Usefulness of antithrombin deficiency phenotypes for risk assessment of venous thromboembolism: type I deficiency as a strong risk factor for venous thromboembolism.
Inherited antithrombin deficiency, an established risk factor for venous thromboembolism (VTE), can be classified into type I (quantitative deficiency) or type II (qualitative deficiency). In the present study, we assessed the VTE risk associated with the phenotypes of antithrombin deficiency in patients admitted to our hospital. We found that patients with type I deficiency (n = 21) had more VTE events and earlier onset of VTE than those with type II deficiency (n = 10). The VTE-free survival analysis showed that the risk for VTE in patients with type I deficiency was sevenfold greater than that in patients with type II deficiency (hazard ratio: 7.3; 95% confidence interval: 1.9-12.2; P = 0.0009). The prevalence of type I deficiency in the VTE group (5.6%, 6/108) was higher than that in the general population (0.04%, 2/4,517) (odds ratio: 132.8; 95% confidence interval: 26.5-666.1; P < 0.0001). However, the prevalence of type II deficiency was not different between the VTE group and the general population. Our study indicated that the risk for VTE in patients with type I deficiency was much higher than that in patients with type II deficiency. Thus, simple phenotypic classification of antithrombin deficiency is useful for assessment of VTE risk in Japanese.


Food Processing Antioxidants.
Food processing has been carried out since ancient times as a way to preserve and improve food nutritional and organoleptic properties. Although it has some undesirable consequences, such as the losses of some nutrients and the potential formation of toxic compounds, a wide range of benefits can be enumerated. Among them, the increased total antioxidant capacity of many processed foods has been known for long. This consequence has been related to both the release or increased availability of natural antioxidants and the de novo formation of substances with antioxidant properties as a consequence of the produced reactions. This review analyzes the chemical changes produced in foods during processing with special emphasis on the formation of antioxidants as a consequence of carbonyl-amine reactions produced by both carbohydrate- and lipid-derived reactive carbonyls. It discusses the lastest advances produced in the characterization of carbonyl-amine adducts and their potential action as primary (free radical scavengers), secondary (chelating and other ways to prevent lipid oxidation), and tertiary (carbonyl scavengers as a way to avoid lipid oxidation consequences) antioxidants. Moreover, the possibility of combining amino compounds with different hydrophobicity, such as aminophospholipids and proteins, with a wide array of reactive carbonyls points out to the use of carbonyl-amine reactions as a new way to induce the formation of a great variety of substances with antioxidant properties and very variable hydrophilia/lipophilia. All presented results point out to carbonyl-amine reactions as an effective method to generate efficacious antioxidants that can be used in food technology.


Continuous monitoring of alveolar and inspiratory concentrations of anesthetic and respiratory gases is difficult and potentially unsafe.
One essayist suggests that continuous monitoring of alveolar and inspiratory concentrations of anesthetic and respiratory gases has little or no positive effect on patient outcome and may even be detrimental to patients. Such monitoring, he says, tends to remove anesthesiologists from personal contact with their patients. He recommends careful monitoring of fresh gas concentrations leaving the anesthetic machine, careful monitoring of inspired gas in a circle absorption breathing system, and improved training of anesthesiologists to prevent human error. Another essayist suggests that continuous monitoring of alveolar and inspiratory concentrations of anesthetic and respiratory gases is cost-effective and relatively simple. He says that such monitoring, without being a source of legal problems for its users, improves the quality of patient care.


Exploring the effect of Weifuchun capsule on the toll-like receptor pathway mediated HES6 and immune regulation against chronic atrophic gastritis.
Weifuchun capsule (WFC) is a traditional Chinese patent medicine for chronic atrophic gastritis (CAG) in clinic. However, the mechanism of action of WFC for CAG still remains unclear due to its complex composition. The study was projected to uncover the mechanism of action of WFC and the corresponding pharmacodynamic substance of WFC against CAG as well as providing a standard example for the research of traditional Chinese medicine (TCM) from the perspective of the network and the system. We identified the compounds of WFC through LC-MS/MS analysis and performed a systematic network targets analysis for WFC in the treatment of CAG which thoroughly described the mechanism of action of WFC for CAG. Based on analysis integrating omics data and algorithms, we focused on the specific immune regulatory role of WFC in the treatment of CAG, especially on a hub pathway, Toll-like receptor signaling pathway and thus deciphered the role of WFC in immune regulation, anti-inflammation and mediation of HES6. In experiments part, MNNG-GES-1-cell line and rat models were used to validate our findings. In this study, compounds of WFC are identified through LC‒MS/MS and network target analysis is performed to dissect the specific immunoregulatory effect as well as mediation of HES6, a newly discovered biomolecule related to gastritis carcinoma progression, of WFC on CAG through the Toll-like receptor signaling pathway. Based on cell line and rat models, we verify the mechanism of action of WFC for CAG in inhibiting inflammatory cytokines, regulating immune cells like T cells and macrophages, related genes including TLR2 and CD14. It is also validated that WFC inhibits the expression of HES6 (P < 0.05). Based on the combination of computational strategy and experiments, our study offers a comprehensive analysis to reveal the role of WFC in regulating immune response, inhibiting inflammation in the treatment of CAG, and provides a standard example for the research of TCM from the perspective of the network and the system.


Atypical incomplete femoral neck fracture in patients taking long-term bisphosphonate: Case report, a report of 2 cases.
We present 2 cases of lateral incomplete impending fracture of the femoral neck without trauma in elderly patients taking long-term bisphosphonate (BP) treatment, and we defined it as atypical femoral neck fracture (AFNF). To the best of our knowledge, this is the first report on the follow-up results of AFNF. Patients in both cases had been taking BP drugs for a long time with osteoporosis. The duration of BP treatment was 6 years, and there was no history of repeated stresses. All fractures were linear at the lateral aspect of the mid portion of the femoral neck, and the BMD of the femoral neck was -0.9, and -1.8, respectively. Internal fixation was performed in both cases (73 years, 68 years) using cannulated screws. In both patients who underwent screw fixation, the fracture line started to extend distally at 4 weeks and 2 weeks following surgery. In the 3-month follow-up image, the length of the fracture increased by 20.1 mm and 9.9 mm, respectively. There was a problem with active rehabilitation, and the possibility of revision was also found to be a burden in terms of mortality and cost in older patients. In the case of AFNF, guidelines for treatment should be set in consideration of the decreased bone healing, even when the fracture pattern is simple. Arthroplasty based on a wider indication may be worth considering.


CCL18 from tumor-cells promotes epithelial ovarian cancer metastasis via mTOR signaling pathway.
CCL18 is a chemotactic cytokine involved in the pathogenesis and progression of various disorders, including cancer. Previously, our results showed high levels of CCL18 in the serum of epithelial ovarian carcinoma patients suggesting its potential as a circulating biomarker. In this study, we determined that CCL18 expression was up-regulated in ovarian carcinoma compared with adjacent tissue and was expressed in carcinoma cells in the tumor and not in normal ovarian epithelial cells by laser capture microdissection coupled with real-time RT-PCR. Moreover, correlation analysis showed that the CCL18 level was positively correlated with the metastasis of patients with ovarian cancer. Survival analysis also revealed that an increased level of CCL18 was associated with worse survival time in ovarian cancer patients. Over-expression of CCL18 led to enhanced migration and invasion of the Skov3 ovarian cancer cell line in vitro and in vivo. Finally, proteomics analysis demonstrated that CCL18-mediated ovarian cancer invasiveness was strongly correlated with the mTORC2 pathway. These findings suggest that the CCL18 chemokine has an important role in chemokine-mediated tumor metastasis, and may serve as a potential predictor for poor survival outcomes for ovarian cancer. © 2015 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.


Screening and detection of hepatocellular carcinoma.
The increasing incidence of hepatocellular carcinoma (HCC) has led to the need to identify patients at risk for HCC so that a program of screening can be undertaken. Screening for HCC has led to earlier diagnosis of tumors and thus has aided in initiating optimal medical treatment earlier in the disease course. Advances in radiological techniques and the identification of more accurate serum tests to diagnose HCC continue to be important areas of study and exploration. In particular, there have been efforts to develop new tumor markers to aid in the diagnosis of HCC and guide therapy of tumors.


Differential effects of epithelium removal on the responsiveness of guinea-pig tracheal smooth muscle to bronchoconstrictors.
1 The influence of the epithelium on contractions produced by the peptidoleukotrienes, 5-hydroxytryptamine (5-HT) and the thromboxane mimetic, U-44069, was examined in trachea from control and ovalbumin-sensitized guinea-pigs. 2 In control tissues removal of the epithelium produced an approximately 2 to 4 fold leftward shift in leukotriene C4 (LTC4) and LTD4 concentration-response curves, but no effect on LTE4-induced contractions. Similar results were obtained in preparations from ovalbumin-sensitized animals. 3 Responses produced by 5-HT or U-44069 were similar in the presence and absence of the epithelium in control guinea-pigs. 4 Indomethacin produced contrasting effects on leukotriene-induced contractions in control guinea-pigs: an increase in sensitivity to LTC4 in the presence but not absence of the epithelium, no effect on LTD4-induced contractions and a decrease in sensitivity to LTE4 in both epithelium-containing and epithelium-free preparations. 5 These results indicate that there is selectivity in the effects of epithelium removal on agonist-induced contractions of the guinea-pig trachea. This provides further evidence for the modulatory influence of the epithelium on the reactivity of mammalian airway smooth muscle and supports the postulated existence of an epithelium-derived inhibitory factor. The observation that in intact trachea indomethacin mimics the effects of epithelium removal on LTC4-induced responses, suggests the involvement of a prostanoid(s) in this phenomenon.


Bacterial burden in the operating room: impact of airflow systems.
Wound infections present one of the most prevalent and frequent complications associated with surgical procedures. This study analyzes the impact of currently used ventilation systems in the operating room to reduce bacterial contamination during surgical procedures. Four ventilation systems (window-based ventilation, supported air nozzle canopy, low-turbulence displacement airflow, and low-turbulence displacement airflow with flow stabilizer) were analyzed. Two hundred seventy-seven surgical procedures in 6 operating rooms of 5 different hospitals were analyzed for this study. Window-based ventilation showed the highest intraoperative contamination (13.3 colony-forming units [CFU]/h) followed by supported air nozzle canopy (6.4 CFU/h; P = .001 vs window-based ventilation) and low-turbulence displacement airflow (3.4 and 0.8 CFU/h; P < .001 vs window-based ventilation and supported air nozzle canopy). The highest protection was provided by the low-turbulence displacement airflow with flow stabilizer (0.7 CFU/h), which showed a highly significant difference compared with the best supported air nozzle canopy theatre (3.9 CFU/h; P < .001). Furthermore, this system showed no increase of contamination in prolonged durations of surgical procedures. This study shows that intraoperative contamination can be significantly reduced by the use of adequate ventilation systems.


