asthma (21 subjects, 24%). Two distinct clinical presentations of irritant-induced asthma emerged: the first was sudden onset (29 subjects) and the second was not so sudden in onset (25 subjects). Sudden-onset, irritant-induced asthma was analogous to the reactive airways dysfunction syndrome. Clinical manifestations began immediately or within a few hours (always within 24 h) following an accidental, brief, and massive exposure. In contrast, for the not-so-sudden-onset asthma subjects, the causative irritant exposure was not brief, usually not massive, continued for > 24 h, and the initiation of asthma took longer to evolve. Eighty-eight percent of individuals with not-so-sudden irritant-induced asthma displayed an atopy/allergy status (p < 0.01). Some of the atopy/allergy subjects with presumed new-onset asthma were found to have suffered preexisting asthma that had been clinically quiescent for at least 1 year before the triggering exposure (16 persons). We conclude that preexisting allergic/atopy and/or preexisting asthma were significant contributors to the pathogenesis of not-so-sudden, irritant-induced asthma and emphasizes a critical interaction between environmental and host factors in the pathogenesis of asthma.


Testosterone plays a permissive role in angiotensin II-induced hypertension and cardiac hypertrophy in male rats.
Sex hormones contribute to sex differences in blood pressure. Inappropriate activation of the renin-angiotensin system is involved in vascular dysfunction and hypertension. This study evaluated the role of androgens (testosterone) in angiotensin II (Ang II)-induced increase in blood pressure, vascular reactivity, and cardiac hypertrophy. Eight-week-old male Wistar rats underwent sham operation, castration, or castration with testosterone replacement. After 12 weeks of chronic changes in androgen status, Ang II (120 ng/kg per minute) or saline was infused for 28 days via subcutaneous miniosmotic pump, and changes in blood pressure was measured. Vascular reactivity and Ang II receptor levels were examined in mesenteric arteries. Heart weight, cardiac ANP mRNA levels, and fibrosis were also assessed. Ang II infusion increased arterial pressure in intact males. The Ang II-induced increase in hypertensive response was prevented in castrated males. Testosterone replacement in castrated males restored Ang II-induced hypertensive responses. Castration reduced vascular AT1R/AT2R ratio, an effect that was reversed by testosterone replacement. Ang II-induced hypertension was associated with increased contractile response of mesenteric arteries to Ang II and phenylephrine in intact and testosterone-replaced castrated males; these increases were prevented in castrated males. Ang II infusion induced increased left ventricle-to-body weight ratio and ANP mRNA expression, indicators of left ventricular hypertrophy, and fibrosis in intact and testosterone-replaced castrated males, and castration prevented the increase in these parameters caused by Ang II. This study demonstrates that testosterone plays a permissive role in development and maintenance of Ang II-induced vascular dysfunction, hypertension, and cardiac hypertrophy.


Synthesis and characterization of mononuclear ruthenium(III) pyridylamine complexes and mechanistic insights into their catalytic alkane functionalization with m-chloroperbenzoic acid.
A series of mononuclear RuIII complexes [RuCl2(L)]+, where L is tris(2-pyridylmethyl)amine (TPA) or one of four TPA derivatives as tetradentate ligand, were prepared and characterized by spectroscopic methods, X-ray crystallography, and electrochemical measurements. The geometry of a RuIII complex having a non-threefold-symmetric TPA ligand bearing one dimethylnicotinamide moiety was determined to show that the nicotine moiety resides trans to a pyridine group, but not to the chlorido ligand. The substituents of the TPA ligands were shown to regulate the redox potential of the ruthenium center, as indicated by a linear Hammett plot in the range of 200 mV for RuIII/RuIV couples with a relatively large rho value (+0.150). These complexes act as effective catalysts for alkane functionalization in acetonitrile with m-chloroperbenzoic acid (mCPBA) as terminal oxidant at room temperature. They exhibited fairly good reactivity for oxidation of cyclohexane (C--H bond energy 94 kcal mol(-1)), and the reactivity can be altered significantly by the electronic effects of substituents on TPA ligands in terms of initial rates and turnover numbers. Catalytic oxygenation of cyclohexane by a RuIII complex with 16O-mCPBA in the presence of H2 18O gave 18O-labeled cyclohexanol with 100% inclusion of the 18O atom from the water molecule. Resonance Raman spectra under catalytic conditions without the substrate indicate formation of a RuIV==O intermediate with lower bonding energy. Kinetic isotope effects (KIEs) in the oxidation of cyclohexane suggest that hydrogen abstraction is the rate-determining step and the KIE values depend on the substituents of the TPA ligands. Thus, the reaction mechanism of catalytic cyclohexane oxygenation depends on the electronic effects of the ligands.


Analysis of Changes in Oil Palm Canopy Architecture From Basal Stem Rot Using Terrestrial Laser Scanner.
Basal stem rot (BSR), caused by the Ganoderma fungus, is an infectious disease that affects oil palm (Elaeis guineensis) plantations. BSR leads to a significant economic loss and reductions in yields of up to Malaysian Ringgit (RM) 1.5 billion (US$400 million) yearly. By 2020, the disease may affect ∼1.7 million tonnes of fresh fruit bunches. The plants appear symptomless in the early stages of infection, although most plants die after they are infected. Thus, early, accurate, and nondestructive disease detection is crucial to control the impact of the disease on yields. Terrestrial laser scanning (TLS) is an active remote-sensing, noncontact, cost-effective, precise, and user-friendly method. Through high-resolution scanning of a tree's dimension and morphology, TLS offers an accurate indicator for health and development. This study proposes an efficient image processing technique using point clouds obtained from TLS ground input data. A total of 40 samples (10 samples for each severity level) of oil palm trees were collected from 9-year-old trees using a ground-based laser scanner. Each tree was scanned four times at a distance of 1.5 m. The recorded laser scans were synched and merged to create a cluster of point clouds. An overhead two-dimensional image of the oil palm tree canopy was used to analyze three canopy architectures in terms of the number of pixels inside the crown (crown pixel), the degree of angle between fronds (frond angle), and the number of fronds (frond number). The results show that the crown pixel, frond angle, and frond number are significantly related and that the BSR severity levels are highly correlated (R2 = 0.76, P < 0.0001; R2 = 0.96, P < 0.0001; and R2 = 0.97, P < 0.0001, respectively). Analysis of variance followed post hoc tests by Student-Newman-Keuls (Newman-Keuls) and Dunnett for frond number presented the best results and showed that all levels were significantly different at a 5% significance level. Therefore, the earliest stage that a Ganoderma infection could be detected was mildly infected (T1). For frond angle, all post hoc tests showed consistent results, and all levels were significantly separated except for T0 and T1. By using the crown pixel parameter, healthy trees (T0) were separated from unhealthy trees (moderate infection [T2] and severe infection [T3]), although there was still some overlap with T1. Thus, Ganoderma infection could be detected as early as the T2 level by using the crown pixel and the frond angle parameters. It is hard to differentiate between T0 and T1, because during mild infection, the symptoms are highly similar. Meanwhile, T2 and T3 were placed in the same group, because they showed the same trend. This study demonstrates that the TLS is useful for detecting low-level infection as early as T1 (mild severity). TLS proved beneficial in managing oil palm plantation disease.


Atomic scale surface structure and morphology of InAs nanowire crystal superlattices: the effect of epitaxial overgrowth.
While shell growth engineering to the atomic scale is important for tailoring semiconductor nanowires with superior properties, a precise knowledge of the surface structure and morphology at different stages of this type of overgrowth has been lacking. We present a systematic scanning tunneling microscopy (STM) study of homoepitaxial shell growth of twinned superlattices in zinc blende InAs nanowires that transforms {111}A/B-type facets to the nonpolar {110}-type. STM imaging along the nanowires provides information on different stages of the shell growth revealing distinct differences in growth dynamics of the crystal facets and surface structures not found in the bulk. While growth of a new surface layer is initiated simultaneously (at the twin plane interface) on the {111}A and {111}B nanofacets, the step flow growth proceeds much faster on {111}A compared to {111}B leading to significant differences in roughness. Further, we observe that the atomic scale structures on the {111}B facet is different from its bulk counterpart and that shell growth on this facet occurs via steps perpendicular to the ⟨112⟩B-type directions.


Snake venom VEGF Vammin induces a highly efficient angiogenic response in skeletal muscle via VEGFR-2/NRP specific signaling.
Vascular Endothelial Growth Factors (VEGFs) are promising molecules for the treatment of ischemic diseases by pro-angiogenic therapy. Snake venom VEGFs are a novel subgroup with unique receptor binding profiles and as such are potential new therapeutic agents. We determined the ligand-receptor interactions, gene regulation and angiogenic properties of Vipera ammodytes venom VEGF, Vammin, and compared it to the canonical angiogenic factor VEGF-A to evaluate the use of Vammin for therapeutic angiogenesis. Vammin efficiently induced VEGFR-2 mediated proliferation and expression of genes associated with proliferation, migration and angiogenesis. VEGF-A165 and especially VEGF-A109 induced less pronounced effects. Vammin regulates a number of signaling pathways by inducing the expression of NR4A family nuclear receptors and regulators of calcium signaling and MAP kinase pathways. Interestingly, MARC1, which encodes an enzyme discovered to catalyze reduction of nitrate to NO, was identified as a novel VEGFR-2 regulated gene. In rabbit skeletal muscle adenoviral delivery of Vammin induced prominent angiogenic responses. Both the vector dose and the co-receptor binding of the ligand were critical parameters controlling the type of angiogenic response from sprouting angiogenesis to vessel enlargement. Vammin induced VEGFR-2/NRP-1 mediated signaling more effectively than VEGF-A, consequently it is a promising candidate for development of pro-angiogenic therapies.


