Effects of resorbable membrane placement and human osteogenic protein-1 on hard tissue healing after periradicular surgery in cats.
Periradicular surgeries were performed on the maxillary cuspid teeth of twelve cats. Before reapproximation of the surgical flaps, eight of the osteotomies were covered with a resorbable membrane and eight were filled with human osteogenic protein-1 (hOP-1) on a collagen carrier. The remaining eight sites received no further treatment and served as controls. The animals were euthanized after 12 wk, and the specimens were examined histomorphometrically for the presence or absence of osseous regeneration, inflammation, and cementum formation on the root ends. The results showed that the sites treated with the membrane exhibited significantly more inflammation adjacent to the resected root ends (p < 0.05), and that the use of the membrane had no statistically significant effect on osseous healing or new cementum formation. The use of hOP-1 was associated with a significant decrease in the thickness of new cementum formed on the resected root ends (p < 0.05), but had no statistically significant effect on osseous healing or degree of inflammation. Based on these results, it seems that neither the use of hOP-1 nor resorbable membranes have a positive effect on periradicular tissue healing in endodontic surgery.


Evaluation of recombinant A/Victoria/3/75 (H3N2) influenza neuraminidase mutants as potential broad-spectrum subunit vaccines against influenza A.
Current influenza vaccines require repeated administration for long-term protection. Failure to develop broad-spectrum vaccines may be attributed to the chronic presentation of hypervariable, immunodominant epitopes displayed on the viral surface that keep the immune response somewhat fixed and limited by suppression of broadly neutralizing, low-titered antibodies. To test this hypothesis, we have attempted to dampen the immunogenicity of variable epitopes and potential immunodominant domains of the A/Victoria/3/75 (H3N2) neuraminidase by site-directed mutagenesis. The results suggest that the neuraminidase structure is extremely flexible, since many substitution combinations were tolerated, and constitute proof-of-principle that the antigenicity of this protein can be modulated to a large extent. However, mice immunized with neuraminidase mutants containing multiple amino acid substitutions showed a reduced protection rate against heterologous virus in comparison with the reference groups.


An iron catalyzed regioselective oxidation of terminal alkenes to aldehydes.
Fe(BF(4))(2)·6H(2)O with pyridine-2,6-dicarboxylic acid and PhIO can efficiently catalyze the regioselective oxidation of terminal alkene derivatives to aldehydes under mild and benign reaction conditions.


In vitro evaluation of the therapeutic effectiveness of EBV-LMP2 recombinant adenovirus vaccine in nasopharyngeal carcinoma.
Immunotherapeutic strategies based on Epstein-Barr virus (EBV) latent membrane protein 2 (LMP2) antigen-specific cytotoxic T lymphocytes (CTLs) have been proven to boost LMP2-specific CTL responses in patients with nasopharyngeal carcinoma (NPC). Such strategies can produce clinical benefits in some patients with NPC. Currently, the major challenge limiting the use of immunotherapy for NPC is its low clinical response rate. The efficacy of immunotherapy based on EBV-LMP2 specific CTLs depends mainly on their cytotoxic activity, but no studies have been conducted to elucidate this activity. In this study, laser confocal scanning microscopy (LCSM) and real-time cell analysis (RTCA) were used to evaluate the killing function and its underlying mechanism of LMP2-specific CTLs. LCSM showed that LMP2-specific CTLs recognize and kill target cells expressing viral escape protein LMP2, and that the killing rate is related to the number of CTLs adhering to the target cells. LMP2-specific CTL-mediated cytotoxicity is rate limited by the time required for effective contact and recognition between CTLs and target cells. RTCA showed that the protective effect of LMP2-specific CTLs required an appropriate effector-to-target ratio, and that LMP2-specific CTLs could not eradicate residual target cells at a low effector-to-target ratio. Moreover, our results revealed that LMP2-specific CTL responses involve two independent but complementary mechanisms: the perforin/granzyme and Fas/FasL pathways. Therefore, we have elucidated, for the first time, the selective cytotoxicity and mechanism by which LMP2-specific CTLs induced by the rAd-LMP2 vaccine kill target cells and have explored the killing mode and several key parameters of killing mediated by LMP2-specific CTLs. Our study will contribute to the knowledge of vaccines targeting EBV-LMP2 and to the improvement of immunotherapeutic strategies.


Adaptive finite time controller design for switched systems with unknown parameters, mismatched uncertain terms, external disturbances and input perturbations.
The main objective of this study concerns with the problem of control and stabilization design schemes for a class of nonlinear switching systems whose dynamics are excited with an undetermined switching logic. Several conditions are taken into account for the subsystems of the whole structure to mimic the natural properties of the real-world nonlinear physical systems. The first is to assume that there is no prior information about the values of the system parameters. The second is to add matched and mismatched uncertain terms to the system dynamics. Furthermore, the effects of the input fluctuations in the actuator model are reflected via gain variations. We assume that the dynamic of a part of the system is uncertain and fully unknown with no control inputs to be relaxed as mismatching uncertainties. And, it is supposed that there is no previous knowledge about the bounds of the lumped uncertainties. To cope the mentioned issues, a robust adaptive control methodology is proposed in this paper. One of the main attributes of the designed control approach is that it guarantees the fast convergence of the system responses to zero with a (practical) finite settling time. A Lyapunov function tactic is then constructed to confirm the theoretic findings of the study. It is also demonstrated that the same controller is applicable for the switched systems perturbed by unknown input saturation nonlinearities. As a result, the chief contributions of this article involve: (1) handling the effects of the system unknown dynamics, external perturbations, unmatched uncertainties, control input variations, unknown parameters and input saturation limiter with no prior information about them and (2) providing a simple effective adaptive algorithm which ensures the fast finite time stability of the entire system under any arbitrary switch schemes. The provided computer simulations highlight the effective performance of the introduced adaptive control technology.


In vitro chemosensitivity of brain tumors to cisplatin and its analogues, iproplatin and carboplatin.
The human tumor stem-cell assay was used to investigate the in vitro chemosensitivity of 27 evaluable samples to cisplatin and its analogues, iproplatin and carboplatin, as well as to BCNU, teniposide, vindesine, and dibromodulcitol. All agents exhibited some antitumor activity with the exception of dibromodulcitol (zero response out of 19 evaluable samples). Vindesine, BCNU, and carboplatin were the three most active compounds, with response rates of 29%, 23%, and 22%, respectively. There was a lack of complete cross-resistance between carboplatin and cisplatin as well as between carboplatin and BCNU. Our data suggest that clinical studies with carboplatin and combinations of vindesine plus cisplatin and its analogues may be worthwhile.


Long-term postoperative survival of a gastric cancer patient with numerous para-aortic lymph node metastases.
A56-year-old man with advanced gastric cancer was referred to our hospital. Preoperative abdominal computed tomography revealed numerous enlarged lymph nodes, including the lymph nodes of the paraaortic region. The patient underwent total gastralectomy, splenectomy, left-adrenalectomy and resection of the body and tail of the pancreas by Appleby's method, along with paraaortic lymph node dissection. Microscopic examination revealed that the tumor was a solid type, poorly differentiated adenocarcinoma, which displayed invasion of the serosal surface. There were apparently many lymph node metastases. We identified 31 cancer-positive paraaortic nodes, while the total number of lymph node metastases was 81. It was not possible to administer sufficient postoperative adjuvant chemotherapy, as the patient experienced postoperative complications, including pancreatic fistula and watery diarrhea. Despite the lack of sufficient chemotherapy, the patient has subsequently remained disease-free for 9 years and 3 months, and continues to visit our hospital as an outpatient. In conclusion, we wish to emphasize the need for a critical application of paraaortic lymph node dissection as one modality of multidisciplinary treatment in patients with advanced gastric cancer in whom paraaortic lymph node metastasis is strongly suspected preoperatively.


The role of the lectin pathway of the complement system in SARS-CoV-2 lung injury.
Although some evidence showed the activation of complement systems in COVID-19 patients, proinflammatory status and lectin pathway remain unclear. Thus, the present study aimed to demonstrate the role of MBL and ficolin-3 in the complement system activation and compared to pandemic Influenza A virus H1N1 subtype infection (H1N1pdm09) and control patients. A total of 27 lungs formalin-fixed paraffin-embedded samples (10 from H1N1 group, 6 from the COVID-19 group, and 11 from the control group) were analyzed by immunohistochemistry using anti-IL-6, TNF-alfa, CD163, MBL e FCN3 antibodies. Genotyping of target polymorphisms in the MBL2 gene was performed by real-time PCR. Proinflammatory cytokines such as IL-6 and TNF-alpha presented higher tissue expression in the COVID-19 group compared to H1N1 and control groups. The same results were observed for ICAM-1 tissue expression. Increased expression of the FCN3 was observed in the COVID-19 group and H1N1 group compared to the control group. The MBL tissue expression was higher in the COVID-19 group compared to H1N1 and control groups. The genotypes AA for rs180040 (G/A), GG for rs1800451 (G/A) and CC for rs5030737 (T/C) showed a higher prevalence in the COVID-19 group. The intense activation of the lectin pathway, with particular emphasis on the MBL pathway, together with endothelial dysfunction and a massive proinflammatory cytokines production, possibly lead to a worse outcome in patients infected with SARS-Cov-2. Moreover, 3 SNPs of our study presented genotypes that might be correlated with high MBL tissue expression in the COVID-19 pulmonary samples.


Opioid abuse surveillance in patients with endocarditis.
Opioid abuse is a significant cause of morbidity and mortality in the United States, and injection drug use (IDU) is a common form of opioid abuse. IDU is a major risk factor for infections including infective endocarditis (IE). To determine the prevalence of opioid abuse among patients with IE in both patient problem lists and diagnostic codes and describe underlying patient characteristics. A retrospective chart review from 1-1-2010 to 11-19-2018 of a large academic medical center's patients with documented IE was performed. Demographic, comorbidity, opioid prescription data and records of drug abuse in both the patient's problem list and ICD9/10 codes were recorded. Of the 796 patients with documented IE, 105 patients (13.2%) had opioid abuse or related IDU in their problem list, but only 22 received an ICD-9/10 code associated with drug abuse. IE patients with opioid abuse were generally younger (43.6 vs 61.7 years [P < 0.001]), had fewer chronic comorbidities, and were prescribed opioids more often (86.7% vs 53.8% [P < 0.001]). Opioid abuse and IDU are commonly recorded in the problem list of patients with IE, but opioid abuse is frequently not listed as a diagnosis in administrative billing codes.


