[Successful Anesthetic Management of a Patient with Critical Bleeding during Hepatectomy Using Recombinant Activated Factor VII and Intraoperative Blood Salvage].
A 58-year-old 79 kg male with metastatic liver cancer was scheduled for hepatectomy. Preoperative examination did not reveal any hemostatic abnormalities. Nine hours into the surgery, a vascular clip attached to the middle hepatic vein was disconnected and rapid bleeding followed. Unscheduled intraoperative cell salvage was employed. Despite surgical hemostasis as well as transfusion with fresh frozen plasma and platelets, significant oozing persisted for 10 hours, and cumulative blood loss amounted to 30,000 ml. Therefore, we administered fibrinogen products and recombinant activated factor VLL (rFVIIa, NovoSeven), a potent hemostatic initiator used in treating congenital factor VII deficient patients. After injecting 5 mg of rFVIIa, the bleeding was controlled almost immediately, and the surgery was completed within an hour. Although postoperative computed tomography detected subclinical but extensive thrombosis in the middle hepatic vein, the inferior vena cava, and the deep femoral veins, the thrombus spontaneously dissolved within seven months postoperatively. There was no evidence of metastatic disease 24 months postoperatively. Off-label use of rFVIIa and intraoperatively salvaged autologous blood transfusions are life-saving procedures for cancer patients who have massive bleeding during surgery, although we cannot completely exclude the possibility of serious postoperative thrombotic events and/or hematogenous cancer dissemination.


Relation of electrocardiographic left ventricular hypertrophy to blood pressure, body mass index, serum lipids and blood sugar levels in adult Nigerians.
Left ventricular hypertrophy (LVH) is considered an independent risk factor even in the absence of systemic hypertension. Electrocardiographic (ECG) LVH with repolarisation changes has been found in some countries to carry more coronary risk than LVH alone. How far this observation is true among adult Nigerians is not known. We therefore decided to study adult Nigerians with ECG-LVH with or without ST-T waves changes and compare them with normal age matched controls (without ECG-LVH) in relation with established modifiable risk factors such as systemic hypertension (BP), body mass index (BMI), fasting blood sugar (FBS) and serum lipids such as total cholesterol (Tc), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride (TG). Adult Nigerians who were consecutively referred to the ECG laboratory were randomly recruited. Three hundred patients were studied. Their blood pressures (BP) as well as body mass indices were recorded after recording their resting 12 read ECG using portable Seward 9953 ECG machine. Their waist-hip ratio (WHR) was also recorded. Blood samples were taken to determine their fasting blood sugar and serum lipids. Their ECG tracings were read by the cardiologists involved in the study while the blood samples were analysed by the chemical pathologist also involved in the study. At the end of the ECG reading, the patients were divided into 3 groups according to whether there was no ECG-LVH (control group A), ECG-LVH alone (group B), and ECG-LVH with ST-T waves changes (group C). One hundred and fifty (50%) patients belonged to group A, 100 (33.3%) patients to group B and 50 (16.7%) group C. Group B patients were found to have higher modifiable risk factors in form of systemic BP. Tc, LDL-C, and WHR compared to group A. However, the group C patients had increased load of these coronary risk factors in terms of BP elevation, higher BMI, FBS, and scrum cholesterol compared to group B. In addition, more female patients were involved in group C. The mean age of group C patients compared to group B was also significantly higher (P<0.001) even though no significant age difference was noted between group C and group A patients. It is concluded that Nigerians with ECG-LVH with ST-T waves changes have increased risk of cardiovascular risk factors compared to normal group A patients and even patients with EGC-LVH (group B) alone. Hence, they represent subset of patients to be aggressively followed up with multiple risk factors intervention.