Release of Nile red from thermoresponsive gold nanocomposites by heating a solution and the addition of glutathione.
Thermoresponsive gold nanocomposites encapsulating Nile red were fabricated by the conjugation of gold nanoparticles containing Nile red with a thermoresponsive polymer, poly(N-isopropylacrylamide(90 mol%)-co-N-acryloyldiethylenetriamine(10 mol%)). They were then examined as a model of drug delivery carriers and colloidal fluorescence sensors. Nile red, as a fluorophore to be released, was introduced to the surface of gold nanoparticles prior to conjugation with thermoresponsive polymers. Heating a solution at 90°C resulted in shrinkage of the thermoresponsive polymers, which facilitated disassembly of the gold nanocomposites in the presence of glutathione. This disassembly caused a replacement of Nile red with glutathione at the surface of the gold nanoparticles, followed by the release of Nile red from the gold nanocomposites. Nile red liberated from the gold surface recovered its inherent fluorescence properties that had been quenched by gold nanoparticles through fluorescence resonance energy transfer. The fluorescence intensity of the liberated Nile red increased linearly as the glutathione concentration increased up to 1.0 × 10(-5) mol/L, demonstrating that thermoresponsive gold nanocomposites can be used as colloidal sensors or drug delivery carriers that can be manipulated by the concentration of glutathione and the solution temperature. The applicability of the thermoresponsive gold nanocomposites to colloidal fluorescence probes was also checked by assay of glutathione in tablets.


[Current therapeutic possibilities for uveal ocular hypertension].
to evaluate the efficacy of combination therapy with three antiglaucoma agents (dorzolamide + brimonidine/timolol) for uveal ocular hypertension. The study enrolled 20 patients with anterior uveitis complicated by intraocular pressure (IOP) elevation. Besides standard anti-inflammatory agents, the treatment included IOP-lowering instillations, namely dorzolamide 2% 3 times daily and timolol 0.5% 2 times daily. Those patients whose IOP remained uncompensated were then switched to a three-drug regimen: dorzolamide 2% 3 times daily and a fixed combination of brimonidine 0.2%, an aLPHA2-receptor agonist, and timolol 0.5%, a 3-blocker, 2 times daily (Combigan, Allergan). IOP was measured with Maklakov tonometer three times during the day before the treatment and then three times daily while performing the two- or three-drug combination therapy. The mean initial IOP was 34.57 +/- 0.09 mmHg with daily fluctuations of 5.2 +/- 0.08 mmHg. After starting the unfixed combination therapy (dorzolamide + timolol) the mean IOP decreased by 7.86 +/- 0.07 mmHg. Switching to the three-drug therapy (dorzolamide+ brimonidine/timolol) enabled an additional decrease in IOP by 5.43 +/- 0.06 mmHg. Thus, with the new regimen the total decrease in IOP averaged 13.29 +/- 0.09 mmHg with daily fluctuations of 2.5?0.06 mmHg, which ensured that the target IOP was achieved in all patients. All the drugs were well-tolerated. Combination therapy with three antiglaucoma agents in the form of two medications--dorzolamide 2% and brimonidine/timolol fixed combination (Combigan)--is shown to be effective in uveal ocular hypertension patients.


Comparison of 120-200 W 2 μm thulium:yttrium-aluminum-garnet vapoenucleation of the prostate.
To evaluate efficacy and safety of 200 W 2 μm thulium:yttrium-aluminum-garnet vapoenucleation of the prostate (ThuVEP) for patients with benign prostatic obstruction (BPO). Twenty-eight consecutive patients with symptomatic BPO were treated with 200 W ThuVEP. Patients were matched for age and preoperative prostate volume with 28 patients from our 120 W ThuVEP database. Patient data and postoperative outcome at 12-month follow-up were compared. Mean prostate volume (65.39 vs 68.62 cc) and resected weight (40.72 vs 53.18 g) differed not significantly between 200 and 120 W ThuVEP. The percentage of resected tissue was lower with 200 W compared with 120 W (58.48 vs 72.93%, P=0.047) because of the higher rate of ablated tissue. There were no differences in mean operative (69.21 vs 78.67 min), laser (45.43 vs 48.58 min), morcellation (16.52 vs 20.48 min), and catheter (2.2 vs 2.1 d) time between the devices. Three patients needed immediate re-treatment (hemorrhage necessitating coagulation 1=200 W, secondary apical resection 2 120/200 W). One (1.79%) patient (120 W) needed a blood transfusion postoperatively. Fifty-one (91%) patients completed 12-month follow-up. Quality of life, International Prostate Symptom Score, peak urinary flow rate, postvoid residual urine, prostate-specific antigen level, and prostate volume improved significantly (P≤0.019) and were not different between the devices. At follow-up, two (3.57%) patients (120/200 W) had a bladder neck contracture. ThuVEP is a safe and efficacious procedure for patients with symptomatic BPO. 120 and 200 W ThuVEP had an equivalent clinical outcome at 12-month follow-up.


Hall effect imaging.
This paper presents a new imaging method based on the classical Hall effect (HE), which describes the origin of a detectable voltage from a conductive object moving in a magnetic field. HE images are formed using ultrasound imaging techniques in a magnetic field. These images reflect the electrical properties of the sample. To demonstrate the feasibility of this method, images of plastic and biological samples are collected. The contrast mechanism and signal-to-noise issues are discussed. Since electrical parameters vary widely among tissue types and pathological states, HE imaging may be a useful tool for biological research and medical diagnosis.


Audiological Results in SSD With an Active Transcutaneous Bone Conduction Implant at a Retrosigmoidal Position.
One option for patients with single sided deafness (SSD) who experience problems with insufficient hearing in different surroundings is the treatment with percutaneous bone-anchored hearing aids. Common medical problems associated to a skin penetrating abutment can be avoided by active transcutaneous bone conduction hearing implants. The purpose of our study was to evaluate the benefit of an active transcutaneous bone conduction hearing implant in patients with SSD. Patients suffering from SSD who are implanted with an active transcutaneous bone conduction hearing implant in retrosigmoidal position were audiologically analyzed. The audiological test battery included air and bone conduction thresholds, word recognition score (WRS) in quiet and speech intelligibility (Oldenburg Sentence Test [OLSA]) in noise. Patient satisfaction was evaluated with the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Bern-Benefit in Single-Sided Deafness (BBSS) questionnaire. The monosyllable WRS and the signal-to-noise ratio (SNR) assessed by the OLSA was significantly better in all aided conditions. Also, the APHAB categories ease of communication and reverberation and the average benefit in the BBSS improved significantly if using the device. The Bonebridge is a transcutaneous alternative to the well-established percutaneous bone conducting devices in patients with single sided deafness. An improvement in hearing in noise and quiet as well as a decrease of the head shadow effect can be expected.


[Tibiotalocalcaneal arthrodesis using a retrograde nail locked in the sagittal plane].
To evaluate our experience with the use of a retrograde nail locked in the sagittal plane for tibiotalocalcaneal arthrodesis indicated in severe post-traumatic arthritis of the ankle. Twenty patients, 16 men and four women at an average age of 58.7 years (range, 23 to 72) were evaluated. All patients had severe post-traumatic changes in the talocrural and talocalcaneal joints. Five patients also had an equinus deformity. In two patients arthrodesis followed the treatment of purulent arthritis of the talocrural joint. A local fasciocutaneous flap was used for soft tissue reconstruction in three patients. All patients were operated on using the standard surgical technique. METHODS With the patient in a supine position, reamed by hand with the use of a driving rod, a straight retrograde AAN Orthofix nail was inserted through the heel bone and talus into the distal tibia and locked in these bones in the sagittal plane. No complications such as injury to the neurovascular plexus or pseudoarthrosis were recorded. Four patients showed a reaction to the proximal locking screw on the proximal tibial surface, which was treated by earlier screw removal under topical anaesthesia. Due to infectious complications, the nail had to be removed prematurely in one patient. The average Foot Function Index was 12 points (range, 10 to 15) and the average ankle-hindfoot score was 67.6 points (range, 59 to 84). Thirteen patients (65 %) were not limited in their daily activities or recreational sports, six (30 %) experienced pain in sports but not daily activities and one patient (5 %) reported pain even when walking. All fusions healed in the correct position within 18 weeks. Tibiotalocalcaneal arthrodesis is not a frequent surgical procedure in either trauma surgery or orthopaedics. For this complicated procedure, rather than intramedullary nails, internal fixation with screws or plates or external fixation are preferred. The high rate of bony healing can be explained by maintenance of exact nail locking in the sagittal plane. The antero- posterior approach provides a more secure locking in the bone and assists in neutralizing sagittal forces at the site of arthrodesis. The use of reamed interlocking nails can therefore be accepted not only for treatment of long-bone fractures, but also for treating pseudoarthrosis and in complicated or failed arthrodesis. Patients' satisfaction is the primary goal we strive to achieve in severe post-traumatic conditions of the talus and foot. Repeat surgery, spongioplasty, external fixation revision for pin-tract infection, persistent pain, activity restriction and poor clinical results reduce patients' satisfaction. In our group, the rate of healed arthrodesis was high and the number of complications was low, therefore our patients' satisfaction was high.


