Static and dynamic postural stability in veterans with combat-related mild traumatic brain injury.
Persistent post-concussive symptoms are reported by 10-15% of individuals who suffer mild traumatic brain injury (mTBI), but their basis is often uncertain. One such symptom is disequilibrium, a sensation of impaired balance during standing and walking. The hypothesis for this study was that this subjective symptom is associated with objective and measurable deficits in static and dynamic postural stability. An infrared motion tracking system was used to record body motion during quiet standing and in response to waist perturbations in fourteen veterans (age 22-40 years, 13 male) of the Operations Enduring Freedom (OEF) and Iraqi Freedom (OIF), who had a history of mTBI that occurred 7 months to 7 years prior to testing. We compared body sway between veterans with mTBI reporting persistent disequilibrium (TD, n=8) and those with no vestibular symptoms (n=6), as well as to a group of non-veterans with no balance symptoms (n=10). Static postural stability was reduced in TD veterans in comparison to each of the other two groups (p<0.0002), most notably on a compliant surface with eyes closed. The TD group also had decreased dynamic stability of the upper trunk (p<0.05) and enhanced postural oscillations (p<0.02) following waist perturbations. Our findings support a physiological basis for persistent disequilibrium after mTBI and are consistent with impaired vestibular processing. Disruption of semicircular canal inputs is unlikely to be the cause, as head impulse responses were normal in all groups. The unexpected finding of dynamic postural oscillations requires further study but may indicate enhanced instability in sensorimotor networks responsible for postural control.


Thermal radiosensitization in Chinese hamster (V79) and mouse C3H 10T 1/2 cells. The thermotolerance effect.
The sensitivity of V79 cells and normal or morphologically transformed C3H-10T 1/2 cells to X-rays, heat or heat plus X-rays was examined. The normal and transformed C3H-10T 1/2 cell lines were equally sensitive to heat at 42.0 degrees C and radiation. The V79 cells were more heat sensitive. Thermal radiosensitization occurred for all 3 cell lines for the combined heat and radiation treatments and was greatest for simultaneous treatment. Recovery occurred when the treatments were separated by an incubation interval at 37 degrees C. For the V79 cells, recovery was much greater for X-rays preceding heat compared to X-rays following heat. This difference was not as great in the C3H-10T 1/2 cell lines. The transformed C3H-10T 1/2 cells were more sensitive compared to the normal for the simultaneous treatment or for heating followed by irradiation. For prolonged heating at 42.0 degrees C, after which thermotolerance occurred in all 3 cell lines, the radiosensitivity still increased as a function of heating time even though no additional cell killing occurred from the heat treatment alone. For heating V79 cells at 41.0 degrees C no further increase in radiosensitivity occurred, as cells became thermotolerant during prolonged heating. Also for the development of thermotolerance during incubation at 37 degrees C between two heat treatments, thermal radiosensitization decreased demonstrating that thermotolerance can affect radiosensitization by hyperthermia.


CoA-persulphide: a possible in vivo inhibitor of mammalian short-chain acyl-CoA dehydrogenase.
The characteristic green colour of native short-chain acyl-CoA dehydrogenases (EC 188.8.131.52) results from a charge transfer complex between the FAD prosthetic group and a tightly bound molecule of CoA-persulphide. The native enzyme from ox liver mitochondria was found to have about 60% of its FAD cofactor liganded with CoA-persulphide. When artificially fully liganded with CoA-persulphide, this enzyme was inhibited by 90% in comparison to unliganded enzyme. Enzymic activity could be slowly restored by displacing the CoA-persulphide with high concentrations of butyryl-CoA, the enzyme's physiological substrate. The results show that CoA-persulphide is a potent inhibitor of short-chain acyl-CoA dehydrogenase and may have a physiological role in the regulation of beta-oxidation.


Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines.
New targeted agents like antibodies or small molecules against tyrosine and lipid kinases clearly expand the standard therapy options in oncology. However, tumour resistance is still a challenge, often induced by mutations in growth-related signalling cascades. Twenty and ten percentage of all patients with colorectal and gastric cancers, respectively, carry phosphatidyl-3-kinase (PI3K) mutations and do not respond to receptor-blocking therapies. Recently, selective kinase inhibitors have been generated, which block the PI3K signalling pathway in tumour cells. So far, their therapeutic role for the treatment of mutated versus wild-type human gastrointestinal cancers has not been clarified in detail. To define the inhibitory and pro-apoptotic effects of the two PI3K inhibitors BEZ235 and BKM120 in three human colon cancer (HT-29, HCT-116 and DLD-1) and three gastric cancer (NCI-n87, AGS and MKN-45), cell lines with different PIK3CA gene mutation status were used. Firstly, viability, apoptosis and caspase assays were performed during incubation with either the inhibitors alone or combined with different cytotoxic agents. Secondly, the molecular consequences for the cell cycle and signalling pathways were analysed by defining the protein levels by FACS and Western blot analysis. Both the PI3K inhibitors BEZ235 and BKM120 induced a clear concentration-dependent reduction in cell viability and an increase in apoptotic cell death, with the mutated cells being more sensitive to treatment. However, single-agent BEZ235 caused a G1 arrest in tumour cells, whilst BKM120 induced a G2 shift in a half of the gastrointestinal cancer cell lines. There was a clear downregulation in the protein levels of the PI3K-AKT pathway at the concentrations of 100 nM for both agents and for BEZ235 the additional inhibition of the mTOR pathway. Furthermore, BEZ235 caused synergistic induction of apoptosis when combined with irinotecan in colon cancer cell lines. Human gastric cancer cells were less sensitive to both BEZ235 and BKM120. BEZ235 and BKM120 induced pro-apoptotic effects in all cell lines and especially with an increased response in the PI3KCA mutated cells. Our data support the clinical development of these PI3K inhibitors for patients with wild-type or mutated colon cancers.


Phage anti-CBASS and anti-Pycsar nucleases subvert bacterial immunity.
The cyclic oligonucleotide-based antiphage signalling system (CBASS) and the pyrimidine cyclase system for antiphage resistance (Pycsar) are antiphage defence systems in diverse bacteria that use cyclic nucleotide signals to induce cell death and prevent viral propagation1,2. Phages use several strategies to defeat host CRISPR and restriction-modification systems3-10, but no mechanisms are known to evade CBASS and Pycsar immunity. Here we show that phages encode anti-CBASS (Acb) and anti-Pycsar (Apyc) proteins that counteract defence by specifically degrading cyclic nucleotide signals that activate host immunity. Using a biochemical screen of 57 phages in Escherichia coli and Bacillus subtilis, we discover Acb1 from phage T4 and Apyc1 from phage SBSphiJ as founding members of distinct families of immune evasion proteins. Crystal structures of Acb1 in complex with 3'3'-cyclic GMP-AMP define a mechanism of metal-independent hydrolysis 3' of adenosine bases, enabling broad recognition and degradation of cyclic dinucleotide and trinucleotide CBASS signals. Structures of Apyc1 reveal a metal-dependent cyclic NMP phosphodiesterase that uses relaxed specificity to target Pycsar cyclic pyrimidine mononucleotide signals. We show that Acb1 and Apyc1 block downstream effector activation and protect from CBASS and Pycsar defence in vivo. Active Acb1 and Apyc1 enzymes are conserved in phylogenetically diverse phages, demonstrating that cleavage of host cyclic nucleotide signals is a key strategy of immune evasion in phage biology.


Biologic implications of the expression of vascular endothelial growth factor subtypes in ovarian carcinoma.
Vascular endothelial growth factor (VEGF) has been identified as an important factor for tumor angiogenesis, which is essential for the growth, invasion, and metastasis of solid tumors. This study examines the clinical significance of VEGF subtypes in ovarian carcinoma. Tumor specimens from 128 patients with ovarian carcinoma were evaluated for VEGF and its mRNA expression. The expression of VEGF, especially its subtypes, was determined by Western blot analysis with a sandwich enzyme immunoassay in ovarian carcinomas and reverse transcription-polymerase chain reaction and Southern blot analysis in normal ovaries that served as controls, and the relation between VEGF expression and the histologic types and clinical stages of ovarian carcinomas was analyzed. Among the four subtypes of VEGF, the populations of VEGF165 and VEGF121 were dominant in normal ovaries and ovarian carcinomas. The levels of VEGF and VEGF165 mRNA in ovarian carcinomas were significantly higher than in normal ovaries (P < 0.05). On the other hand, there was no significant difference in the levels of VEGF and VEGF165 mRNA among ovarian carcinomas classified according to histopathologic type or clinical stage. This analysis suggests that VEGF165 may be elevated in all stages of ovarian carcinoma via angiogenic activity, regardless of histopathologic type.


Mechanical and enzymatic thrombolysis for massive pulmonary embolism.
To assess the efficacy and safety of mechanical fragmentation combined with intrapulmonary thrombolysis in massive pulmonary thromboembolism (PTE) with hemodynamic impairment. Fifty-nine patients diagnosed with massive PTE with hemodynamic impact were treated. The initial clinical symptoms were shock in 23 patients (38.9%), syncope in eight (13.5%), and dyspnea at rest in 28 (47.4%). Mean O2 saturation was 67.8%. Mean pulmonary artery pressure (PAP) was 42.1 mm Hg. During fragmentation, thrombolysis was administered in the form of a urokinase bolus of 200,000-500,000 U in 57 patients and 20 mg of recombinant tissue plasminogen activator (rt-PA) in two patients. The mean urokinase dose used was 2,500,000 IU, whereas the total dose of rt-PA was 100 mg. Heparin sodium infusion was performed to reach activated partial thromboplastin time ratios of 2. The follow-up consisted of clinical assessment, pulmonary scintigraphy, and echocardiography. The patients received treatment with dicoumarin for 6 months after the procedure. Clinical improvement was seen in 56 patients (94%). Three patients died. The mean PAP after the treatment was 21.8 mm Hg. The mean posttreatment Miller index was 0.35. Technical success was achieved in all cases and clinical symptoms improved in all cases except those in which the patients died. Pulmonary scintigraphy showed improved perfusion in all cases. Echocardiography was performed after 3-6 months, showing a mean pressure of 22.8 mm Hg (corrected values). There were no signs of recurrent PTE or arterial hypertension in the follow-up. The data provided confirm the efficacy and safety of mechanical fragmentation and pharmacologic thrombolysis in the treatment of massive PTE with hemodynamic impairment, showing improvement of symptoms and a decrease in PAP.