Foveal splitting causes differential processing of Chinese orthography in the male and female brain.
Chinese characters contain separate phonetic and semantic radicals. A dominant character type exists in which the semantic radical is on the left and the phonetic radical on the right; an opposite, minority structure also exists, with the semantic radical on the right and the phonetic radical on the left. We show that, when asked to pronounce isolated tokens of these two character types, males responded significantly faster when the phonetic information was on the right, whereas females showed a non-significant tendency in the opposite direction. Recent research on foveal structure and reading suggests that the two halves of a centrally fixated character are initially processed in different hemispheres. The male brain typically relies more on the left hemisphere for phonological processing compared with the female brain, causing this gender difference to emerge. This interaction is predicted by an implemented computational model. This study supports the existence of a gender difference in phonological processing, and shows that the effects of foveal splitting in reading extend far enough into word recognition to interact with the gender of the reader in a naturalistic reading task.


Stereotactic radiosurgery for fractionated radiation: a proposal applicable to linear accelerator and proton beam programs.
A stereotactic radiosurgery technique is described which allows stereotactic radiation therapy to be easily fractionated on a daily or weekly basis. This permits adequate and safe radiation therapy to lesions larger than 2.5 cm, such as large arteriovenous malformations, and possibly safer radiation to smaller lesions near crucial intracranial structures. The technique utilizes external scalp landmarks and avoids the need for standard stereotactic head devices.


Test-retest reliability, minimal detectable change and minimal clinically important differences in modified shuttle walk test in children and adolescents with cystic fibrosis.
In youths with cystic fibrosis (CF) the modified shuttle walk test (MSWT) has been shown to be useful for assessing exercise tolerance; however, no studies to date have evaluated the reliability of MSWT, the minimal detectable change (MDC) and the minimal clinically important differences (MCID) for the MSWT distance for children and adolescents with CF. Test-retest reliability: 35 CF patients and 34 healthy controls performed two MSWTs (separated by 2-4 days). MCID: 33 patients were invited to participate in a 6-week home-based exercise program consisting of 30-60-min sessions, 5 days a week. The test-retest reliability of the MSWT distance for children and adolescents with CF was excellent, obtaining a MDC90 and MDC95 of 97.08 m and 115.32 m, respectively. The test-retest reliability also was excellent in healthy controls, founding a MDC90 and MDC95 of 69.12 m and 82.11 m, respectively. The ROC curve analysis established (with a sensitivity of 82% and specificity of 76%) that a change of 60 m represented MCID. The MSWT is a reliable tool to measure of exercise tolerance in children/adolescents with CF and those without CF. We propose a change in the score of at least 97.08 m (MDC90) as the most appropriate value for assessing the exercise response of children and adolescents with CF, given that this value exceeds the MCID based on the children's perception.


Axillary reverse mapping: mapping and preserving arm lymphatics may be important in preventing lymphedema during sentinel lymph node biopsy.
Several recent reports have shown a lymphedema rate of about 7% with sentinel lymph node biopsy (SLNB) only. We hypothesized that this higher than expected rate of lymphedema may be secondary to disruption of arm lymphatics during an SLNB procedure. This IRB-approved study, from May 2006 to June 2007, involved patients undergoing SLNB with or without axillary lymph node dissection. After sentinel lymph node (SLN) localization with subareolar technetium was assured, 2 to 5 mL of dermal blue dye was injected in the upper inner arm for localization of lymphatics draining the arm (axillary reverse mapping, ARM). The SLNB was then performed through an incision in the axilla. Data were collected on identification rates of hot versus blue nodes, variations in ARM lymphatic drainage that might impact SLNB, crossover between the hot and the blue lymphatics, and final pathologic nodal diagnosis. Median age was 57.6+/-12.5 years. Lymphatics draining the arm were near or in the SLN field in 42.7% (56 of 131) of the patients, placing the patient at risk for disruption if not identified and preserved during an SLNB or axillary lymph node dissection. ARM demonstrated that arm lymphatics do not cross over with the SLN drainage of the breast 96.1% of the time and that none of the ARM lymph nodes removed were positive, even when the SLN was (5 of 12). Seven (5.5%) blue ARM lymphatics were juxtaposed to the hot SLNBs. Disruption of the blue ARM node because of proximity to the hot SLN may explain the surprisingly high rate of lymphedema seen after SLNB. Identifying and preserving the ARM blue nodes may translate into a lower incidence of lymphedema with SLNB and axillary lymph node dissection.


Optimization of the preserved processing of all parts of the gabiroba fruit (Campomanesia adamantium (Cambess.) O. Berg) using response surface methodology.
The Amazon region hosts several species of exotic fruits with great functional potential which are important sources of nutrients and biologically active compounds. These fruits are widely consumed by the local population, but unknown to the general population and the scientific community. In addition, the seasonality inherent in these fruits limits their consumption. In this context, the processing of food products is one of the main tools for improving sensory quality and increasing the useful life of fruits. This work aims to make use of all parts of the gabiroba fruit in the form of preserves with the replacement of commercial pectin by passion fruit albedo, as well as the characterization of the fruit and the processed product. To optimize the preserves, a response surface methodology was used with a complete factorial design 23 with 11 formulations and 3 independent variables, citric acid concentration, pulp/sugar ratio and albedo concentration, which were subjected to microbiological analysis, sensory analysis and physical-chemistry analysis. The results showed that the gabiroba fruit has a low lipid content, 1.09%, in addition to 51.20 g/100 g vitamin C, 4.09% fiber, 79.83% moisture, 1.29% protein, 13.23% carbohydrates, 019% titratable acid and 0.47% ash. The result of the sensorial analysis indicated an optimal formulation with smaller amounts of citric acid and albedo and a lower pulp/sugar ratio. The gabiroba fruit was suitable for its full use in preserve processing. Processed preserves showed desirable physical-chemical characteristics, with consumer preference for formulations with a lower pulp/sugar ratio indicating the impact of consumer unfamiliarity with the fruit on their decision to consume it.


The problem of nuclease activity in nucleic acid hybridization reactions. Theoretical considerations.
The presence of nuclease during DNA-DNA or DNA-RNA hybridization reactions alters the kinetics of hybrid formation. Unfortunately, while the effect (even of small amounts of nucleas) on the Cot curve may be large, it may not be readily detectable. The effect of various types of nuclease is shown. As many nucleases cause a shift in the position rather than a change in shape of the curve, all studies involving nucleic acid hybridization should assay for the presence of nucleases and care must be taken to avoid their presence as contaminants.


Editorial on the Special Issue on Microelectrode Arrays and Application to Medical Devices.
In this editorial note, we briefly review the major findings of the 10 articles published in the Special Issue on microelectrode arrays and application to medical devices [...].


[Diagnostic image (246). A man with faecal production of the umbilicus].
A 19-year-old man with Crohn's disease presented with faecal production of the umbilicus due to an entero-urachal fistula.


Consulting a neurosurgeon upon initial medical assessment reduces the time to the first surgery and potentially contributes to improved prognosis for glioblastoma patients.
The neurological status of glioblastoma patients rapidly deteriorates. We recently demonstrated that early diagnosis and surgery within 3 weeks from the initial symptoms are associated with improved survival. While glioblastoma is a semi-urgent disease, the prehospital behaviors and clinical outcomes of glioblastoma patients are poorly understood. We aimed to disclose how prehospital patient behavior influences the clinical outcomes of glioblastoma patients. Isocitrate dehydrogenase-wildtype glioblastoma patients treated at our institution between January 2010 and December 2019 were reviewed. Patients were divided into two groups, neurosurgeon and non-neurosurgeon groups, based on the primary doctor whom patients sought for an initial evaluation. Patient demographics and prognoses were examined. Of 170 patients, 109 and 61 were classified into the neurosurgeon and non-neurosurgeon groups, respectively. The median age of neurosurgeon group was significantly younger than the non-neurosurgeon group (61 vs. 69 years old, P = 0.019) and in better performance status (preoperative Karnofsky performance status scores $\ge$80: 72.5 vs. 55.7%, P = 0.027). The neurosurgeon group exhibited a significantly shorter duration from the first hospital visit to the first surgery than the non-neurosurgeon group (18 vs. 29 days, P < 0.0001). Furthermore, the overall survival of the neurosurgeon group was significantly more prolonged than that of the non-neurosurgeon group (22.9 vs. 14.0 months, P = 0.038). Seeking an initial evaluation by a neurosurgeon was potentially associated with prolonged survival in glioblastoma patients. A short duration from the first hospital visit to the first surgery is essential in enhancing glioblastoma patient prognosis.


Interaction of polyene antibiotics with sterols in phosphatidylcholine bilayer membranes as studied by spin probes.
Interaction of filipin and amphotericin B with sterols in phosphatidylcholine membranes has been studied using various spin probes; epiandrosterone, cholestanone, phosphatidylcholine with 12-nitroxide or 5-nitroxide stearate attached to 2 position and also with tempocholine at the head group. Filipin caused increase in the fluidity of cholesterol-containing phosphatidylcholine membranes near the center, while it rather decreased the fluidity near the polar surface. On the other hand, amphotericin B did not apparently affect the fluidity. In the electron spin resonance spectrum of steriod spin probes in the antibiotic-containing membranes, both bound and free signals were observed and the association constant was calculated from the siganal intensity. In the binding of steriods with filipin, both 3 and 17 positions were involved, while the 17 positions was less involved in the binding with amphotericin B. Phase change in the host membrane markedly affected the interaction of filipin with epiandrosterone probe. The bound fraction jumped from 0.4 to 0.8 on going to the crystalline state and increased further with decrease in temperature. The overall splitting of the bound signal also increased on lowering the temperature below phase transition. This change was attributed to aggregate formation of filipin-steriod complexes in the crystalline state. On the other hand, effect of phase transition was much smaller on the interaction of amphotericin B with the steriod probe.