Marrow toxicity of 33P-versus 32P-orthophosphate: implications for therapy of bone pain and bone metastases.
Several bone-seeking radiopharmaceuticals, such as 32P-orthophosphate, 89Sr-chloride, 186Re-1,1 hydroxyethylidene diphosphonate (HEDP), and 153Sm-ethylene diamine tetramethylene phosphonic acid (EDTMP), have been used to treat bone pain. The major limiting factor with this modality is bone marrow toxicity, which arises from the penetrating nature of the high-energy beta particles emitted by the radionuclides. It has been hypothesized that marrow toxicity can be reduced while maintaining therapeutic efficacy by using radionuclides that emit short-range beta particles or conversion electrons. In view of the significant clinical experience with 32P-orthophosphate, and the similarity in pain relief afforded by 32P-orthophosphate and 89Sr-chloride, this hypothesis is examined in this study using 32P- and 33P-orthophosphate in a mouse femur model. Survival of granulocyte macrophage colony-forming cells (GM-CFCs) in femoral marrow was used as a biologic dosimeter for bone marrow. 32P- and 33P-orthophosphate were administered intravenously, and GM-CFC survival was determined as a function of time after injection and, at the nadir, as a function of injected activity. The kinetics of radioactivity in the marrow, muscle, and femoral bone were also determined. The biologic dosimeter was calibrated by assessing GM-CFC survival at its nadir after chronic irradiation of Swiss Webster mice with exponentially decreasing dose rates of gamma rays (relative biologic effectiveness equivalent to that of beta particles) from a low-dose rate 137Cs irradiator. Dose-rate decrease half-times (Td) (time required for 137Cs gamma ray dose rate to decrease by one half) of 62, 255, and 425 h and infinity were used to simulate the dose rate patterns delivered by the radiopharmaceuticals as dictated by their effective clearance half-times from the mouse femurs. These data were used to experimentally determine the mean absorbed dose to the femoral marrow per unit injected activity. Finally, a theoretical dosimetry model of the mouse femur was developed, and the absorbed doses to the femoral marrow, bone, and endosteum were calculated using the EGS4 Monte Carlo code. When the animals were irradiated with exponentially decreasing dose rates of 137Cs gamma rays, initial dose rates required to achieve 37% survival were 1.9, 0.98, 0.88, and 0.79 cGy/h for dose rate decrease half-times of 62, 255, and 425 h and infinity, respectively. The D37 values were 144 +/- 15, 132 +/- 12, 129 +/- 3, and 133 +/- 10 cGy, respectively, compared with a value of 103 cGy for acute irradiation. When 32P and 33P were administered, the injected activities required to achieve 37% survival were 313 and 2,820 kBq, respectively. Theoretical dosimetry calculations show that 33P offers a 3- to 6-fold therapeutic advantage over 32P, depending on the source and target regions assumed. The low-energy beta-particle emitter 33P appears to offer a substantial dosimetric advantage over energetic beta-particle emitters (e.g., 32p, 89Sr, 186Re) for irradiating bone and minimizing marrow toxicity. This suggests that low-energy beta or conversion electron emitters may offer a substantial advantage for alleviation of bone pain as well as for specifically irradiating metastatic disease in bone.


Second cancer following cancer of the respiratory system in Connecticut, 1935-1982.
The risk of a person developing a second primary cancer was evaluated in approximately 30,000 persons who developed cancer of the respiratory system in Connecticut between 1935 and 1982. A significant 44% excess of all second cancers was observed following cancer of the lung (614 observed vs. 426 expected). The excess of second tumors was 72% following cancer of the larynx (541 vs. 314) and 34% following cancer of the nasal cavities and sinuses (43 vs. 32). For cancers of the lung and larynx, second cancers arose mainly along the respiratory tract or other sites associated with cigarette smoking (oral cavity, bladder, kidney). A threefold excess of esophageal cancer followed cancer of the larynx, which was indicative of risk factors in common (alcohol and tobacco) and possibly an effect of radiotherapy. Radiotherapy may have contributed also to the increased risk of second lung and breast cancers. A slight excess risk of leukemia after lung cancer points to a possible effect of chemotherapy given for certain histologic types. An unexpected finding was a significant 50% increased risk of colon cancer following cancer of the larynx. Significant excesses of prostate cancer are probably artifacts associated with increased medical surveillance and higher autopsy rates among cancer patients than in the general population. No deficits of any second cancers were observed. The risk of a second cancer developing did not appear to vary by sex or time since initial diagnosis, except that the risks following cancer of the nasal cavities and sinuses returned to normal levels among long-term survivors. Among persons observed for 10 or more years after their initial diagnosis of cancers of the lung or larynx, the risk of developing a second cancer remained high, i.e., on the order of 50% above expectation. Further analytic studies should clarify the role of smoking, alcohol, other life-style and host factors, and various forms of therapy on the risk of second cancers following cancer of the respiratory system.


Learning anatomy changes from patient populations to create artificial CT images for voxel-level validation of deformable image registration.
The purpose of this study was to develop an approach to generate artificial computed tomography (CT) images with known deformation by learning the anatomy changes in a patient population for voxel-level validation of deformable image registration. Using a dataset of CT images representing anatomy changes during the course of radiation therapy, we selected a reference image and registered the remaining images to it, either directly or indirectly, using deformable registration. The resulting deformation vector fields (DVFs) represented the anatomy variations in that patient population. The mean deformation, computed from the DVFs, and the most prominent variations, which were captured using principal component analysis (PCA), composed an active shape model that could generate random known deformations with realistic anatomy changes based on those learned from the patient population. This approach was applied to a set of 12 head and neck patients who received intensity-modulated radiation therapy for validation. Artificial planning CT and daily CT images were generated to simulate a patient with known anatomy changes over the course of treatment and used to validate the deformable image registration between them. These artificial CT images potentially simulated the actual patients' anatomies and also showed realistic anatomy changes between different daily CT images. They were used to successfully validate deformable image registration applied to intrapatient deformation.


The eye and tick-borne disease in the United States.
Tick-borne diseases are increasing in incidence and geographic distribution. Several diseases endemic to the United States have ophthalmic manifestations, including the most common tick-borne disease, Lyme borreliosis. As ocular complaints may lead a patient to seek medical evaluation, it is important to be aware of the systemic and ophthalmic manifestations of tick-borne diseases in order to make the correct diagnosis. Vision-threatening ophthalmic manifestations are relatively common in Lyme disease and Rocky Mountain spotted fever. Ocular involvement is rare in babesiosis, tick-borne relapsing fever, Powassan encephalitis, ehrlichiosis, anaplasmosis, and Colorado tick fever.There are clear guidelines for diagnosis and treatment of Lyme disease; however, confusion and misinformation among the general public as well as controversy about chronic or late-stage Lyme disease can impact the evaluation of ophthalmic disease. Furthermore, there are many gaps in our knowledge regarding the pathophysiology of ocular borreliosis although it seems likely that Lyme uveitis is rare in the United States. Knowledge of systemic and ophthalmic manifestations combined with an understanding of the epidemiology of disease vectors is crucial for the diagnosis of tick-borne diseases.


Efficacy of cola ingestion for oesophageal food bolus impaction: open label, multicentre, randomised controlled trial.
To determine the efficacy and safety of cola in resolving complete oesophageal food bolus impaction. Open label, multicentre, randomised controlled trial. Emergency departments of five Dutch hospitals at the secondary and tertiary level, between 22 December 2019 and 16 June 2022. 51 adults presenting with complete oesophageal food bolus impaction, defined as a sudden inability to pass saliva after consumption of foods. Patients who ingested meat that contained bones, and patients with an American Society of Anesthesiologists (ASA) physical status classification of IV or higher were excluded. 28 patients in the intervention group were instructed to consume 25 mL cups of cola at intervals up to a maximum total volume of 200 mL. 23 patients in the control group awaited spontaneous passage. In either group, if complete resolution of symptoms did not occur, endoscopic removal was performed following current guidelines: within 6 hours for patients with complete obstruction, and within 24 hours for partial obstruction. In case of complete resolution of symptoms, elective diagnostic endoscopy was required. Improvement of oesophageal food bolus obstruction as reported by patients (ie, aggregate of complete and partial passage), and evaluation of complete passage. The secondary outcome was any intervention related adverse event. Cola did not have a meaningful effect on the improvement of food bolus obstruction (17/28 (61%) intervention v 14/23 (61%) control; odds ratio 1.00, 95% confidence interval 0.33 to 3.1; relative risk reduction 0.0, 95% confidence interval -0.55 to 0.36; P>0.99). Complete passage was reported more often in the intervention group but this difference was not significant (12/28 (43%) intervention v 8/23 (35%) control; odds ratio 1.4 (0.45 to 4.4); relative risk reduction -0.23 (-1.5 to 0.39); P=0.58). No severe adverse events occurred. However, six (21%) patients in the intervention group experienced temporary discomfort after drinking cola. In this study, cola consumption did not lead to a higher rate of improvement of complete oesophageal food bolus impaction. Given the lack of adverse events in the treatment group and some events of resolution after treatment, cola might be considered as a first line treatment, but should not delay any planning of endoscopic management. Netherlands Trial Register (currently International Clinical Trial Registry Platform) NL8312.


Effects of facial expression and gaze direction on approach-avoidance behaviour.
Humans must coordinate approach-avoidance behaviours with the social cues that elicit them, such as facial expressions and gaze direction. We hypothesised that when someone is observed looking in a particular direction with a happy expression, the observer would tend to approach that direction, but that when someone is observed looking in a particular direction with a fearful expression, the observer would tend to avoid that direction. Twenty-eight participants viewed stimulus faces with averted gazes and happy or fearful expressions on a computer screen. Participants were asked to grasp (approach) or withdraw from (avoid) a left- or right-hand button depending on the stimulus face's expression. The results were consistent with our hypotheses about avoidance responses, but not with respect to approach responses. Links between social cues and adaptive behaviour are discussed.