Differential interactions of beta particles with liquid enantiomers and internal timing of chiral molecules.
The Cerenkov and liquid scintillation technique was applied to detect differential interactions between beta particles and chiral molecules. The highly helical beta emitting 32P and the barely helical beta emitting 3H were dissolved in the liquid enantiomers of 2-phenylbutyric acid. The interactions of the beta particles with the enantiomers were compared. Differential interactions were observed in case of 32P. The stopping power of R enantiomers was greater than that of the S enantiomer. The apparent decay of 32P was faster in the S enantiomer than in the R enantiomer. It is not clear whether this is due to some mistake in measurement or reflects the postulated difference of internal timing of the two enantiomers. Since, in spite of all efforts, contamination could not totally be excluded and data are significant only to one sigma, results must be considered preliminary. The method, however, seems to be more sensitive than all previously used methods. The differential effect was always in the same direction in at least 5 replicas.


From crystal to amorphous: A novel route to unjamming in soft disk packings.
Numerical studies on the unjamming packing fraction of bi- and polydisperse disk packings, which are generated through compression of a monodisperse crystal, are presented. In bidisperse systems, a fraction f(+) = 0.400 up to 0.800 of the total number of particles has their radii increased by [Formula: see text] R , while the rest has their radii decreased by the same amount. Polydisperse packings are prepared by changing all particle radii according to a uniform distribution in the range [-ΔR, ΔR] . The results indicate that the critical packing fraction is never larger than the value for the initial monodisperse crystal, Φ(o) = π/√12, and that the lowest value achieved is approximately the one for random close packing. These results are seen as a consequence of the interplay between the increase in small-small particle contacts and the local crystalline order provided by the large-large particle contacts.


Chinese cross-cultural adaptation and validation of the Oxford shoulder score.
The Oxford Shoulder Score (OSS) is a reliable and valid construct measuring non-specific shoulder pain, which are widely used to evaluate shoulder related quality of life. This study was to cross-culturally adapt and psychometrically validate a simplified Chinese version of the OSS (SC-OSS). Cross-cultural adaptation was performed according to the international recognized guidelines. Consecutive patients with nonspecific shoulder pain were recruited to test the psychometric properties of SC-OSS. Item response trend and item-total correlation were evaluated to measure homogeneity. Principal component analysis (PCA) was used to evaluate the factorial structure. Cronbach's α and intra-class correlations were used to determine the reliability. Construct validity was analyzed by evaluating the correlations between SC-OSS and the Constant-Murley shoulder outcome score (CMSOS), the short form (36) health survey (SF-36) containing eight domains, and pain visual analogue scale (VAS). Overall, 121 patients were recruited. Each of the 12 items was properly responded and correlated with the total items. PCA extracted one factor for SC-OSS. SC-OSS had excellent reliability, with a Cronbach's α of 0.92 and intra-class correlation coefficient of 0.97 (95 % CI: 0.94-0.98). SC-OSS had a high correlation with CMSOS, physical functioning (PF) and bodily pain (BP) domains of SF-36 and VAS (r = -0.70, -0.65, -0.53, and -0.66, respectively). SC-OSS moderately correlated with role-physical (RP), social functioning (SF), general health perception (GH) and vitality (VT) (r = -0.45, -0.42, -0.39 and -0.36, respectively), but had a low correlation with role-emotional (RE) and mental health (MH) domains of SF-36 (r = -0.28 and -0.23, respectively). SC-OSS demonstrated excellent acceptability, internal consistency, reliability and construct validity, which can be recommended for application in mainland China.


Vitexin attenuates autoimmune hepatitis in mouse induced by syngeneic liver cytosolic proteins via activation of AMPK/AKT/GSK-3β/Nrf2 pathway.
Autoimmune hepatitis (AIH) is a chronic progressive liver disease that currently does not have a successful therapeutic option. Vitexin, a bioflavonoid isolated from various medicinal plants, possesses a variety of activities; however, whether vitexin protects against AIH remains unclear. Therefore, the current study aims to investigate the hepatoprotective effects and mechanism of action of vitexin in both an experimental autoimmune hepatitis (EAH) mouse model and in D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced hepatocyte injury. Syngeneic liver antigen S100 was used to establish EAH. Vitexin treatment significantly decreased the infiltration of inflammatory and CD4+ T cells in the liver, reduced ALT and AST levels in the serum and attenuated hepatic injury due to oxidative stress. Moreover, vitexin mitigated the upregulation of Bax and cleaved caspase-3 and the downregulation of Bcl-2 in the livers of AIH mice. These regulations were accompanied by not only increased phosphorylation of AMPK, AKT and GSK-3β but also activation of Nrf2. Furthermore, vitexin inhibited apoptosis and the overexpression of inflammatory cytokines in D-GalN/LPS-treated AML12 cells. In addition, vitexin enhanced the phosphorylation of AMPK, AKT and GSK-3β. When AML12 cells were treated with an inhibitor of AMPK/AKT or specific siRNA targeting Nrf2, vitexin did not further induce the activation of Nrf2/HO-1. A molecular docking study confirmed that vitexin could interact with AMPK through hydrogen bonding interactions. In conclusion, vitexin ameliorated hepatic injury in EAH mice through activation of the AMPK/AKT/GSK-3β pathway and upregulation of the Nrf2 gene.


Induction of anomalous killing activity from antigen-specific CTL clones by adding high doses of human recombinant interleukin 2.
Four out of six long-term murine cytotoxic T lymphocyte (CTL) clones specific for trinitrophenyl (TNP)-modified spleen cells could develop an anomalous cytotoxicity against syngeneic and allogeneic tumor cells upon stimulation with TNP-modified spleen cells and high doses of human recombinant interleukin 2 (rIL-2). On FACS analysis, hyperactivated CTLs were positive for Thy-1, Ly 2 and LFA-1, but negative for L3T4 and asialo GM1. The staining profile of the cells with each antibody indicated that the CTL clones consisted of just one cell type. Monoclonal anti-Ly 2.2 and anti-LAA (lymphokine-activated cell-associated antigen) antibodies inhibited cytolysis of CTL and hyperactivated CTL clones against TNP-modified spleen cells, but failed to inhibit the anomalous killing of the hyperactivated CTL. The cold target competition test suggested the degeneracy of antigen specificity. The present study demonstrated that the CTL clone acquired a new specificity for tumor target cells upon stimulation with a high dose of rIL-2.


Effects of fibrinogen degradation fragments D and E on cell-mediated immunity.
Serum taken from severely traumatized victims suppresses in vitro the response of normal lymphocytes to the mitogenic stimulant phytohemagglutinin (PHA). In the postburn period, fibrin degradation products (fragments D and E) are elevated in a high percentage. Controversy exists as to whether these fragments contribute to what is clinically evident as cell-mediated immune (CMI) suppression. Purified fragments D and E were isolated over an ion exchange cellulose column after activating, with streptokinase, a solution containing fibrinogen and plasminogen. Lymphocytes from six volunteers were cultured with PHA and serial dilutions of fragments D and E; each was analyzed for ability to incorporate radiolabeled thymidine. Fragment E possessed in vitro CMI suppression at pharmacologic doses. Fragment D demonstrated immune suppressive capabilities at doses approximating those estimated to occur in the acute postburn phases of injury.


Suppressive effect of ipriflavone on bone depletion in the experimental diabetic rat: dose response of ipriflavone.
The dose dependent effect of ipriflavone (7-isopropoxy-isoflavone) on the femoral bone in streptozotocin-induced diabetic rats was studied by microdensitometric analysis. Diabetic rats showed severe hyperglycemia, glucosuria, hypoinsulinemia, associated with increased urinary calcium and hydroxyproline. Microdensitometric analysis revealed decreases in femoral length, bone width, and bone density. The dietary administration of ipriflavone (about 270 mg/kg/day) to the diabetic rats for 6 weeks prevented reduction of the cortical thickness index in the diaphysis and depletion of bone density in the distal metaphysis, and also reduced the inner diameter of the diaphysis; diabetic state was not improved. A simple correlation and linear regression analysis revealed that ipriflavone also significantly reduced the inner diameter in the diaphysis at a dose of 90 mg/kg/day, but not at one of 25 mg/kg/day. These results suggest that ipriflavone suppresses the depletion of the femoral bone through inhibition of bone resorption in a dose dependent fashion; its minimum effective dose is 90 mg/kg/day in experimental diabetes.


Surgical results in 657 patients with colorectal cancer.
Six hundred fifty-seven patients with colorectal cancer who were operated upon at the Second Department of Surgery, Helsinki University Central Hospital during the period 1966 to 1975 had a 40.5 per cent crude five-year survival rate and 54.2 per cent relative (corrected) rate. The survival rates of patients with Dukes' A lesions were 80.7 per cent, Dukes' B, 61.6 per cent, Dukes' C, 40.4 per cent, and Dukes' D, 2.7 per cent. One hundred two patients (15.5 per cent) underwent emergency operations; 91 were occlusive cancers, eight were perforations and three were cancer bleedings. The operative mortality for the whole series was 6.5 per cent (4.7 per cent in elective and 16.7 per cent in emergency operations). A definite improvement of the five-year survival rates could be seen in both the colonic and rectal cancer series. This was due to earlier detection of the disease, reflecting a decreasing number of palliative operations. Patients at high risk for colorectal cancer (inflammatory bowel disease, inherited intestinal polyposis, cancer family syndrome, multiple colorectal cancers, and neoplastic polyps) might benefit from more effective cancer surveillance and prophylactic surgery to find and treat cancers in earlier stages, to prevent recurrences, and to facilitate follow-up. The controversial findings on postoperative adjuvant therapy presented in this study indicate the need for further controlled studies to define the patients who really benefit from it.


Simple method to isolate the intact duct system of the rat submandibular gland.
The excurrent duct system of the rat submandibular gland consists of a number of distinct segments. Using the direction of salivary flow as a reference point, these segments are, in order, intercalated duct, granular convoluted tubule, striated duct, excretory duct, main excretory duct (MED), and salivary bladder (which is an expanded portion of the MED). Because these ducts (with the exception of the MED and the salivary bladder) are encased in secretory endpieces, they are difficult to locate and to observe by scanning electron microscopy. A simple method has been devised to rid the gland of these obscuring endpieces so that the detailed architecture of the duct system can be examined. Rat submandibular glands were fixed initially by vascular perfusion with half-strength Karnovsky's fixative. The connective tissue capsule was removed from extirpated glands and the glands remained in fixative for varying lengths of time. For our purposes, a 30-minute immersion in the aldehyde mixture was optimum. After the sublingual gland was removed, the submandibular gland was softly struck with forceps having rounded tips, then shaken in fixative or buffer. The tissue that remained was postfixed in osmium tetroxide. This method results in the complete divestment of nonductular parenchyma from the rat submandibular gland, leaving the duct system clean and ready for microscopic examination.