Clinical outcomes of root coverage with subepithelial connective tissue graft according to site specific factors - longitudinal retrospective clinical study.
This study investigated these possible correlations by a retrospective evaluation of patients with multiple GR treated with SCTG + CAF after 12 months postoperatively. Data were collected before surgery and at 6- and 12-month follow-up related to depth (RD) and width (RW) of GR, width (KTW) and thickness (KTT) of keratinized tissue, bone dehiscence (BD), vertical (VC) and Additionally, data on the technique employed, Miller classification of GR and location of GR were analyzed. The values were described as means and standard deviations, and the variations of parameters were assessed by ANOVA for repeated measures and Tukey test or paired t test. Comparison between periodontal and nominal variables was performed by the t test, and the relationship between periodontal parameters was assessed by the Pearson correlation test. A significance level of 5% (p less than 0.05) was adopted. The results indicated significant reduction in RD, RW and SEN values and increase in KTW between the initial period and 6 and 12 months, but not between 6 and 12 months. The KTT was increased in all periods analyzed. The VC was greater in the maxilla at 6 months, but with no significant difference between 6 to 12 months. The same relationship was observed for RD between GR class I and II. At 12 months, no difference was observed between root coverage techniques employed. It may be concluded that several site-specific and technical factors influencedxthe middle- and long-term results of root coverage in multiple GR.


Conversion of retinol to 3,4-didehydroretinol in the tadpole.
The conversion of retinol to 3,4-didehydroretinol in bullfrog tadpoles was studied by injecting [3H] all-trans retinol into the peritoneal cavity. The specific activities of retinoids in the eye and the rest of the body at various time intervals after the injection were then determined by HPLC (high-performance liquid chromatography). Radioactivity was observed in ocular 3,4-didehydroretinyl esters after 2 days and their specific activity increased throughout the 2 weeks of experiment. This demonstrates that tadpoles can convert retinol to its 3,4-didehydro derivative. In vitro experiments performed on isolated eye cups also suggested that the ocular tissues could convert retinol to 3,4-didehydroretinol. In the eye, the specific activity of porphyropsin or all-trans 3,4-didehydroretinal (extracted by the denaturing solvent acetone) exceeded that of the all-trans 3,4-didehydroretinyl esters in storage. This suggests that the main ocular store of 3,4-didehydroretinyl esters does not constitute a precursor pool for porphyropsin synthesis.


Association of Mutation Profiles with Postoperative Survival in Patients with Non-Small Cell Lung Cancer.
Findings on mutations, associated with lung cancer, have led to advancements in mutation-based precision medicine. This study aimed to comprehensively and synthetically analyze mutations in lung cancer, based on the next generation sequencing data of surgically removed lung tumors, and identify the mutation-related factors that can affect clinical outcomes. Targeted sequencing was performed on formalin-fixed paraffin-embedded surgical specimens obtained from 172 patients with lung cancer who underwent surgery in our hospital. The clinical and genomic databases of the hospital were combined to determine correlations between clinical factors and mutation profiles in lung cancer. Multivariate analyses of mutation-related factors that may affect the prognosis were also performed. Based on histology, TP53 was the driver gene in 70.0% of the cases of squamous cell carcinoma. In adenocarcinoma cases, driver mutations were detected in TP53 (26.0%), KRAS (25.0%), and epidermal growth factor receptor (EGFR) (23.1%). According to multivariate analysis, the number of pathogenic mutations (≥3), presence of a TP53 mutation, and TP53 allele fraction >60 were poor prognostic mutational factors. The TP53 allele fraction tended to be high in caudally and dorsally located tumors. Moreover, TP53-mutated lung cancers located in segments 9 and 10 were associated with significantly poorer prognosis than those located in segments 1-8. This study has identified mutation-related factors that affect the postoperative prognosis of lung cancer. To our knowledge, this is the first study to demonstrate that the TP53 mutation profile varies with the site of lung tumor, and that postoperative prognosis varies accordingly.


Do patients with chronic pain diseases believe in guardian angels: even in a secular society? A cross-sectional study among German patients with chronic diseases.
We intended to analyze whether patients with chronic diseases believe in guardian angels (GdA) as a coping resource. In a cross-sectional survey, we analyzed data from 576 German patients with chronic diseases (mean age 51.3 ± 15.4 years). We found that 56 % of the patients often or even regularly believed in GdA, with significantly more women than men believing. Particularly interesting was the fact that 38 % of patients who were identified as neither religious nor spiritual (R-S-) believed in GdAs. This belief may indicate that patients are interested in bridging the gap between the concrete struggle to manage illness and non-rational/transcendent realms.


Characterization of an antifreeze protein from the polar diatom Fragilariopsis cylindrus and its relevance in sea ice.
Antifreeze proteins (AFPs), characterized by their ability to separate the melting and growth temperatures of ice and to inhibit ice recrystallization, play an important role in cold adaptation of several polar and cold-tolerant organisms. Recently, a multigene family of AFP genes was found in the diatom Fragilariopsis cylindrus, a dominant species within polar sea ice assemblages. This study presents the AFP from F. cylindrus set in a molecular and crystallographic frame. Differential protein expression after exposure of the diatoms to environmentally relevant conditions underlined the importance of certain AFP isoforms in response to cold. Analyses of the recombinant AFP showed freezing point depression comparable to the activity of other moderate AFPs and further enhanced by salt (up to 0.9°C in low salinity buffer, 2.5°C at high salinity). However, unlike other moderate AFPs, its fastest growth direction is perpendicular to the c-axis. The protein also caused strong inhibition of recrystallization at concentrations of 1.2 and 0.12 μM at low and high salinity, respectively. Observations of crystal habit modifications and pitting activity suggested binding of AFPs to multiple faces of the ice crystals. Further analyses showed striations caused by AFPs, interpreted as inclusion in the ice. We suggest that the influence on ice microstructure is the main characteristic of these AFPs in sea ice.


rBAT, related to L-cysteine transport, is localized to the microvilli of proximal straight tubules, and its expression is regulated in kidney by development.
We have recently isolated a renal cDNA clone (rBAT) that induces amino acid transport in oocytes either as a component or as a specific activator of a system bo,(+)-like transporter. (Bertran, J., Werner, A., Moore, M. L., Stange, G., Markovich, D., Biber, J., Testar, X., Zorzano, A., Palacín, M., and Murer, H. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 5601-5605. In order to obtain additional information on the rBAT protein, we have investigated the cellular localization of rBAT and its expression during development in rat kidney. A polyclonal antibody raised against rBAT recognizes a specific protein band of approximately 90 kDa, which is highly enriched in rat renal brush border membranes. Immunofluorescence and immunoelectron microscopy studies demonstrated that rBAT is expressed in the microvilli domain of S3 epithelial cells (i.e. straight tubules). The onset of rBAT mRNA expression in kidney was detected during late fetal life. In keeping with this, induction in oocytes of L-cystine uptake due to fetal rBAT-related mRNA was approximately 10% of the induction obtained with rBAT-related mRNA from adult kidneys. rBAT mRNA levels were low in early postnatal life, and only at the end of lactation did they increase steeply, attaining approximately 50% of adult values after weaning. rBAT protein was undetectable in total membrane preparations of kidneys from fetuses and early neonates, weakly detected during lactation, and represented < 15% of adult values after weaning. The postnatal expression of rBAT and its specific location in the microvilli of epithelial cells from the S3 segment of the proximal tubule coincide with postnatal maturation of cystine resorption and with the site of high affinity resorption of cysteine in kidney. This is consistent with the involvement of rBAT in a b(o,+)-like high-affinity resorption system for cysteine in the proximal straight tubule of the nephron.


Decoding the annulus fibrosus cell atlas by scRNA-seq to develop an inducible composite hydrogel: A novel strategy for disc reconstruction.
Low back pain is one of the most serious public health problems worldwide and the major clinical manifestation of intervertebral disc degeneration (IVDD). The key pathological change during IVDD is dysfunction of the annulus fibrosus (AF). However, due to the lack of an in-depth understanding of AF biology, the methods to reconstruct the AF are very limited. In this study, the mice AF cell atlas were decoded by single-cell RNA sequencing to provide a guide for AF reconstruction. The results first identify a new population of AF cells, fibrochondrocyte-like AF cells, which synthesize both collagen I and collagen II and are potential functional cells for AF reconstruction. According to the dual features of the AF extracellular matrix, a composite hydrogel based on the acylation of methacrylated silk fibroin with methacrylated hyaluronic acid was produced. To obtain the ability to stimulate differentiation, the composite hydrogels were combined with a fibrochondrocyte-inducing supplement. Finally, reconstruction of the AF defects, by the novel AF stem cell-loaded composite hydrogel, could be observed, its amount of chondroid matrices recovered to 31.7% of AF aera which is significantly higher than that in other control groups. In summary, this study decodes the AF cell atlas, based on which a novel strategy for AF reconstruction is proposed.


Inhibitor of growth 4 induces NFκB/p65 ubiquitin-dependent degradation.
As a tumor suppressor protein, the inhibitor of growth 4 (ING4) has an important role in many cellular processes including cell cycle progression, proliferation, apoptosis, DNA damage response, tumor angiogenesis and contact inhibition. Here, we report that ING4 functions as an E3 ubiquitin ligase to induce nuclear factor-κB (NFκB)/p65 degradation. The plant homeodomain finger of ING4 interacted with p65 to undergo robust ubiquitination and degradation. ING4 bound to p65 and delivered the Lys-48-linked polyubiquitin to Lys-62 residue of p65, leading to ubiquitination of p65 and degradation. Lys-62 residue of p65 was required for ING4-mediated ubiquitination of p65 and degradation. Further analysis shows that C239 of ING4 was critical for ING4-induced p65 degradation. These findings demonstrate that ING4 acts as an E3 ubiquitin ligase to induce ubiquitination of p65 and degradation, which is critical to terminate NFκB activation.