Rescue Treatment with Infliximab for a Bilateral, Severe, Sight Threatening Frosted Branch Angiitis Associated with Concomitant Acute Onset of Presumed Dermatomyositis.
To report a severe bilateral frosted branch angiitis associated with acute onset of systemic dermatomyositis. History and clinical examination, laboratory evaluation, fundus' and skin's color pictures, fluorescein angiography (FA), optical coherence tomography (OCT). A 32-year-old female was referred for a bilateral frosted branch angiitis and vitreitis, with skin rash, muscle pain, weakness, severe headache, compatible with dermatomyositis. After an initial improvement following an aggressive treatment by systemic steroids and mycophenolate mofetil, she was switched to intravenous infliximab (RemicadeTM, Janssen Biotech, Inc. USA) due to lack of efficacy. Nine months later, her visual acuity was improved up to 20/20 in OU, with both retinal vasculitis and vitreitis being solved. Dermatomyositis is a severe multiorgan disease which might severely involve eye structures. Anti-TNF-Alpha agents, particularly Infliximab, might offer a rapid control and long-term remission.


Failure of peritoneal lavage to prevent operative site infection and peritoneal tumor recurrence in pancreatic surgery.
Although intraoperative peritoneal lavage often is performed routinely with the aim of reducing peritoneal contamination, evidence of lavage benefit in elective pancreatic surgery is limited. We retrospectively classified patients who had undergone pancreatic surgery to groups given or not given peritoneal lavage, then comparing clinical results. This saline lavage was performed at the end of the operation. The primary endpoint was rate of surgical site infection. Frequency of peritoneal recurrence also was evaluated. Among all 104 patients in the study, incidence of infectious complications in the lavage group (n = 65) was significantly higher than in the non-lavage group (n = 39; 35% vs. 15%, P = 0.041), while incidences of postoperative complications overall and surgical site infection did not differ between lavage (80% and 26%) and non-lavage groups (67% and 10%, P = 0.162 and 0.076, respectively). Among 63 patients undergoing pancratoduodenectomy, frequencies of positive bacterial cultures of drainage fluids on postoperative days 1 and 3 were greater in the non-lavage group (P < 0.001 and P = 0.012), but surgical site infection was significantly more frequent in the lavage group (P = 0.043). Among patients with pancreatic and biliary cancers, lavage did not affect frequency of peritoneal recurrence. Intraoperative lavage did not prevent surgical site infection or peritoneal recurrence of pancreatobiliary cancer.


Efalizumab.
Efalizumab is a novel immunomodulator that blocks T-cell migration and activation. The drug was initially approved in October 2003 for the treatment of adult patients with chronic moderate to severe plaque psoriasis. This review will discuss the efficacy and safety data for efalizumab in the treatment of psoriasis. In clinical use, efalizumab has utility as a first-line biologic therapy for plaque psoriasis, as well as a first-line choice for hand and foot psoriasis, overweight patients, and those who have had inadequate response to a TNF inhibitor. In addition, several off-label applications of efalizumab will be reviewed.


Neuroendoscopic Resection of Trigeminal Schwannoma in the Pterygopalatine/Infratemporal Fossa via the Transnasal Perpendicular Plate Palatine Bone or Transnasal Maxillary Sinus Approach.
Both the pterygopalatine fossa (PPF) and the infratemporal fossa (ITF) lie outside the midline of the skull base. Lesions in the PPF or ITF include trigeminal schwannoma (trigeminal schwannoma, TS), which originates from the second or third branch of the trigeminal nerve (maxillary nerve or mandibular nerve). Due to their typically deep anatomic location, lesions in the PPF or ITF can be difficult to treat using traditional surgical approaches. In recent years, because of their advantages, which include the fact that they allow the problem to be observed close up, neuroendoscopic techniques are increasingly being applied in skull base surgery, especially in treatment of lesions around the midline of the base of the skull. This study aims to 1) evaluate the neuroendoscopic treatment of lesions in PPF or ITF via the transnasal palate bone perpendicular plate or transnasal maxillary sinus approach and 2) analyze the clinical significance of this approach. We retrospectively analyzed 3 cases of PPF TSs and 1 case of ITF TS treated between January 2015 and May 2017. All of the cases underwent neuroendoscopic resection of TSs located in the PPF via the nasal perpendicular plate palatine bone (or nasal maxillary sinus) approach. Two cases of PPF TSs were characterized by a thin palate bone perpendicular plate due to oppressed absorption of the tumor. Therefore the endoscopic transnasal palate bone perpendicular plate approach was employed. Additionally, 1 case of PPF TSs and 1 case of ITF TS were resected via the transnasal maxillary sinus approach. All 4 patients received total resection under endoscopy and recovered well after their respective operations without cerebrospinal fluid leakage, although 1 patient experienced postoperative dry eye symptoms and 1 other patient showed no improvement in facial numbness before and after the operation. Neuroendoscopic surgery performed via the transnasal perpendicular plate palatine bone or transnasal maxillary sinus approach has its own unique advantages in removing TSs in PPF and in ITF: Notably, the tumor can be exposed and dealt with under direct vision, which prevents damage to important structures, such as the internal carotid and maxillary nerves, while at the same time helping to achieve total removal of TSs. Furthermore, by adopting this approach versus traditional skull base surgery, postoperative trauma can be reduced significantly, which should be advocated for in this time of minimal invasive surgery.


Incretin-based therapy and acute cholecystitis: a review of case reports and EudraVigilance spontaneous adverse drug reaction reporting database.
Glucagon-like peptide-1 (GLP-1) receptor agonists delay gastric and bowel emptying. A similar inhibitory effect of GLP-1 on gallbladder motility has been suggested, possibly leading to an increased risk of cholecystitis related to incretin-based medications, which include GLP-1 antagonists. Our objective was to review evidence in EudraVigilance, the European spontaneous reporting database and the scientific literature on this issue. Increasing evidence suggests an association of incretins with gallbladder adverse events. Pharmacovigilance data from EudraVigilance includes 200 serious ADR reports concerning cholecystitis related to the use of incretin-based therapies. Several mechanisms may explain this increased risk of cholecystitis, including rapid weight loss, inhibition of gallbladder contraction and emptying, reduced bile acids production, modulation of inflammation. The available data suggest the possibility of gallbladder disease in diabetic subjects treated with incretins and highlight the importance of evaluating risk factors for cholelithiasis and gallbladder diseases in patients with diabetes before starting this therapy.


Fatal accidental asphyxia in a jack-knife position.
Accidental death from postural or positional asphyxia takes place when the abnormal position of the victim's body compromises the process of respiration. Diagnosis is largely made by circumstantial evidence supported by absence of any other significant pathology or trauma explaining death. This case report is about a 50-year-old male who had been drinking the previous night and was found dead in the morning inside a tire repair shop. His jack-knifed body had been encompassed, buttocks-down, within the hollow core made by 3 big tires stacked on top of each other. The author was called to the scene of death and had hands-on encounter with the body in-situ where scene photographs were taken. Apart from a blood alcohol of 290 mg/100 ml, marked congestion of the face, petechial hemorrhages on the conjunctivae and lung edema and congestion, autopsy findings were unremarkable. Abrasions on shoulders, lateral aspects of arms and posterior aspects of lower legs indicated friction with internal rims of tires while slipping down. There were no other injuries or pathology to account for his death. Death was determined to be due to accidental postural asphyxia secondary to intoxication by alcohol.


Heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) is a growing complication of a common medication used to prevent deep vein thrombosis (DVT) in hospitalized patients. The purpose of this article is to review the mechanism that causes paradoxical thrombus formation in HIT and ways to recognize this important complication with various testing modalities and to discuss the approaches to treatment once a diagnosis has been made. HIT is a clinical diagnosis that can be further supported by utilizing the "4 Ts": thrombocytopenia, timing of platelet count fall, thrombosis or other complications, and other causes for thrombocytopenia. Diagnosis of HIT can be established using an HIT antibody test. Once a drop in platelet count is observed in a patient, it is important to rule out HIT. When HIT is first suspected, it is important to discontinue all heparin products. The gold standard in diagnosing HIT is the 14C-serotonin release assay (14C-SRA) assay, which has high sensitivity and specificity but is technically demanding and more time consuming than other antibody-detecting immunoassays. Anticoagulation in HIT patients is essential due to the increased risk of thrombosis. Treatment consists of utilizing alternative, nonheparin anticoagulants like lepirudin, argatroban, bivalirudin, or fondaparinux (although fondaparinux is not formally approved by the US Food and Drug Administration for this condition). Each of these agents should be individually formulated based on the patient and the presence/absence of liver or renal failure. Treatment duration has yet to be determined. However, in patients requiring long-term anticoagulation (pulmonary embolism, DVT, stroke), the transition to warfarin can be made once the platelet count recovers and there has been at least 5 days of overlap with a nonheparin anticoagulant.


Assessment of the abuse potential of MDMA in the conditioned place preference paradigm: role of CB1 receptors.
Numerous reports have highlighted the role of the endocannabinoid system in the addictive potential of MDMA (3,4-methylenedioxy-methamphetamine). A previous report showed that CB1 knockout (KOCB1) mice do not acquire MDMA self-administration, despite developing conditioned place preference (CPP). This contradiction could be due to the particular procedure of place conditioning used. The present work compares MDMA-induced CPP in KOCB1 mice using unbiased and biased procedures of place conditioning. In the unbiased procedure, MDMA induced CPP and reinstatement of the extinguished preference in wild type (WT) mice, but not in KOCB1 mice. In contrast, in a biased protocol of CPP, MDMA produced preference in both types of mice. The anxiolytic response induced by MDMA in the elevated plus maze (EPM) was observed only in KOCB1 mice and may have been responsible, at least partially, for the CPP in the biased procedure. A neurochemical analysis revealed that KOCB1 mice presented higher striatal DA and DOPAC levels in response to MDMA, but no alterations in their levels of monoamine transporters. In line with previous self-administration studies, our data suggest that CB1 receptors play an important role in the reinforcing effects of MDMA, and that the experimental procedure of CPP employed should be taken into account when drawing conclusions.


Effects of recombinant human soluble thrombomodulin on neutrophil extracellular traps in the kidney of a mouse model of endotoxin shock.
Sepsis is a life-threatening condition characterized by multi-organ dysfunction due to host immune system dysregulation in response to an infection. During sepsis, neutrophils release neutrophil extracellular traps (NETs) as part of the innate immune response. However, excessive NETs play a critical role in the development of organ failure during sepsis. Although recombinant human soluble thrombomodulin (rTM) can inhibit NET formation in the lungs and liver of a mouse model of endotoxin shock, its effects on the kidneys are unclear. The specific effects of NETs and rTM on the renal cortex and renal medulla were examined in a mouse model of endotoxin shock generated by intraperitoneal (i.p.) injection of lipopolysaccharide (LPS), followed by i.p. injection of rTM or an identical volume of saline 1 h later. LPS injection increased serum creatinine, blood urea nitrogen, and histone H3 levels. However, rTM administration significantly decreased histone H3 and citrullinated histone H3 (citH3) levels. Immunohistochemical analysis revealed no significant changes in citH3 quantity in the renal cortex of any group. However, in the renal medulla, the increase in citH3 induced by LPS was abolished in the LPS+rTM group. Our findings demonstrate that rTM can suppress NETs in the renal medulla of mice with endotoxin-induced acute kidney injury.