Containing COVID-19 Among 627,386 Persons in Contact With the Diamond Princess Cruise Ship Passengers Who Disembarked in Taiwan: Big Data Analytics.
Low infection and case-fatality rates have been thus far observed in Taiwan. One of the reasons for this major success is better use of big data analytics in efficient contact tracing and management and surveillance of those who require quarantine and isolation. We present here a unique application of big data analytics among Taiwanese people who had contact with more than 3000 passengers that disembarked at Keelung harbor in Taiwan for a 1-day tour on January 31, 2020, 5 days before the outbreak of coronavirus disease (COVID-19) on the Diamond Princess cruise ship on February 5, 2020, after an index case was identified on January 20, 2020. The smart contact tracing-based mobile sensor data, cross-validated by other big sensor surveillance data, were analyzed by the mobile geopositioning method and rapid analysis to identify 627,386 potential contact-persons. Information on self-monitoring and self-quarantine was provided via SMS, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests were offered for symptomatic contacts. National Health Insurance claims big data were linked, to follow-up on the outcome related to COVID-19 among those who were hospitalized due to pneumonia and advised to undergo screening for SARS-CoV-2. As of February 29, a total of 67 contacts who were tested by reverse transcription-polymerase chain reaction were all negative and no confirmed COVID-19 cases were found. Less cases of respiratory syndrome and pneumonia were found after the follow-up of the contact population compared with the general population until March 10, 2020. Big data analytics with smart contact tracing, automated alert messaging for self-restriction, and follow-up of the outcome related to COVID-19 using health insurance data could curtail the resources required for conventional epidemiological contact tracing.


Personalized chemotherapy in clear cell adenocarcinoma of the urethra: A case report.
Clear cell adenocarcinoma of the urethra is a rare type of aggressive cancer with a poor prognosis. Clear cell carcinoma of the urethra represents less than 0.02% of all malignancies in women. Adenocarcinomas account for 10% of female urethral carcinomas, of which 40% are the clear cell variant. Determining the presence or absence of certain mutations through genetic testing may predict whether a patient with cancer may benefit from a particular chemotherapy regimen. A 40-year-old woman presented with a 3-year history of slow urinary flow and a 3-mo history of urinary urgency and frequency as well as gross hematuria. An abdominal and pelvic computed tomography scan demonstrated enlarged lymph nodes in the abdomen and pelvis. A biopsy of a left inguinal lymph node microscopically confirmed a metastatic adenocarcinoma of the urethra. Specialized genetic testing determined personalized chemotherapy. She was treated successfully with a non-platinum-based chemotherapy consisting of paclitaxel and bevacizumab. Following 3 cycles of paclitaxel and bevacizumab, she attained significant clinical improvement, and response by FDG-Positron emission tomography (PET) imaging showed a definite improvement in size and metabolic activity. She achieved complete response after 6 cycles of therapy by PET scan. The patient concluded 11 cycles of paclitaxel and bevacizumab, and a subsequent PET scan confirmed progression of metastatic disease. The patient was then treated with two cycles of doxorubicin after which a PET scan revealed a mixed response to the treatment. We report the first case of a patient with metastatic clear cell adenocarcinoma of the urethra who underwent personalized chemotherapy after testing for cancer gene alterations. Our unique case represents the safe and effective use of non-platinum-based chemotherapy in clear cell adenocarcinoma of the urethra.


Growth and endocrine function after renal transplantation.
Longitudinal height data and physical development were assessed in 45 boys and 34 girls after renal transplantation. All children received alternate day steroids and either azathioprine or cyclosporin A for immunosuppression. There was a significant increase in growth velocity after transplantation in prepubertal children. Growth velocity declined at the expected age of the normal pubertal growth spurt, however, with delay in the appearance of secondary sexual characteristics. Overnight hormone profiles in 17 adolescent subjects with short stature or maturational delay, or both, showed blunting of growth hormone and gonadotrophin pulsatility. It is likely that long term steroid treatment after renal transplantation induces the clinical and endocrine picture of delayed puberty. Failure of growth to accelerate at this time is a cause of short stature, which may have an effect on adult height.


In vivo activation of synthetic hormonogens of lysine vasopressin: Na-glycyl-glycyl-glycyl-[8-lysine]vassopressin in the cat.
The urine and plasma levels of vasopressin-like immunological activity and of antidiuretic activity were examined following injection of Na-glycyl-glycyl-glycyl-[8-lysine]vasopressin (triglycylvassopressin, TGLVP) in 3 cats. The plasma levels of immunoreactive material were initially high, and fell rapidly. The levels of antidiuretic activity showed considerable variation; the overall pattern was strikingly different from that demonstrated by radioimmunoassay, and all 3 animals showed a rise in plasma antidiuretic activity in the early part of the experiment. Following injection of lysine vasopressin (LVP) the pattern of disappearance of both biological and immunological activity was similar. The total amount of immunoreactive material found in the urine was greater than the amount of antidiuretically active material. These results clearly demonstrate that the antidiuretic activity of TGLVP is mainly due to its conversion to LVP in vivo.