Incidence and Outcomes of Non-ST Elevation Myocardial Infarction in Patients Hospitalized with Decompensated Diabetes.
Single center studies suggested that non-ST elevation myocardial infarction (NSTEMI) in patients admitted with acute decompensated diabetes is associated with poor long-term prognosis. We hypothesize that acute decompensated diabetes is also associated with worse early morbidity and mortality in patients admitted with NSTEMI. Adult patients with a primary discharge diagnosis of diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS) were identified in the national inpatient sample. We then assessed contemporary trends in the incidence and management patents of NSTEMI in patients admitted with DKA/HHS and compared in-hospital morbidity and mortality, resource utilization, and cost between DKA/HHS patients with and without NSTEMI. In 431,037 patients admitted with decompensated diabetes from 2003 to 2014, 13,069 (3.03%) suffered a NSTEMI during their hospitalization. Patients with NSTEMI were older and had higher prevalence of atherosclerotic and nonatherosclerotic comorbidities. After propensity score matching, NSTEMI was associated with a 60% increase in in-hospitalmortality (9.1% vs 5.5%; p < 0.001), higher incidences of stroke, acute kidney injury, blood transfusion, longer hospitalizations, and higher costs. A minority (35%) ofNSTEMI patients underwent invasive coronary assessment, and those had lower in-hospitalmortality compared with NSTEMI patients who did not undergo invasive assessment(3.3% vs 12.2%, adjusted OR 0.30, 95%CI 0.24 to 0.36, p < 0.001). About 3% of patients admitted with decompensated diabetes suffer a NSTEMI and those experience higher in-hospital morbidity and mortality, longer hospitalization, and higher cost.


Frontotemporal Dementia.
Frontotemporal dementia (FTD) is a not-uncommon explanation for progressive cognitive deficit in patients who often have a genetic susceptibility for such a neurodegenerative process. However, FTD does not seem to identify one particular pathogenetic mechanism but rather a spectrum of pathologies with particular predilection for the frontal and temporal lobes of the brain. There have been various subcategorizations of this form of dementia that have a tendency to be of earlier onset than typical Alzheimer disease and heralded by behavioral or communication manifestations. There is a behavioral variant and a language variant, referred to as primary progressive aphasia.


rGREAT: an R/bioconductor package for functional enrichment on genomic regions.
GREAT (Genomic Regions Enrichment of Annotations Tool) is a widely used tool for functional enrichment on genomic regions. However, as an online tool, it has limitations of outdated annotation data, small numbers of supported organisms and gene set collections, and not being extensible for users. Here, we developed a new R/Bioconductorpackage named rGREAT which implements the GREAT algorithm locally. rGREAT by default supports more than 600 organisms and a large number of gene set collections, as well as self-provided gene sets and organisms from users. Additionally, it implements a general method for dealing with background regions. The package rGREAT is freely available from the Bioconductor project: https://bioconductor.org/packages/rGREAT/. The development version is available at https://github.com/jokergoo/rGREAT. Gene Ontology gene sets for more than 600 organisms retrieved from Ensembl BioMart are presented in an R package BioMartGOGeneSets which is available at https://github.com/jokergoo/BioMartGOGeneSets. Supplementary data are available at Bioinformatics online.


RNA-binding protein RBM24 represses colorectal tumourigenesis by stabilising PTEN mRNA.
RNA-binding motif protein 24 (RBM24) functions as a splicing regulator, which is critical for organ development and is dysregulated in human cancers. Here, we aim to uncover the biological function of RBM24 in colorectal tumourigenesis. Xenograft tumour model, Rbm24 knockout and Apcmin/+ mouse models were utilised. Colorectal cancer cells overexpressing or silencing RBM24 were established. RNA immunoprecipitation (RIP) assay was conducted to detect protein-RNA associations. Gene expression was measured by immunohistochemistry, western blotting, or quantitative PCR (qPCR). Rbm24-knockout mice developed spontaneous colorectal adenomas with lower expression of phosphatase and tensin homolog (PTEN). Immunohistochemical staining for the proliferation markers Ki-67 and pHH3 and BrdU assay showed intestinal hyperplasia in Rbm24-knockout mice compared to wild-type mice. RBM24 expression in colorectal adenoma tissues of Apcmin/+ mouse was downregulated compared with adjacent normal samples and was positively correlated with PTEN expression. In vitro, RBM24 overexpression suppressed cell proliferation, migration, invasion and increased sensitivity to 5-FU or cisplatin in CRC cells. Mechanistically, RBM24 maintained PTEN mRNA stability by directly binding to the GT-rich region at positions 8101-8251 in the 3'-UTR of PTEN mRNA, prolonging the half-life of PTEN mRNA, thereby increasing PTEN expression. Hence, low expression of RBM24 downregulated PTEN mRNA, causing the activation of PI3K-Akt signalling in CRC cells. Furthermore, RBM24 expression in CRC tissues was lower than adjacent normal samples. RBM24 expression was positively correlated with PTEN expression and negatively correlated with Ki-67 level. CRC patients with high RBM24 expression had a favourable outcome. Taken together, RBM24 expression is markedly lower in colorectal tumours than in para-carcinoma tissues. Rbm24-knockout mice develop spontaneous colorectal adenomas. RBM24 directly binds and stabilises PTEN mRNA, which could cause the suppression of CRC cell proliferation, migration and invasion, thereby repressing colorectal tumourigenesis. These findings support the tumour-suppressive role of RBM24. Targeting RBM24 holds strong promise for the diagnosis and treatment of CRC.


Apoptotic SKOV3 cells stimulate M0 macrophages to differentiate into M2 macrophages and promote the proliferation and migration of ovarian cancer cells by activating the ERK signaling pathway.
Ovarian cancer has a high rate of recurrence, with M2 macrophages having been found to be involved in its progression and metastasis. To examine the relationship between macrophages and ovarian cancer in the present study, M0 macrophages were stimulated with apoptotic SKOV3 cells and it was found that these macrophages promoted tumor proliferation and migration. Subsequently, the mRNAs and proteins expressed at high levels in these M2 macrophages were examined by RNA‑Seq and quantitative proteomics, respectively, which revealed that M0 macrophages stimulated by apoptotic SKOV3 cells also expressed M2 markers, including CD206, interleukin‑10, C‑C motif chemokine ligand 22, aminopeptidase‑N, disabled homolog 2, matrix metalloproteinase 1 and 5'‑nucleotidase. The abundance of phosphorylated Erk1/2 in these macrophages was increased. The results indicate that apoptotic SKOV3 cells stimulate M0 macrophages to differentiate into M2 macrophages by activating the ERK pathway. These results suggest possible treatments for patients with ovarian cancer who undergo chemotherapy; inhibiting M2 macrophage differentiation during chemotherapy may reduce the rate of tumor recurrence.


Long-term survival of young women receiving fertility-sparing surgery for ovarian cancer in comparison with those undergoing radical surgery.
To compare the clinical outcome of patients with stage I epithelial ovarian cancer (EOC) who received with fertility-sparing surgery (FSS) with those who underwent radical surgery (RS). After a central pathological review and search of the medical records from multiple institutions, a total of 572 patients were retrospectively evaluated. All patients were divided into three groups: group A {FSS (n=74); age, ≤ 40}; groups B and C [RS; age, 40 ≥{(B), n=52}; 40<{(C), n=446}]. Five-year overall survival (OS) and disease-free survival (DFS) rates of patients in the groups were as follows: group A, 90.8% (OS)/87.9% (DFS); group B, 88.3% (OS)/84.4% (DFS); group C, 90.6% (OS)/85.3% (DFS), respectively (OS, P=0.802; DFS, P=0.765). Additionally, there was no significant difference in OS and DFS among the three groups stratified to stage IA or IC (OS (IA), P=0.387; DFS (IA), P=0.314; OS (IC), P=0.993; DFS (IC), P=0.990, respectively). Furthermore, patients with a grade 1-2 or 3 tumours in the FSS group did not have a poorer prognosis than those in the RS group. Stage I EOC patients treated with FSS showed an acceptable prognosis compared with those who underwent RS.


ATP-dependent and DCCD-insensitive Cl- uptake by membrane vesicles from the rat brain plasma membrane fractions.
ATP-dependent Cl- uptake by membrane vesicles from the rat brain plasma membrane fractions was not affected by the addition of 40 mM of K+, Na+ or HCO3- to the assay medium. Na+ and K+ did not alter the uptake even in the presence of a K+ ionophore, valinomycin (10 microM), or a H+/K+ exchanger, nigericin (10 microM), whereas in the presence of both of these ionophores, K+, but not Na+, reduced the Cl- uptake. Inhibitors of proton pump activity, N,N'-dicyclohexylcarbodiimide (1 mM) and 5-(N,N-hexamethylene)amiloride (40 microM), however, did not affect the Cl- uptake. These findings suggest the presence of a primary Cl- transport system probably associated with passive H+ flux in the brain plasma membranes.


Fast optical cooling of a nanomechanical cantilever by a dynamical Stark-shift gate.
The efficient cooling of nanomechanical resonators is essential to exploration of quantum properties of the macroscopic or mesoscopic systems. We propose such a laser-cooling scheme for a nanomechanical cantilever, which works even for the low-frequency mechanical mode and under weak cooling lasers. The cantilever is coupled by a diamond nitrogen-vacancy center under a strong magnetic field gradient and the cooling is assisted by a dynamical Stark-shift gate. Our scheme can effectively enhance the desired cooling efficiency by avoiding the off-resonant and undesired carrier transitions, and thereby cool the cantilever down to the vicinity of the vibrational ground state in a fast fashion.


Hedgehog-responsive PDGFRa(+) fibroblasts maintain a unique pool of alveolar epithelial progenitor cells during alveologenesis.
The lung alveolus is lined with alveolar type 1 (AT1) and type 2 (AT2) epithelial cells. During alveologenesis, increasing demand associated with expanding alveolar numbers is met by proliferating progenitor AT2s (pAT2). Little information exists regarding the identity of this population and their niche microenvironment. We show that during alveologenesis, Hedgehog-responsive PDGFRa(+) progenitors (also known as SCMFs) are a source of secreted trophic molecules that maintain a unique pAT2 population. SCMFs are in turn maintained by TGFβ signaling. Compound inactivation of Alk5 TβR2 in SCMFs reduced their numbers and depleted the pAT2 pool without impacting differentiation of daughter cells. In lungs of preterm infants who died with bronchopulmonary dysplasia, PDGFRa is reduced and the number of proliferative AT2s is diminished, indicating that an evolutionarily conserved mechanism governs pAT2 behavior during alveologenesis. SCMFs are a transient cell population, active only during alveologenesis, making them a unique stage-specific niche mesodermal cell type in mammalian organs.