Ventilatory and integrated physiological responses to chronic hypercapnia in goats.
Chronic hypercapnia per se has distinct effects on the mechanisms regulating steady-state ventilation and the CO2 /H+ chemoreflex. Chronic hypercapnia leads to sustained hyperpnoea that exceeds predicted ventilation based upon the CO2 /H+ chemoreflex. There is an integrative ventilatory, cardiovascular and metabolic physiological response to chronic hypercapnia. Chronic hypercapnia leads to deterioration of cognitive function. Respiratory diseases such as chronic obstructive pulmonary disease (COPD) often lead to chronic hypercapnia which may exacerbate progression of the disease, increase risk of mortality and contribute to comorbidities such as cognitive dysfunction. Determining the contribution of hypercapnia per se to adaptations in ventilation and cognitive dysfunction within this patient population is complicated by the presence of multiple comorbidities. Herein, we sought to determine the role of chronic hypercapnia per se on the temporal pattern of ventilation and the ventilatory CO2 /H+ chemoreflex by exposing healthy goats to either room air or an elevated inspired CO2 (InCO2 ) of 6% for 30 days. A second objective was to determine whether chronic hypercapnia per se contributes to cognitive dysfunction. During 30 days of exposure to 6% InCO2 , steady-state (SS) ventilation ( V̇I ) initially increased to 335% of control, and then within 1-5 days decreased and stabilized at ∼230% of control. There was an initial respiratory acidosis that was partially mitigated over time due to increased arterial [HCO3- ]. There was a transient decrease in the ventilatory CO2 /H+ chemoreflex, followed by return to pre-exposure levels. The SS V̇I during chronic hypercapnia was greater than predicted from the acute CO2 /H+ chemoreflex, suggesting separate mechanisms regulating SS V̇I and the chemoreflex. Finally, as assessed by a shape discrimination test, we found a sustained decrease in cognitive function during chronic hypercapnia. We conclude that chronic hypercapnia per se results in: (1) a disconnect between SS V̇I and the CO2 /H+ chemoreflex, and (2) deterioration of cognitive function.


Monitoring peptide tyrosine nitration by spectroscopic methods.
Oxidative stress can lead to various derivatives of the tyrosine residue in peptides and proteins. A typical product is 3-nitro-L-tyrosine residue (Nit), which can affect protein behavior during neurodegenerative processes, such as those associated with Alzheimer's and Parkinson's diseases. Surface enhanced Raman spectroscopy (SERS) is a technique with potential for detecting peptides and their metabolic products at very low concentrations. To explore the applicability to Nit, we use SERS to monitor tyrosine nitration in Met-Enkephalin, rev-Prion protein, and α-synuclein models. Useful nitration indicators were the intensity ratio of two tyrosine marker bands at 825 and 870 cm-1 and a bending vibration of the nitro group. During the SERS measurement, a conversion of nitrotyrosine to azobenzene containing peptides was observed. The interpretation of the spectra has been based on density functional theory (DFT) simulations. The CAM-B3LYP and ωB97XD functionals were found to be most suitable for modeling the measured data. The secondary structure of the α-synuclein models was monitored by electronic and vibrational circular dichroism (ECD and VCD) spectroscopies and modeled by molecular dynamics (MD) simulations. The results suggest that the nitration in these peptides has a limited effect on the secondary structure, but may trigger their aggregation.


Photoinduced electron-transfer from imidazole derivative to nano-semiconductors.
Bioactive imidazole derivative absorbs in the UV region at 305 nm. The interaction of imidazole derivative with nanoparticulate WO3, Fe2O3, Fe3O4, CuO, ZrO2 and Al2O3 has been studied by UV-visible absorption, FT-IR and fluorescence spectroscopies. The imidazole derivative adsorbs strongly on the surfaces of nanosemiconductor, the apparent binding constants for the association between nanomaterials and imidazole derivative have been determined from the fluorescence quenching. In the case of nanocrystalline insulator, fluorescence quenching through electron transfer from the excited state of the imidazole derivative to alumina is not possible. However, a possible mechanism for the quenching of fluorescence by the insulator is energy transfer, that is, energy transferred from the organic molecule to the alumina lattice. Based on Forster's non-radiation energy transfer theory, the distance between the imidazole derivative and nanoparticles (r0∼2.00 nm) as well as the critical energy transfer distance (R0∼1.70 nm) has been calculated. The interaction between the imidazole derivative and nanosurfaces occurs through static quenching mechanism. The free energy change (ΔGet) for electron transfer process has been calculated by applying Rehm-Weller equation.


A whole blood sample-to-answer polymer lab-on-a-chip with superhydrophilic surface toward point-of-care technology.
An innovative sample-to-answer (S-to-A) polymer lab-on-a-chip (LOC) with a blood plasma separator based on asymmetric capillary force has been proposed, developed, and completely characterized for point-of-care technology (POCT) applications. A spray layer-by-layer (LbL) nanoassembly coating has been applied for the superhydrophilic surface onto the cyclic olefin copolymer (COC). Then, the developed superwetting surfaces were designed and optimized for three device applications such as lateral transportation of whole blood in the device by capillary pumping, on-chip whole blood/plasma separation with an asymmetric capillary force, and detection using a capillary-driven lateral flow colorimetric assay. Integrating three primary components of the devices, the S-to-A polymer LOC platform has been effectively confirmed for the lateral flow colorimetric assay of bovine serum albumin (BSA) from unprocessed human whole blood without an external power resource.


Interaction between postural asymmetry and visual feedback effects in undisturbed upright stance control in healthy adults.
The technique of additional visual feedback has been shown to significantly decrease the center of pressure (CP) displacements of a standing subject. Body-weight asymmetry is known to increase postural instability due to difficulties in coordinating the reaction forces exerted under each foot and is often a cardinal feature of various neurological and traumatic diseases. To examine the possible interactions between additional visual feedback and body-weight asymmetry effects, healthy adults were recruited in a protocol with and without additional visual feedback, with different levels of body-weight asymmetry. CP displacements under each foot were recorded and used to compute the resultant CP displacements (CPRes) and to estimate vertically projected center of gravity (CGv) and CPRes-CGv displacements. Overall, six conditions were randomly proposed combining two factors: asymmetry with three BW percentage distributions (50/50, 35/65 and 20/80; left/right leg) and feedback (with or without additional VFB). The additional visual feedback technique principally reduces CGv displacements, whereas asymmetry increases CPRes-CGv displacements along the mediolateral axis. Some effects on plantar CP displacements were also observed, but only under the unloaded foot. Interestingly, no interaction between additional visual feedback and body-weight asymmetry was reported. These results suggest that the various postural effects that ensue from manipulating additional visual feedback parameters, shown previously in healthy subjects in various studies, could also apply independently of the level of asymmetry. Visual feedback effects could be observed in patients presenting weight-bearing asymmetries.


Hysteroscopic treatment of uterine tumor resembling ovarian sex cord-like tumor (UTROSCT).
The decision to preserve the uterus in a young nulliparous woman with an extremely rare tumor is challenging. Uterine tumor resembling ovarian sex cord-like tumor (UTROSCT) belongs to the rarest uterine pathologies. A 22-year-old nulligravida with uterine bleeding underwent a hysteroscopic resection of an intrauterine mass presumed as grade-1 submucous myoma. According to the presence of sex cord-like differentiation and positivity for calretinin, CD99, estrogen receptor, vimentin, WT1 and Melan-A, the tumor was diagnosed as UTROSCT. After 28 months, without any adjuvant therapy, the patient is still free of recurrence. This is the youngest patient with UTROSCT reported so far, with the longest follow-up among all five cases treated via hysteroscopy. Although UTROSCT has been traditionally treated with hysterectomy (with or without bilateral salpingo-oophorectomy), no established treatment protocol for UTROSCT exists. UTROSCT shows a low-malignant potential, but metastasizing and recurrent cases occur. In light of the probably less aggressive tumor biology and with respect to the patient's autonomy, a conservative, uterus preserving treatment appears to be justified in selected cases in which close follow-up can be guaranteed. Further case reports are needed to prove the safety of organ-preserving strategy in UTROSCT.


Pharmacotherapy for the core symptoms in autistic disorder: current status of the research.
The current review covers extant literature on pharmacotherapy for core symptoms of autism. The core symptoms of autism include impairments in social interaction and communication, as well as the presence of restricted and repetitive behaviors. There are no known efficacious treatments for the core social symptoms, although effects on repetitive behaviors are indicated with some data. While studies of fenfluramine, secretin, opiates, and mood stabilizers generally find no effect, mixed results suggest more research is needed on antidepressants and atypical antipsychotics. Newer lines of research, including cholinergic and glutamatergic agents and oxytocin, will be of considerable interest in the future. However, research on the treatment of core symptoms is plagued by limitations in study design, statistical power, and other issues inherent to the study of treatments for autism (e.g., heterogeneity of the disorder) that continue to prevent the elucidation of efficacious treatments.


Contrasting expression of membrane metalloproteinases, MT1-MMP and MT3-MMP, suggests distinct functions in skeletal development.
Membrane-type 1 matrix metalloproteinase (MT1-MMP) is the most ubiquitous and widely studied of the membrane-type metalloproteinases (MT-MMPs). It was thus surprising to find no published data on chicken MT1-MMP. We report here the characterization of the chicken gene. Its low sequence identity with the MT1-MMP genes of other species, high GC content, and divergent catalytic domain explains the absence of data and our difficulties in characterizing the gene. The absence of structural features in the chicken gene that have been suggested to be critical for the activation of MMP-2 by MT1-MMP; for the effect of MT1-MMP on cell migration and for the recycling of MT1-MMP suggest these features are either not essential or that MT1-MMP does not perform these functions in chickens. Comparison of the expression of chicken MT1-MMP with MT3-MMP and with MMP-2 and MMP-13 has confirmed the previously recognized co-expression of MT1-MMP with MMP-2 and MMP-13 in fibrous and vascular tissues, particularly those surrounding the developing long bones in other species. By contrast, MT3-MMP expression differs markedly from that of MT1-MMP and of both MMP-2 and MMP-13. MT3-MMP is expressed by chondrocytes of the developing articular surface. Similar expression patterns of this group of MT-MMPs and MMPs have been observed in mouse embryos and suggest distinct and specific functions for MT1-MMP and MT3-MMP in skeletal development.