Salvage intensive care following initial recovery from pulmonary resection: is it justified?
There is little objective evidence concerning the outcome of thoracic surgical patients who suffer postoperative complications. We assessed the outcome and cost of care for patients admitted to the intensive care unit after initial recovery from pulmonary resection in a high dependency unit. In a single surgeon's practice, over a 3-year period, 28 patients [22 male, median age 66 years old (range 48-80 years old)] required intensive care admission. Preoperative pulmonary function, reason for initial operation, cause of intensive care admission, interventions, and outcome in hospital and at 6 months was studied. The cost of care provided was estimated. The major reason for intensive care admission was respiratory failure; 61% of patients required mechanical ventilation and 54% renal support. All 4 patients who required both mechanical ventilation and hemofiltration died. Intensive care and 6-month survival were 54% and 36%, respectively. On univarate analysis mechanical ventilation and renal support predicted both hospital mortality (p < 0.001 and p = 0.003) and 6-month mortality (p = 0.003 and p = 0.01). Patients who died in intensive care stayed longer (median stay 9 vs 3 days; p = 0.04) at a higher cost per patient (median cost $6975 vs $19,375; p = 0.04) than those who survived. Patients who suffer complications after lung resection and require salvage intensive care, particularly mechanical ventilation, have a poor prognosis. In the light of this data the onset of two-organ failure should prompt an informed discussion as to whether escalation of treatment is in the patient's best interest.


Association of Hospital Payment Profiles With Variation in 30-Day Medicare Cost for Inpatients With Heart Failure or Pneumonia.
Some uncertainty exists about whether hospital variations in cost are largely associated with differences in case mix. To establish whether the same patients admitted with the same diagnosis (heart failure or pneumonia) at 2 different hospitals incur different costs associated with the hospital's Medicare payment profile. This observational cohort study used Centers for Medicare & Medicaid Services (CMS) discharge data of patients with a principal diagnosis of heart failure (n = 1615) or pneumonia (n = 708) occurring between July 1, 2013, and June 30, 2016. Patients were individuals aged 65 years or older who were enrolled in Medicare fee-for-service Part A and Part B and were discharged from nonfederal, short-term, acute care or critical access hospitals in the United States. Data were analyzed from March 16, 2018, to September 25, 2019. The CMS heart failure and pneumonia payment measure cohorts were divided into 2 random samples. In the first sample, hospitals were classified into payment quartiles for heart failure and pneumonia. In the second sample, patients with 2 admissions for heart failure or pneumonia, one in a lowest-quartile hospital and one in a highest-quartile hospital more than 1 month apart, were identified. Standardized Medicare payments for these patients were compared for the lowest- and the highest-quartile payment hospitals. The study sample included 1615 patients with heart failure (mean [SD] age, 78.7 [8.0] years; 819 [50.7%] male) and 708 with pneumonia (mean [SD] age, 78.3 [8.0] years; 401 [56.6%] male). The observed 30-day mortality rates for patients among lowest- compared with highest-payment hospitals were not significantly different. The median (interquartile range) hospital 30-day risk-standardized mortality rates were 8.1% (7.7%-8.5%) for heart failure and 11.3% (10.7%-12.1%) for pneumonia. The 30-day episode payment for hospitalization for the same patients at the lowest-payment hospitals was $2118 (95% CI, $1168-$3068; P < .001) lower for heart failure and $2907 (95% CI, $1760-$4054; P < .001) lower for pneumonia than at the highest-payment hospitals. More than half of the difference was associated with the payment during the index hospitalization ($1425 [95% CI, $695-$2154; P < .001] for heart failure and $1659 [95% CI, $731-$2588; P < .001] for pneumonia). This study found that the same Medicare beneficiaries who were admitted with the same diagnosis to hospitals with the highest payment profiles incurred higher costs than when they were admitted to hospitals with the lowest payment profiles. The findings suggest that variations in payments to hospitals are, at least in part, associated with the hospitals independently of non-time-varying patient characteristics.


SQLE promotes pancreatic cancer growth by attenuating ER stress and activating lipid rafts-regulated Src/PI3K/Akt signaling pathway.
Pancreatic cancer (PC), a highly lethal malignancy, commonly exhibits metabolic reprogramming that results in therapeutic vulnerabilities. Nevertheless, the mechanisms underlying the impacts of aberrant cholesterol metabolism on PC development and progression remain elusive. In this study, we found that squalene epoxidase (SQLE) is a crucial mediator of cholesterol metabolism in PC growth. We observed a profound upregulation of SQLE in PC tissues, and its high expression was correlated with poor patient outcomes. Our functional experiments demonstrated that SQLE facilitated cell proliferation, induced cell cycle progression, and inhibited apoptosis in vitro, while promoting tumor growth in vivo. Mechanistically, SQLE was found to have a dual role. First, its inhibition led to squalene accumulation-induced endoplasmic reticulum (ER) stress and subsequent apoptosis. Second, it enhanced de novo cholesterol biosynthesis and maintained lipid raft stability, thereby activating the Src/PI3K/Akt signaling pathway. Significantly, employing SQLE inhibitors effectively suppressed PC cell proliferation and xenograft tumor growth. In summary, this study reveals SQLE as a novel oncogene that promotes PC growth by mitigating ER stress and activating lipid raft-regulated Src/PI3K/Akt signaling pathway, highlighting the potential of SQLE as a therapeutic target for PC.


Interferon gamma and interleukin 2 synergize to induce selective monokine expression in murine peritoneal macrophages.
We have examined the effects of interleukin 2 (IL-2) treatment either alone or in combination with interferon (IFN) gamma or beta on the expression of several activation associated genes (e.g. tumor necrosis factor alpha (TNF alpha), IFN-inducible 10-kDa protein (IP-10] in murine peritoneal macrophages. IL-2 alone did not induce the expression of either gene while IFN gamma or IFN beta had a modest inductive effect on IP-10 but no effect on TNF alpha expression. When either form of IFN was used in combination with IL-2 there was a marked synergistic induction of both mRNAs. IFN gamma and IL-2 were maximally effective when both agents were added simultaneously, and induced mRNA expression declined over a 24-h period in cells pretreated with IFN gamma prior to addition of IL-2. Expression of both genes following combination lymphokine treatment was mediated by increased transcriptional activity. The responses to all three lymphokines were dose dependent; the concentration requirement for IL-2 indicated interaction with an intermediate or low affinity receptor. The expression of both monokine genes was transient and was comparable although not identical to that seen in cells stimulated with lipopolysaccharide. IFN gamma and IL-2 could synergize to stimulate the expression of either TNF alpha or IP-10 mRNA using sequential non-overlapping treatment periods regardless of the order in which the two stimuli were applied to the cells. The effect of either agent alone induced a transient (1-5 h) responsive state with respect to subsequent stimulation with the second agent. Expression of both monokine genes in response to IFN gamma/IL-2 treatment was independent of protein synthesis as cycloheximide did not inhibit the accumulation of specific mRNA. Interestingly, the combination of IL-2 and cycloheximide was as effective as IFN gamma and IL-2 together. In concert, these results indicate that both IFN and IL-2 generate independent intracellular signals which alone are incapable of inductive effect but which are potent activators of inflammatory gene expression when coincidentally expressed.


Transcervical amnioinfusion of antibiotics: a basic study for managing premature rupture of membranes.
To determine the best method of preventing ascending infection in the management of premature rupture of membranes, antibiotics such as latamoxef sodium, cefoperazone sodium, and cefotaxime sodium were infused directly into the amniotic cavity in 64 patients undergoing induction of labor at term. A single infusion of 100 or 500 mg of each drug resulted in a concentration of 200 to 1000 micrograms/ml immediately after infusion, and the concentration remained above 10 micrograms/ml for about 24 hours without significant increase in fetal or maternal blood levels. Consequently, a daily single dose of 100 mg or more is probably effective prophylaxis in cases of premature rupture of membranes. When intrauterine infection is suspected, the dose can be increased to 500 mg or more, and transplacental administration may be added to achieve a higher concentration in fetal blood. The present study simulates well premature rupture of membranes, and an amnioinfusion of antibiotics will be reliable and effective in managing premature rupture of membranes.


Two genes for chloramphenicol resistance common to staphylococci and streptococci.
Southern blot hybridization and pneumococcal transformation were used to study the epidemiology at a molecular level of the genes for chloramphenicol resistance (cat) in streptococci and staphylococci. The cat gene of staphylococcal plasmid pC194 showed homology to the cat genes of the chromosomal elements of 5 different strains of Streptococcus pneumoniae and of Streptococcus agalactiae B109. DNA sequence homology was also detected between the cat gene of staphylococcal plasmid pC221 and the cat gene of broad host range conjugative plasmid pIP501, originally isolated from S. agalactiae. Two different cat genes appear to be present in clinical isolates of both streptococci and staphylococci.


[The therapy allergens ordinance ("Therapieallergene-Verordnung"). Background and effects].
Medicinal products for specific immunotherapy as causal treatment of allergies exist in Germany as authorized medicinal products manufactured batchwise in advance and as named patient products (NPPs) which are exempted from the authorization procedure. With the therapy allergens ordinance ("Therapieallergene-Verordnung (TAV)") which has been in effect since 14 November 2008, this exemption was restricted to therapy allergens indicated for the treatment of rare allergies. NPPs containing at least one of the therapy allergens listed in the annex of the TAV had to be notified to the Paul-Ehrlich-Institut (PEI) by 14 May 2009 to retain their marketability. It had to be stated whether applications for marketing authorization will be submitted for the respective NPPs or if they will be sold off by 14 November 2011. The bulks which are used for manufacturing of the NPPs have been subject to official batch release by PEI since October 2009. Nearly 7,000 NPPs of 10 pharmaceutical entrepreneurs were notified. Marketing authorization applications were submitted for 123 NPPs. This illustrates that, although there are authorized therapy allergens available for all allergens listed in the annex of the TAV, a large number of NPPs with unknown quality, safety, and efficacy have been marketed.


Neural mechanisms of visual sensitive periods in humans.
Sensitive periods in brain development are phases of enhanced susceptibility to experience. Here we discuss research from human and non-human neuroscience studies which have demonstrated a) differences in the way infants vs. adults learn; b) how the brain adapts to atypical conditions, in particular a congenital vs. a late onset blindness (sensitive periods for atypical brain development); and c) the extent to which neural systems are capable of acquiring a typical brain organization after sight restoration following a congenital vs. late phase of pattern vision deprivation (sensitive periods for typical brain development). By integrating these three lines of research, we propose neural mechanisms characteristic of sensitive periods vs. adult neuroplasticity and learning.