Construction and pilot screening of a signature-tagged mutant library of Sinorhizobium fredii.
Sinorhizobium fredii is well known for its ability to establish symbiosis with diverse legumes such as Glycine max (soybean, determinate nodules) and Cajanus cajan (pigeon pea, indeterminate nodules). In order to make screening of S. fredii genes related to symbiosis cost-effective, we constructed a large Tn5 insertion mutant library of S. fredii CCBAU45436 using the signature-tagged mutagenesis (STM) technique. This STM library contains a total of 25,500 independent mutants distributed in 17 sublibraries tagged by corresponding distinct DNA bar-code sequences. After the pilot screening of 255 mutants in 15 batches, Tag85-4, Tag4-17, Tag4-11 and Tag10-13 were found to have attenuated competitiveness (0-30 % in nodule occupation) compared to the wild-type strain when inoculated on soybean. Further characterization of these mutants suggests that Tag4-11 (a pyrC mutant) and Tag10-13 (a nrdJ mutant) are defective in establishing symbiosis with soybean. The pyrC mutant induced uninfected pseudonodules while the nrdJ mutant formed significantly more nodules containing bacteroids with poor persistence ability. When these two mutants were tested on pigeon pea, host-specific symbiotic defects were found. These results demonstrated the STM library as a valuable resource for identifying S. fredii genes relevant to symbiosis.


Faecal prevalence of extended-spectrum Beta-lactamase (ESBL)-producing coliforms in a geriatric population and among haematology patients.
Antimicrobial resistance to the extended-spectrum cephalosporins is increasingly reported worldwide. In the local setting, nosocomial infections with multi-resistant Gram-negative bacilli are not uncommon and are a growing concern. However, there is limited data on the carriage rates of such organisms in the local setting. In May 2001, a prospective study was carried out to determine the enteric carriage rates of ceftazidime-resistant Gram negative bacilli (CAZ-R GNB) among residents of nursing homes and from in-patients of the geriatric and adult haematology wards of University Malaya Medical Centre. Ceftazidime-resistant Gram-negative bacilli (CAZ-R GNB) were detected in 25 samples (30%), out of which 6 were from nursing home residents, 5 from geriatric in-patients and 14 from the haematology unit. A total of 28 CAZ-R GNB were isolated and Escherichia coli (10) and Klebsiella pneumoniae (7) were the predominant organisms. Resistance to ceftazidime in E. coli and Klebsiella was mediated by extended-spectrum beta-lactamases (ESBLs). Although the majority of the CAZ-R GNB were from patients in the haematology ward, the six nursing home residents with CAZ-R GNB were enteric carriers of ESBL-producing coliforms. Prior exposure to antibiotics was associated with carriage of ESBL organisms and to a lesser extent, the presence of urinary catheters.


Polyelectrolyte multilayers on PTMSP as asymmetric membranes for gas separations: Langmuir-Blodgett versus self-assembly methods of anchoring.
Polyelectrolyte multilayers derived from poly(diallyldimethylamonium chloride) and poly(sodium 4-styrenesulfonate) have been deposited onto poly[1-(trimethylsilyl)-1-propyne] (PTMSP) with anchoring layers formed by Langmuir-Blodgett and self-assembly methods. Using gas permeation selectivity as a basis for judging the efficacy of each anchoring method, we have found that similar CO2/N2 selectivities (ranging from 110 to 140) could be achieved by both methods and that their permeances were also similar. Although LB anchors require fewer layers of polyelectrolyte to reach this level of selectivity, the greater ease associated with self-assembly and its applicability to curved, high-surface-area supports (e.g., PTMSP-coated hollow fibers) encourage its use with PTMSP in creating new membrane materials for the practical separation of gases.