Determining HIV risk for Adolescent Girls and Young Women (AGYW) in relationships with "Blessers" and age-disparate partners: a cross-sectional survey in four districts in South Africa.
HIV incidence among adolescent girls and young women (AGYW) remains high, with their male partners a prominent factor in sustaining these elevated rates. Partnership characteristics remain important metrics for determining HIV risk, with evidence indicating that AGYW engaged in transactional and age-disparate relationships face greater HIV exposure. This study examines the risk posed to AGYW in a relationship with a "Blesser", defined as male who provides his female partner with their material needs or desires in exchange for a sexual relationship, an age-disparate (5 or more years older) partner, and the potential compounded risk of being a relationship with a partner or partners who are considered both a "Blesser" and age-disparate. A cross -sectional household based representative sample of AGYW (aged between 12-24 years) were enrolled in the study (n = 18 926) from the districts of City of Johannesburg and Ekurhuleni in the Gauteng province and the Districts of eThekwini and uMgungundlovu in the province of KwaZulu-Natal (KZN) in South Africa between March 13, 2017 to June 22, 2018. Participants completed a structured questionnaire and provided finger-prick blood samples for laboratory measurements. Our analysis used descriptive statistics and multiple binary logistic regressions accounting for survey weights, clustering and stratification. The median age of the sample was 21 years old (Interquartile range: 19-23) and nearly three quarters (73.7%) were currently attending school. Whilst all relationships exposed AGYW to potential HIV risk, multiple binary logistic regression analysis revealed that AGYW in a relationship with both a Blesser and an age-disparate partner were more likely to be HIV positive (AOR: 3.12, 95% CI: 1.76-5.53, p < 0.001), diagnosed with an STI (AOR: 4.60, 95% CI: 2.99-7.08, p < 0.001), had 2 or more sexual partners in the previous 12 months (AOR: 6.37, 95% CI: 3.85-10.54, p < 0.001), engaged in sexual activity at age 15 or younger (AOR: 3.67, 95% CI: 2.36-5.69, p < 0.001) and more likely to have ever been pregnant (AOR: 2.60, 95% CI: 1.24-5.45, p < 0.05) than those not in a relationship with either a Blesser or age-disparate partner. Different relationships present different HIV risk to AGYW. AGYW who had engaged in relationships with both a Blesser and an age-disparate partner were at greater HIV risk when examined against these relationships independent of one another. The data reveals the compounded HIV risk of being in both a transactional and age-disparate relationship.


Repurposing Fostamatinib to Combat SARS-CoV-2-Induced Acute Lung Injury.
A screen by Kost-Alimova et al.1 suggests that the FDA-approved SYK inhibitor fostamatinib inhibits MUC1 in the respiratory tract and has the potential to treat serious outcomes of coronavirus COVID-19, including acute respiratory distress syndrome (ARDS) and acute lung injury (ALI).


Multifocal intraocular lenses in cataract surgery: literature review of benefits and side effects.
This literature review looks at the current status of multifocal intraocular lenses (IOLs) in cataract surgery. The results of implantation of multifocal IOLs of diffractive, refractive, and hybrid diffractive-refractive design are described with regard to uncorrected near and distance visual acuity and spectacle independence. The occurrence of photic phenomena and contrast sensitivity loss with multifocal IOLs are also addressed. Neither author has a financial or proprietary interest in any material or method mentioned.


Dysregulated tumor-associated macrophages in carcinogenesis, progression and targeted therapy of gynecological and breast cancers.
Gynecological and breast cancers are a group of heterogeneous malignant tumors. Although existing treatment strategies have ameliorated the clinical outcomes of patients, the overall survival rate of advanced diseases remains unsatisfactory. Increasing evidence has indicated that the development and prognosis of tumors are closely related to the tumor microenvironment (TME), which restricts the immune response and provokes malignant progression. Tumor-associated macrophages (TAMs) are the main component of TME and act as a key regulator in tumor metastasis, immunosuppression and therapeutic resistance. Several preclinical trials have studied potential drugs that target TAMs to achieve potent anticancer therapy. This review focuses on the various functions of TAMs and how they influence the carcinogenesis of gynecological and breast cancers through regulating cancer cell proliferation, tumor angiogenesis and tumor-related immunosuppression. Besides, we also discuss the potential application of disabling TAMs signaling as a part of cancer therapeutic strategies, as well as CAR macrophages, TAMs-based vaccines and TAMs nanobiotechnology. These research advances support that targeting TAMs combined with conventional therapy might be used as effective therapeutics for gynecological and breast cancers in the future.


High-efficiency grating coupler for an ultralow-loss Si3N4-based platform.
Integrated silicon nitride waveguides of 100 nm height can achieve ultralow propagation losses below 0.1 dB/cm at the 1550 nm wavelength band but lack the scattering strength to form efficient grating couplers. An enhanced grating coupler design based on an amorphous silicon layer on top of silicon nitride is proposed and demonstrated to improve the directionality of the coupler. The fabrication process is optimized for a self-alignment process between the amorphous silicon and silicon nitride layers without increasing waveguide losses. Experimental coupling losses of 5 dB and a 3 dB bandwidth of 75 nm are achieved with both regular and focusing designs.


Phosphorylation of the alpha-chain of fibrinogen by a platelet kinase activity enhanced by interferon.
Treatment of patients with interferon or inducers of interferon results in an enhanced level of a protein kinase activity found in platelets (1,3). The kinase activity is responsible for the phosphorylation of a 70-72,000 molecular weight protein (72K protein) found in blood plasma. By the means of a technique based on the precipitation of this protein kinase system (the protein kinase and its substrate), we show here that the 72K protein is the alpha-chain of fibrinogen. During the coagulation process induced by thrombin, the 32P-labelled 72K protein is recovered in the clot. After incubation in the presence of thrombin, the 72K protein looses a small polypeptide of 2-3000 in molecular weight resulting a shift in its isoelectric point (pI) from 6.8-7.0 to 7.5. At the end of the coagulation process, the 32P-labelled 72K protein becomes undetectable since it gives rise to a covalently linked alpha-polymer of a high molecular weight. In accord with these results, the 72K protein could be precipitated by antibodies against human fibrinogen.


Species variation in bladder cell and liver cell activation of acetylaminofluorene.
The metabolism and mutagenicity of 2-acetylaminofluorene were measured using freshly prepared intact bladder and liver cells from the cow, dog and rat. High pressure liquid chromatography was used to separate 2-acetylaminofluorene metabolites, and Salmonella typhimurium, strain TA98, was used to detect mutagenic intermediates. Species differences as well as animal-to-animal variation within a species were observed. Mutagenic activity with 2-acetylaminofluorene was greater with cow bladder cells than with dog or rat bladder cells. However, dog bladder cells were most active in metabolizing 2-acetylaminofluorene, and rat bladder cells were least active. Liver cells from all three species metabolized 2-acetylaminofluorene to mutagens for Salmonella, with dog and cow cells being more active than rat liver cells. However, cow liver cells were the most active in metabolizing 2-acetylaminofluorene, followed by rat and dog cells. With all cell types studied, except rat bladder cells, aminofluorene was the major metabolite detected. Carbon and N-hydroxylated products were produced by liver and bladder cells of the three species and glucuronide and sulfate conjugates of the metabolites were detected from both cell types. Correlations between mutagenic activity and the level of metabolism or any individual metabolite were not apparent. The data suggest that the relative contribution of bladder cell metabolism in aromatic amine induced bladder cancer may vary with the species.


The psychosocial outcomes of individuals with hematological cancers: Are we doing enough high quality research, and what is it telling us?
This systematic review assessed the quantity and quality of research examining the psychosocial outcomes among hematological cancer patients. Studies were categorised as either measurement, descriptive or intervention. Intervention studies were further assessed according to Effective Practice and Organisation of Care (EPOC) methodological criteria. A total of 261 eligible papers were identified. The number of publications increased by 8.8% each year (95% CI=7.5-10.2%; p<0.0001). The majority of studies were descriptive (n=232; 89%), with few measurement (n=8; 3%) and intervention (n=21; 8%) studies identified. Ten intervention studies met EPOC design criteria, however only two interventions, one targeted at individuals with Hodgkin's or Non-Hodgkin's lymphoma and one targeted at individuals with leukaemia, lymphoma or myelomatosis were successful in improving patients' psychosocial outcomes. Despite an increasing volume of research examining psychosocial outcomes of hematological cancer patients, there is a need for robust measurement and methodologically rigorous intervention research in this area.


A study on As, Cu, Pb and Zn (bio)availability in an abandoned mine area (São Domingos, Portugal) using chemical and ecotoxicological tools.
The aim of this study was to relate the results obtained by chemical methods, used to assess environmental (bio)availability, with the ecotoxic response and bioaccumulation of trace elements (TE) by the earthworm Eisenia fetida exposed to field-contaminated, metal-polluted soils from a sulphide mine. The extracting solution 0.5 M NH4CH3COO, 0.5 M CH3COOH and 0.02 M EDTA (pH 4.7), was able to predict environmental bioavailability of TE to E. fetida. However, the toxicological bioavailability could not be predicted from the results of the chemical extractions or from the bioaccumulation results: E. fetida reproduction was higher in soils where environmental bioavailability of TE and bioaccumulation values were also higher. In this study, the toxic response of the organism seemed to be more influenced by the overall nutritional status of the soil (e.g. pH, organic matter, plant nutrient availability and cation exchange capacity) than by its TE contamination. In the case of anthropogenic multi-contaminated sites, the different soil characteristics exert an important and confounding influence in the toxic response and the relationship between different bioavailable fractions cannot be easily established, emphasising the need to combine results from chemical methods with those from bioassays when evaluating the bioavailability of TE in these soils.


Extensive Tumor Thrombosis of Portal Venous System Demonstrated on 68Ga-DOTATATE and 68Ga-NODAGA-LM3 PET/CT in a Patient With Well-Differentiated Neuroendocrine Tumor.
We present a case with a pancreatic neuroendocrine tumor and extensive tumor thrombosis in portal venous system. The tumor was first identified on contrast-enhanced CT and later confirmed using Ga-DOTATATE and Ga-NODAGA-LM3 PET/CT. Both tracers demonstrated similar pattern with higher tumor affinity and tumor-to-background ratio using Ga-NODAGA-LM3.