[Experimental study of facial nerve regeneration through polytetraflouroethylene tube with Schwann cells self-planted].
To observe the effect of using polytetraflouroethylene (e-PTFE) tube with self-Schwann cells implanted to repair facial nerve defect. Enzymatic digest method was used to get pure Schwann cells in short time. The e-PTFE membrane tube was used to bridge the 1.0 cm defect of facial nerve and pure self-Schwann cells were injected into the tube. As control group, the e-PTFE tube without self-Schwann cells was used in the same way. Electric physiological and histological examinations were taken in different times. The effect of nerve regeneration of the experimental group was better than control group at any time. The nerve conduction velocity of the experimental group was 29.70 m/s in the 16th week, while the control groups was 23.00 m/s respectively at the same time. It is possible to obtain sufficient active Schwann cells by enzymatic digest method. Using e-PTFE tube to bridge the defect of facial nerve with self-Schwann cells implanted can get effect of nerve regeneration.


Frequency and significance of vocalizations in Sydenham's chorea.
Sydenham's chorea (SC) is a complication of Streptococcus infection characterized by a combination of motor and non-motor features. We have investigated the presence of vocalizations in 89 consecutive patients with SC evaluated during a one-year period in the UFMG Movement Disorders Clinic. Seven (4/3 M/F) of the 89 patients (29/60 M/F) presented with simple vocalizations not preceded by premonitory sensations but in association with facial chorea in five patients. These findings suggest that vocalizations are not a common feature in SC and their phenomenology is quite distinct from the characteristics of vocal tics in tic disorders.


Fast vaporization solid phase microextraction and ion mobility spectrometry: A new approach for determination of creatinine in biological fluids.
In this work a rapid and simple method for creatinine determination in urine and plasma samples based on aqueous derivatization of creatinine and complete vaporization of sample (as low as 10 µL), followed by ion mobility spectrometry analysis has been proposed. The effect of four important parameters (extraction temperature, total volume of solution, desorption temperature and extraction time) on ion mobility signal has been studied. Under the optimized conditions, the quantitative response of ion mobility spectrometry for creatinine was linear in the range of 0-500 mg L(-1) with a detection limit of 0.6 mg L(-1) in urine and 0-250 mg L(-1) with a detection limit of 2.6 mg L(-1) in plasma sample. The limit of quantitation of creatinine was 2.1 mg L(-1) and 8.7 mg L(-1) in urine and plasma samples, respectively. The relative standard deviation of the method was found to be 13%. The method was successfully applied to the analysis of creatinine in biological samples, showing recoveries from 92% to 104% in urine and 101-110% in plasma samples.


Topography and organization of cranial nerve nuclei in the sand lizard, Lacerta agilis.
Cobaltic-lysine complex compound was used to label cranial nerves of the ventrolateral (branchiomotor) and dorsomedial (somatomotor) nuclear columns in the sand lizard, Lacerta agilis. The dendritic arborizations and axonal trajectories of neurons of the respective nuclei were reconstructed from serial sections. A fairly uniform neuronal morphology was found in the nuclei of the ventrolateral column: a spindle-shaped perikaryon gave rise to dorsomedial and ventrolateral dendritic trees, the latter arborizing in a characteristic broomlike manner within a narrow region in the lateral white matter. Axons of all neurons converged upon the medial longitudinal fasciculus and after making a hairpin turn formed the corresponding motor roots. A group of small neurons constituted a separate subnucleus within the V motor nucleus. The VII and IX nuclei were fused into a single nuclear complex. The nucleus ambiguus was found dorsal to the XII nucleus and lateral to the dorsal vagal nucleus. The latter nucleus extended rostrally to the caudal pole of the VI nucleus, and its neurons sent axons to the VII, IX, and X nerves. The term "dorsal visceromotor column" designates the extended dorsal vagal nucleus. A number of small polygonal neurons lying scattered in the lateral part of the medulla were labeled via the VII, IX, and X nerves. This loose aggregate of labeled neurons was termed the "lateral visceromotor area." On the basis of nuclear topography and cellular morphology, the existence of a bulbar XI nucleus was excluded. Three different types of neurons could be distinguished in the dorsomedial nuclear column. Neurons with oval or spherical perikarya and radially oriented dendrites constituted the nuclei innervating external eye muscles. Except for the IV nucleus, axons followed a ventral trajectory. The accessory VI nucleus was composed of a second type of neuron with elongated soma and dorsoventral dendrite orientation; the dorsally directed axon turned ventrally at the VI nucleus. The XII nucleus contains a third type of neuron with strongly decussating dendrites. The distinct differences in the neuronal morphology did not support the classical assumption that all of the nuclei of the dorsomedial motor column supply muscles derived from somitic mesoderm. Sensory fibers of the trigeminal nerve formed the familiar spinal tract, which partially decussated in the medullospinal transition zone and could be followed as far as the lumbar segments on the ipsilateral side of the spinal cord. Neurons of the mesencephalic root of the trigeminal nerve were localized in the optic tectum; their descending fibers joined the medial aspect of the spinal tract.(ABSTRACT TRUNCATED AT 400 WORDS)


Subungual hematoma: association with occult laceration requiring repair.
Subungual hematomas are one of the most common injuries involving the hand. On conducting a literature search, we were unable to find any studies that investigated the association between subungual hematomas, fractures, and the presence of an occult laceration of the nail bed requiring repair. Forty-seven consecutive patients who presented to the emergency department with subungual hematoma involving more than one fourth of the nail bed were included in this study. In these cases, radiographs were taken, and the nail was lifted to look for a laceration. In the subgroup of patients who had subungual hematoma associated with a fracture, all of them had a laceration requiring repair. Patients with a subungual hematoma greater than one half of the size of the nail bed had a 60% incidence of a laceration requiring repair. The authors believe that patients presenting with a subungual hematoma involving greater than one half of the nail surface and a fracture of the distal phalanx should have the nail lifted and the nail bed explored and repaired.


Folding strategy to prepare Co(II)-substituted metallo-beta-lactamase L1.
In an effort to overcome previous problems with the preparation of Co(II)-substituted metallo-beta-lactamase L1, two strategies were undertaken. Attempts to prepare Co(II)-substituted L1 using biological incorporation resulted in an enzyme that contained only 1 Eq of cobalt and exhibited no catalytic activity. Co(II)-substituted L1 could be prepared by refolding metal-free L1 in the presence of Co(II), and the resulting enzyme contained 1.8 Eq of cobalt, yielded a UV-Vis spectrum consistent with 5-coordinate Co(II), and exhibited a k(cat) of 63 s(-1) and K(m) of 20 microM when using nitrocefin as the substrate. Pre-steady-state fluorescence and UV-Vis studies demonstrated that refolded, Co(II)-substituted L1 uses the same kinetic mechanism as Zn(II)-containing L1, in which a reaction intermediate is formed when using nitrocefin as substrate. The described refolding strategy can be used to prepare other Co(II)-substituted Zn(II)-metalloenzymes, particularly those that contain a solvent-exposable disulfide, which often causes oxidation of Co(II) to Co(III).


The Role of Systemic Steroids in Sciatica Due to Herniated Lumbar Disc: A Systematic Review and Meta-analysis.
Systematic review and meta-analysis. Evaluate the role of systemic steroids in treating patients with sciatica due to lumbar disk herniation (LDH). The association between LDH and sciatica has been well described. The use of steroids seems logical in this context; however, their efficacy is not well described, and their use remains controversial. A comprehensive search on PubMed, EMBASE, and Scopus databases (up to February 15, 2022) was performed to identify randomized clinical trials that included patients with symptoms of sciatica due to LDH that were treated with systemic steroids. The risk of bias was judged using the Cochrane risk-of-Bias2 tool. Meta-analysis was conducted using a random-effects model to estimate the between-group effect size for pain and functional outcomes. The risk of developing adverse events (AE) was computed using relative risks. All pooled results are reported with their 95% confidence interval (CI) and certainty of evidence analyzed using the Grading of Recommendations Assessment, Development, and Evaluation framework. Ten studies met inclusion criteria, comprising a total of 1017 participants: 540 in the treatment group and 477 in the control group. Steroid treatment was associated with a significant superior reduction of pain (SMD = -0.42, 95% CI -0.76 to -0.08, weak effect, very-low certainty) and reduction in disability (SMD = -0.30, 95% CI -0.51 to -0.10, weak effect, very-low certainty). Corticosteroid administration was associated with a significant increased risk of developing an AE (relative risks = 2.00, 95% CI 1.40 to 2.85, low certainty). The use of systemic steroids in the treatment of sciatica due to LDH seems reasonable despite a 2-fold higher risk of developing mild AEs. However, the effect size is small for reducing pain in the short term and improving functional outcomes at long-term follow-up.


Combined effects of a high-fat diet and polyethylene microplastic exposure induce impaired lipid metabolism and locomotor behavior in larvae and adult zebrafish.
Microplastics (MP), tiny plastic particles, can be ingested by fish through their habitat or contaminated food sources. When combined with a high-fat diet (HFD), MP exposure may lead to increased MP accumulation in fish and negative impacts on their health. However, the underlying mechanisms of how MP and HFD interact to promote fat accumulation in fish remain poorly understood. In this study, we aimed to evaluate the combined effect of HFD and polyethylene MP (PE-MP) in the zebrafish model (Danio rerio) and decipher its molecular mechanisms. Adult zebrafish exposed to the combined HFD and PE-MP showed elevated lipid accumulation, total cholesterol, triglycerides, and abnormal swimming behavior compared to HFD-fed fish. Histological and gene expression analysis revealed severe hepatic inflammation and injury, resembling nonalcoholic fatty liver disease (NAFLD) in the HFD + PE-MP exposed zebrafish. Moreover, HFD and PE-MP exposure upregulated genes related to lipogenesis (SREBP1, FAS, and C/EBPα) and inflammation (tnfα, il1β, and il-6) in the liver. These findings underscore the interactive effect of environmental pollutants and fish diet, emphasizing the importance of improving fish culture practices to safeguard fish health and human consumers from microplastic contamination through the food chain. This research sheds light on the complex interactions between microplastics and diet, providing valuable insights into the potential risks of microplastic pollution in aquatic ecosystems and the implications for human health. Understanding the underlying molecular mechanisms will contribute to international research efforts to mitigate the adverse effects of microplastics on both environmental and public health.


The WELL diet score correlates with the alternative healthy eating index-2010.
The quality of one's overall diet has proven to be of great importance to health and well-being. Unfortunately, diet quality is time-consuming to assess. The Stanford Wellness Living Laboratory (WELL) administered an online survey that included the WELL Diet Score (a novel diet quality assessment calculated from 12 diet-related items). Subsequently, WELL participants were asked to complete the 127-item Block Food Frequency Questionnaire (FFQ) online. The present study's primary objective was to compare the WELL Diet Score with the established FFQ-based Alternative Healthy Eating Index-2010 (AHEI-2010), in a subset of WELL participants (n = 248) who completed both dietary measures through WELL's online platform. The two scores were significantly correlated (r = .69; p < .0001). Regression analyses demonstrated that the WELL Diet Score was positively significantly associated with sociodemographic determinants of diet quality and protective health factors, including older age, higher education, lower BMI, and higher physical activity. In summary, the WELL Diet Score, derived from 12 small diet-related items that can be completed in 5 min, was significantly positively correlated with the AHEI-2010 derived from the lengthy 127-item FFQ, suggesting the potential utility of the WELL Diet Score in future large-scale studies, including future WELL studies.