[Effectiveness of using a hardware complex with biofeedback in the rehabilitation of children with dysfunction of the upper limbs].
The upper limb is of exceptional importance for human life as an organ of cognitive and practical activity. Fine motor skills of hands are a set of small, highly coordinated, precise and coordinated movements of varying degrees. Diseases and injuries of the musculoskeletal and nervous systems lead to violations of fine motor skills. Effective programs for medical rehabilitation of hand and fingers include using biofeedback devices (BFB). Efficiency evaluation of the hardware-software complex with BFB in restoring the impaired function of the upper limb in children. The clinical study included 79 patients aged 4 to 18 years with dysfunction of the upper limb not higher than level III according to MACS (The Manual Ability Classification System), who were divided by simple randomization into the main group (49 patients) who received 21 days of a comprehensive rehabilitation program (physiotherapy exercises, paretic muscle massage, mechanotherapy, hydrokinesiotherapy, methods of apparatus physiotherapy) using a hardware-software complex, and a comparison group (30 patients), in which the complex rehabilitation program did not include biofeedback procedures. This performed prospective open randomized comparative study revealed the effectiveness of the standard rehabilitation program in combination with training on the BFB complex (main group) to be higher than using only the standard program. After treatment, patients of the main group showed a noticeable decrease in the degree of muscle spasticity in the affected limb, strengthening of muscle strength, improvement of fine and gross motor skills of the hands, and improvement of manual skills. The use of a hardware-software complex with biofeedback in children with dysfunction of upper limbs increases effectiveness of the rehabilitation program.


Appraisal and Consequences of Cadaver Dissection.
First exposure to human cadaver dissection has the potential to be an actual stressor which can cause psychological trauma. This study examines the relationship between anatomy students' experience of this potential stressor and various psychological and personal factors. Questionnaires measuring emotional reactions to cadaver dissection, coping strategies, personality and attitudes to death were administered to anatomy students at two medical schools immediately after their first exposure to human cadaver dissection. Emotional reactions to recalling this experience were assessed 4 months later. Data on these variables were obtained from 141 students. Students found the experience mostly challenging and, on average, did not report serious emotional difficulties. However, a minority of students (10/141) experienced serious adverse consequences. It is possible that the typical student who undertakes an anatomy course is already psychologically prepared for such transactions. However, low cost desensitization programs could be made available for the minority of individuals who may experience adverse reactions in this situation.


Characterization and quantification of flavonoids and organic acids over fruit development in American cranberry (Vaccinium macrocarpon) cultivars using HPLC and APCI-MS/MS.
Cranberry flavonoids, including anthocyanins, flavonol glycosides and proanthocyanidins, and organic acids were characterized and quantified by HPLC and LC-MS/MS during fruit development and ripening in eight cranberry cultivars. Anthocyanin biosynthesis initiated at early fruit development and reached highest level in mature fruit, with significant differences between cultivars. Major flavonol glycosides, including the most abundant quercetin-3-galactoside and myricetin-3-galactoside, showed consistent concentrations during the season with moderate fluctuation, and were at similar levels in mature fruits of the eight cultivars. Proanthocyanidins declined during fruit development and then increased slightly in later maturation stages. Levels of various proanthocyanidin oligomers/polymers with different degree-of-polymerization were highly correlated within a cultivar during fruit development. Cultivars with coancestry exhibited similar levels (high/low) of anthocyanins or proanthocyanidins, indicating genetic effects on biosynthesis of such flavonoids. All cultivars showed similar levels of malic and citric acids, and declining levels of quinic acid during fruit development. Benzoic acid was extremely low early in the season and increased sharply during fruit ripening. Levels of quinic and citric acids were significantly different among cultivars in the mature fruit. Concentrations of proanthocyanidins, anthocyanins, quinic acid and benzoic acid have a strong developmental association in developing ovaries.