[Maintenance of the hypnotic component of general anesthesia with feed-back regulation].
The purpose of the study was to design and investigate the closed-loop propofol system (CLPS) with a mean arterial pressure (MAP) controller in open-heart surgery. CLPS consists of a 386 PC, a blood pressure sensor and an infusion pump. The C language computer program sets the propofol infusion rate based on an empirical algorithm including proportional component to maintain the measured MAP more closely to the target MAP (85% of patient standard MAP). The propofol concentrations were calculated by the pharmacokinetic/pharmacodynamic model differential equations solving every 30s. CLPS was used in 214 NYHA II-IV patients, aged 16-74, undergoing various open-heart procedures. The mean target MAP was 75.2 +/- 4.5 mm Hg. The measured and target MAP difference did not exceed 22% perioperatively. The bispectral index varied from 42.7 +/- 1.2 (tracheal intubation) to 41.8 +/- 0.1 (skin suture) with a variation of the propofol site effect concentration ranging from 2.9 +/- 0.09 to 1.8 +/- 0.1 microg/ml. It was a closed negative correlation (r = 0.84; p < 0.01) between the propofol site effect and the MAP during the initial period of anesthesia. There were not any significant changes in the blood cortisole level during the procedures. The recovery time was 1.4 +/- 1.5 min after propofol infusion; 95.5% of patients were extubated in the operating room.


Is electrolyte transfer across the urothelium important?: ICI-RS 2015.
This article summarizes discussion at the International Consultation on Incontinence Research Society (ICI-RS) 2015 meeting of urine modification in the urinary tract by the urothelium. It considers the literature and proposes pertinent questions that need to be addressed to understand this phenomenon within a physiological context. Following the ICI-RS meeting, publications in PubMed relating to urine modification in the renal pelvis, ureter, and bladder were reviewed. Historically, the urothelium has been simply considered as a passive, impermeable barrier, preventing contact between urine and the underlying cells. In addition to the ability of the umbrella cells to modify the surface area of the urothelium during bladder filling, the urothelium may also be involved in modifying urine composition. Several lines of evidence support the hypothesis that electrolytes and water can be reabsorbed by the urothelium and that this may have physiological relevance. Firstly, urothelial cells express several types of aquaporins and ion channels; the membrane expression of which is modulated by the extracellular concentration of ions including Na+ . Secondly, studies of urine composition in the renal pelvis and bladder demonstrate urine modification, indicating that water and/or electrolyte transport has occurred. Thirdly, hibernating mammals, with urothelial and bladder wall histology similar to non-hibernating mammals are known to produce and reabsorb urine daily, during long periods of hibernation. The phenomenon of urine modification by the urothelium may be physiologically important during normal bladder filling. Research should be focused on investigating how this may change in conditions of urinary dysfunction.


Puerarin protects rat kidney from lead-induced apoptosis by modulating the PI3K/Akt/eNOS pathway.
Puerarin (PU), a natural flavonoid, has been reported to have many benefits and medicinal properties. However, its protective effects against lead (Pb) induced injury in kidney have not been clarified. The aim of the present study was to investigate the effects of puerarin on renal oxidative stress and apoptosis in rats exposed to Pb. Wistar rats were exposed to lead acetate in the drinking water (500mg Pb/l) with or without puerarin co-administration (100, 200, 300 and 400mg PU/kg intragastrically once daily) for 75days. Our data showed that puerarin significantly prevented Pb-induced nephrotoxicity in a dose-dependent manner, indicated by both diagnostic indicators of kidney damage (serum urea, uric acid and creatinine) and histopathological analysis. Moreover, Pb-induced profound elevation of reactive oxygen species (ROS) production and oxidative stress, as evidenced by increasing of lipid peroxidation level and depleting of intracellular reduced glutathione (GSH) level in kidney, were suppressed by treatment with puerarin. Furthermore, TUNEL assay showed that Pb-induced apoptosis in rat kidney was significantly inhibited by puerarin. In exploring the underlying mechanisms of puerarin action, we found that activities of caspase-3 were markedly inhibited by the treatment of puerarin in the kidney of Pb-treated rats. Puerarin increased phosphorylated Akt, phosphorylated eNOS and NO levels in kidney, which in turn inactivated pro-apoptotic signaling events including inhibition of mitochondria cytochrome c release and restoration of the balance between pro- and anti-apoptotic Bcl-2 proteins in kidney of Pb-treated rats. In conclusion, these results suggested that the inhibition of Pb-induced apoptosis by puerarin is due at least in part to its antioxidant activity and its ability to modulate the PI3K/Akt/eNOS signaling pathway.


A large case series of travel-related Mansonella perstans (vector-borne filarial nematode): a TropNet study in Europe.
Infection with Mansonella perstans is a neglected filariasis, widely distributed in sub-Saharan Africa, characterized by an elusive clinical picture; treatment for mansonellosis is not standardized. This retrospective study aimed to describe the clinical features, treatment schemes and evolution, of a large cohort of imported cases of M. perstans infection seen in four European centres for tropical diseases. Mansonella perstans infections, diagnosed by identification of blood microfilariae in migrants, expatriates and travellers, collected between 1994 and 2018, were retrospectively analysed. Data concerning demographics, clinical history and laboratory examinations at diagnosis and at follow-up time points were retrieved. A total of 392 patients were included in the study. Of the 281 patients for whom information on symptoms could be retrieved, 150 (53.4%) reported symptoms, abdominal pain and itching being the most frequent. Positive serology and eosinophilia were present in 84.4% and 66.1%, respectively, of those patients for whom these data were available. Concomitant parasitic infections were reported in 23.5% of patients. Treatment, administered to 325 patients (82.9%), was extremely heterogeneous between and within centres; the most commonly used regimen was mebendazole 100 mg twice a day for 1 month. A total of 256 (65.3%) patients attended a first follow-up, median 3 months (interquartile range 2-12) after the first visit; 83.1% of patients having received treatment based on mebendazole and/or doxycycline, targeting Wolbachia, became amicrofilaremic, 41.1-78.4% of whom within 12 months from single treatment. Lack of specific symptoms, together with the inconstant positivity of parasitological and antibody-based assays in the infected population, makes the clinical suspicion and screening for mansonellosis particularly difficult. Prospective studies evaluating prevalence of infection in migrants from endemic areas, infection-specific morbidity, presence of Wolbachia endosymbionts in M. perstans populations from different geographical areas and efficacy of treatment regimens are absolutely needed to optimize the clinical management of infection.


Synthesis and Biological Evaluation of 2-Substituted Quinazolin-4(3H)-Ones with Antiproliferative Activities.
Sixteen new 2-substituted quinazolines were synthesized using a straightforward methodology starting from 2-methoxybezoic acid or 3-methoxy-2-naphthoic acid. The anti-proliferative activity of the target compounds was evaluated against nine cancer cell lines. Additionally, all the compounds were screened for their potency and selectivity against a panel of 109 kinases and four bromodomains, using Differential Scanning Fluorimetry (DSF). Compound 17 bearing a 2-methoxyphenyl substitution along with a basic side chain displayed a remarkable profile against the majority of the tested cell lines.


Dual-task training of children with neuromotor disorders during robot-assisted gait therapy: prerequisites of patients and influence on leg muscle activity.
Walking in daily life is complex entailing various prerequisites such as leg strength, trunk stability or cognitive and motor dual task (DT) activities. Conventional physiotherapy can be complemented with robot-assisted gait therapy (RAGT) and exergames to enhance the number of step repetitions, feedback, motivation, and additional simultaneously performed tasks besides walking (e.g., dual-task (DT) activities). Although DT gait training leads to improvements in daily ambulation in adult patient groups, no study has evaluated RAGT with a DT exergame in children with neurological gait disorders. Therefore, we investigated children's functional and cognitive prerequisites to walk physiologically during RAGT with a DT exergame and analysed the influence of DT on leg muscle activity. Children and adolescents (6-18 years) with neurological gait disorders completed RAGT with and without a DT exergame in this quasi-experimental study. We assessed several measures on the body function and activity domains (according to the International Classification of Functioning, Disability, and Health (ICF)) and determined whether these measures could distinguish well between children who walked physiologically during the DT RAGT or not. We measured leg muscle activity with surface electrodes to identify changes in EMG-amplitudes and -patterns. Twenty-one children participated (7 females, 6.5-17.3 years, Gross Motor Function Classification System (GMFCS) levels I-IV). Most activity measures distinguished significantly between participants performing the DT exergame physiologically or not with moderate to good sensitivity (0.8 ≤ sensitivity≤1.0) and specificity (0.5 ≤ specificity≤0.9). Body function measures differentiated less well. Despite that the EMG-amplitudes of key stance muscles were significantly lower during DT versus no DT exergaming, the mean activation patterns of all muscles correlated high (ρ > 0.75) between the conditions. This study is the first that investigated effects of a DT exergame during RAGT in children with neurological gait disorders. Several performance measures could differentiate well between patients who walked with physiological versus compensatory movements while performing the DT exergame. While the DT exergame affected the leg muscle activity amplitudes, it did not largely affect the activity patterns of the muscles.


Strategy, demand, management, and costs of an international cholera vaccine stockpile.
In this article, we review the feasibility of mass vaccination against cholera and estimate the global population at risk for epidemic cholera. We then examine the cost of establishing and managing a cholera vaccine stockpile and summarize published mathematical models of the estimated impact of reactive vaccination campaigns developed for the current Haitian outbreak and a recent outbreak in Zimbabwe. On the basis of these evaluations, we recommend a stockpile that starts at 2 million doses, with an estimated annual cost of $5.5-$13.9 million in 2013, and grows to 10 million doses per year by 2017, with an annual cost of $27-$51 million. We believe that the stockpile can enhance efforts to mitigate future cholera outbreaks by guaranteeing the availability of cholera vaccines and, through use of the stockpile, by revealing knowledge about the efficient use of cholera vaccines during and after crises.