Plasmapheresis reduces cytokine and immune cell levels in COVID-19 patients with acute respiratory distress syndrome (ARDS).
In December 2019, pneumonia associated with a novel coronavirus (COVID-19) was reported in Wuhan, China. Acute respiratory distress syndrome (ARDS) is the most frequently observed complication in COVID-19 patients with high mortality rates. To observe the clinical effect of plasmapheresis on excessive inflammatory reaction and immune features in patients with severe COVID-19 at risk of ARDS. In this single-center study, we included 15 confirmed cases of COVID-19 at Masih Daneshvari Hospital, in March 2020 in Tehran, Iran. COVID-19 cases were confirmed by RT-PCR and CT imaging according to WHO guidelines. Plasmapheresis was performed to alleviate cytokine-induced ARDS. The improvement in oxygen delivery (PaO2/FiO2), total number of T cells, liver enzymes, acute reaction proteins, TNF-α and IL-6 levels were evaluated. Inflammatory cytokine levels (TNF-α, IL-6), and acute phase reaction proteins including ferritin and CRP were high before plasmapheresis. After plasmapheresis, the levels of PaO2/FiO2, acute phase reactants, inflammatory mediators, liver enzymes and bilirubin were significantly reduced within a week (p < 0.05). In contrast, although the number of T helper cells decreased immediately after plasmapheresis, they rose to above baseline levels after 1 week. Nine out of fifteen patients on non-invasive positive-pressure ventilation (NIPPV) survived whilst the six patients undergoing invasive mechanical ventilation (IMV) died. Our data suggests that plasmapheresis improves systemic cytokine and immune responses in patients with severe COVID-19 who do not undergo IMV. Further controlled studies are required to explore the efficacy of plasmapheresis treatment in patients with COVID-19.


Comparative analysis of secreted proteins from normal and preeclamptic trophoblastic cells using proteomic approaches.
Preeclampsia (PE) is a pathology of pregnancy which represents the main cause of maternal and perinatal morbidity and mortality. Defective placentation is the first event of this pathology. The purpose of this study was to identify the proteins secreted by cytotrophoblastic cells (CTB) using proteomic approach that are associated with PE. Comparison of secreted proteins by mass spectrometry allowed us to identify 21 proteins which were significantly differentially secreted by control and PE CTB. One protein has been detected exclusively in supernatant of control CTB and was identified as factor XIII chain A. To determine if this observation is due to a difference of protein secretion or gene expression, its mRNA was quantified in all CTB. We found that it was significantly decreased in PE CTB compared to control. Collectively, these data suggest that decrease of factor XIII chain A might be associated with development of PE.


The prostatic utricle: An under-recognized condition resulting in significant morbidity in boys with both hypospadias and normal external genitalia.
Pediatric presentations of a prostatic utricle have received only scant attention. Though recognized with increased frequency in boys with hypospadias, little is described about their incidence and potential for morbidity in boys with normal external genitalia. We initially reviewed a cohort of 64 patients with hypospadias seen over a 3-year period to determine the frequency of investigative lower urinary tract studies and utricle identification. Children with disorders of sexual differentiation were excluded from this review. A subsequent group of 70 boys with hypospadias and 23 boys with normal external genitalia presenting with lower urinary tract symptoms (LUTS) who were found to have an unsuspected utricle were reviewed. This comparative group was investigated since symptomatology was the indication for evaluation, contrasting with those in the hypospadias group who were investigated because of hypospadias presence alone. In our initial review of 64 patients only 24 (37.5%) underwent an investigative study and six (9.4%) had a utricle. Three (50%) required surgical excision, allowing their hypospadias repair to proceed. Results in the subsequent group with hypospadias confirmed these findings with increased rates of investigation and identification. The boys with normal external male genitalia all required surgery since symptoms were the result of the utricle alone. Penile pain with voiding, hematuria, epididymitis, and urinary infection were the most common causes for interventions. The prostatic utricle should be considered as a cause of morbidity in boys with both normal external genitalia and those with hypospadias. Endoscopic or radiological evaluation (see Figure) should be undertaken in all boys with proximal hypospadias, boys with hypospadias and associated cryptorchidism, and those with hypospadias with associated urinary symptoms. Boys with normal external genitalia with lower urinary tract symptoms not explained with imaging should undergo cystoscopy, as an unidentified unsuspected utricle may be the underlying cause.


Enhanced Masses on Contrast-Enhanced Breast: Differentiation Using a Combination of Dynamic Contrast-Enhanced MRI and Quantitative Evaluation with Synthetic MRI.
The addition of synthetic MRI might improve the diagnostic performance of dynamic contrast-enhanced MRI (DCE-MRI) in patients with breast cancer. To evaluate the diagnostic value of a combination of DCE-MRI and quantitative evaluation using synthetic MRI for differentiation between benign and malignant breast masses. Retrospective, observational. In all, 121 patients with 131 breast masses who underwent DCE-MRI with additional synthetic MRI were enrolled. 3.0 Tesla, T1 -weighted DCE-MRI and synthetic MRI acquired by a multiple-dynamic, multiple-echo sequence. All lesions were differentiated as benign or malignant using the following three diagnostic methods: DCE-MRI type based on the Breast Imaging-Reporting and Data System; synthetic MRI type using quantitative evaluation values calculated by synthetic MRI; and a combination of the DCE-MRI + Synthetic MRI types. The diagnostic performance of the three methods were compared. Univariate (Mann-Whitney U-test) and multivariate (binomial logistic regression) analyses were performed, followed by receiver-operating characteristic curve (AUC) analysis. Univariate and multivariate analyses showed that the mean T1 relaxation time in a breast mass obtained by synthetic MRI prior to injection of contrast agent (pre-T1 ) was the only significant quantitative value acquired by synthetic MRI that could independently differentiate between malignant and benign breast masses. The AUC for all enrolled breast masses assessed by DCE-MRI + Synthetic MRI type (0.83) was significantly greater than that for the DCE-MRI type (0.70, P < 0.05) or synthetic MRI type (0.73, P < 0.05). The AUC for category 4 masses assessed by the DCE-MRI + Synthetic MRI type was significantly greater than that for those assessed by the DCE-MRI type (0.74 vs. 0.50, P < 0.05). A combination of synthetic MRI and DCE-MRI improves the accuracy of diagnosis of benign and malignant breast masses, especially category 4 masses. Level of Evidence 4 Technical Efficacy Stage 2 J. MAGN. RESON. IMAGING 2021;53:381-391.


Synergistic protection by specific antibodies and interferon against infection by Trypanosoma cruzi in vitro.
Trypanosoma cruzi infects many mammalian cell types in vitro, including fibroblasts and macrophages. We have analyzed and compared the infection of mouse 3T3 fibroblasts and J774 macrophage-like tumor cells by cloned Y-A1.2 T. cruzi trypomastigotes. The effects of T. cruzi-specific antibodies and of interferon (IFN) on infection were considered. Specific antibodies protected 3T3 fibroblasts from infection by T. cruzi, but increased the relative infectivity for J774 cells due to binding of the opsonized parasite to J774 Fc receptors. It was also apparent that IFN-alpha, beta (produced by fibroblasts) and IFN-gamma (produced by T lymphocytes) activated trypanocidal activities in both 3T3 and J774 cells, although IFN-gamma was 100 to 2000 times more effective than IFN-alpha, beta on the basis of IFN antiviral units added per culture. When anti-T. cruzi antibodies and IFN-alpha, beta or IFN-gamma were used jointly, a synergistic protective effect was observed with both 3T3 fibroblasts and J774 cells. These results suggest that B and T lymphocytes might collaborate in vivo in the protection against T. cruzi infections by the production of anti-trypomastigote antibodies and IFN-gamma, respectively.


Self-polarization and directional motility of cytoplasm.
Directional cell motility implies the presence of a steering mechanism and a functional asymmetry between the front and rear of the cell. How this functional asymmetry arises and is maintained during cell locomotion is, however, unclear. Lamellar fragments of fish epidermal keratocytes, which lack nuclei, microtubules and most organelles, present a simplified, perhaps minimal, system for analyzing this problem because they consist of little other than the motile machinery enclosed by a membrane and yet can move with remarkable speed and persistence. We have produced two types of cellular fragments: discoid stationary fragments and polarized fragments undergoing locomotion. The organization and dynamics of the actin-myosin II system were isotropic in stationary fragments and anisotropic in the moving fragments. To investigate whether the creation of asymmetry could result in locomotion, a transient mechanical stimulus was applied to stationary fragments. The stimulus induced localized contraction and the formation of an actin-myosin II bundle at one edge of the fragment. Remarkably, stimulated fragments started to undergo locomotion and the locomotion and associated anisotropic organization of the actin-myosin II system were sustained after withdrawal of the stimulus. We propose a model in which lamellar cytoplasm is considered a dynamically bistable system capable of existing in a non-polarized or polarized state and interconvertible by mechanical stimulus. The model explains how the anisotropic organization of the lamellum is maintained in the process of locomotion. Polarized locomotion is sustained through a positive-feedback loop intrinsic to the actin-myosin II machinery: anisotropic organization of the machinery drives translocation, which then reinforces the asymmetry of the machinery, favoring further translocation.


Directed enzyme evolution via small and effective neutral drift libraries.
Small libraries for directed evolution can be obtained by neutral drifts that maintain the protein's original function, yielding highly polymorphic, stable and evolvable variants. We describe methods for preparing such libraries, using serum paraoxonase (PON1). An optimized GFP variant fused to PON1 reported levels of soluble, functional enzyme, enabling selection by flow cytometry and identification of enzyme variants exhibiting improved specific and total activities toward several substrates, including toxic organophosphates.


Postoperative demand for analgesics in relation to individual levels of endorphins and substance P in cerebrospinal fluid.
Fourteen adult patients were allowed to self-administer small intravenous doses of pethidine to relieve postoperative pain. Thirteen of the patients obtained subjectively satisfactory analgesia while establishing steady-state levels of pethidine in plasma. The individual demand for pethidine was related to individual levels of fraction I endorphins and substance P-like immunoreactivity in the cerebrospinal fluid (CSF). There was a significant and inverse relationship between preoperative fraction I concentrations in CSF and the individual mean pethidine concentrations in plasma (P less than 0.05) and CSF (P less than 0.02) during self-administration. In the 24 h period encompassing surgery and postoperative self-administered analgesia, substance P decreased in 7 patients with calculated CSF pethidine great than 200 ng/ml, but remained virtually unchanged in 7 patients with calculated CSF pethidine less than 200 ng/ml. The results suggest a role for endorphins in the modulation of acute pain and are compatible with experimental evidence for an inhibitory effect of opiates on substance P release.