Asthma, Airflow Obstruction, and Eosinophilic Airway Inflammation Prevalence in Western Kenya: A Population-Based Cross-Sectional Study.
Objectives: Determine the prevalence of airway disease (e.g., asthma, airflow obstruction, and eosinophilic airway inflammation) in Kenya, as well as related correlates of airway disease and health-related quality of life. Methods: A three-stage, cluster-randomized cross-sectional study in Uasin Gishu County, Kenya was conducted. Individuals 12 years and older completed questionnaires (including St. George's Respiratory Questionnaire for COPD, SGRQ-C), spirometry, and fractional exhaled nitric oxide (FeNO) testing. Prevalence ratios with 95% confidence intervals (CIs) were calculated. Multivariable models were used to assess correlates of airflow obstruction and high FeNO. Results: Three hundred ninety-two participants completed questionnaires, 369 completed FeNO testing, and 305 completed spirometry. Mean age was 37.5 years; 64% were women. The prevalence of asthma, airflow obstruction on spirometry, and eosinophilic airway inflammation was 21.7%, 12.3% and 15.7% respectively in the population. Women had significantly higher SGRQ-C scores compared to men (15.0 vs. 7.7). Wheezing or whistling in the last year and SGRQ-C scores were strongly associated with FeNO levels >50 ppb after adjusting for age, gender, BMI, and tobacco use. Conclusion: Airway disease is a significant health problem in Kenya affecting a young population who lack a significant tobacco use history.


The Healthy Crew, Clean Vessel, and Set Departure Date Triad: Successful Control of Outbreaks of COVID-19 On Board Four Cargo Vessels.
A variety of infectious diseases can cause outbreaks on board vessels, with both health and economic effects. Internationally, Coronavirus Disease 2019 (COVID-19) outbreaks have occurred on numerous cruise and cargo vessels and the containment measures, travel restrictions, and border closures continue to make it increasingly difficult for ship operators world-wide to be granted pratique, effect crew changes, and conduct trade. An effective outbreak management strategy is essential to achieve the outcome triad - healthy crew, clean vessel, and set departure date - while maintaining the safety of the on-shore workers and broader community and minimizing disruption to trade. This report describes the principles of COVID-19 outbreak responses on four cargo vessels, including the successful use of one vessel as a quarantine facility. Established principles of management and the experiences of COVID-19 outbreaks on cruise ships elsewhere informed a health-lead, multi-agency, strict 14-day quarantine (Q) regime based on: population density reduction on board; crew segregation; vessel cleaning and sanitation; infection risk zones, access, and control measures; health monitoring; case identification and management; food preparation and delivery; waste management control; communication; and welfare and security. Sixty-five crew were diagnosed with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection (range 2-25; attack rate 10%-81%; 15 asymptomatic). No deaths were recorded, and only one crew was hospitalized for COVID-19-related symptoms but did not require intensive care support. Catering crew were among the cases on three vessels. All non-essential crew (n-EC) and most of the cases were disembarked. During the vessel's Q period, no further cases were diagnosed on board, and no crew became symptomatic after completion of Q. The outbreak response duration was 15-17 days from initial decision.No serious health issues were reported, no response staff became infected, and only two Q protocol breaches occurred among crew. Despite increasing risk of outbreaks on cargo vessels, maritime trade and crew exchanges must continue. The potential consequences of COVID-19 outbreaks to human life and to trade necessitate a balanced response. The principles described can offer health, financial, operational, and safety advantages.


Rapid radioimmunoassay for prostate-specific acid phosphatase in human serum.
We describe a rapid radioimmunoassay for human prostatic acid phosphatase (EC 188.8.131.52) in serum, with use of monospecific antisera raised in rabbits against the primary highly purified acid phosphatase (pl 4.9) from human prostates, and with a second antibody-polyethylene glycol porecipitation. This radioimmunoassay is sensitive and can be performed within 5 h. Concentrations of the immunoreactive acid phosphatase in sera of healthy men (n = 394) ranged from 0.3 to 3.6 microgram/L (mean 1.94, SD 0.66 microgram/L). Concentrations of the enzyme in sera of men with benign prostatic hyperplasia (n = 56) or with carcinoma of nonprostatic origin (n = 24) were identical with those of the reference group. Serum concentrations of immunoreactive prostatic acid phosphatase of patients with occult, non-metastatic, and metastatic prostatic carcinoma varied from 1.7 to 9.3 (n = 9), 4.2 to 59.4 (n = 12), and 20 to 198 (n = 10) microgram/L, respectively. The amount of immunoassayable prostatic acid phosphatase was unchanged for at least five days in serum stored at 4 degrees C.