Aperiodic nature of nanograting inscribed by femtosecond pulses.
A systematic study was performed, both experimentally and theoretically, to investigate the structural periodicity of nanogratings inscribed by focused femtosecond pulses on the surface of dielectrics. The results surprisingly show that although nanogratings generally appear periodic they are in fact intrinsically aperiodic. In the perpendicular writing scheme, the groove spacing gradually decreases from the middle part towards both sides. In the parallel writing scheme, the groove spacing varies quasiperiodically and the variation differs with respect to pulse-to-pulse spacing. Constant groove spacing was obtained only for a particular pulse-to-pulse spacing. These Gaussian-apodized and quasiperiodic variations are found to be intrinsic. They arise from the fact that the grooves are created, depending on the writing scheme, either by a series of local-lobes with different amplitudes and material feedbacks or by a repeated generated leading side-lobe with similar but not identical amplitudes and material feedbacks. The production of each single grooves result from a nonlinear and localized process from which arises its aperiodic nature. All these intrinsically Gaussian-apodized and quasiperiodic variations can be well interpreted based on the incubation-based nanoplasmonic model.


[Pollution of the agricultural lands of Bashkortostan by the herbicide 2,4-D and dioxins].
The ecologic and toxicologic studies evaluated pollution of agriculture lands with 2,4-D herbicide, polychlorinated dioxins and furans in 6 regions of Bashkortostan Republic. Soils of exposed and reference objects were proved to be polluted with those chemicals. Concentrations of 2,4-D herbicide and dioxins depend on natural climate and soil conditions, pesticide treatment of agricultural plants. Dioxin and 2,4-D herbicide appeared to have migration ability--penetration to 1 m depth was noted.


Substrate-initiated synthesis of cell-penetrating poly(disulfide)s.
Lessons from surface-initiated polymerization are applied to grow cell-penetrating poly(disulfide)s directly on substrates of free choice. Reductive depolymerization after cellular uptake should then release the native substrates and minimize toxicity. In the presence of thiolated substrates, propagators containing a strained disulfide from asparagusic or, preferably, lipoic acid and a guanidinium cation polymerize into poly(disulfide)s in less than 5 min at room temperature at pH 7. Substrate-initiated polymerization of cationic poly(disulfide)s and their depolymerization with dithiothreitol causes the appearance and disappearance of transport activity in fluorogenic vesicles. The same process is further characterized by gel-permeation chromatography and fluorescence resonance energy transfer.


A faculty on the move into the community.
Faculty at the University of Rochester School of Nursing initiated a curricular redesign to prepare students for the evolving demands of the health care job market and the changing nature of the nursing profession. The concept of the "Learning Community" serves as the metaphor for the new vision of clinical education: a set of collaborative and dynamic relationships of students, faculty, clinicians, health care consumers and institutional and community sites with the mutual responsibility for the education of students and the health of all partners. Students experience firsthand the new capabilities required of professionals in the new context of health care as more than illness care.


BRAF and MEK inhibitor combinations induce potent molecular and immunological effects in NRAS-mutant melanoma cells: Insights into mode of action and resistance mechanisms.
About 25% of melanoma harbor activating NRAS mutations, which are associated with aggressive disease therefore requiring a rapid antitumor intervention. However, no efficient targeted therapy options are currently available for patients with NRAS-mutant melanoma. MEK inhibitors (MEKi) appear to display a moderate antitumor activity and also immunological effects in NRAS-mutant melanoma, providing an ideal backbone for combination treatments. In our study, the MEKi binimetinib, cobimetinib and trametinib combined with the BRAF inhibitors (BRAFi) encorafenib, vemurafenib and dabrafenib were investigated for their ability to inhibit proliferation, induce apoptosis and alter the expression of immune modulatory molecules in sensitive NRAS-mutant melanoma cells using two- and three-dimensional cell culture models as well as RNA sequencing analyses. Furthermore, NRAS-mutant melanoma cells resistant to the three BRAFi/MEKi combinations were established to characterize the mechanisms contributing to their resistance. All BRAFi induced a stress response in the sensitive NRAS-mutant melanoma cells thereby significantly enhancing the antiproliferative and proapoptotic activity of the MEKi analyzed. Furthermore, BRAFi/MEKi combinations upregulated immune relevant molecules, such as ICOS-L, components of antigen-presenting machinery and the "don't eat me signal" molecule CD47 in the melanoma cells. The BRAFi/MEKi-resistant, NRAS-mutant melanoma cells counteracted the molecular and immunological effects of BRAFi/MEKi by upregulating downstream mitogen-activated protein kinase pathway molecules, inhibiting apoptosis and promoting immune escape mechanisms. Together, our study reveals potent molecular and immunological effects of BRAFi/MEKi in sensitive NRAS-mutant melanoma cells that may be exploited in new combinational treatment strategies for patients with NRAS-mutant melanoma.


Clinical course of patients with squamous cell carcinoma of the upper respiratory and digestive tracts with no evidence of disease 5 years after initial treatment.
Eleven hundred sixty-three patients with squamous cell carcinoma of the upper respiratory and digestive tracts, treated from January 1948 through December 1965, had no evidence of disease five years after the initial treatment and no other manifestation of squamous cell carcinoma within the first five years. After five years, the incidence of disease at the initial location, in the vicinity, or in remote sites was found to be identical in the surgical and irradiation groups. There is a correlation between severe late complications in the irradiated patients and the volume of tissue irradiated.


Unmasking herbal medication-induced lead poisoning in a geriatric patient with gastrointestinal symptoms.
Lead poisoning, often associated with occupational exposure, can also arise from intake of traditional and herbal medicines with high lead content. Geriatric patients displaying gastrointestinal symptoms from such sources are frequently misdiagnosed. An individual in his 70s reported to our geriatric clinic with vomiting, constipation and anaemia. A meticulous history unveiled his recent intake of herbal remedies. Heavy metal assay indicated elevated lead levels in his blood and urine, consistent with the high lead content we measured in the herbal medication. Following supportive treatment, nutritional supplementation and chelation therapy with calcium disodium EDTA, he improved. Follow-up tests indicated a decrease in lead levels and resolution of anaemia. This case emphasises the importance of considering lead poisoning as a potential diagnosis in patients with unexplained symptoms, particularly when there is a history of herbal or alternative medication intake. Timely recognition and appropriate management can lead to better outcome.


Familial thrombophilia and the prothrombin 20210A mutation: association with increased thrombin generation and unusual thrombosis.
The 20210A prothrombin mutation has recently been associated with an increased risk of venous thrombosis, but the mechanism of the increased thrombotic risk in affected persons has not been elucidated. We report on a thrombophilic family in which the proband presented with cerebral vein thrombosis and homozygosity for the 20210A prothrombin mutation as her only identifiable risk factor for venous thrombosis. Extended genotyping of family members revealed seven other affected, but asymptomatic, first-degree relatives (one A/A homozygote and six G/A heterozygotes). Plasma levels of prothrombin, prothrombin fragments 1 + 2 and thrombin-antithrombin complexes were highest in A/A homozygotes, intermediate in G/A heterozygotes and lowest in those with the G/G homozygous normal genotype, while D-dimer levels were elevated only in A/A homozygotes. Our results suggest that the 20210A prothrombin mutation is associated with activation of coagulation and increased thrombin generation, not only in patients with a past history of thrombosis but also in otherwise healthy asymptomatic persons. In a similar fashion to the homozygous factor V Leiden mutation, patients with the homozygous 20210A prothrombin mutation could be at highest risk of thrombosis, as suggested by our patient who presented with unusual thrombosis.


Association between pre-operative right ventricular impairment on transthoracic echocardiography and outcomes after conventional and minimally invasive mitral valve surgery.
Right ventricular (RV) impairment may have prognostic value in patients undergoing mitral valve surgery. It is unclear whether RV dysfunction predicts long-term mortality, especially in the era of minimally invasive mitral surgery. We performed a retrospective analysis of consecutive patients referred for conventional (via sternotomy) and minimally invasive mitral valve surgery (MIMVS) between 01 January 2013 and 29 August 2018 in a tertiary cardiac centre. We truncated follow-up times at 25 March 2020. RV impairment was defined by reduced RV longitudinal function (TAPSE <17 mm) and/or dilated basal RV diameter (RVD1 > 42 mm). Primary outcome was all-cause mortality. The study cohort included 359 patients followed up for a median period of 4.2 (1.8) years. MIMVS approach was performed in 127 (35.4%) and conventional approach in 232 (64.6%) patients of whom 36 (28%) and 45 (19%), respectively, had RV impairment. EuroSCORE II was significantly higher in patients with RV impairment compared with patients with preserved RV function, irrespective of the surgical approach. Consequently, in both groups, patients with RV impairment had significantly higher mortality compared to patients with preserved RV function. RV impairment adjusted for EuroSCORE II predicted mortality in the whole cohort (HR 2.139, 95% CI 1.249-3.663) and in conventional approach (HR 2.361, 95% CI 1.249-4.465) in contrast to MIMVS (HR 1.570, 95% CI 0.493-4.997). In this real world cohort, patients with RV impairment and/or dilation had reduced long-term survival following both conventional surgery and MIMVS. Patients should be referred to surgery prior to worsening of RV function.