[Pelvic fractures in children: clinic, late results, biomechanic (author's transl)].
From 1917--1976 68 pelvis fractures of children (up to 14 years) were hospitalized at the department of Surgery, University of Göttingen. About 75% were traffic accidents. The lesions prefer the iliosacral joints, symphysis and the biogenic connections. Experimental compressions confirm the clinical fractures. The controls show sufficient subjective results. Because of pelvis dislocation and scoliosis controls are necessary.


Evaluation of response to induction chemotherapy in esophageal cancer: is barium esophagography or PET-CT useful?
To determine whether sequential barium esophagograms can predict histopathological response to treatment in esophageal cancer. Two radiologists retrospectively reviewed esophagograms pre- and post- chemotherapy in 32 patients for tumor length decrease of at least 15% and luminal width increase of at least 15%. Positron emission tomography-computed tomography (PET-CT) was reviewed for tumor maximum standardized uptake value (SUVmax) decrease of at least 35%. The reference standard was 90% or more tumor necrosis at histopathologic examination of the excised specimen. Pathologic response ranged from 10% to 100% necrosis. For prediction of tumor response, the sensitivity, specificity, positive and negative predictive values for length ranged from 43.8 to 56.3% and for width from 41.2% to 66.7% and for SUVmax from 47.1% to 53.3%. Performance characteristics for barium esophagograms in our group of patients were similar to PET-CT in predicting tumor response. Both tests were inadequate in predicting tumor response.


Persistently circulating C3 nephritic factor (C3 NeF)-stabilized alternative pathway C3 convertase (C3 CoF) in serum of an 11-year-old girl with meningococcal septicemia--simultaneous occurrence with free C3 NeF.
Hemolytic complement was found to be absent in the serum of an 11-yr-old girl (R.N.) with meningococcal septicemia. C1, C4, and C2 were slightly decreased, C3 was absent, C5-C9 within the normal range. B levels immunochemically and electrophoretic mobility of B were normal. C3d was greater than 1000% of a pooled EDTA-plasma standard indicating hypercatabolism of C3. On incubation of the patient's serum with normal human serum activation of C3 occurred even in the presence of 0.04 M EDTA. The amount of C3b generated was, however, greater without any chelating agent or in Mg-EGTA. On gel filtration of the serum two protein containing peaks were found to be responsible for activation of C3: the IgG containing peak was able to activate C3 in normal human serum without chelating agents and in Mg-EGTA but not in the presence of EDTA. The IgM-containing peak activated the third component of complement even in the presence of EDTA. The factor responsible for this phenomenon was termed C3 converting factor (C3 CoF). The IgG fraction of the patients serum caused activation of C3 in Mg-EGTA. However, in the presence of EDTA no activation of C3 could be induced even if physiological concentrations of the patients IgG were added to normal human EDTA-plasma. Thus the activity of the patient's IgG did not differ from typical C3 nephritic factor. The decay of C2 in EAC42 intermediates in the presence of the patient's IgG was uninfluenced indicating that it did not carry autoantibody activity against the classical pathway convertase C4b,2a, an activity recently termed NFc.(ABSTRACT TRUNCATED AT 250 WORDS)


Leaf physiological traits of plants from the Qinghai-Tibet Plateau and other arid sites in China: Identifying susceptible species and well-adapted extremophiles.
Extreme environments, such as deserts and high-elevation ecosystems, are very important from biodiversity and ecological perspectives. However, plant physiology at those sites has been scarcely studied, likely due to logistic difficulties. In the present study, leaf physiological traits in native plants were analyzed from arid zones across an elevational transect in Western China, from Turpan Basin to the Qinghai-Tibet Plateau (QTP) at Delingha. The aim of this study was to use leaf physiological traits to help identifying potentially threatened species and true extremophiles. Physiological measurements in the field, and particularly in situ measurements of gas exchange and chlorophyll fluorescence, have been determined to be useful to determine the current state of plants at a given environment. Using this approach plus a combination of leaf traits, several species performing particularly well at the QTP were identified, e.g. Hedysarum multijugum, as well as at Manas drylands, e.g. Peganum harmala and Setaria viridis. On the other hand, several species showed marked signs of severe stress, in particular a very low photosynthetic rate over its potential maximum, as well as other negative traits, like low water and/or nitrogen-use-efficiency, which should be considered in conservation plans. Interestingly, all C4 species studied except Setaria viridis were among the most stressed species. Despite their higher water use efficiency and drought-tolerance reputation, they presented a much larger photosynthesis depression than most C3 species. This is an intriguing and interesting observation that deserves further studies.


Investigation and Computational Analysis of the Sulfotransferase (SOT) Gene Family in Potato (Solanum tuberosum): Insights into Sulfur Adjustment for Proper Development and Stimuli Responses.
Various kinds of primary metabolisms in plants are modulated through sulfate metabolism, and sulfotransferases (SOTs), which are engaged in sulfur metabolism, catalyze sulfonation reactions. In this study, a genome-wide approach was utilized for the recognition and characterization of SOT family genes in the significant nutritional crop potato (Solanum tuberosum L.). Twenty-nine putative StSOT genes were identified in the potato genome and were mapped onto the nine S. tuberosum chromosomes. The protein motifs structure revealed two highly conserved 5'-phosphosulfate-binding (5' PSB) regions and a 3'-phosphate-binding (3' PB) motif that are essential for sulfotransferase activities. The protein-protein interaction networks also revealed an interesting interaction between SOTs and other proteins, such as PRTase, APS-kinase, protein phosphatase, and APRs, involved in sulfur compound biosynthesis and the regulation of flavonoid and brassinosteroid metabolic processes. This suggests the importance of sulfotransferases for proper potato growth and development and stress responses. Notably, homology modeling of StSOT proteins and docking analysis of their ligand-binding sites revealed the presence of proline, glycine, serine, and lysine in their active sites. An expression essay of StSOT genes via potato RNA-Seq data suggested engagement of these gene family members in plants' growth and extension and responses to various hormones and biotic or abiotic stimuli. Our predictions may be informative for the functional characterization of the SOT genes in potato and other nutritional crops.


Pilot survey of expressed sequence tags (ESTs) from the asexual blood stages of Plasmodium vivax in human patients.
Plasmodium vivax is the most widely distributed human malaria, responsible for 70-80 million clinical cases each year and large socio-economical burdens for countries such as Brazil where it is the most prevalent species. Unfortunately, due to the impossibility of growing this parasite in continuous in vitro culture, research on P. vivax remains largely neglected. A pilot survey of expressed sequence tags (ESTs) from the asexual blood stages of P. vivax was performed. To do so, 1,184 clones from a cDNA library constructed with parasites obtained from 10 different human patients in the Brazilian Amazon were sequenced. Sequences were automatedly processed to remove contaminants and low quality reads. A total of 806 sequences with an average length of 586 bp met such criteria and their clustering revealed 666 distinct events. The consensus sequence of each cluster and the unique sequences of the singlets were used in similarity searches against different databases that included P. vivax, Plasmodium falciparum, Plasmodium yoelii, Plasmodium knowlesi, Apicomplexa and the GenBank non-redundant database. An E-value of <10(-30) was used to define a significant database match. ESTs were manually assigned a gene ontology (GO) terminology A total of 769 ESTs could be assigned a putative identity based upon sequence similarity to known proteins in GenBank. Moreover, 292 ESTs were annotated and a GO terminology was assigned to 164 of them. These are the first ESTs reported for P. vivax and, as such, they represent a valuable resource to assist in the annotation of the P. vivax genome currently being sequenced. Moreover, since the GC-content of the P. vivax genome is strikingly different from that of P. falciparum, these ESTs will help in the validation of gene predictions for P. vivax and to create a gene index of this malaria parasite.


Origins of Stereoselectivity in Chiral Aminoalcohol Catalysis of Oxyallyl Cation-Indole Reactions.
The enantioselective coupling of indoles with racemic α-tosyloxy ketones mediated by a chiral amino alcohol catalyst is studied with density functional theory (DFT) calculations. The addition of indole to an oxyallyl cation intrinsically favors the (S,S) and (R,R) stereoisomeric products through electrostatic interactions in the transition state. Our model shows that the enantioselectivity is controlled by the cyclohexane moiety of the catalyst; selectivity diminishes upon removal of the cyclohexane ring. Substitution to enhance the enantioselectivity of this reaction is proposed.


The effect of guanidine on transmitter release in the ciliary ganglion of the chick.
1. The effect of guanidine hydrochloride on synaptic transmission at the chick ciliary ganglion was studied. 2. In bathing solution containing low calcium concentrations, guanidine produced a dose-dependent increase in the number of quanta released by the presynaptic action potential. No post-synaptic effects were observed. 3. Intracellular presynaptic recordings and monitoring of the presynaptic action potential post-synaptically via the coupling potential showed that the action of guanidine was independent of any alterations in the presynaptic spike.


Impaired ATM activation in B cells is associated with bone resorption in rheumatoid arthritis.
Patients with rheumatoid arthritis (RA) may display atypical CD21-/lo B cells in their blood, but the implication of this observation remains unclear. We report here that the group of patients with RA and elevated frequencies of CD21-/lo B cells shows decreased ataxia telangiectasia-mutated (ATM) expression and activation in B cells compared with other patients with RA and healthy donor controls. In agreement with ATM involvement in the regulation of V(D)J recombination, patients with RA who show defective ATM function displayed a skewed B cell receptor (BCR) Igκ repertoire, which resembled that of patients with ataxia telangiectasia (AT). This repertoire was characterized by increased Jκ1 and decreased upstream Vκ gene segment usage, suggesting improper secondary recombination processes and selection. In addition, altered ATM function in B cells was associated with decreased osteoprotegerin and increased receptor activator of nuclear factor κB ligand (RANKL) production. These changes favor bone loss and correlated with a higher prevalence of erosive disease in patients with RA who show impaired ATM function. Using a humanized mouse model, we also show that ATM inhibition in vivo induces an altered Igκ repertoire and RANKL production by immature B cells in the bone marrow, leading to decreased bone density. We conclude that dysregulated ATM function in B cells promotes bone erosion and the emergence of circulating CD21-/lo B cells, thereby contributing to RA pathophysiology.