Possible linkage of schizophrenia and bipolar affective disorder to chromosome 3q29; a follow-up.
The present linkage study is a follow-up within the chromosome 3q29 region in schizophrenia and bipolar affective disorder families, based on our recently published genome scan, resulting in evidence for linkage of both disorders to this region (marker D3S1265: NPL [non parametric lod] score Z(all)=3.74, P=0.003). Using the same family sample (five pedigrees with schizophrenic index patients and three pedigrees with index bipolar disorder patients N=86; 50 of them were available for genotyping), genotyping of eight additional markers close to D3S1265 was done. Five of those new markers (three centromeric and two telomeric of D3S1265) spanning 4.14 cM (centiMorgan) could be used for statistical analyses ("new markers"). Moreover, marker D3S1265, genotyped within the published genome scan, was used for additional calculations. Linkage analysis was performed using the GENEHUNTER program version 2.1r3. Within newly genotyped markers the highest NPL score Z(all) observed was 1.93296 with the telomeric SNP (single nucleotide polymorphism) rs1835669, corresponding to P=0.032166. Statistical analysis including D3S1265, located in between the newly genotyped markers, resulted in a peak NPL score Z(all)=4.00179 with marker D3S1265, that is P=0.000128. Doing subset analyses of the bipolar disorder and schizophrenia families separately with new markers and D3S1265, linkage signals arose substantially from bipolar disorder families, with contribution from schizophrenia families, too. The results of our follow-up study support our previous linkage finding of schizophrenia and bipolar affective disorder to chromosome 3q29.


The reaction of secondary school and university students toward COVID-19-induced lockdown.
The Coronavirus pandemic triggered a worldwide partial lockdown. The lockdown instigated the school's shutdown making the students follow their courses in the virtual modalities while staying at home. The data were collected using an online survey using a semi-structured questionnaire. The study involved anonymous as well as voluntary 77 secondary schools (Grades 9th to 12th) and 132 university students (class standing 1st to 5th year). The lockdown introduced excruciating experiences for most of the students; however, it also created unanticipated opportunities to learn new skills and develop insights on how to mitigate unforeseen crises while remaining reasonably productive. The steps taken to reduce exposure to the coronavirus infection showed a gender discrepancy. Accordingly, males were disproportionately taken risks regardless of the curfew imposed, while females were deeply concerned about the lockdown-induced break of social connections. Students who were attending public schools, presumably from low-income families were found to be more productive during the lockdown compared to their private school counterparts. This shows that, in some instances, the Coronavirus pandemic is a blessing in disguise. The lockdown created mixed feelings; accordingly, the students reported significantly varied responses towards it. This also introduced some inconsistencies in the response of the students. Perceptions about the lockdown and its impact in most instances significantly varied among students, which unlocked the opportunities to learn new lessons on how to manage unprecedented crises. Policymakers need to take into account gender and living standard while developing strategies to mitigate unprecedented challenges.


Effect of imidazobenzoimidazole derivatives RU-353, RU-563, and lidocaine on cerebral circulation in rats.
We demonstrated a dose-dependent inhibitory effect of novel imidazobenzoimidazole derivatives RU-353 and RU-563 on cerebral blood flow and systemic blood pressure in narcotized rats. The effects of RU-353 increased, while the effect of RU-563 decreased with increasing the dose.


Bioaugmentation of Lactobacillus delbrueckii ssp. bulgaricus TISTR 895 to enhance bio-hydrogen production of Rhodobacter sphaeroides KKU-PS5.
Bioaugmentation or an addition of the desired microorganisms or specialized microbial strains into the anaerobic digesters can enhance the performance of microbial community in the hydrogen production process. Most of the studies focused on a bioaugmentation of native microorganisms capable of producing hydrogen with the dark-fermentative hydrogen producers while information on bioaugmentation of purple non-sulfur photosynthetic bacteria (PNSB) with lactic acid-producing bacteria (LAB) is still limited. In our study, bioaugmentation of Rhodobacter sphaeroides KKU-PS5 with Lactobacillus delbrueckii ssp. bulgaricus TISTR 895 was conducted as a method to produce hydrogen. Unfortunately, even though well-characterized microorganisms were used in the fermentation system, a cultivation of two different organisms in the same bioreactor was still difficult because of the differences in their metabolic types, optimal conditions, and nutritional requirements. Therefore, evaluation of the physical and chemical factors affecting hydrogen production of PNSB augmented with LAB was conducted using a full factorial design followed by response surface methodology (RSM) with central composite design (CCD). A suitable LAB/PNSB ratio and initial cell concentration were found to be 1/12 (w/w) and 0.15 g/L, respectively. The optimal initial pH, light intensity, and Mo concentration obtained from RSM with CCD were 7.92, 8.37 klux and 0.44 mg/L, respectively. Under these optimal conditions, a cumulative hydrogen production of 3396 ± 66 mL H2/L, a hydrogen production rate (HPR) of 9.1 ± 0.2 mL H2/L h, and a hydrogen yield (HY) of 9.65 ± 0.23 mol H2/mol glucose were obtained. KKU-PS5 augmented with TISTR 895 produced hydrogen from glucose at a relatively high HY, 9.65 ± 0.23 mol H2/mol glucose, i.e., 80 % of the theoretical yield. The ratio of the strains TISTR 895/KKU-PS5 and their initial cell concentrations affected the rate of lactic acid production and its consumption. A suitable LAB/PNSB ratio and initial cell concentration could balance the lactic acid production rate and its consumption in order to avoid lactic acid accumulation in the fermentation system. Through use of appropriate environmental conditions for bioaugmentation of PNSB with LAB, a hydrogen production could be enhanced.


[Facilitated PCI: did the concept fail?].
Direct percutaneous coronary intervention (PCI) can be considered the gold standard of reperfusion therapy. For patients with need for transfer, the question of antithrombotic pretreatment arises. With the concept of facilitated PCI the advantages of fibrinolysis, namely the rapid and ubiquitous availability, should be combined with the advantages of immediate PCI. With a pretreatment using fibrinolytics, glycoprotein IIb/IIIa inhibitors (GPI) or the combination of both (in that case a fibrinolytic in half dosage only), it was aimed to achieve reperfusion before a planned PCI. Facilitated PCI was expected to improve the rate of open vessels prior to PCI, thereby reducing infarct size, improving clinical outcome, and the success rate of PCI. The concept of facilitated PCI was evaluated in two major randomized trials (ASSENT-4 PCI, FINESSE) as well as in one meta-analysis. Despite an increase of 20% of patients with patent infarct-related arteries (TIMI 3) before PCI, the clinical outcome, especially mortality, reinfarction rate and heart failure rate, did not improve. Moreover, the bleeding rate increased and even a higher rate of cerebral bleeds was seen, predominantly with full-dose fibrinolysis. Patency (TIMI 3) of the coronary arteries was 20% higher in the facilitated PCI arms of the trials. However, all patients were at risk of bleeding complications. Also the inclusion of patients with myocardial infarction in a later phase and the inclusion of patients at lower risk may have contributed to the somewhat disappointing results of facilitated PCI. Recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend facilitated PCI (class IIb), if all of the following criteria are met: (1) patients at high risk, (2) PCI not available within 90 min, (3) low risk of bleed. A planned reperfusion strategy using full-dose fibrinolysis followed by immediate PCI may be harmful (class III). In addition, a further restriction to patients in the early phase of myocardial infarction (< 3 h) should be considered. In the small subset of carefully selected patients, a combination of GPI and half-dose fibrinolytic could be appropriate.


Distinct protease pathways control cell shape and apoptosis in v-src-transformed quail neuroretina cells.
Intracellular proteases play key roles in cell differentiation, proliferation and apoptosis. In nerve cells, little is known about their relative contribution to the pathways which control cell physiology, including cell death. Neoplastic transformation of avian neuroretina cells by p60(v-src) tyrosine kinase results in dramatic morphological changes and deregulation of apoptosis. To identify the proteases involved in the cellular response to p60(v-src), we evaluated the effect of specific inhibitors of caspases, calpains and the proteasome on cell shape changes and apoptosis induced by p60(v-src) inactivation in quail neuroretina cells transformed by tsNY68, a thermosensitive strain of Rous sarcoma virus. We found that the ubiquitin-proteasome pathway is recruited early after p60(v-src) inactivation and is critical for morphological changes, whereas caspases are essential for cell death. This study provides evidence that distinct intracellular proteases are involved in the control of the morphology and fate of v-src-transformed cells.


The pro-apoptotic Bax gene modifies susceptibility to craniofacial dysmorphology following gastrulation-stage alcohol exposure.
During early development, alcohol exposure causes apoptotic cell death in discrete regions of the embryo which are associated with distinctive patterns of later-life abnormalities. In gastrulation, which occurs during the third week of human pregnancy, alcohol targets the ectoderm, the precursor of the eyes, face, and brain. This midline tissue loss leads to the craniofacial dysmorphologies, such as microphthalmia and a smooth philtrum, which define fetal alcohol syndrome (FAS). An important regulator of alcohol-induced cell death is the pro-apoptotic protein Bax. The current study determines if mice lacking the Bax gene are less susceptible to the pathogenic effects of gastrulation-stage alcohol exposure. Male and female Bax+/- mice mated to produce embryos with full (-/- ) or partial (+/- ) Bax deletions, or Bax+/+ wild-type controls. On Gestational Day 7 (GD 7), embryos received two alcohol (2.9 g/kg, 4 hr apart), or control exposures. A subset of embryos was collected 12 hr later and examined for the presence of apoptotic cell death, while others were examined on GD 17 for the presence of FAS-like facial features. Full Bax deletion reduced embryonic apoptotic cell death and the incidence of fetal eye and face malformations, indicating that Bax normally facilitates the development of alcohol-induced defects. An RNA-seq analysis of GD 7 Bax+/+ and Bax-/- embryos revealed 63 differentially expressed genes, some of which may interact with the Bax deletion to further protect against apoptosis. Overall, these experiments identify that Bax is a primary teratogenic mechanism of gastrulation-stage alcohol exposure.


Malaria in pregnancy.
This review summarizes the epidemiology, clinical course, and diagnosis of malaria. The influence of infection during pregnancy upon maternal and neonatal anemia, stillbirth, preterm labor, low birth weight, and congenital malaria is discussed. Options for treatment and prophylaxis during pregnancy are presented.


Holographic and speckle encryption using deep learning: publisher's note.
This publisher's note contains a correction to Opt. Lett.46, 5794 (2021)10.1364/OL.443398.


Near-field quantification of complement receptor 1 (CR1/CD35) protein clustering in human erythrocytes.
We investigate the distribution of the membrane protein complement receptor 1 (CR1/CD35) in human erythrocyte membrane ghosts using scanning near-field optical microscopy. Recent studies have demonstrated that levels of Aβ peptide, associated with Alzheimers disease (AD) and present in brain and peripheral blood, vary significantly when bound by complement C3b-dependent adherence to CR1. It is unknown why patients with AD have a markedly impaired ability to bind Aβ to CR1 via this mechanism, but one possibility is a defect in the localization and/or conformation of CR1 in the membrane. Scanning near-field optical microscopy does not require the harsh preparation of electron microscopy techniques and may therefore be better suited for measuring membrane protein distributions. The clustering phenomenon of CR1 identified in electron microscopy studies is confirmed and quantified. The standard deviation of the inter-cluster spacing of CR1 is constant (79 ± 9 nm) across erythrocytes with between 61 and 124 clusters per membrane ghost.