Forage conservation efficiency and lactation response to bahiagrass conserved as barn-stored hay, outdoor-stored hay, or baleage.
A study was conducted to determine the effect of conserving bahiagrass as outdoor-stored hay (OSH), barn-stored hay (BSH), or baleage (BAL) on storage losses and lactation performance by Holstein cows. For baleage production, bahiagrass forage was cut and allowed to dry for 20 h in windrows, baled (1.2 × 1.4 m), and individually wrapped with white stretch film. Forage cut on the same day was dried to hay stage, baled (1.2 × 1.6 m round bales), and stored either outdoors (OSH) or in an enclosed hay barn (BSH). Bales were core sampled and weighed at harvest and again following a 6-mo storage period. At the end of the storage period, 30 multiparous mid-lactation Holstein cows [39.2 ± 5.6 kg of 3.5% fat-corrected milk and 142 ± 27 d in milk (DIM)] were stratified according to milk yield and DIM and randomly assigned to 1 of the 3 forage conservation treatments. Cows were trained to Calan feeding gates and were offered a common partial mixed ration in a 10-d covariate period followed by a 42-d treatment feeding period. Forage dry matter losses were highest for OSH, but were similar between BSH and baleage. Conservation method had little effect on poststorage crude protein levels, but acid detergent fiber and neutral detergent fiber concentrations were higher in OSH than in either BSH or BAL, which resulted in a 12.8% depression in net energy for OSH compared with the other treatments. Dry matter intake (20.5 vs. 22.1 kg/d) and milk yield (28.2 vs. 30.2 kg/d) tended to be lower for OSH than for BSH. Lactation performance was similar between BSH and BAL: 29.6 versus 28.7 kg/d of fat-corrected milk, respectively. No differences in milk composition, feed efficiency, body weight, or body condition score change related to conservation system were observed. In this study, dry matter losses and lactation performance from bahiagrass conserved as baleage were similar to that of similar forage stored indoors as hay, whereas hay stored outside resulted in less satisfactory forage quality.


Initial testing (stage 1) of the polyamine analog PG11047 by the pediatric preclinical testing program.
PG11047 is a novel conformationally restricted analog of the natural polyamine, spermine that lowers cellular endogenous polyamine levels and competitively inhibits natural polyamine functions leading to cancer cell growth inhibition. The activity of PG11047 was evaluated against the PPTP's in vitro and in vivo panels. PG11047 was evaluated against the PPTP in vitro panel using 96 hr exposure at concentrations ranging from 10 nM to 100 µM. It was tested against the PPTP in vivo panels at a dose of 100 mg/kg administered by the intraperitoneal route weekly for 6 weeks. In vitro PG11047 demonstrated a concentration-response pattern consistent with cytostatic activity. The median EC(50) for PG11047 was 71 nM. Cell lines of the Ewing sarcoma panel had a lower median EC(50) value compared to the remaining cell lines in the panel, while cell lines of the neuroblastoma panel had a higher median EC(50) value. In vivo PG11047 induced significant differences in EFS distribution compared to control in 5 of 32 (15.6%) of the evaluable solid tumor xenografts and in 0 of 7 (0%) of the evaluable ALL xenografts. The single case of tumor regression occurred in an ependymoma xenograft. Further pediatric development of PG11047 will require better defining a target population and identifying combinations for which there is a tumor-selective cytotoxic effect. The regression observed for an ependymoma xenograft and the exquisite sensitivity of some Ewing sarcoma cell lines to the antiproliferative effects of PG11047 provide leads for further preclinical investigations.


Fluorescence behavior of Euglena photoreceptor.
To provide new information on the series of structural changes that Euglena photoreceptive proteins undergo inside the photoreceptor in response to light, we measured in vivo emission fluorescence spectra in the stable intermediates of its photocycle. Our emission spectra give a certain indication that fluorescent proteins are present in the Euglena photoreceptor and that they undergo a photocycle. On the basis of our data, we suggested that at least two stable intermediates, one of which is fluorescent, can be discriminated at room temperature and with our time resolution.


DNA repair inhibitors: the next major step to improve cancer therapy.
Modern cancer therapies, mainly ionizing radiation and certain classes of chemotherapies target DNA. Although these treatments disrupt the genome, their rationale is clear. They prevent cancer cells from dividing and proliferating. Nevertheless, cancer cells can survive by over-activating a wide range of DNA repair pathways to eliminate the induced damage. In this context, DNA repair mechanisms are considered to be a vital target to improve cancer therapy and reduce the resistance to many DNA damaging agents currently in use as standard-of-care treatments. Here, we focus on two important DNA repair pathways, namely base excision repair (BER) and nucleotide excision repair (NER). Specifically, our focus is on two protein targets that are linked to the hallmark "relapse" and "drug resistance" phenomena. These are Excision Repair Cross-Complementation Group 1 (ERCC1), and DNA polymerase beta (pol β). The former is a key player in NER, while the latter is the error-prone polymerase of BER. Our objective is to list all known inhibitors for the two targets and provide an overview of the great efforts that were made in their discovery. While in the DNA pol β case more than sixty inhibitors were identified, very few inhibitors have been discovered on the ERCC1 side. It is hoped that this review will assist in the discovery of novel, potent and specific drug candidates aimed at improving existing cancer therapies including ionizing radiation, bleomycin, monofunctional alkylating agents and cisplatin.


Syntheses of the ω-pyridinium-containing very-long-chain ceramides PyrCer(24:1(15Z)) and PyrCer(24:0) and their anticancer activity.
Ceramides, crucial sphingolipids in cellular biology, play various roles ranging from structural membrane integrity to signaling pathway regulation. Structurally, a ceramide consists of a fatty acid connected to a sphingoid base. The characteristics of the fatty acid chain, including length and saturation, determine the physiological properties of the ceramide. Ceramides typically fall into the following categories based on chain length: medium, long, very-long, and ultra-long. Among them, two very-long-chain ceramides, Cer(24:1(15Z)) and Cer(24:0), have been extensively studied, and they are known for their regulatory functions. However, the hydrophobic natures of ceramides, arising from their long hydrocarbon chain impedes their solubilities and levels of cellular delivery. Although ω-pyridinium ceramide analogs (ω-PyrCers) have been developed to address this issue, ω-PyrCers with very-long fatty acid chains or unsaturation have not been developed, presumably due to limited access to the corresponding ω-bromo fatty acids required in their syntheses. In this study, we prepared the ω-PyrCers of Cer(24:1(15Z)) and Cer(24:0), PyrCer(24:1(15Z)) and PyrCer(24:0), respectively. The key in the synthesis is the Wittig reaction to prepare the ω-bromo fatty acid with an appropriate chain length and (Z)-double bond position. Preliminary evaluation of the PyrCer(24:1(15Z)) and PyrCer(24:0) revealed their potential in hepatocellular carcinoma treatment.


Transient ischaemic attacks : new approaches to management.
The fact that transient ischaemic attacks are a harbinger for the possible development of ischaemic stroke has been recognised for several decades. However, within the past decade, our concepts regarding transient ischaemic attacks as a distinct entity from stroke and the prognosis for transient ischaemic attack patients have been challenged. In addition, clinical trials have clarified that modern transient ischaemic attack management is more complex than in the past, with the addition of newer pharmacological options to the stroke prevention armamentarium. Recent information regarding newer antiplatelet agents is reviewed in this article, along with results of clinical trials pertaining to warfarin in stroke prevention. The evolving role of statins, ACE inhibitors and estrogen replacement is reviewed. Finally, the appropriate use of surgery following transient ischaemic attacks is outlined. Recent studies have shown that many patients will benefit from a multimodal pharmacological approach following transient cerebral ischaemia, and the potential for combination therapy is highlighted.


In Vitro Evaluation of the Anti-Diabetic Potential of Aqueous Acetone Helichrysum petiolare Extract (AAHPE) with Molecular Docking Relevance in Diabetes Mellitus.
Diabetes mellitus (DM) is a chronic metabolic condition that can lead to significant complications and a high fatality rate worldwide. Efforts are ramping up to find and develop novel α-glucosidase and α-amylase inhibitors that are both effective and potentially safe. Traditional methodologies are being replaced with new techniques that are less complicated and less time demanding; yet, both the experimental and computational strategies are viable and complementary in drug discovery and development. As a result, this study was conducted to investigate the in vitro anti-diabetic potential of aqueous acetone Helichrysum petiolare and B.L Burtt extract (AAHPE) using a 2-NBDG, 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxy-d-glucose uptake assay. In addition, we performed molecular docking of the flavonoid constituents identified and quantified by liquid chromatography-mass spectrometry (LC-MS) from AAHPE with the potential to serve as effective and safe α-amylase and α-glucosidase inhibitors, which are important in drug discovery and development. The results showed that AAHPE is a potential inhibitor of both α-amylase and α-glucosidase, with IC50 values of 46.50 ± 6.17 (µg/mL) and 37.81 ± 5.15 (µg/mL), respectively. This is demonstrated by a significant increase in the glucose uptake activity percentage in a concentration-dependent manner compared to the control, with the highest AAHPE concentration of 75 µg/mL of glucose uptake activity being higher than metformin, a standard anti-diabetic drug, in the insulin-resistant HepG2 cell line. The molecular docking results displayed that the constituents strongly bind α-amylase and α-glucosidase while achieving better binding affinities that ranged from ΔG = -7.2 to -9.6 kcal/mol (compared with acarbose ΔG = -6.1 kcal/mol) for α-amylase, and ΔG = -7.3 to -9.0 kcal/mol (compared with acarbose ΔG = -6.3 kcal/mol) for α-glucosidase. This study revealed the potential use of the H. petiolare plant extract and its phytochemicals, which could be explored to develop potent and safe α-amylase and α-glucosidase inhibitors to treat postprandial glycemic levels in diabetic patients.