A Study of Correlation of Various Growth Indicators with Chronological Age.
The aim of this study was to assess the relationship of chronological age with cervical vertebrae skeletal maturation, frontal sinus width and antegonial notch depth and a correlation, if any, among the three variables. The samples were derived from lateral cephalometric radiographs of 80 subjects (40 males, 40 females; age range: 10 to 19 years). Cervical vertebral development was evaluated by the method of Hassel and Farman, frontal sinus width was measured by the method described by Ertürk and antegonial notch depth as described by Singer et al. The Pearson's correlation coefficients were estimated to assess the relationship of chronological age with cervical vertebrae skeletal maturation, frontal sinus width and antegonial notch depth. The Pearson's correlation coefficient were 0.855 (p < 0.001) between chronological age and cervical vertebrae skeletal maturation, and 0.333 (p < 0.001) between chronological age and frontal sinus width. A highly significant positive correlation was found between chronological age and cervical vertebrae skeletal maturation, and between chronological age and frontal sinus width. Nonsignificant correlation was found between chronological age and antegonial notch depth. How to cite this article: Singh S, Sandhu N, Puri T, Gulati R, Kashyap R. A Study of Correlation of Various Growth Indicators with Chronological Age. Int J Clin Pediatr Dent 2015;8(3): 190-195.


Biofortification of iron and zinc in rice and wheat.
Iron and zinc are critical micronutrients for human health. Approximately two billion people suffer from iron and zinc deficiencies worldwide, most of whom rely on rice (Oryza sativa) and wheat (Triticum aestivum) as staple foods. Therefore, biofortifying rice and wheat with iron and zinc is an important and economical approach to ameliorate these nutritional deficiencies. In this review, we provide a brief introduction to iron and zinc uptake, translocation, storage, and signaling pathways in rice and wheat. We then discuss current progress in efforts to biofortify rice and wheat with iron and zinc. Finally, we provide future perspectives for the biofortification of rice and wheat with iron and zinc.


Habitat shifts in rainbow trout: competitive influences of brown trout.
We compared habitat use by rainbow trout sympatric (three streams) and allopatric (two streams) with brown trout to determine whether competition occurred between these two species in the southern Appalachian Mountains. We measured water depth, water velocity, substrate, distance to overhead vegetation, sunlight, and surface turbulence both where we collected trout and for the streams in general. This enabled us to separate the effects of habitat availability from possible competitive effects. The results provided strong evidence for asymmetrical interspecific competition. Habitat use varied significantly between allopatric and sympatric rainbow trout in 68% of the comparisons made. Portions of some differences refelected differences in habitats available in the several streams. However, for all habitat variables measured except sunlight, rainbow trout used their preferred habitats less in sympatry with brown trout than in allopatry if brown trout also preferred the same habitats. Multivariate analysis indicated that water velocity and its correlates (substrate particle size and surface turbulence) were the most critical habitat variables in the interaction between the species, cover in the form of shade and close overhead vegetation was second most important, and water depth was least important.


Contrast-enhanced ultrasound to ultrasound fusion during microwave ablation: feasibility study in a perfused porcine liver model.
To obtain a complete response with thermal ablation, the margin and entire tumor volume must be treated. Real-time ultrasound visualization is limited during ablation due to gas production. This study assesses the feasibility of fusing volumetric contrast-enhanced ultrasound (CEUS), obtained immediately prior to microwave ablation, with real-time CEUS during and following ablation in a machine-perfused porcine liver. Ten, 3-4 cm microwave ablations were performed in five explanted perfused livers. Prior to ablation, microbubbles were injected into the vasculature while an ultrasound sweep across the liver captured a volumetric image during maximum enhancement. This volumetric image was then fused to overlay the real-time ultrasound imaging. Since the perfused livers did not have tumors, a spherical marker circumscribing a target volume was placed on the images. Approximatively, 75% of the total intended circumscribed spherical volume was ablated. Following ablation, a second bolus injection of ultrasound contrast was administered demonstrating continued enhancement of the intentionally non-ablated 25%. A second volumetric image of the post-ablation CEUS was then fused to overlay the real-time ultrasound images for guidance during ablation of the remaining enhancing volume. Technical success was achieved in 100% of the cases. The pre- and then the post-ablation CEUS volume was fused with real-time imaging during antenna placement for initial and subsequent ablation. CEUS-CEUS fusion during thermal ablation is feasible and greatly improves the workflow. The approach may augment the use of dynamic CEUS for guidance, improving antenna placement, and aiding in the identification and ablation of initial and residual enhancing tissue.


Doubling Förster Resonance Energy Transfer Efficiency in Proteins with Extrinsic Thioamide Probes: Implications for Thiomodified Nucleobases.
Designing a potential protein-ligand pair is pivotal, not only to track the protein structure dynamics, but also to assist in an atomistic understanding of drug delivery. Herein, the potential of a small model thioamide probe being used to study albumin proteins is reported. By monitoring the Förster resonance energy transfer (FRET) dynamics with the help of fluorescence spectroscopic techniques, a twofold enhancement in the FRET efficiency of 2-thiopyridone (2TPY), relative to that of its amide analogue, is observed. Molecular dynamics simulations depict the relative position of the free energy minimum to be quite stable in the case of 2TPY through noncovalent interactions with sulfur, which help to enhance the FRET efficiency. Finally, its application is shown by pairing thiouracils with protein. It is found that the site-selective sulfur atom substitution approach and noncovalent interactions with sulfur can substantially enhance the FRET efficiency, which could be a potential avenue to explore in the design of FRET probes to study the structure and dynamics of biomolecules.


The downside of 'inappropriate messaging': new insight into the development of testicular germ cell tumours in young men?
How invasive testicular germ cell tumours (TGCTs) develop from precursor carcinoma in situ/intratubular germ cell neoplasia unclassified (CIS/IGCNU) cells, and only after puberty, is unknown. In the current issue of The Journal of Pathology, Jørgensen and colleagues have compared the protein expression profile of CIS before and after puberty and in pre-invasive versus invasive TGCT and show that the mitosis-meiosis controller DMRT1 switches off in CIS cells postpubertally and is associated with invasiveness. They also show that CIS cells express a 'confusing' mix of pro- and anti-meiotic proteins; this may predispose CIS cells to accumulate extra chromosomal material which ultimately leads to tumourigenesis.


Older cancer patients' information and communication needs: what they want is what they get?
To evaluate what information and communication aspects older cancer patients (≥65) consider important in preparing for chemotherapy treatment (CT), the extent to which this corresponds with what oncology nurses consider important, and the extent to which nurses attend to these aspects during real-life educational visits in oncology. The QUOTE(chemo) was used to have patients (n=116) and nurses (n=123) rate the importance of 66 aspects of patient education. Subsequently, the implementation of these 66 aspects during videotaped nursing visits (n=155) with older cancer patients receiving CT for the first time was examined. Older cancer patients attached most importance to 'treatment-related information', 'rehabilitation information', 'affective communication' and discussing 'realistic expectations'. Nurses placed great importance to almost all aspects except to discussing 'realistic expectations'. Discrepancies were found between expressed importance and the actual performance during the videotaped consultations, particularly in discussing realistic expectations, coping information, interpersonal communication, and tailored communication. Results pointed to aspects that need improvement to ensure high quality patient education tailored to the patients' needs. To make sure older cancer patients' needs are met, more attention should be paid to the development of interventions supporting both needs assessment and fulfillment.


Integrated dose-response metabolomics with therapeutic effects and adverse reactions may demystify the dosage of traditional Chinese medicine.
Traditional Chinese medicine (TCM) has been used to treat various diseases for thousands of years. However, the uncertainty of dosage as well as the lack of systemic evaluation of pharmacology and toxicology is one major reason why TCM remains mysterious and is not accepted worldwide. Hence, we aimed to propose an integrated dose-response metabolomics strategy based on both therapeutic effects and adverse reactions to guide the TCM dosage in treatment. The proposed methodology of integrated dose-response metabolomics includes four steps: dose design, multiple comparison of metabolic features, response calculation and dose-response curve fitting. By comparing the changes of all metabolites under different doses and calculating these changes through superposition, it is possible to characterize the global disturbance and thus describe the overall effect and toxicity of TCM induced by different doses. Rhubarb, commonly used for constipation treatment, was selected as a representative TCM. This developed strategy was successfully applied to rhubarb. The dose-response curves clearly showed the efficacy and adverse reactions of rhubarb at different doses. The rhubarb dose of 0.69 g/kg (corresponding to 7.66 g in clinic) was selected as the optimal dose because it was 90% of the effective dose and three adverse reactions were acceptable in this case. An integrated dose-response metabolomics strategy reflecting both therapeutic effects and adverse reactions was established for the first time, which we believe is helpful to uncover the mysterious veil of TCM dosage. In addition, this strategy benefits the modernization and internationalization of TCM, and broadens the application of metabolomics.


Therapeutic metformin concentrations positively regulate proliferation in endometrial epithelial cells via mTOR activation and augmented mitochondrial strength.
Metformin, an antidiabetic drug, has recently been repositioned in the treatment of several nondiabetic disorders, including reproductive disorders such as polycystic ovarian syndrome, where it improves endometrial functions. In vitro studies employing supratherapeutic concentrations (5-20 mmol/L) of metformin have reported antiproliferative effects on endometrial epithelial and stromal cells. However, animal and human studies have revealed that therapeutic serum concentrations of metformin range between 20 and 70 µmol/L. In the present study, the effect of therapeutic concentrations of metformin was studied on endometrial epithelial cells (EECs). Therapeutic concentrations of metformin induced proliferation in Ishikawa and HEC-1A cells. The proliferation of EECs was found to be mammalian target of rapamycin (mTOR) dependent. Interestingly, therapeutic metformin concentrations were not able to activate the classical AMP-activated protein kinase (AMPK) signaling. On the contrary, supratherapeutic metformin concentration (10 mmol/L) inhibited mTOR and activated AMPK signaling. Microarray analysis of metformin-treated HEC-1A cells revealed dose-dependent differential effects on biological pathways associated with translation, ribosomal RNA processing, mitochondrial translation, and cell proliferation. Therapeutic concentrations of metformin upregulated mitochondrial number as demonstrated by increased MitoTracker™ Red staining and enhanced succinate dehydrogenase expression; however, higher concentration (10 mmol/L) abrogated the same. Our results suggest that therapeutic concentrations of metformin augment mitochondrial strength and induce mTOR-dependent endometrial cell proliferation.