Asymmetrical than symmetrical cerebral arterial bifurcations are more vulnerable to aneurysm presence.
In order to investigate the role of lateral angle ratio (LA ratio) and daughter artery ratio (DA ratio) for predicting aneurysmal presence in main cerebral arterial bifurcations, three-dimensional cerebral angiographic data of major cerebral artery bifurcations were used for measurement of artery diameters and bifurcation angles including 115 middle cerebral arteries (MCAs), 59 basilar arteries (BAs), 35 internal carotid arteries (ICAs) and 115 anterior cerebral arteries (ACAs) with bifurcation aneurysms and control subjects of 1921 bifurcations with no aneurysms. The LA ratio (larger lateral angle/smaller lateral angle) and DA ratio (larger branch diameter/smaller branch diameter) were calculated, and ROC curve analysis of LA and DA ratios between normal and aneurysmal cases was performed. The LA and DA ratios of MCA bifurcations and the LA ratios of BA and ICA bifurcations with aneurysms were all significantly larger than normal bifurcations (P < 0.05), and the DA ratio of ACA bifurcations with aneurysms was significantly smaller than normal cases (P < 0.01). Moreover, the LA ratio or DA ratio between the normal and aneurysm cases in MCA, BA and ACA bifurcations demonstrated significant differences by ROC analysis (P < 0.01) except in the ICA bifurcations. No significant difference was observed (P > 0.05) between ruptured and unruptured aneurysms in MCA, BA, ICA and ACA bifurcations. In summary, normal MCA, BA and ICA bifurcations show symmetrical morphology in the lateral angles and daughter branches, whereas aneurysmal bifurcations show asymmetrical morphology. Normal ACA bifurcations have asymmetrical bilateral daughter branches while symmetrical branches are associated with ACA bifurcation aneurysm presence.


Immunoblotting of hydrophobic integral membrane proteins.
For diagnosis and research purposes it is frequently desirable to measure by immunoblotting small amounts of proteins in complex mixtures such as tissue biopsy homogenates. Standard immunoblot procedures that give excellent results for soluble proteins unexpectedly gave low and irreproducible signals with some hydrophobic membrane proteins. We found that this was due to inefficient electrophoretic transfer to nitrocellulose, which could be corrected by modification of the transblot buffer. Hydrophobic integral membrane proteins of peroxisomes as well as other rat and human liver proteins were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to nitrocellulose filters. The nitrocellulose-bound proteins were detected both by staining and by immunoblotting with an antiserum against the 22-kDa integral membrane protein of peroxisomes plus 125I-labeled protein A. A modified transblot buffer with 0.7 M glycine and 25 mM Tris (pH 7.7) but no methanol allowed use of a much shorter transfer time and strikingly improved the electrophoretic transfer of membrane proteins such that a peroxisomal integral membrane protein could be easily detected in human liver biopsy homogenates.


A ten-residue domain (Y11-A20) in the NH2-terminus modulates membrane association of annexin A7.
Annexin A7 (synexin, annexin VII) is postulated to promote membrane fusion during surfactant secretion in alveolar type II cells and catecholamine secretion in adrenal chromaffin cells. Recently, we demonstrated that the 1-29 residues in the NH(2)-terminus could, possibly by interaction with the COOH-terminus, influence the Ca(2+)-dependent membrane binding, aggregation, and fusion properties of annexin A7 (A7). In this study, we further investigated this 29-residue domain by evaluating several deletion and point mutations for membrane-associated functions of A7. In comparison to A7, the mutants lacking 1-29 residues (A7Delta(1-29)) or 1-21 residues (A7Delta(1-21)), but not those lacking 1-10 residues (A7Delta(1-10)) or 21-29 residues (A7Delta(21-29)), showed diminished membrane binding. Segmental deletion of 10-20 residues (A7Delta(10-20)) also decreased the protein binding to membranes. The Ca(2+)-dependent membrane aggregation of PLV with A7Delta(1-29) was maximally diminished but less so with A7Delta(10-20) or A7Delta(1-21) in comparison to that with A7. However, phospholipid vesicle (PVL) aggregation was unaffected with A7Delta(1-10) or A7Delta(21-29). The Ca(2+)-dependent membrane fusion of PLV was also diminished with A7Delta(10-20) and A7Delta(1-29), but not with A7Delta(1-10). Since the mode of annexin A7 association and function with biological membranes could be different, we also evaluated these proteins for functional changes with isolated lung lamellar bodies. In comparison to A7, the binding to lamellar bodies was diminished for A7Delta(1-29) and A7Delta(1-21) but not for A7Delta(1-10). The Ca(2+)-dependent fusion of isolated lamellar bodies with PLV was also diminished with A7Delta(1-29), but not with A7Delta(10-20) or A7Delta(1-21). Taken together, our studies suggest that the 10-residue domain (Y(11)-A(20)) in the NH(2)-terminus modifies the phospholipid binding and aggregation properties of annexin A7. For binding and fusion of biological membranes, the 10-29-residue domain may be required although the annexin A7 properties are primarily modulated through the Y(11)-A(20) domain.


In vivo role of 20-hydroxyecdysone in the regulation of the vitellogenin mRNA and egg development in the American dog tick, Dermacentor variabilis (Say).
Injection of the hormone 20-hydroxyecdysone (20-E) into partially fed (virgin) female adults of the American dog tick, Dermacentor variabilis, while they are attached and feeding on the rabbit host, initiated the expression of the vitellogenin (Vg) gene, and Vg protein secretion and uptake by the ovary. The induction of egg production by 20-E in this bioassay was dose dependent in the range of 1-50 times the concentration normally found in a replete, vitellogenic female. Ticks examined 4 d after the 50 x treatment were still attached to the host, had numerous enlarged vitellin-filled (brown) oocytes in their ovaries, but had not engorged to repletion. The ovaries reached weights similar to those found in untreated, replete (mated) females (pre-oviposition) while solvent-injected controls demonstrated no increase in oocyte size or increase in ovary weight. An increase in the levels of a putative Vg protein was observed in hemolymph samples collected 1, 2 and 3d post-20-E injection but was not observed in the corresponding solvent controls as determined by native PAGE. Analysis of the ecdysteroid-induced protein by tryptic digestion-mass fingerprinting and BLASTP found that the putative Vg had the strongest match to GP80 (U49934), the partial sequence for the vitellogenin protein from Boophilus microplus. A partial Vg cDNA was cloned and sequenced from replete females of D. variabilis with a high similarity to GP80. Using this message as a probe, Northern blots conducted with RNA collected from partially fed, virgin females 1, 2 and 3d post-20-E injection showed upregulation of the Vg mRNA on all 3 days. Controls injected with solvent only showed no Vg mRNA. Injections with juvenile hormone III did not stimulate Vg expression, oocyte growth or full engorgement. These studies indicate that ecdysteroids and not JH can initiate expression of the Vg gene, Vg protein synthesis and release into hemolymph, and Vg uptake into developing oocytes under bioassay conditions mimicking normal feeding on the host.


Effects of Long-Term Food Restriction Under Thermoneutral Conditions on Brown Adipose Tissue of Laboratory Mice.
Long-term food restriction (3 weeks, 60% of normal consumption of control animals) was followed by an increase in DNA and protein content in the intercapsular brown fat of mice. As the animals were kept under thermoneutral conditions, these changes are thought to be a result of food restriction.


An unusual case of fulminant myocarditis closely mimicking ST-segment elevation myocardial infarction and presenting as refractory cardiogenic shock complicated by multiple life-threatening arrhythmias.
We report a case of severe fulminant myocarditis that closely mimicked acute inferior ST-segment elevation myocardial infarction (STEMI) and presented with refractory cardiogenic shock, multiple life-threatening arrhythmias and rapidly progressive liver failure. This case was successfully differentiated from STEMI by emergency coronary angiography. Recurrent cardiogenic shock was reversed by intra-aortic balloon pumping (IABP). Life-threatening arrhythmias including ventricular tachycardia, ventricular fibrillation, and high-degree atrioventricular block (AVB) were terminated by immediate cardioversion and temporary pacemaker. High-dose hydrocortisone effectively attenuated the inflammatory injury to the myocardium. The patient recovered and was well at the follow-up visit four months after discharge.


Carotid plaque components and other carotid artery features associated with risk of stroke: A systematic review and meta-analysis.
To compare the difference in the risk of stroke for four kinds of carotid artery plaque and carotid artery stenosis. Literature was collected by searching the PubMed, Embase, Cochrane library and Ovid databases up to June 2022, using the free search terms "carotid plaque" and "stroke". Meta-analysis was performed on the selected articles using Stata16 to analyse the relationship of stroke risk factors. A total of 11 studies including 6661 participants were included. Meta-analysis results showed that the incidence of stroke was statistically significantly different between IPH (intraplaque haemorrhage) plaques and LRNC (lipid-rich necrotic core) plaques (RR: 1.27, 95% CI: 1.04-1.55, P < 0.05) and IPH plaques and calcification plaques (RR: 2.99, 95% CI: 1.74-5.14, P < 0.0001). Furthermore, there was a statistically significant difference between TRFC (thinned or ruptured fibrous caps) plaques and carotid artery stenosis (RR: 10.84, 95% CI: 5.60-20.98, P < 0.0001) and calcification plaques and carotid artery stenosis (RR: 0.83, 95% CI: 0.75-0.92, P < 0.0001). However, there was no statistically significant difference between the IPH and carotid artery stenosis (RR: 1.55, 95% CI: 0.68-3.52, P > 0.05), LRNC and TRFC (RR: 0.80, 95% CI: 0.11-5.82, P > 0.05), LRNC and calcification (RR: 1.81, 95% CI: 0.90-3.66, P > 0.05) and LRNC and carotid artery stenosis (RR: 1.40, 95% CI: 0.69-2.81, P > 0.05). IPH was associated with a higher incidence of stroke compared to LRNC and calcification plaques and TRFC has a higher risk of stroke than calcification plaques and carotid stenosis. This evidence suggests that IPH and TRFC may play an important role in predicting stroke.


Retinal Neurodegeneration as an Early Manifestation of Diabetic Eye Disease and Potential Neuroprotective Therapies.
Diabetic retinopathy (DR) is a major cause of visual impairment and blindness throughout the world. Microvascular changes have long been regarded central to disease pathogenesis. In recent years, however, retinal neurodegeneration is increasingly being hypothesized to occur prior to the vascular changes classically associated with DR and contribute to disease pathogenesis. There is growing structural and functional evidence from human and animal studies that suggests retinal neurodegeneration to be an early component of DR. Identification of new therapeutic targets is an ongoing area of research with several different molecules undergoing testing in animal models for their neuroprotective properties and for possible use in humans. Retinal neurodegeneration may play a central role in DR pathogenesis. As new therapies are developed, it will be important to develop criteria for clinically defining retinal neurodegeneration. A standardization of the methods for monitoring neurodegeneration along with more sensitive means of detecting preclinical damage is also needed.