The dose in water surrounding point isotropic gamma-ray emitters.
A Monte Carlo method has been used to calculate the dose distribution around point gamma-ray emitters in water. Five gamma-ray emitting radionuclide, 60Co, 137Cs, 192Ir, 198Au and 226Ra, which are commonly used in radiotherapy interstitial implants have been considered. The results are in substantial agreement with those derived using a combination of experimental and theoretical data.


Impact of proton pump inhibitors on the risk of small bowel or colorectal bleeding: A systematic review and meta-analysis.
Several studies have suggested that the mucosal protective effects of proton pump inhibitors (PPIs) do not extend beyond the duodenum; however, PPIs may cause lower gastrointestinal (LGI) injury, although these relationships have not yet been fully elucidated. We searched all the relevant studies published until September 2022 that examined the risk of PPIs for LGI bleeding. We performed a meta-analysis of the risk of LGI bleeding (small bowel (SB) or colorectal bleeding) between PPI users and non-users. A subgroup analysis of patients consuming aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) was also performed. Twelve studies with 341,063 participants were included in this meta-analysis. The use of PPIs was associated with the risk of LGI bleeding (odds ratio [OR] [95% confidence interval [CI]] = 1.42 [1.16-1.73]; hazard ratio [HR] [95% CI] = 3.23 [1.56-6.71]). An association between PPI use and the risk of LGI bleeding was also identified in the subgroup of aspirin or NSAID users (OR [95% CI] = 1.64 [1.49-1.80]; HR [95% CI] = 6.55 [2.01-21.33]). In the bleeding site-specific analyses, the risk of SB bleeding was associated with PPI use (OR [95% CI] = 1.54 [1.30-1.84]). PPI use was associated with an increased risk of LGI bleeding, particularly SB bleeding. This association was particularly pronounced among aspirin and NSAID users. Inappropriate PPI prescriptions should be avoided in patients with LGI bleeding and a low risk of upper gastrointestinal disease.


Senile plaques stimulate microglia to release a neurotoxin found in Alzheimer brain.
Senile plaques found in the brains of patients with Alzheimer's disease (AD) are surrounded by clusters of reactive microglia. Isolated human microglia placed in contact with plaques in vitro are activated to release a factor which is toxic to neurons. This same neurotoxin is found in AD brain tissue and causes damage to pyramidal neurons in vivo when infused into rat hippocampus. Highest concentrations of the neurotoxin are in those brain structures most burdened by reactive microglia, suggesting that plaque-activated cells contribute to the neuronal damage and impaired cognition seen in patients with Alzheimer's dementia.


Identifying the individual metabolic abnormities from a systemic perspective using whole-body PET imaging.
Distinct physiological states arise from complex interactions among the various organs present in the human body. PET is a non-invasive modality with numerous successful applications in oncology, neurology, and cardiology. However, while PET imaging has been applied extensively in detecting focal lesions or diseases, its potential in detecting systemic abnormalities is seldom explored, mostly because total-body imaging was not possible until recently. In this context, the present study proposes a framework capable of constructing an individual metabolic abnormality network using a subject's whole-body 18F-FDG SUV image and a normal control database. The developed framework was evaluated in the patients with lung cancer, the one discharged after suffering from Covid-19 disease, and the one that had gastrointestinal bleeding with the underlying cause unknown. The framework could successfully capture the deviation of these patients from healthy subjects at the level of both system and organ. The strength of the altered network edges revealed the abnormal metabolic connection between organs. The overall deviation of the network nodes was observed to be highly correlated to the organ SUV measures. Therefore, the molecular connectivity of glucose metabolism was characterized at a single subject level. The proposed framework represents a significant step toward the use of PET imaging for identifying metabolic dysfunction from a systemic perspective. A better understanding of the underlying biological mechanisms and the physiological interpretation of the interregional connections identified in the present study warrant further research.


The segment-polarity gene fused is highly conserved in Drosophila.
The segment polarity gene fused (fu) is involved in specification of positional information inside embryonic segments in Drosophila melanogaster (Dm). The predicted Fused (Fu) protein contains a serine/threonine kinase domain and a second domain with unknown function. We cloned and sequenced the fu homologous gene from Drosophila virilis (Dv) and made an interspecific DNA sequence comparison to identify regions that have been conserved during evolution. Comparison of the predicted amino acid (aa) sequences reveals two regions of strong homology, one corresponding to the kinase domain (268 aa), the other located in the third exon of the Dm fu gene, suggesting a functional importance for this region. Stretches of significantly conserved sequences are also observed in the 5' and 3' untranslated regions. Weak homology is seen in the intronic sequences although the adjacent exonic sequences are mostly conserved. These findings indicate a high conservation of the predicted Fu protein during the evolution of Drosophila.


Impact of meningococcal C conjugate vaccination four years after introduction of routine childhood immunization in Brazil.
Routine infant immunization with meningococcal C conjugate (MCC) vaccination started in Brazil in November 2010, scheduled at three and five months plus a booster at 12-15months of age. No catch-up was implemented. We assessed the impact of vaccination on meningococcal C disease (MenC) four years after vaccination start in the National Immunization Program. We performed an ecological quasi-experimental design from 2008 to 2014 using a deterministic linkage between the National Notification and the National Reference Laboratory databases for meningitis. We conducted an interrupted time-series analysis considering Brazil except for Salvador municipality, because an epidemic of serogroup C disease occurred in this city, which prompted a mass vaccination campaign with catch-up for adolescents in 2010. Observed MenC rates in the post-vaccination period were compared to expected rates calculated from the pre-vaccination years. Results for Salvador were presented as descriptive data. An additional time-series analysis was performed for the state of São Paulo. A total of 18,136 MenC cases were analyzed. The highest incidence rates were observed for infants aged <12months and no second incident peak was observed for adolescents. For Brazil, MenC rates were reduced by 67.2% (95%CI 43.0-91.4%) for infants <12months of age, 92.0% (77.3-106.8%) for the age-group 12-23months, and 64.6% (24.6-104.5%) for children aged 2-4years. For children 5-9years old, MenC rates reduced 19.2% (9.5-28.9%). Overall, 955 MenC cases were averted in Brazil in individuals aged <40years after MCC vaccination. Results from São Paulo State, mirror the patterns seen in Brazil. After four years of infants and toddlers vaccination start, MenC invasive disease reduced in the target population. This investigation provide a robust baseline to ascertain how much the upcoming catch-up dose in 12-13years of age will accelerate the decrease in MenC incidence rates among youths in Brazil.


To evaluate the prevalence of spontaneous portosystemic shunts in decompensated cirrhosis patients and its prognostic significance.
Spontaneous portosystemic shunts (SPSS) are frequent in liver cirrhosis and their prevalence increases as liver function deteriorates, probably as a consequence of worsening portal hypertension, but without achieving an effective protection against cirrhosis complications. This study was conducted to detect the prevalence of portosystemic shunts in liver cirrhosis patients and analyze its prognostic role. We conducted a prospective observational study, where 92 patients with decompensated cirrhosis were evaluated based on history, physical examination, biochemical tests and abdominal computed tomography (CT) angiography findings. A follow-up was done after six months for the development of cirrhosis-related complications. Of the 92 cirrhotic patients, 57.6% had SPSS (large SPSS + small SPSS) detected by multi-detector computed tomographic angiography. Overall, we found large SPSS in 24 (26.1%) patients, small SPSS in 29 (31.5%) patients and no shunt in 39 (42.4%) patients. Among the shunts, the splenorenal shunt is the most frequent type (25, 27.2%) followed by the paraumbilical shunt (20.7%). Previous decompensating events, including hepatic encephalopathy, ascites, spontaneous bacterial peritonitis and gastrointestinal bleed, were experienced more frequently by the large SPSS group followed by the small SPSS and without SPSS groups. Regarding follow-up, decompensating episodes of hepatic encephalopathy developed more frequently in patients with large SPSS (41.7%) than in patients with small SPSS (24.1%) followed by patients without SPSS (12.8%). In summary, all cirrhotic patients should be studied with radiological imaging to detect the presence of portosystemic shunts. In several cases, patients with large SPSS had a more impaired liver function and more frequent complications of portal hypertension. So, these patients would probably benefit from a closer surveillance and more intensive therapy.


Fetoscopic laser photocoagulation versus expectant management for stage I twin-to-twin transfusion syndrome: A systematic review and meta-analysis.
To investigate the outcomes of asymptomatic stage I twin-to-twin transfusion syndrome (stage I TTTS) among patients treated with fetoscopic laser photocoagulation (FLP) versus expectant management. Databases such as PubMed, Web of Science and Scopus were systematically searched from inception up to March 1st, 2022. The primary outcome was at least one fetal survival at birth and secondary outcomes included gestational age at delivery, preterm premature rupture of membranes < 32 weeks, preterm birth < 32 weeks, and single and dual fetal survival. Five studies were included in the meta-analysis. There was no significant difference in terms of at least one survival (odds ratio (OR) = 1.40, 95%CI= (0.26, 7.43), P = 0.70), single survival (OR = 0.87, 95%CI= (0.51, 1.48), P = 0.60) and dual survival (OR = 1.63, 95%CI= (0.74, 3.62), P = 0.23) among FLP and expectant groups. Gestational age at delivery (mean difference = 1.19, 95%CI= (-0.25, 2.63), P = 0.10), the risk of PTB<32 weeks (OR = 0.88, 95%CI= (0.50, 1.54), P = 0.65), and pPROM<32 weeks (OR = 1.80, 95% CI= (0.41, 7.98), P = 0.44) were also comparable between the groups. Routine FLP of the placental anastomoses before 26 weeks of gestation is unlikely to be beneficial among asymptomatic stable stage I TTTS patients without cervical shortening as the procedure does not offer a survival advantage compared with expectant management.


Tick neurobiology: recent advances and the post-genomic era.
Increasing worldwide resistance to acaricides necessitates greater research on the identification of potential acaricide targets in ticks to aid in the control of these serious pests of medical and veterinary importance. Historically, and most likely in the future, acaricide targets are largely of neural origin, but our knowledge of tick neurobiology is surprisingly limited. The tick central nervous system is a fused nerve mass, termed the synganglion. Tick synganglion material is relatively easily accessible to most researchers and employing modern amplification methods of complementary-DNA construction is readily amenable for gene cloning investigations. The various tick neurotransmitter systems are described with emphasis on our current knowledge of both existing and potential acaricide targets at the molecular level. We describe the impact of mass gene sequencing (expressed sequence tag and genome projects), advances in bioinformatics and RNA-interference on target identification and validation.