A Randomized Trial on the Effect of Phosphate Reduction on Vascular End Points in CKD (IMPROVE-CKD).
Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain. To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate >1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism. A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m2; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings. In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia. Australian Clinical Trials Registry, ACTRN12610000650099.


Diagnostic yield of combined cranial and large vessel PET/CT, ultrasound and MRI in giant cell arteritis: A systematic review and meta-analysis.
To estimate the diagnostic accuracy of combined cranial and large vessel imaging by PET/CT, ultrasound and MRI for giant cell arteritis (GCA). PubMed, Embase, Cochrane and Web of Science databases were searched from inception till August 31, 2022. Studies were included if they involved patients with suspected GCA and assessed the diagnostic accuracy of combined cranial and large vessel imaging by PET/CT, ultrasound or MRI with the final clinical diagnosis as reference standard. Eleven (1578 patients), 3 (149 patients) and 0 studies were included for the diagnostic accuracy of ultrasound, PET/CT and MRI, respectively. Combined cranial and large vessel ultrasound had a sensitivity of 86% (76-92%) and specificity of 96% (92-98%). PET/CT of both cranial and large vessels yielded a sensitivity of 82% (61-93%) and specificity of 79% (60-90%). No studies assessed both PET/CT and ultrasound, which precluded head-to-head comparison. Addition of large vessel ultrasound to ultrasound of the temporal arteries (7 studies) significantly increased sensitivity (91% versus 80%, p < 0.001) without decrease in specificity (96% versus 95%, p = 0.57). Evaluating cranial arteries in addition to large vessels on PET/CT (3 studies) tended to increase the sensitivity (82% versus 68%, p = 0.07) without decrease in specificity (81% versus 79%, p = 0.70). Combined cranial and large vessel ultrasound and PET/CT provided excellent accuracy for the diagnosis of GCA. Either PET/CT or ultrasound may be preferred depending on setting, expertise and clinical presentation. The diagnostic accuracy of combined cranial and large vessel MRI needs to be determined in future studies.


Prediction of disease comorbidity using explainable artificial intelligence and machine learning techniques: A systematic review.
Disease comorbidity is a major challenge in healthcare affecting the patient's quality of life and costs. AI-based prediction of comorbidities can overcome this issue by improving precision medicine and providing holistic care. The objective of this systematic literature review was to identify and summarise existing machine learning (ML) methods for comorbidity prediction and evaluate the interpretability and explainability of the models. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework was used to identify articles in three databases: Ovid Medline, Web of Science and PubMed. The literature search covered a broad range of terms for the prediction of disease comorbidity and ML, including traditional predictive modelling. Of 829 unique articles, 58 full-text papers were assessed for eligibility. A final set of 22 articles with 61 ML models was included in this review. Of the identified ML models, 33 models achieved relatively high accuracy (80-95%) and AUC (0.80-0.89). Overall, 72% of studies had high or unclear concerns regarding the risk of bias. This systematic review is the first to examine the use of ML and explainable artificial intelligence (XAI) methods for comorbidity prediction. The chosen studies focused on a limited scope of comorbidities ranging from 1 to 34 (mean = 6), and no novel comorbidities were found due to limited phenotypic and genetic data. The lack of standard evaluation for XAI hinders fair comparisons. A broad range of ML methods has been used to predict the comorbidities of various disorders. With further development of explainable ML capacity in the field of comorbidity prediction, there is a significant possibility of identifying unmet health needs by highlighting comorbidities in patient groups that were not previously recognised to be at risk for particular comorbidities.


Purification and some properties of the endogenous, autolytic N-acetylmuramoylhydrolase of Streptococcus faecium, a bacterial glycoenzyme.
The latent form of the endogenous, autolytic N-acetylmuramoylhydrolase of Streptococcus faecium ATCC 9790 was purified to near homogeneity by affinity chromatography on concanavalin A-Sepharose 4B. The latent enzyme had Mr approximately 130,000 on sodium dodecyl sulfate-gel electrophoresis. Upon proteinase treatment (trypsin or endogenous proteinase), the latent form is converted to an active form Mr approximately 87,000. The enzyme was shown to be glycoprotein, containing monomeric and oligomeric glucose substituents. Some of the substrate specificity requirements of this enzyme are described.


Visfatin expression is not associated with adipose tissue abundance in the porcine model.
Visfatin was recently identified as a novel adipokine highly enriched in visceral adipose tissue and suggested to play a role in the pathophysiology of obesity and type 2 diabetes mellitus. However, the biological role of visfatin remains elusive since subsequent studies failed to repeat some of the original findings. We report here the cloning of six porcine visfatin transcript variants, resulting from alternate polyadenylation or alternate splicing of exons. It is further demonstrated that the porcine visfatin gene and protein expression measured in fat tissues correlate negatively with subcutaneous (s.c.), visceral and total body fat tissue weights. Moreover, there was no correlation between visfatin mRNA or protein levels and fasting glucose or insulin. No correlation could be found between circulating visfatin and any of the carcass and metabolic parameters. Our results also demonstrate that the tumor necrosis factor (TNF)alpha increases porcine visfatin gene expression in stromal-vascular (SV) cell cultures, thus suggesting an intermediary role for TNFalpha in visfatin response. In conclusion, our results demonstrate that the porcine visfatin gene cannot be considered as a marker of fat accumulation since the highest visfatin expression levels were associated with the leaner animals.


Metabolism of caffeine by mouse liver microsomes: GSH or cytosol causes a shift in products from 1,3,7-trimethylurate to a substituted diaminouracil.
Incubation of [14C]caffeine with hepatic microsomes from male AKR/J mice resulted in the formation of several metabolites including 1,3,7-trimethylurate and 6-amino-5-(N-formylmethyl-amino)-1,3-dimethyluracil. These two compounds comprised about 60% of products and are major urinary metabolites in several animals. When cytosol was included during incubation, there was a 14-fold increase in yield of the uracil at the expense of the urate; the combination of the two metabolites remained about 60% of total products. Cytosol alone was catalytically inert. Glutathione and other sulfhydryl compounds reproduced the effect of cytosol, and the action of cytosol was accounted for quantitatively by its sulfhydryl content. We propose that an oxidized intermediate of caffeine en route to trimethylurate is reduced by glutathione to the ring-opened uracil derivative.


Ethnobotanical study of traditionally used plants in the municipality of Zavidovići, BiH.
Bosnia and Herzegovina (BiH) is a country with a highly diverse ecosystem, containing over 5000 confirmed taxa of vascular plants. The traditional medicinal use of plants has always played a crucial role and gained in importance in the time of war in the 1990s due to a lack of medical facilities. Still nowadays, the health care system is poorly developed, which altogether makes the region interesting for ethnopharmacological researches. Focusing on the area of Zavidovići Municipality in the central part of the country, we aimed to document the diversity of the used medicinal plants and the knowledge of their therapeutic usages. Data was collected in individual open and semi-structured interviews. Therapeutic uses were classified into 14 disease categories following the International Classification of Primary Care-2 (ICPC-2), a classification system recognized by the World Health Organization's Family of International Classifications (WHO-FIC). Use reports have been used to evaluate the acquired knowledge. The findings revealed a total of 113 species belonging to 46 families. 14 informants well respected for their knowledge in the area listed 77 therapeutic uses for the indicated plants. Based on a comparison with other ethnobotanical surveys of BiH and to other important relating literature, three taxa have not been previously reported in BiH and for 19 species, new medicinal uses were stated. Based on use reports, oral application of remedies is far more common (76,7%) than external application (23,3%), the dominant mode of preparation thereby is an infusion. Usages of most concern were digestive, urological and respiratory diseases, their consensus factor ranging between 0,63 and 0,71. These results summarize the usage of traditional plants among people who are highly valued in their community of Zavidovići Municipality for their knowledge and thereby aim to preserve the indigenous knowledge associated with the medicinal plants of the area.


Pigment exchange of photosystem II reaction center by chlorophyll d.
Pigment exchanges among photosystem reaction centers (RCs) are useful for the identification and functional analysis of chromophores in photosynthetic organisms. Pigment replacement within the spinach Photosystem II RC was performed with Chl d derived from the oxygenic alga Acaryochloris marina, using a protocol similar to that reported previously [Gall et al. (1998) FEBS Lett 434: 88-92] based on the incubation of reaction centers with an excess of other pigments. In this study, we analyzed Chl d-modified monomeric RC which was separated from Chl d-modified dimeric RC by size-exclusion chromatography. Based on the assumption of a constant ratio of two Pheo a molecules per RC, the number of Chl a molecules in Chl d-modified monomeric RCs was found to decrease from six to four. The absorption spectrum of the Chl d-modified monomeric RC at room temperature showed a large peak at 699.5 nm originating from Chl d and a small peak at 672.5 nm orignating from Chl a. Photoaccumulation of the Pheo a- in Chl d-modified monomeric RC, in the presence of sodium dithionate and methyl viologen, did not differ significantly from that in control RC, showing that the Chl d-modified monomeric RC retains its charge separation activity and photochemically active Pheo a.


Is bronchoscopic view a reliable method in diagnosis of tracheobronchial aspergillosis in critically ill non-neutropenic patients?
Pulmonary aspergillosis is the main respiratory fungal infection however; its diagnosis is missed or delayed in critically ill non-neutropenic patients. Despite the utility of fiberoptic bronchoscopy for the evaluation of tracheobronchial aspergillosis (TBA) in immunocompromised patients has been extensively studied, however its utility in critically ill non-neutropenic patients is underestimated. To assess the bronchoscopic changes suspected TBA relative to the microbiological and histopathological aspects in critically ill non-neutropenic patients admitted to respiratory intensive care unit (RICU). We prospectively studied 139 critically ill non-neutropenic patients admitted to RICU and had a clinical suspicion of broncho-pulmonary Aspergillus infection. Those patients were subjected to clinical and bronchoscopic assessment for the evaluation of suspected TBA. Microbiological culture of bronchoalveolar lavage (BAL) and histopathological examination of tracheobronchial biopsies were done. Bronchoscopic changes suspected TBA were found in 48.2% of patients (67/139), where Aspergillus infection was confirmed microbiologically in 59.7% (40/67) and histopathologically in 56.7% (38/67). Of these changes, whitish plaques ± ulcers, pseudomembrane and/or sticky secretion with hyperemic mucosa were detected in 68.7%, 26.9% and 16.4% respectively. These changes were mostly seen in the main bronchi (54/67; 80.6%). The sensitivity, specificity, positive, negative predictive values and overall accuracy of these bronchoscopic changes as compared with BAL fluid results were 83.3%, 70.3%, 53.2%, 91.2% and 74.1% respectively. Bronchoscopy could be a reliable procedure for TBA diagnosis in critically ill non-neutropenic patients. Whitish plaques ± ulcers were the prominent bronchoscopic changes with reasonable diagnostic accuracy for prediction of TBA.