[In vitro susceptibility of vaginal isolates of Candida vs clotrimazole and nystatin].
The susceptibility in vitro of 123 isolates of Candida against clotrimazole and nystatin was determined. The isolates were obtained by vaginal smears from 404 women that attended "Ramón Gonzalez Coro" Gynecoobstetric Hospital, in Havana City According to the number of colonies obtained in the primary isolation, the strains were separated into 2 categories: colonization and infection. The inhibitory minimum concentration (IMC) was detemined for each antigunfal by a method of microdilution in casitone broth. The geometrical means of the IMC values were higher against nystatin (1.08 mg/mL) than against clotrimazole (0.22 mg/mL), eventhough the features were similar (< or = 0.125-16 mg/ml,) For (Candida albicans, that was the most frequently isolated species (54.5 %), the geometrical means of the IMC values were 0.17 and 0.16 mg/mL for clotrimazole and 0.71 and 0.92 for nystatin, in both categories. C glabrata showed the highest IMC values (16 mg/mL) against antifungals. Only the isolates of C. lusitaniae showed a significant difference (p < 0.001) between the IMC values of nystatin according to the number of colonies in the primary isolation. In isolates from women treated with clotrimazole and/or nystatin in previous episodes of candidiasis, there were observed more elevated values of the means of IMC against nystatin than against clotrimazole, although this difference was not statistically remarkable.


[Endemic Situation and Control of Malaria in Baoying County of Jiangsu Province from 2005 to 2014].
Malaria information was collected through online systems in Baoying County from 2005 to 2014 and descriptive analysis was performed on the data. A total of 175 cases of malaria were reported in the years, with no report of death. During 2005-2008, vivax malaria cases constituted 86.4%(19/22) of all cases reported, and all infected locally with diease onset mainly occurred from May to November. During 2009-2014, falciparum malaria cases constituted 82.4%(126/153), and all imported cases, which showed a trend of increase, from one case in 2007 to 22 in 2009. All the cases reported during 2010-2014 were imported cases. As to malaria control, there was an overall regular treatment rate of 100%, 195 patients had radical cure during the resting stage, and blood test was conducted in 52 827 fevered patients, resulting in a positive rate of 0.3%(149/52 827). Although no local malaria cases were reported since 2010, the imported malaria is still an important issue.


Magnitude of metabolic syndrome and its associated factors among patients with type 2 diabetes mellitus in Ayder Comprehensive Specialized Hospital, Tigray, Ethiopia: a cross sectional study.
The objective of this study was to assess magnitude of metabolic syndrome and its associated factors among type 2 diabetes mellitus patients in Ayder Comprehensive Specialized Hospital. A hospital based cross sectional study design was used. Binary logistic regression model was used. A total of 419 respondents (208 males and 211 females) were enrolled; the mean age was 56.39 (SD 10.18), 51.1% of the respondents had metabolic syndrome according to international diabetes federation. Sex and age were statistically associated with metabolic syndrome with [AOR (95% CI) 1.93 (1.057, 3.533) and 1.04 (1.012, 1.072)] respectively. Regular physical exercise, overweight and obesity were statistically associated with metabolic syndrome with [AOR (95% CI) 1.84 (1.002, 3.362), 2.68 (1.518, 4.747) and 3.55 (1.254, 10.074)] respectively. To conclude, Magnitude of metabolic syndrome was high. The associated factors for metabolic syndrome are physical inactivity, inadequate intake of fruits, family history, overweight, and obesity.


Noninvasive cardiac psychophysiology as a tool for translational science with marmosets.
The importance of marmosets for comparative and translational science has grown in recent years because of their relatively rapid development, birth cohorts of twins, family social structure, and genetic tractability. Despite this, they remain understudied in investigations of affective processes. In this methodological note, we establish the validity of using noninvasive commercially available equipment to record cardiac physiology and compute indices of autonomic nervous system activity-a major component of affective processes. Specifically, we recorded electrocardiogram and impedance cardiogram, from which we derived heart rate, respiration rate, measures of high-frequency heart rate variability (indices of parasympathetic autonomic nervous system activity), and ventricular contractility (an index of sympathetic autonomic nervous system activity). Our methods produced physiologically plausible data, and further, animals with increased heart rates during testing were also more reactive to isolation from their social partner and presentation of novel objects, though no relationship was observed between reactivity and specific indices of parasympathetic or sympathetic nervous system activity.


Evaluation of a policy to integrate physical activity into the school day.
Implementing physical activity (PA) within academic curricula increases energy expenditure and enhances academic achievement in elementary students. The purposes of the study were to determine the extent teachers met the 20-minute PA policy, identify how teachers met the policy, and measure the level of intensity of PA provided. Four elementary schools (grades K-5; 68 classroom teachers) implemented a district-mandated 20-minute PA policy. Teachers recorded PA for 1 week in September 2010 and February 2011. A sample of 142 students (grades K-5) wore accelerometers to measure school day PA. While 40% and 4% of teachers in September and February respectively met the policy all 5 days, 72.5% and 45.7% of teachers in September and February respectively implemented PA at least 3 days/week. Accelerometry results indicated curriculum-based lessons (CBL; 59.92 ± 20.38 min) or walk/run periods (51.56 ± 18.67 min) significantly increased school day MVPA (P < .05) above no additional activity (30.96 ± 22.57 min). Although the teachers did not meet the 20-minute policy every day, the increased amount of PA achieved each week through the teachers' efforts is a significant contributor to total daily PA levels of children.


Gastrointestinal pseudo-obstruction due to pheochromocytoma.
A patient with a pheochromocytoma is described whose intermittent symptoms and clinical findings suggested upper gastrointestinal obstruction. The nature of this illness proved elusive until severe paroxysmal hypertension was noted during a periodic examination. The case report and gastrointestinal x-rays confirm the intermittent nature of both the gastrointestinal motility disturbances and the hypertension. The resolution of the gastrointestinal symptoms during a 3-years postoperative follow-up confirms the association. Gastrointestinal symptoms are rarely the predominant manifestation of pheochromocytoma, but recognition of this association may permit earlier diagnosis.


Self-administered cocaine causes long-lasting increases in impulsive choice in a delay discounting task.
Cocaine use is associated with high levels of impulsive choice (preference for immediate over delayed rewards), but it is not clear whether cocaine use causes elevated impulsive choice, or whether elevated impulsive choice is solely a predisposing factor for cocaine use. This study examined the effects of prior cocaine self-administration on rats performing a delay discounting task commonly used to measure impulsive choice. Male Long-Evans rats were implanted with intravenous catheters, and following recovery, were trained to self-administer 30 mg/kg/day cocaine HCl (approx. 0.5 mg/kg/infusion) for 14 consecutive days (a control group received yoked intravenous saline infusions). Following three weeks of withdrawal, all rats were food-restricted and began training on the delay discounting task in standard operant chambers. On each trial, rats were given a choice between two levers. A press on one lever delivered a small food reward immediately, and a press on the other delivered a large food reward after a variable delay period. Rats that self-administered cocaine displayed greater impulsive choice (enhanced preference for the small immediate over the large delayed reward, as reflected by shorter indifference points) compared to controls, but were no different from controls on a "probabilistic discounting" task in which they chose between small certain and large uncertain rewards. These data suggest that self-administered cocaine can cause lasting elevations in impulsive choice, and that the high levels of impulsive choice observed in human cocaine users may be due in part to long-term effects of cocaine on brain function.


Chicken MAR-binding protein ARBP is homologous to rat methyl-CpG-binding protein MeCP2.
Here, we describe the cloning and further characterization of chicken ARBP, an abundant nuclear protein with a high affinity for MAR/SARs. Surprisingly, ARBP was found to be homologous to the rat protein MeCP2, previously identified as a methyl-CpG-binding protein. A region spanning 125 amino acids in the N-terminal halves is 96.8% identical between chicken ARBP and rat MeCP2. A deletion mutation analysis using Southwestern and band shift assays identified this highly conserved region as the MAR DNA binding domain. Alignment of chicken ARBP with rat and human MeCP2 proteins revealed six trinucleotide amplifications generating up to 34-fold repetitions of a single amino acid. Because MeCP2 was previously localized to pericentromeric heterochromatin in mouse chromosomes, we analyzed the in vitro binding of ARBP to various repetitive sequences. In band shift experiments, ARBP binds to two chicken repetitive sequences as well as to mouse satellite DNA with high affinity similar to that of its binding to chicken lysozyme MAR fragments. In mouse satellite DNA, use of several footprinting techniques characterized two high-affinity binding sites, whose sequences are related to the ARBP binding site consensus in the chicken lysozyme MAR (5'-GGTGT-3'). Band shift experiments indicated that methylation increased in vitro binding of ARBP to mouse satellite DNA two- to fivefold. Our results suggest that ARBP/MeCP2 is a multifunctional protein with roles in loop domain organization of chromatin, the structure of pericentromeric heterochromatin, and DNA methylation.


Effects of Superparamagnetic Iron Nanoparticles on Electrocatalysts for the Reduction of Oxygen.
It is of great research interest to understand the nanostructures contributing to the activity observed in the reduction of oxygen by non-platinum group metal (PGM) electrocatalysts in acidic media. Iron- and nitrogen-containing carbon networks are often the most studied structures, among which single-atom iron-coordinated nitrogen (FeNx) moieties have often been proposed to be the structures leading to the high activity in these non-PGM electrocatalysts. Iron nanoparticles embedded within a carbon support are also formed under certain conditions as a result of the synthetic processes in making non-PGM electrocatalysts. In this study, we present a study to understand the oxygen reduction reaction (ORR) activity of prepared iron- and nitrogen-containing non-PGM electrocatalysts obtained through the pyrolysis of metal-organic framework (MOF) precursors. We studied the structure-property relationship among nanostructures made from the MOF precursor ZIF-8 under different pyrolysis conditions. Density functional theory calculations were used to explain the effect of structural moieties on the ORR activity. Our results suggest that iron-coordinated C-N structures and iron nanoparticles act synergistically to catalyze the ORR.