Benzo(a)pyrene metabolism in mouse epidermis. Analysis by high pressure liquid chromatography and DNA binding.
Mouse epidermal homogenates contain an inducible aryl hydrocarbon hydroxylase (AHH) complex that catalyzes the formation of benzo(a)pyrene-7,8-dihydrodiol from benzo(a)pyrene (BP) as assessed by high pressure liquid chromatography (HPLC). 5,6-Benzoflavone (5,6-BF), 7,8-benzoflavone (7,8-BF) and 17-beta-estradiol decreased and butylated hydroxytoluene (BHT) enhanced oxidative metabolism of BP when added in vitro. Epoxide hydrase activity (hydration of benzo(a)pyrene-4,5-epoxide) (BP-4,5-epoxide) was enhanced by 17-beta-estradiol, 5,6-BF, and 7,8-BF. BHT exhibited no significant effect and 1,2-epoxy-3,3,3-trichloropropane (TCPO) inhibited hydrase activity. The capacity of epidermal homogenates to catalyze the covalent binding of BP to DNA indicated that addition of both 5,6-BF and 7,8-BF decreased binding. BHT and TCPO did not significantly affect DNA-binding.


Colonoscopy after Hinchey I and II left-sided diverticulitis: utility or futility?
Modern 64- to 128-slice computed tomography (CT) scanners have questioned the need for routine colonoscopy after hospital admission for presumed uncomplicated diverticulitis. This is a retrospective review of all patients (>18 years) who underwent planned colonoscopy after admission for Hinchey I or II acute diverticulitis (January 2009 to January 2014). The findings on the final radiologist report were then correlated with the colonoscopy results. In total, 110 patients (mean age, 55.2 ± 16; 46.4% female) underwent a subsequent colonoscopy (median, 60 days) after admission for diverticulitis. Overall, 102 patients (92.7%) had CT findings consistent with definitive diverticulitis, 6 patients had a diagnosis suggestive of diverticulitis on CT scan, and 2 patients had masses on their admission CT scans. Within the group with definitive diverticulitis, follow-up colonoscopy identified diverticulosis in 99 (97.0%), whereas the other 3 had normal findings. Of the patients with CT scans suggestive of diverticulitis, follow-up colonoscopy showed 3 with diverticulosis, 2 with malignancies, and 1 with nonspecific inflammation. The reliability of CT scans for diverticulitis compared with colonoscopy was found to have a kappa = .829 (P < .001; 95% confidence interval, .629, 1.21). Follow-up colonoscopy should be performed when a CT scan suggests malignancy, nonspecific inflammatory findings, or the patient is otherwise due for routine screening or surveillance. In this study, there was no benefit of follow-up colonoscopy in patients with CT-confirmed diverticulitis in the absence of other concerning or indeterminate findings.


Purification of membrane proteins from Acholeplasma laidlawii by agarose suspension electrophoresis in Tween 20 and polyacrylamide and dextran gel electrophoresis in detergent-free media.
Four of the membrane proteins from Acholeplasma laidlawii that are soluble in the nonionic detergent Tween 20 have been purified by preparative electrophoretic techniques utilizing different supporting media. The last purification step for two of the major proteins was a preparative polyacrylamide gel electrophoresis performed in the absence of any detergent. The proteins were recovered by continuous elution. The purity of the fractions was examined by analytical polyacrylamide gel electrophoresis and crossed immunoelectrophoresis. Two of the minor proteins were purified by dextran gel electrophoresis as the final step, which was also performed in a detergent-free buffer. The separation was followed by scanning the dextran gel in ultraviolet light. The proteins were recovered by slicing the gel and degrading the gel slices with dextranase. The homogeneity of the fractions was checked by electroimmunoassay.


Magnetic Resonance Imaging of Pectoralis Major Injuries in an Active Duty Military Cohort: Mechanism Affects Tear Location.
Pectoralis major (PM) tendon tears are common injuries in athletic patient populations, where operative repair is largely recommended for maximum functional recovery. The repair varies in difficulty and technique based on the location of the tear within the muscle-tendon unit. Magnetic resonance imagining (MRI) has been reported to be sensitive and specific for identifying the tear location, but the effect of injury mechanism on tear pattern has not been previously investigated. To examine PM tears in a military patient population and assess the effect of injury mechanism (weightlifting vs high-energy trauma) on the tear pattern and accuracy of MRI interpretation. Cohort study; Level of evidence, 3. Active duty military servicemembers undergoing operative repair of PM tendon tears with corresponding preoperative MRIs from 2 medical centers were identified. Two musculoskeletal fellowship-trained radiologists reviewed imaging studies, reporting the location of the tear within the muscle-tendon unit and the severity of the tear (sternal head vs clavicular head vs both). Radiographic findings were compared against intraoperative findings. Mechanism of injury and timing from injury to imaging and surgery were assessed to determine whether they affected the accuracy of MRI interpretations. A total of 72 patients were included (mean ± SD age, 33.7 ± 7.0 years; 100% male). Mechanisms of injury consisted of 46 weightlifting injuries and 26 high-energy injuries. Interrater reliability was poor for tear location (kappa, 0.162; P = .003) but substantial for extent of tear (kappa, 0.637; P < .0001). MRI had a 51.3% sensitivity and 63.6% specificity for identifying complete tears. MRI had a sensitivity of 73.9% and specificity of 72.2% for avulsion injuries and sensitivity of 75% and specificity of 79.3% for musculotendinous injuries. Mechanism of injury had no effect on extent of the tear but did affect the location of the tear, with a higher rate of avulsion injuries in the high-energy mechanism cohort (81% vs 40%; P = .02). The mechanism of injury was found to significantly affect the location of tendon tears. A higher rate of avulsion injuries was found in high-energy injuries than weightlifting injuries. MRI appeared to be less sensitive and specific than previous reports for traumatic PM tendon injuries.


Real-world evidence on the strategy of olmesartan-based triple single-pill combination in Korean hypertensive patients: a prospective, multicenter, observational study (RESOLVE-PRO).
In this prospective, multicenter, non-comparative observational study, the effectiveness and safety of the triple single-pill combination (SPC) of olmesartan/amlodipine/hydrochlorothiazide (OM/AML/HCTZ) were evaluated in a real clinical practice setting in Korean patients with essential hypertension. A total of 3752 patients were enrolled and followed for 12 months after administration of OM/AML/HCTZ. Primary endpoint was change from baseline to month 6 in the mean systolic blood pressure (SBP). Secondary endpoints included changes from baseline in the mean SBP at month 3, 9, 12 and the mean diastolic blood pressure (DBP) at month 3, 6, 9, 12; changes in the mean SBP/DBP according to age and underlying risk factors; and blood pressure control rate (%) at different time points. Adherence to and satisfaction with OM/AML/HCTZ treatment among patients and physicians were assessed by medication possession ratio (MPR) and numeric rating scale, respectively, as exploratory endpoints. Safety was evaluated by the incidence and severity of adverse events (AEs) as well as the discontinuation rate due to AEs. OM/AML/HCTZ administration led to significant reductions in the mean SBP/DBP by 11.5/6.6, 12.3/7.0, 12.3/7.2, and 12.8/7.4 mmHg from baseline to month 3, 6, 9 and 12, respectively (P < 0.0001). The BP reductions were maintained throughout the 1-year observation period in all patients with different age groups and risk factors (diabetes mellitus, cardiovascular disease, and renal disease). The BP control rate (%) of < 140/90 mmHg was 65.9, 67.9, 68.9, and 70.6% at month 3, 6, 9, and 12, respectively. The mean MPR during the observation period was 0.96. The safety results were consistent with the previously reported safety profile of OM/AML/HCTZ. Treatment with the triple SPC of OM/AML/HCTZ demonstrated significant effectiveness in reducing SBP/DBP and achieving target BP control with high adherence over the 1-year observation period in Korean hypertensive patients and was well-tolerated. CRIS, KCT0002196 , Registered 3 May 2016.


Blood-Based Biomarkers for Managing Workload in Athletes: Perspectives for Research on Emerging Biomarkers.
At present, various blood-based biomarkers have found their applications in the field of sports medicine. This current opinion addresses biomarkers that warrant consideration in future research for monitoring the athlete training load. In this regard, we identified a variety of emerging load-sensitive biomarkers, e.g., cytokines (such as IL-6), chaperones (such as heat shock proteins) or enzymes (such as myeloperoxidase) that could improve future athlete load monitoring as they have shown meaningful increases in acute and chronic exercise settings. In some cases, they have even been linked to training status or performance characteristics. However, many of these markers have not been extensively studied and the cost and effort of measuring these parameters are still high, making them inconvenient for practitioners so far. We therefore outline strategies to improve knowledge of acute and chronic biomarker responses, including ideas for standardized study settings. In addition, we emphasize the need for methodological advances such as the development of minimally invasive point-of-care devices as well as statistical aspects related to the evaluation of these monitoring tools to make biomarkers suitable for regular load monitoring.


Prospective neoadjuvant analysis of PET imaging and mechanisms of resistance to Trastuzumab shows role of HIF1 and autophagy.
Although Trastuzumab has improved survival of HER2+ breast cancer patients, resistance to the agent pre-exists or develops through the course of therapy. Here we show that a specific metabolism and autophagy-related cancer cell phenotype relates to resistance of HER2+ breast cancer to Trastuzumab and chemotherapy. Twenty-eight patients with locally advanced primary breast cancer were prospectively scheduled to received one cycle of Trastuzumab followed by a new biopsy on day 21, followed by taxol/Trastuzumab chemotherapy for four cycles before surgery. FDG PET/CT scan was used to monitor tumour response. Tissue samples were immunohistochemically analysed for metabolism and autophagy markers. In pre-Trastuzumab biopsies, the LC3A+/HER2+ cell population was correlated with HIF1α expression (P=0.01), while GLUT1 and LC3B expression were correlated with Ki67 proliferation index (P=0.01 and P=0.01, respectively). FDG PET tumour dimensions before therapy were correlated with LC3B expression (P=0.005). Administration of Trastuzumab significantly reduced clinical and PET-detected tumour dimensions (P<0.01). An inverse association of tumour response with the percentage of cells expressing HIF1α at baseline was documented (P=0.01). Administration of Trastuzumab resulted in a decrease of the proliferation index (P=0.004), GLUT1 (P=0.04) and HER2 (P=0.01) expression. In contrast, the percentage of LC3A+/HER2+ cells was increased (P=0.01). High baseline HIF1α expression was the only parameter associated with poorer pathological response to preoperative chemotherapy (P=0.001). As the HER2+/LC3A+ phenotype, which often overexpresses HIF1α, is a major subpopulation increasing after therapy with Trastuzumab, LC3A- and HIF1α-targeting therapies should be investigated for the augmentation of anti-HER2 therapy efficacy.