[Development and/or increase of rheumatoid nodules in RA patients following leflunomide therapy].
This is the first description of the development of rheumatoid nodules in 3 rheumatoid arthritis patients following leflunomide therapy. The nodules were localized at typical sites with preference of the extensor side of hands and elbow. One nodule examined histologically revealed the typical architecture of RA nodules. In all 3 patients the time of onset of nodulosis was about 6 months after initiating the leflunomide therapy. In all 3 patients leflunomide was clinically efficacious concerning RA: remission or near remission was achieved. Due to the extent of nodulosis, the leflunomide therapy had to be stopped in 2 patients. Progression and acceleration of nodulosis is well known following MTX therapy in RA patients. It is caused by adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes. Leflunomide has no known influence on adenosine metabolism, so different pathogenetic mechanisms must be assumed for the induction of nodulosis by leflunomide.


The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy.
Cancer is characterized as a complex disease caused by coordinated alterations of multiple signaling pathways. The Ras/RAF/MEK/ERK (MAPK) signaling is one of the best-defined pathways in cancer biology, and its hyperactivation is responsible for over 40% human cancer cases. To drive carcinogenesis, this signaling promotes cellular overgrowth by turning on proliferative genes, and simultaneously enables cells to overcome metabolic stress by inhibiting AMPK signaling, a key singular node of cellular metabolism. Recent studies have shown that AMPK signaling can also reversibly regulate hyperactive MAPK signaling in cancer cells by phosphorylating its key components, RAF/KSR family kinases, which affects not only carcinogenesis but also the outcomes of targeted cancer therapies against the MAPK signaling. In this review, we will summarize the current proceedings of how MAPK-AMPK signalings interplay with each other in cancer biology, as well as its implications in clinic cancer treatment with MAPK inhibition and AMPK modulators, and discuss the exploitation of combinatory therapies targeting both MAPK and AMPK as a novel therapeutic intervention.


Argentinean consensus recommendations for the use of telemedicine in clinical practice in adult people with multiple sclerosis.
The use of telemedicine has quickly increased during of the COVID-19 pandemic. Given that unmet needs and barriers to multiple sclerosis (MS) care have been reported, telemedicine has become an interesting option to the care of these patients. The objective of these consensus recommendations was to elaborate a guideline for the management of people with MS using telemedicine in order to contribute to an effective and high-quality healthcare. A panel of Argentinean neurologist's experts in neuroimmunological diseases and dedicated to the diagnosis, management,and care of MS patients gathered virtually during 2021 and 2022 to conduct a consensus recommendation on the use of telemedicine in clinical practice in adult people with MS. To reach consensus, the methodology of "formal consensus RAND/UCLA Appropriateness method" was used. Recommendations were established based on relevant published evidence and expert opinion focusing on definitions, general characteristics and ethical standards, diagnosis of MS, follow-up (evaluation of disability and relapses of MS), identification and treatment of relapses, and finally disease-modifying treatments using telemedicine. The recommendations of this consensus would provide a useful guide for the proper use of telemedicine for the assessment, follow-up, management, and treatment of people with MS. We suggest the use of these guidelines to all the Argentine neurologists committed to the care of people with MS.


The role of screening blood tests in patients with arterial disease attending vascular outpatients.
To evaluate the benefits of a policy of performing screening blood tests in new patients with arterial disease referred to the vascular outpatients department. Clinical audit over a 12-month period of all new referrals with arterial disease to the vascular outpatients department at the Leicester General Hospital. Two hundred and seventy-two patients had at least one blood test performed at their outpatient visit. All of these patients had a full blood count performed, of which 21 results (21%) were abnormal. Further investigation of patients with abnormal results revealed one case of bladder cancer, one case of leukaemia and one patient with polycythaemia. Urea and electrolytes were measured in 269 patients (99%). Of these, 26 (10%) were expectedly abnormal in patients with known renal impairment. A further 27 patients (10%) were identified to have some degree of unrecognised renal impairment. Serum non-fasting glucose was measured in 252 patients (93%). There were 11 unexpectedly raised results, but further investigation of these patients only diagnosed one of these patients as diabetic. Serum cholesterol was measured in 201 patients (74%). One hundred and thirty-two patients (66%) had an abnormally raised serum cholesterol level. Of these, only 12 patients (6%) were known to have hyperlipidaemia. Screening new patients with arterial disease in vascular outpatients does identify significant abnormalities, in particular renal impairment and hyperlipidaemia. Correction of these abnormalities may reduce the morbidity associated with contrast induced nephrotoxic acute renal failure, and also contribute to secondary prevention of vascular events associated with raised lipids.


Soluble interleukin-2 receptor and soluble CD8 in liver cirrhosis and obstructive jaundice.
Activated lymphocytes secrete soluble interleukin-2 receptor (sIL-2R); CD8-positive lymphocytes secrete soluble CD8 (sCD8). Liver dysfunction in cirrhosis and obstructive jaundice is known to result in depressed cellular immunity. To evaluate whether this is due to real inactivation of the immune system, we measured sIL-2R and sCD8 in the serum of 46 patients with liver cirrhosis, 25 patients with obstructive jaundice, 32 patients with alcoholic liver disease without evidence of cirrhosis, 23 healthy persons and 43 patients with unrelated disease. sIL-2R in patients with cirrhosis (mean +/- s.e.m. 1499 +/- 140 U/ml) and obstructive jaundice (1517 +/- 204) was significantly increased compared with healthy subjects (363 +/- 29) and patients with unrelated diseases (685 +/- 92); sCD8 was significantly increased in patients with cirrhosis (737 +/- 63) but not in patients with obstructive jaundice (419 +/- 32) compared with healthy subjects (322 +/- 23) and patients with unrelated diseases (375 +/- 22). No difference was found between patients with cirrhosis due to alcohol abuse (n = 15) and chronic hepatitis B (n = 6). The Child-Pugh score had no significant influence on the sIL-2R or sCD8 value. In obstructive jaundice, sIL-2R correlated with alkaline phosphatase as marker of cholestasis (r = 0.43). These data show that in spite of the apparent depressed cellular immune defense both in liver cirrhosis and obstructive jaundice there is a general activation of the immune system but the CD8+ cell compartment is only activated in liver cirrhosis. The great changes of sIL-2R and sCD8 in liver dysfunction are important for the interpretation of studies using these serum proteins as markers for immune activation.


Small-molecule inhibitors of the cancer target, isoprenylcysteine carboxyl methyltransferase, from Hovea parvicalyx.
Isoprenylcysteine carboxyl methyltransferase (Icmt) is enzyme target in anticancer drug discovery. An Icmt natural product high-throughput screening campaign was conducted and a hit extract from the roots of Hovea parvicalyx was identified. 2'-Methoxy-3'-prenyl-licodione and 2'-methoxy-3',3''-diprenyl-licodione, two prenylated beta-hydroxychalcone compounds, together with the known flavanone (S)-glabrol, were isolated and identified as bioactive constituents. Their structures were determined largely by 1D and 2D NMR spectroscopy.


New quinoline derivatives demonstrate a promising antimalarial activity against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.
Malaria continues to be an important public health problem in the world. Nowadays, the widespread parasite resistance to many drugs used in antimalarial therapy has made the effective treatment of cases and control of the disease a constant challenge. Therefore, the discovery of new molecules with good antimalarial activity and tolerance to human use can be really important in the further treatment of the disease. In this study we have investigated the antiplasmodial activity of 10 synthetic compounds derived from quinoline, five of them combined to sulfonamide and five to the hydrazine or hydrazide group. The compounds were evaluated according to their cytotoxicity against HepG2 and HeLa cell lines, their antimalarial activity against CQ-sensitive and CQ-resistant Plasmodium falciparum strains and, finally, their schizonticide blood action in mice infected with Plasmodium berghei NK65. The compounds exhibited no cytotoxic action in HepG2 and HeLa cell lines when tested up to a concentration of 100 μg/mL. In addition, the hydrazine or hydrazide derivative compounds were less cytotoxic against cell lines and more active against CQ-sensitive and CQ-resistant P. falciparum strains, showing high SI (>1000 when SI was calculated using the CC50 from the 3D7 strain as reference). When tested in vivo, the hydrazine derivative 1f compound showed activity against the development of blood parasites similar to that observed with CQ, the reference drug. Interestingly, the 1f compound demonstrated the best LipE value (4.84) among all those tested in vivo. Considering the in vitro and in vivo activities of the compounds studied here and the LipE values, we believe the 1f compound to be the most promising molecule for further studies in antimalarial chemotherapy.


Acute illnesses in children. A description and analysis of the cumulative incidence proportion.
To describe parent-reported morbidity in relation to the psycho-social conditions of the families and to characterize families whose children are frequently ill. The parent-reported morbidity in a two-month prospective period, and the psychosocial conditions of the families were registered by means of a questionnaire. The conditioned probability of parents' reporting an episode of illness was estimated by means of logistic regression analysis, taking the psycho-social conditions into consideration. 18,949 families with at least one child under the age of 8 years, resident in the County of Ringkjøbing in western Denmark at 1 March 1988. An age-stratified random sample of 1982 families was entered in the study. 1588 (82%) families returned the questionnaire. The parents reported considerable morbidity in their children. The cumulative incidence proportion (CIP) for the period was 48%. The multivariate analysis of the parent-reported morbidity led to the following main results: 1) the morbidity was greatest for children aged 6 to 18 months, after which it decreased with age, 2) there was interaction between the care conditions and the child's age--CIP for children up to two years was largest for the children who were cared for in daycare, while the CIP for the older children was largest for the children who were cared for at home, 3) if the parents reported that the child's siblings suffered from chronic or frequently recurring morbidity, the child's morbidity rate was significantly increased, 4) mothers with higher education reported more morbidity in their children than mothers without this education, and 5) parents with a high perception of the general health threat ("worried" parents) reported more morbidity than did parents with a low perception. The results made it possible to characterize families whose children were frequently reported ill.