Immunoscintigraphy of aortic dissection with 99mTc-labeled murine anti-smooth muscle myosin monoclonal antibody in rats.
Aortic dissection is among the most common of fatal conditions of the aorta. Prompt and accurate diagnosis of the site and extent of the lesion is necessary for adequate therapy. However, this catastrophic disease, characterized by extensive damage to smooth muscle cells, lacks specific signs and symptoms. As a result, the diagnosis is still frequently missed today and a new diagnostic method to specifically identify aortic dissection would be attractive. The purpose of this study was to examine the feasibility of radioimmunoscintigraphy using 99mTc-anti-smooth muscle myosin monoclonal antibody (SM-MAb) for the noninvasive diagnosis of aortic dissection in the rat experimental model. The accumulation of 99mTc-anti-SM-MAb was studied, and scintigraphic imaging with 99mTc-anti-SMMAb was performed in rats immediately after experimental aortic dissection and 1 and 2 wk later. The radioactivity of 99mTc-anti-SM-MAb in the dissected aorta showed a significant increase compared both with the normal portion of the aorta and with blood 6 h after injection of the radiotracer; the ratio of the percentage injected dose per gram (%lD/g) in the lesion to that retained in the normal portion was 4.17 +/- 1.47. Scintigraphic imaging with 99mTc-anti-SM-MAb allowed distinct visualization of the dissected aorta with specific accumulation of antibody 6 h after tracer injection. Selective accumulation of the tracer in the dissected portion of the aorta persisted even 1 wk after aortic injury, allowing clear visualization of the dissected lesion by scintigraphy. Radioimmunoscintigraphy using anti-SM-MAb is a potentially useful noninvasive diagnostic method for imaging aortic dissection.


Construction of an acute myeloid leukemia prognostic model based on m6A-related efferocytosis-related genes.
One of the most prevalent hematological system cancers is acute myeloid leukemia (AML). Efferocytosis-related genes (ERGs) and N6-methyladenosine (m6A) have an important significance in the progression of cancer, and the metastasis of tumors. The AML-related data were collected from The Cancer Genome Atlas (TCGA; TCGA-AML) database and Gene Expression Omnibus (GEO; GSE9476, GSE71014, and GSE13159) database. The "limma" R package and Venn diagram were adopted to identify differentially expressed ERGs (DE-ERGs). The m6A related-DE-ERGs were obtained by Spearman analysis. Subsequently, univariate Cox and Least Absolute Shrinkage and Selection Operator (LASSO) were used to construct an m6A related-ERGs risk signature for AML patients. The possibility of immunotherapy for AML was explored. The pRRophetic package was adopted to calculate the IC50 of drugs for the treatment of AML. Finally, the expression of characterized genes was validated by quantitative reverse transcription-PCR (qRT-PCR). Based on m6A related-DE-ERGs, a prognostic model with four characteristic genes (UCP2, DOCK1, SLC14A1, and SLC25A1) was constructed. The risk score of model was significantly associated with the immune microenvironment of AML, with four immune cell types, 14 immune checkpoints, 20 HLA family genes and, immunophenoscore (IPS) all showing differences between the high- and low-risk groups. A total of 56 drugs were predicted to differ between the two groups, of which Erlotinib, Dasatinib, BI.2536, and bortezomib have been reported to be associated with AML treatment. The qRT-PCR results showed that the expression trends of DOCK1, SLC14A1 and SLC25A1 were consistent with the bioinformatics analysis. In summary, 4 m6A related- ERGs were identified and the corresponding prognostic model was constructed for AML patients. This prognostic model effectively stratified the risk of AML patients.


No role for protease inhibitors as a mitigation strategy for postpancreatectomy acute pancreatitis (PPAP): Propensity score matching analysis.
While the use of protease inhibitor gabexate mesylate (GM) is still controversial in acute pancreatitis, it has never been tested for postpancreatectomy acute pancreatitis (PPAP). This study aims to assess the impact of GM on postoperative serum hyperamylasaemia (POH) or PPAP after pancreatoduodenectomy (PD). Consecutive patients developing POH after PD between 2016 and 2021 were included. According to GM administration, patients were divided into GM-treated and control (CTR) groups. GM was administered from postoperative day 1-3 in POH patients who underwent surgery before 2017. A 2:1 propensity matching was used to minimize the risk of bias. Overall, 264 patients with POH were stratified in the GM (59 patients) and CTR (104 patients) cohorts, which showed balanced baseline characteristics after matching. No difference in postoperative complications was observed between the groups (all p > 0.05), except for PPAP occurrence, which was significantly higher in the GM group (37% vs. 22%, p = 0.037). A total of 45 patients (28%) evolved to PPAP. Comparing PPAP patients in the GM and CTR groups, no significant differences in POPF, relaparotomy, and mortality (all p > 0.09) were found. No difference in intravenous crystalloid administration was found in patients with PPAP, whether or not they developed major complications or pancreatic fistula (p > 0.05) CONCLUSION: Protease inhibitor seems ineffective in preventing a PPAP after PD once a POH has occurred. Further studies are needed to achieve benchmarks for treating PPAP and identify mitigation strategies to prevent the evolution of POH into additional morbidity.


A study on the consumer's perception of front-of-pack nutrition labeling.
The goal of this research is to investigate the present situation for front of pack labeling in Korea and the perception of consumers for the new system of labeling, front of pack labeling, based on the consumer survey. We investigated the number of processed foods with front of pack labeling in one retailer in Youngin-si. And we also surveyed 1,019 participants nationwide whose ages were from 20 to 49; the knowledge of nutrition labeling, the knowledge of 'front of pack labeling', and the opinion about the labeling system. The data were analyzed using SAS statistics program. The results were as follows: 13.4% of processed foods had front of pack labeling, and 16.8% of the consumers always checked the nutrition labeling, while 32.7% of the consumers seldom checked it. In addition, 44.3% of the consumers think that 'front of pack labeling' is necessary, and 58.3% of the consumers think it is important to show the percentage of daily value as a way of 'front of pack labeling'. However, 32% of the consumer think the possibility of 'front of pack labeling' is slim. Meanwhile, 58.3% of the consumers think that it is important to have the color difference according to contents. The number of favorite nutrients in the front of pack was four or five. It seems that the recognition of current nutrition labeling has the influence on the willingness of using the future 'front of pack labeling'. Along with our study, the policy for 'front of pack labeling' has to be updated and improved constantly since 'front of pack labeling' helps consumer understand nutrition facts.


Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES).
The clinical outcomes for patients with worsening chronic heart failure (WCHF) remain exceedingly poor despite contemporary evidence-based therapies, and effective therapies are urgently needed. Accumulating evidence supports augmentation of cyclic guanosine monophosphate (cGMP) signalling as a potential therapeutic strategy for HF with reduced or preserved ejection fraction (HFrEF and HFpEF, respectively). Direct soluble guanylate cyclase (sGC) stimulators target reduced cGMP generation due to insufficient sGC stimulation and represent a promising method for cGMP enhancement. The phase II SOluble guanylate Cyclase stimulatoR in heArT failurE Study (SOCRATES) programme consists of two randomized, parallel-group, placebo-controlled, double-blind, multicentre studies, SOCRATES-REDUCED (in patients with LVEF <45%) and SOCRATES-PRESERVED (in those with LVEF ≥ 45%), that will explore the pharmacodynamic effects, safety and tolerability, and pharmacokinetics of four dose regimens of the once-daily oral sGC stimulator vericiguat (BAY 1021189) over 12 weeks compared with placebo. These studies will enrol patients stabilized during hospitalization for HF at the time of discharge or within 4 weeks thereafter. The primary endpoint in SOCRATES-REDUCED is change in NT-proBNP at 12 weeks. The primary endpoints in SOCRATES-PRESERVED are change in NT-proBNP and left atrial volume at 12 weeks. SOCRATES will be the first programme to enrol specifically both inpatients and outpatients with WCHF and patients with reduced or preserved ejection fraction. Results will inform the benefits of pursuing subsequent event-driven clinical outcome trials with sGC stimulators in this patient population.


CytoSPADE: high-performance analysis and visualization of high-dimensional cytometry data.
Recent advances in flow cytometry enable simultaneous single-cell measurement of 30+ surface and intracellular proteins. CytoSPADE is a high-performance implementation of an interface for the Spanning-tree Progression Analysis of Density-normalized Events algorithm for tree-based analysis and visualization of this high-dimensional cytometry data. Source code and binaries are freely available at http://cytospade.org and via Bioconductor version 2.10 onwards for Linux, OSX and Windows. CytoSPADE is implemented in R, C++ and Java. firstname.lastname@example.com Additional documentation available at http://cytospade.org.


The very late antigen family of heterodimers is part of a superfamily of molecules involved in adhesion and embryogenesis.
The very late antigen (VLA) protein family contains at least five related heterodimers, including a fibronectin receptor structure, and probably other cell substrate adhesion receptors. These cell-surface VLA proteins were immunopurified from human placenta (VLA-1, VLA-3, and VLA-5), platelets (VLA-2), and Molt-4 cells (VLA-4) using a series of monoclonal antibody-Sepharose immunoaffinity columns. After further purification by gel electrophoresis, the N-terminal amino acid sequence for each of the five VLA alpha subunits was determined. In the first 14 positions, the five VLA alpha subunits showed an average of 42% homology to each other, rising to 59% including conservative amino acid substitutions. In addition, the alpha subunits from the LFA-1, Mac-1 (CR-3), and p150,95 family of heterodimers, the vitronectin receptor-platelet GPIIb/IIIa family, and a position-specific (PS) antigen important in Drosophila embryogenesis each showed average homologies of 31-40% to individual VLA alpha sequences and 46-52% homology to VLA alpha subunits including conservative substitutions. Taken together, these results suggest that the VLA proteins, the LFA-1, Mac-1, and p150,95 family, the GPIIb/IIIa, vitronectin receptor family, and the Drosophila PS antigens have evolved as four subgroups in a highly conserved supergene family of receptors involved in fundamentally important functions, such as cell adhesion, migration, and embryogenesis.