Validation of a robust PCR-based assay for quantifying fragile X CGG repeats.
Sizing of FMR1 trinucleotide repeats in the clinical laboratory requires the use of capillary sequencer by PCR, or by a labor intensive measurement using Southern blot method. Our aim was to validate an accurate and robust PCR assay for quantification of CGG repeats. We performed an analytical and clinical validation of a new PCR-based method that utilizes a low-cost capillary electrophoresis instrument and the FragilEase™ reagent kit. First, analytical performance was demonstrated on 12 Coriell reference samples comprising normal through full mutations. Subsequently, a cohort of 112 archived clinical DNA samples, enriched for premutation and full mutations, was analyzed. All samples were amplified successfully. Quantification of repeat numbers was interpreted by the use of standards with known repeats. Twenty-five full-mutation samples were successfully amplified with the largest allele size measured at 1380 repeats. The repeat numbers from the new assay were concordant with those obtained with the reference method. The intra-assay (CV<2.5%) and inter-assay imprecision was within 1 CGG repeat. This new PCR-based method is reproducible and capable of identifying all Fragile X alleles. It is an accurate and robust method that facilitates Fragile X testing in a broader spectrum of clinical laboratories.


Effect of the nutritional supplement ALAnerv® on the serum PON1 activity in post-acute stroke patients.
Paraoxonase-1 (PON1) is one of the HDL-associated proteins which contributes to the antioxidant properties of these lipoproteins. The aim of this pilot study was to evaluate the effect of the nutritional supplement ALAnerv® on serum PON1 activity in post-acute stroke patients undergoing rehabilitation. We enrolled 28 post-acute stroke patients and randomly divided them into (-) ALA or (+) ALA study groups. All the patients underwent the same rehabilitation program and received comparable standard medications. Moreover, (+) ALA patients received ALAnerv® for two weeks (2 pills/day). The serum PON1 activity was assessed on blood samples taken at the admission and at the discharge moments, respectively. We used paraoxon (paraoxonase activity, PONA), phenyl acetate (arylesterase activity, ARYLA) and dihydrocoumarin (lactonase activity, LACTA) as substrates, the latter activity being regarded as physiologically relevant. A control group of 14 apparently healthy subjects was also created. In the (+) ALA group, LACTA significantly increased during the study period (17.6 ± 3.2 vs. 27.6 ± 3.5, p = 0.002). Moreover, the percentage of LACTA variation between (-) ALA and (+) ALA groups during the study was also statistically different (-11.7 ± 6.9% vs. +95.1 ± 29.7%, p < 0.0001). These preliminary results suggest that ALA nerv® could contribute to the improvement of the physiologically relevant LACTA of PON1 in post-acute stroke patients, enabling this enzyme to contribute to the redox correction. Also, this study raises the question about the effect of a longer treatment period over the other enzymatic activities of serum PON1.


Effect of increasing esomeprazole and pantoprazole doses on acid control in patients with symptoms of gastro-oesophageal reflux disease: a randomized, dose-response study.
In patients with gastro-oesophageal reflux disease (GORD), dose escalation or drug switching may be considered in those with symptoms that persist despite standard-dose proton pump inhibitor (PPI) therapy. This study set out to assess whether increasing the dosage of oral esomeprazole and pantoprazole improves acid control in GORD patients, and to compare the pharmacodynamic efficacy of esomeprazole and pantoprazole administered at different dosages. This was an open-label, randomized, six-way crossover study that included Helicobacter pylori-negative GORD patients (aged 20-60 years) with <30% of time with intragastric pH>4. Patients were treated with oral once-daily esomeprazole 20 mg, 40 mg and 80 mg, and pantoprazole 20 mg, 40 mg and 80 mg, for 5 days. The main outcome measures were time with intragastric pH>4 over 24 hours, median pH over 24 hours and area under the hydrogen ion versus time curve on day 5 for each treatment period. Dose escalation with both PPIs improved acid control. The proportion of time with intragastric pH>4 (day 5) was 46.7% with esomeprazole 20 mg/day, 58.6% with esomeprazole 40 mg/day, and 65.8% with esomeprazole 80 mg/day; the corresponding percentages with pantoprazole were 28.6%, 36.9% and 44.9%, respectively. On a milligram-per-milligram basis, esomeprazole provided greater acid control than pantoprazole (p<0.001). Dose escalation with oral esomeprazole and pantoprazole improves acid control in patients with GORD, although esomeprazole provides significantly greater acid control on a milligram-per-milligram basis.


Mechanism underlying earthworm on the remediation of cadmium-contaminated soil.
Cadmium (Cd) contamination of soil becomes a potential agricultural and global environmental problem due to the need to ensure safe food. In this study, earthworms (Eisenia fetida) and plants (vetiver grass) were prepared for removal Cd from soil. The results showed the Cd concentration in the soil of all experimental groups decreased, notably by 17.60% in the group with 20 mg/kg Cd concentration. In the roots of vetiver, the content of Cd increased by 57% after earthworms were added and the transfer coefficient of Cd was also significantly increased. Moreover, Cd in the soil was generally absorbed by the intestinal tract of earthworms and became concentrated, mainly in the midgut and hindgut accounting for >77.78% of the total. In addition, enteric microorganism analysis demonstrated that the bacterial community structure played an important role in Cd enrichment and metabolism regulation. There was a significant correlation between some bacteria and Cd concentration. Among these bacteria, Pseudomonas brenneri, were involved in the adsorption and metabolism of Cd to reduce the toxicity of Cd to the earthworms. On the other hand, in order to cope with the external Cd stress, the malondialdehyde (MDA) and hydrogen critically (CAT) enzymes in the earthworms increased with the concentration. Therefore, the high tolerance of earthworms to Cd is related to its physiological adjustment and the balance of intestinal bacteria. The combination of earthworms, microorganisms and plants can result a good alternative to diminish the impact of Cd in soils.


Unveiling fungal detoxification pathways of the cruciferous phytoalexin rapalexin A: Sequential L-cysteine conjugation, acetylation and oxidative cyclization mediated by Colletotrichum spp.
The metabolism of the phytoalexin rapalexin A, a unique indole isothiocyanate (ITC) produced by crucifers (family Brassicaceae), was investigated. Three phytopathogenic fungal species were examined: Colletotrichum dematium (Pers.:Fr.) Grove, a broad host range pathogen, C. higginsianum Sacc., a host-selective pathogen of crucifers and C. lentis Damm, a host-selective pathogen of lentils (Lens culinaris Medik.). The metabolism of rapalexin A by C. dematium and C. higginsianum was similar, taking place via one common intermediate and two divergent pathways, but C. lentis was unable to transform rapalexin A. Both C. higginsianum and C. dematium transformed rapalexin A to two previously undescribed metabolites, the structures of which were confirmed by chemical synthesis: N-acetyl-S-(8-methoxy-4H-thiazolo[5,4-b]indol-2-yl)-L-cysteine and 4-hydroxy-3-(4-methoxy-1H-indol-3-yl)-2-thioxothiazolidine-4-carboxylic acid. That is, both fungal pathogens metabolized and detoxified rapalexin A by addition of the thiol group of L-Cys residue to the isothiocyanate carbon of rapalexin A, a transformation usually catalyzed by glutathione transferases. Coincidentally, this metabolic pathway is employed by mammals and insects to detoxify isothiocyanates and other xenobiotics. Hence, C. higginsianum could be a useful model fungus to uncover genes involved in the detoxification pathways of ITCs and related xenobiotics. Our overall results suggest that increasing rapalexin A production in specific crucifers could increase crop resistance to certain fungal pathogens.


Assembly of the Mitochondrial Translation Initiation Complex.
Mitochondria maintain their own translational machinery that is responsible for the synthesis of essential components of the oxidative phosphorylation system. The mammalian mitochondrial translation system differs significantly from its cytosolic and bacterial counterparts. Here, we describe detailed protocols for efficient in vitro reconstitution of the mammalian mitochondrial translation initiation complex, which can be further used for mechanistic analyses of different aspects of mitochondrial translation.


Transfer coefficients of selected radionuclides to animal products. I. Comparison of milk and meat from dairy cows and goats.
The diet-milk transfer coefficient, Fm (Bq L-1 output in milk divided by Bq d-1 intake to the animal) was studied for eight radionuclides that previously had been given little attention. The Fm values for cows and goats, respectively, were: 2.3 X 10(-5) and 1.5 X 10(-4) for 99mTc, 1.4 X 10(-4) and 8.5 X 10(-4) for 95mTc, 1.1 X 10(-2) for 99Tc (goats only); 1.7 X 10(-3) and 9 X 10(-3) for 99Mo; 4.8 X 10(-4) and 4.4 X 10(-3) for 123mTe; 4.8 X 10(-4) and 4.6 X 10(-3) for 133Ba; 5.5 X 10(-7) and 5.5 X 10(-6) for 95Zr; and 4.1 X 10(-7) and 6.4 X 10(-6) for 95Nb. The goat/cow transfer coefficient ratios for milk were approximately 10, but the goat/cow ratios for meat varied by three orders of magnitude.


Learning complex dependency structure of gene regulatory networks from high dimensional microarray data with Gaussian Bayesian networks.
Reconstruction of Gene Regulatory Networks (GRNs) of gene expression data with Probabilistic Network Models (PNMs) is an open problem. Gene expression datasets consist of thousand of genes with relatively small sample sizes (i.e. are large-p-small-n). Moreover, dependencies of various orders coexist in the datasets. On the one hand transcription factor encoding genes act like hubs and regulate target genes, on the other hand target genes show local dependencies. In the field of Undirected Network Models (UNMs)-a subclass of PNMs-the Glasso algorithm has been proposed to deal with high dimensional microarray datasets forcing sparsity. To overcome the problem of the complex structure of interactions, modifications of the default Glasso algorithm have been developed that integrate the expected dependency structure in the UNMs beforehand. In this work we advocate the use of a simple score-based Hill Climbing algorithm (HC) that learns Gaussian Bayesian networks leaning on directed acyclic graphs. We compare HC with Glasso and variants in the UNM framework based on their capability to reconstruct GRNs from microarray data from the benchmarking synthetic dataset from the DREAM5 challenge and from real-world data from the Escherichia coli genome. We conclude that dependencies in complex data are learned best by the HC algorithm, presenting them most accurately and efficiently, simultaneously modelling strong local and weaker but significant global connections coexisting in the gene expression dataset. The HC algorithm adapts intrinsically to the complex dependency structure of the dataset, without forcing a specific structure in advance.