Validation of self-reported khat chewing amongst khat chewers: an exploratory study.
Khat chewing amongst the UK communities originating from Yemen and the East African coast is suggested to create dependency through its main stimulant components (cathinone, norephedrine and norpseudoephedrine) on the central nervous system. To validate self-reported khat chewing behaviours by measuring levels of cathinone, norephedrine and norpseudoephedrine in saliva and to explore their associations with self-reported khat chewing dependency. Face-to-face interviews were conducted amongst 30 male UK-resident khat chewers. Saliva samples were collected from each participant and high-performance liquid chromatography (HPLC) employed to extract and quantify the levels of the biomarkers. The mean (SD) for cathinone and the composite norephedrine and norpseudoephedrine levels were 33.93 (±39.20) and 29.28 (±26.32)μg/mL respectively. These biomarkers were significantly associated (p≤0.05) with khat chewing dependency. Validation of self-reported khat chewing is possible. Khat chewing dependency correlates significantly with biomarker levels in saliva. Replication is required.


Analysis of temporally evolved nanoparticle-protein corona highlighted the potential ability of gold nanoparticles to stably interact with proteins and influence the major biochemical pathways in Brassica juncea.
Nanoparticles (NPs) are known to adsorb proteins from their surroundings, forming NP-protein corona, which determines their fate, distribution, and effects, yet no information of protein corona (PC) has been gathered in the plants so far. Here we report, the analysis of temporally evolved (2 h-36 h) AuNP-protein coronas formed with Brassica juncea leaf crude protein & nuclear-enriched fraction. Protein coronas were characterized by the techniques including SDS PAGE (Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis), spectrophotometry, dynamic light scattering, zeta potential measurements, and Nano LC-MS/MS. Data analysis revealed the formation of two regimes (Regime I from 2 to 8 h & regime II from 16 to 36 h). Interestingly, coated AuNPs had approx. 30% higher zeta potential than pristine AuNPs after 36 h of interactions. The increase in hydrodynamic radii and adsorbed protein concentrations were consistent with the evolution of zeta potential, indicating the probable role of proteins in providing the better stability of AuNPs. MS analysis identified 97 proteins from regime I (soft corona) and 181 proteins from regime II (hard corona) of crude PC. On the other hand, 282 and 308 proteins were identified from nuclear soft and hard corona respectively, indicating better affinity of nuclear proteins. Besides, the high-affinity proteins (fold change ≥5) were found to be rich in lysine residues showing their involvement in promoting the adsorption. Notably, 27% of regime II corona proteins of the crude protein fraction were from energy-yielding pathways highlighting the potential ability AuNPs to influence the yield in Brassica juncea.


Low folate status, and MTHFR 677C > T and MTR 2756A > G polymorphisms associated with colorectal cancer risk in Thais: a case-control study.
Folate plays essential roles in DNA synthesis, repair, and methylation; thus, folate status may affect carcinogenesis. Genetics polymorphisms involved in folate metabolisms have been linked with colorectal cancer (CRC) development. Therefore, we hypothesized that low folate status and related genetic polymorphisms are associated with higher risk of CRC. This case-control study enrolled 105 new cases of CRC, 101 of colorectal adenoma (CRA), and 182 controls from hospitals in Bangkok, Thailand, to examine the association between folate status and methylenetetrahydrofolate reductase (MTHFR) 677C > T, methionine synthase (MTR) 2756A > G, and methionine synthase reductase (MTRR) 66A > G with the risk of CRC and CRA. Regarding CRC risk, the lowest quartile group of serum folate and folate intake had higher risk of CRC than the highest quartile group (odds ratio [OR] = 11.45, 95% confidence interval [CI] = 4.43-29.59) and (OR = 10.29, 95% CI = 4.17-25.41). The lowest quartile group of folate intake also had a higher risk of CRA (OR = 5.22, 95% CI = 2.19-6.09). Low red blood cell folate combined with MTHFR 677C > T polymorphism statistically increased CRC risk (OR = 10.00, 95% CI = 1.36-73.42). Low folate status combined with MTR 2756A > G significantly increased CRA risk (OR = 6.43, 95% CI = 1.38-29.94). Moreover, the risk of CRC was elevated with alcohol consumption and low exercise activity when combined with low folate status (P < .05). This study supported the hypothesis that, in Thais, low folate status is associated with a higher risk of CRC, particularly among those with polymorphisms of the MTHFR 677C > T and MTR 2756 A > G genes.


Aurothiomalate-Based Drugs as Potentially Novel Agents Against Leishmania major: A Mini Review.
Leishmaniasis is a major public health problem worldwide in many parts of the world. Current anti-leishmanial drugs have only limited clinical efficacy. Aurothiomalate derivatives are useful for treating rheumatoid arthritis, but have emerged as a promising therapeutic candidate for leishmaniasis. This paper gives a review of the literature about the usefulness of aurothiomalate derivatives against leishmaniasis. In this study, we reviewed the proposed mechanisms of action of aurothiomalate and related compounds on the metabolism of L. major and collected data by searching relevant articles. Aurothiomalate-based drugs could be effective against leishmaniasis through two direct and indirect mechanisms: first, cytotoxic effects on parasites via thiomalate's false substrate role in the citric acid cycle against malate; and second, immunosuppressive and anti-inflammatory effects of aurothiomalate derivatives with prostaglandin production inhibitory effects. The current study documented that aurothiomalate-based drugs could be effective against leishmaniasis through two direct and indirect mechanisms of action. Gold thiomalate as a promising hit should be evaluated against L. major in vitro and in vivo conditions in the future.


Controlled release of volatile aldehydes and ketones by reversible hydrazone formation--classical" profragrances are getting dynamic.
Dynamic mixtures obtained by reversible covalent acylhydrazone formation of fragrance aldehydes and/or ketones and a hydrazide in water were found to be efficient delivery systems for the controlled release of highly volatile organic molecules.


Analysis of surgical outcomes and risk factors for anastomotic leakage following trans-hiatal resection of esophagogastric junction cancer.
The trans-hiatal lower esophagectomy is considered less invasive than the trans-thoracic esophagectomy for resection of esophagogastric junction (EGJ) cancer. However, the optimal procedure remains controversial and should be determined while considering both oncological and safety aspects. This retrospective study comprised 124 patients that underwent curative resection for EGJ cancer. The study analysis included 93 patients with tumor centers located within 2 cm of the EGJ. Clinicopathological findings and surgical outcomes were compared between patients treated using trans-hiatal and trans-thoracic approaches. Sixty-three patients underwent lower esophagectomy using the trans-hiatal approach (TH-G). The remaining 30 patients underwent esophagectomy using the trans-thoracic approach (TT-E). The TH-G group were older, had a lower prevalence of lymphatic spread, shorter length of esophageal invasion, and shorter operative duration compared to the TT-E group. Although no significant differences in the frequency of postoperative complications, a higher proportion of patients in the TH-G group developed anastomotic leakage (16% vs. 7%, p = 0.33). Univariate and multivariate analyses demonstrated that cardiac comorbidity was an independent risk factor for anastomotic leakage (odds ratio, 5.24; 95% CI, 1.06-25.9; P < 0.05) in TH-G group. Further examination revealed that preoperative cardiothoracic ratio (CTR) with 50% or greater could be surrogate marker as risk factor for anastomotic leakage in TH-G group (35% vs. 7.5%, p < 0.05). The trans-hiatal approach can be used for resection of EGJ cancer. However, special attention should be paid to the prevention of anastomotic leakage in patients with cardiac comorbidities or a large preoperative CTR.


KIR2DS4 and Its Variant KIR1D in KIR-AA Genotype Donors Showed Differential Survival Impact in Patients with Lymphoid Disease after HLA-Matched Unrelated Hematopoietic Stem Cell Transplantation.
Previous studies have illustrated associations between the presence of activating killer cell immunoglobulin-like receptor (KIR) genes and lower susceptibility to hematologic malignancies in humans. In addition, favorable hematopoietic stem cell transplantation (HSCT) outcomes have been reported in patients who received transplants from donors with KIR genotypes dominant for activating KIR receptors. However, the association of activating KIR genes on an allelic level with disease and their impact on HSCT outcome has been little investigated to date. To this end, we genotyped a large transplantation cohort for KIR 2 Ig domains and short cytoplasmic tail 4 (KIR2DS4) polymorphisms and investigated their association with disease. We next investigated the impact of KIR-AA genotype donor KIR2DS4 polymorphisms (AA/KIR2DS4 versus AA/ KIR 1 Ig domain [KIR1D]) on clinical outcomes of HSCT in myeloid versus lymphoid patient subgroups. Among 2810 transplantation donor-recipient pairs, 68.8% (n = 1934) were 10/10 HLA-matched and 31.2% (n = 876) were 9/10 HLA-matched. The distribution of KIR1D was equal in patients and donors (P = .205). Multivariate analysis in 10/10 HLA-matched patients with lymphoid disease showed improved HSCT outcomes when they received grafts from AA/KIR1D donors (overall survival: hazard ratio [HR], .62, P = .002; disease free survival: HR, .70, P = .011; graft-versus-host disease-free and relapse-free survival: HR, .67, P = .002; nonrelapse mortality: HR, .55, P < .001). This effect was not seen in either 9/10 HLA-matched patients with lymphoid disease or patients with myeloid disease. Our study indicates that the presence of KIR1D alleles is not associated with disease in patients, and, interestingly, using grafts from AA/KIR1D donors translated into beneficial survival outcomes in 10/10 HLA-matched patients with lymphoid disease.


From flakes to grooves: a technical shift in antlerworking during the last glacial maximum in southwest France.
The evolution of antlerworking technology in Paleolithic and Mesolithic Europe, especially the production of splinters, is usually described as a cumulative process. A progressive increase in blank standardization and productivity was prompted by the application of a key technical process, the groove and splinter technique (GST). The Badegoulian, however, appears as an interruption in this continuum. According to the original definition of this post-Solutrean, pre-Magdalenian archeological culture, one of its distinctive features is the absence of the GST and the manufacture of antler blanks by knapping only. However, this conception has been recently questioned, leading to an alternative hypothesis suggesting that both GST and knapping were used during the Badegoulian. In this article, we present new evidence from several sites in southwest France, which sheds new light on the issue of Badegoulian antlerworking and the transition with the subsequent Lower Magdalenian. Our study is based on two complementary methods: the technological analysis of antler assemblages well-dated to the Badegoulian (Le Cuzoul de Vers) or to the Lower Magdalenian (La Grotte des Scilles, Saint-Germain-la-Rivière), and the direct (14)C dating of specific antler artifacts from mixed or problematic contexts (Cap-Blanc, Reverdit and Lassac). The results firmly establish that, in southwest France, knapping is the only method used for the production of antler splinters during the Badegoulian, before ca. 20,500 cal BP (calibrated years before present), and that it is rapidly replaced by the GST at the beginning of the Lower Magdalenian, after ca. 20,500 cal BP. This technical shift is not linked to an influx of new human populations, environmental change or the supposed economic advantages of the GST. Instead, it must be understood as one of the expressions of a broader reconfiguration of the technical world that starts to take shape in the middle of the Last Glacial Maximum.