Direct injection of immature dendritic cells into irradiated tumor induces efficient antitumor immunity.
Although there are several ways to load tumor antigens to DCs, in vitro preparation of tumor antigens and manipulation of DCs are usually required. Therefore, to develop a simple antitumor immunization method, we examined if direct injection of DCs into tumor apoptosed by ionizing IR could induce efficient antitumor immunity. Ionizing IR with 15 Gy induced apoptosis in tumor maximally after 6 hr. Injection of DCs i.t. into IR tumor induced strong cytotoxicity of splenocytes against tumor cells compared to i.t. injection of DCs or ionizing IR of tumor, both of which induced weak cytotoxicity. In an animal study, i.t. injection of DCs into IR tumor induced therapeutic antitumor immunity against a tumor established at a distant site. Moreover, when TNF-alpha or LPS was added as a danger/maturation signal to DC suspension before i.t. injection, antitumor immunity was significantly potentiated compared to a group treated with i.t. injection of DCs into IR tumor. Our results suggest that injection of DCs into tumor apoptosed by ionizing IR might be a simple and efficient method of immunization against tumor.


[Dynamics of driven rhythm in neuronal assemblies in sensorimotor and visual cerebral cortices in rabbit].
Coincident activity of pairs of neurons in the sensorimotor and visual areas of the cerebral cortex was studied in naive, learning, and trained rabbits during the formation of a hidden excitation focus in their central nervous system (a defensive dominanta) of the rhythmic nature. In the trained rabbits (as compared to the naive animals), percent of neuronal pairs (both neighboring and distant) in whose coincident activity the rhythm of stimulation prevailed was higher. In the visual cortex, percent of such pairs was significantly higher only for the distant neurons. Analysis of interaction between neurons in the visual and sensorimotor cortices revealed increasing the number of neuronal pairs with the driven rhythm while training. Such an increase was observed when both sensorimotor and visual neurons were considered as leading.


Insular lobe surgery and cognitive impairment in gliomas operated with intraoperative neurophysiological monitoring.
For a long time, surgery of insular gliomas was considered at high risk for postoperative cognitive deficits, but recent studies highlighted the feasibility of the surgical approach. The aims of our study were to investigate the presence of language impairment before and after surgery and the relationship between language impairment and tumor volume preoperatively and extent of resection (EOR) 3 months after surgery. Thirty-five patients with insular gliomas underwent an extensive language assessment before and few days after surgery, and after 3 months. Intraoperative neurophysiological monitoring (IOM) and brain mapping with direct electrical stimulation (DES) were used in all the cases; 8 patients underwent awake craniotomy. Statistical analysis was performed on the language tests administered. Patients with pure left insular lesion showed language impairment before and after surgery. Overall, patients with a left lesion showed a drop of performance after surgery followed by a partial recovery. Moreover, when the tumor involved the insula and adjacent networks, we observed a more severe deficit. No correlations were found between tumor volume, EOR, and language impairment. Left insular lobe is an important hub in language networks; its involvement determines pre- and postsurgical deficits, together with the involvement of white matter connections. Tumor volume and EOR are not risk factors per se directly related to language functioning. Surgery of insular gliomas is possible with a pre- and intraoperative extensive study of the patient with IOM and awake surgery, and encouraged by the trend of cognitive recovery highlighted.


The clinical utility of renal concentrating capacity in polycystic kidney disease.
We studied 177 adult nonazotemic subjects with autosomal dominant polycystic kidney disease (ADPKD) and 123 unaffected family members (NADPKD). In order to assess the factors influencing renal concentrating capacity maximal urinary osmolality (UOsm) after overnight water deprivation and vasopressin was measured. UOsm was reduced in ADPKD (680 +/- 14) compared to NADPKD subjects (812 +/- 13 mOsm/kg). A greater severity of the architectural abnormality as assessed by cyst number and size and remaining volume of normal parenchyma was associated with a greater impairment of renal concentrating capacity. The concentrating defect was present in the youngest ADPKD subjects and the rate of decline of concentrating capacity with age in ADPKD paralleled that in NADPKD subjects. Based on the initial 135 subjects studied, we developed an algorithm for diagnostic screening for ADPKD utilizing blood pressure, serum creatinine and UOsm designed to maximize sensitivity. When applied to a subsequent population of 165 adults, 121 with ADPKD and 44 unaffected relatives, this algorithm would have spared 20% of unaffected subjects from the cost of ultrasound while failing to detect less than 2% of affected subjects. This simple protocol thus offers a rapid and inexpensive way to screen for ADPKD.


Application of electrooxidation process for treating concentrated wastewater from distillery industry with a voluminous electrode.
Experiments in a laboratory scale were carried out to reduce color and chemical oxygen demand (COD) in distillery wastewater by using electrooxidation processes. A cylindrical electrochemical reactor constructed in an axial configuration with 0.2m diameter and 0.35 m height was employed in this study. Two materials including graphite particles and titanium sponge were used as the voluminous anodes. A cathode made from Ti/RuO(2) was placed 0.04-0.05 m above the upper level of anode particles. Effect of parameters including initial pH of wastewater (1-5), time of dilution, current intensity (1-10A), type of additive (H(2)O(2) and NaCl), and additive concentration were investigated. The results indicated that the anode made from titanium sponge showed a higher potential to treat wastewater than the another one. The treatment in acidic condition (pH=1) provided the maximum oxidation of organic pollutants in wastewater. The presence of additives can promote the reduction of COD and color in wastewater approximately 89.62% and 92.24%, respectively. The maximum current efficiency was reached at the first 30 min and decreased slightly as electrolysis time proceeded due to the formation of passivation on the electrode surface. The energy consumption was obtained in the range of 2.82-4.83 kWh/kgCOD or 24.08-28.07 kWh/m(3) wastewater depending upon the concentration of additive. The kinetics of COD reduction was the pseudo first-order reaction with a fast rate constant of 6.78 min(-1).


Synthesis and in vitro evaluation of bis-quaternary 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide derivatives as reactivators against sarin and VX inhibited human acetylcholinesterase (hAChE).
A series of bis-quaternary pyridinium derivatives 3a-3i of 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide (2) have been synthesized. The synthesized pyridinium compounds have an amide group in conjugation to the oxime moiety. These compounds were evaluated in vitro for their reactivation efficacy against organophosphorus (OP) nerve agents (NAs) (sarin and VX) inhibited human erythrocyte ghost acetylcholinesterase (hAChE) and compared with the reactivation efficacy of 2-PAM and obidoxime. The pKa values of the synthesized compounds were found closer to the pKa values of 2- and 4-pyridinium oxime reactivators such as 2-PAM and obidoxime. Some of the compounds have shown better reactivation efficacy than 2-PAM, and obidoxime against sarin and VX inhibited AChE.


Decreased expressions of vascular endothelial growth factor and visfatin in the placental bed of pregnancies complicated by preeclampsia.
The aim of the present study was to examine the expression of vascular endothelial growth factor (VEGF) and visfatin in the third trimester placental bed of pregnancies with and without preeclampsia (PE). The study group consisted of placental bed biopsy tissues obtained from pregnancies with (n = 20) and without (n = 20) PE. The normotensive controls without PE were matched for gestational age at delivery with patients with PE. The expression of VEGF and visfatin in the placental bed tissues were evaluated using reverse transcriptase-polymerase chain reaction (RT-PCR), real-time polymerase chain reaction (PCR), immunohistochemistry and Western blot. There was no statistical difference between the PE group and the normotensive control group in age and body mass index (BMI). The expression of VEGF and visfatin was significantly decreased in the PE group compared with the normotensive control group (P < 0.05). This study showed decreased expressions of VEGF and visfatin in the third trimester placental bed of pregnancies with PE compared with the normotensive controls. This result suggests that decreased expression of these angiogenic factors in placental bed may be associated with the pathogenesis of PE.


Barriers in the brain: a renaissance?
Barrier mechanisms regulate the exchange of molecules between the brain's internal milieu and the rest of the body. Correct functioning of these mechanisms is critical for normal brain activity, maintenance and development. Dysfunctional brain barrier mechanisms contribute to the pathology of neurological conditions, ranging from trauma to neurodegenerative diseases, and provide obstacles for successful delivery of potentially beneficial pharmaceutical agents. Previous decades of research have yielded insufficient understanding for solving brain barrier problems in vivo. However, an awakening of interest and novel approaches are providing insight into these mechanisms in developing and dysfunctional brain, as well as suggesting new approaches to circumventing brain barrier mechanisms to get therapeutic agents into the central nervous system.


Retinal vessel reaction to short-term IOP elevation in ocular hypertensive and glaucoma patients.
Regulation of ocular blood flow might be impaired in glaucoma patients. We compared the reaction of retinal vessels to a short-term increase of intraocular pressure (IOP), using a retinal vessel analyzer (RVA), in normal volunteers, ocular hypertensive patients (OH) and primary open angle glaucoma patients (POAG). Ten healthy subjects (56+/-8 years, IOP 13.7+/-1.6 mmHg), 10 OH patients (55+/-12 years, IOD 23.4+/-4.1 mmHg) and 11 POAG patients (60+/-11 years, IOP 23.3+/-1.95 mmHg) were evaluated. Arterial and venous retinal vessel diameter was measured continuously before, during and after raising IOP to suprasystolic values by the suction cup method, described as ocular oscillo-dynamography. The change in vessel diameter after the IOP rise differed in its temporal sequence and in absolute values depending on the group examined. In the retinal branch veins the reduction of vessel diameter during the IOP rise was significantly different in POAG (0%+/-6.7) and volunteers (-6.7%+/-8.5; p = 0.06) and in POAG and OH (-6.7%+/-7.0; p = 0.04). At 70-130 sec after IOP increase a dilatation occurred, again differing significantly in POAG (+5.8%+/-3.9) and volunteers (+9.7%+/-4.3; p = 0.03). Systemic blood pressure did not show any significant differences between groups or during the course of the examination. At short-term rise in IOP leads to less retinal vessel reaction in POAG patients than in volunteers and OH. This might be due to impaired autoregulation to ocular perfusion changes in POAG patients.


Validation of a Landscape-Based Model for Whitefly Spread of the Cucurbit Yellow Stunting Disorder Virus to Fall Melons.
The cucurbit yellow stunting disorder virus (CYSDV) transmitted by Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) has caused significant reductions in fall melon (Cucumis melo L.) yields in Yuma County, Arizona. In a recent landscape-based study, we found evidence that cotton and spring melon fields increased abundance of B. tabaci and spread of CYSDV infection in fall melon fields. Here, we show that a statistical model derived from data collected in 2011-2012 and based on areas of cotton and spring melon fields located within 1,500 m from edges of fall melon fields was sufficient to retrospectively predict incidence of CYSDV infection in fall melon fields during 2007-2010. Nevertheless, the slope of the association between areas of spring melon fields and incidence of CYSDV infection was three times smaller in 2007-2010 than in 2011-2012, whereas the slope of the association between areas of cotton fields and incidence of CYSDV infection was consistent between study periods. Accordingly, predictions were more accurate when data on areas of cotton alone were used as a basis for prediction than when data on areas of cotton and spring melons were used. Validation of this statistical model confirms that crop isolation has potential for reducing incidence of CYSDV infection in fall melon fields in Yuma County, although isolation from cotton may provide more consistent benefits than isolation from spring melon.