Contemporary Outcomes of Extracorporeal Membrane Oxygenation Used as Bridge to Lung Transplantation.
Extracorporeal membrane oxygenation (ECMO), when used as bridge to lung transplantation, (BTT) identifies high-risk candidates. Recent advances in cannula design and patient selection fosters "awake ambulatory ECMO" as a viable option for critically ill candidates in an attempt to retard deconditioning while awaiting allografts. From 2012 to 2015, 30 patients underwent ECMO as BTT. Candidacy for ECMO was determined before listing for transplant. A dual-lumen single cannula was used first in 13 of 30 patients (43%). Of the remaining 30 patients, 6 (20%) were supported with venoarterial ECMO and 11 (37%) with venovenous ECMO, with double-site cannulation in 11 (37%), and 6 of 11 converted to a dual-lumen single cannula. All ECMO patients were managed in a dedicated heart/lung failure intensive care unit, and early aggressive physical therapy, ambulation, and spontaneous breathing trials were emphasized. BTT was successful in 26 patients (87%). In the 19 patients with dual-lumen single cannula, 5 (26%) were successfully ambulated, and 6 (32%) achieved spontaneous ventilation. Median (25th, 75th percentile) lengths of stay in the intensive care unit and hospital were 33 days (20, 46 days) and 56 days (28, 78 days), respectively, and were 20 and 31 days, respectively, in patients successfully ambulated (intensive care unit: p = 0.5; hospital: p = 0.4). Among all patients who received a transplant, 30-day, 1-year, and 3-year survival were 92%, 85%, and 80%, respectively. Among patients undergoing primary transplants, 3-year survival was 91%. ECMO as BTT has led to encouraging perioperative outcomes and early survival. Careful patient selection and early use of ECMO seems to allow for preservation of vitality while these critically ill candidates await donor organs, which may improve outcomes.


Is alanine aminotransferase a good marker of histologic hepatic damage in renal transplant patients with hepatitis C virus infection?
Renal transplant (RTx) patients with hepatitis C frequently show normal levels of alanine aminotransferase (ALT) and the significance of ALT in this group has not been established. To determine the value of ALT as a marker of histologic hepatic damage in RTx patients with hepatitis C virus (HCV) infection. HCV-RNA-positive RTx patients with a liver biopsy were analyzed regarding staging and the grading of periportal and lobular necroinflammatory activity. Spearman's correlation coefficient was used to determine the correlation between ALT and histologic variables. Sensitivity, specificity and positive and negative predictive values (PPV and NPV) of ALT in the detection of septal fibrosis and interface hepatitis, and/or confluent necrosis were calculated. Fifty-three patients (32 men, 60%), with a mean age of 42 +/- 10 yr and time since transplant of 5 +/- 4 yr were included. Only 27 (51%) patients showed elevated ALT levels, which were associated with septal fibrosis (p = 0.001), interface hepatitis (p < 0.001) and confluent necrosis (p = 0.05). A correlation was observed between ALT and staging (r = 0.50, p < 0.001), periportal necroinflammatory activity (r = 0.59, p < 0.001) and lobular necroinflammatory activity (r = 0.50, p < 0.001). The sensitivity, specificity, PPV and NPV of ALT were 92, 61, 41 and 96%, respectively, for the detection of septal fibrosis, and 87, 77, 74 and 88% for the detection of interface hepatitis and/or confluent necrosis. ALT is a good marker of histologic hepatic lesion in HCV-infected RTx patients and, therefore, liver biopsy can be avoided in patients with persistently normal ALT.


Comparative QSAR- and fragments distribution analysis of drugs, druglikes, metabolic substances, and antimicrobial compounds.
A number of binary QSAR models have been developed using methods of artificial neural networks, k-nearest neighbors, linear discriminative analysis, and multiple linear regression and have been compared for their ability to recognize five types of chemical compounds that include conventional drugs, inactive druglikes, antimicrobial substituents, and bacterial and human metabolites. Thus, 20 binary classifiers have been created using a variety of 'inductive' and traditional 2D QSAR descriptors which allowed up to 99% accurate separation of the studied groups of activities. The comparison of the performance by four computational approaches demonstrated that the neural nets result in generally more accurate predictions, followed closely by k-nearest neighbors methods. It has also been demonstrated that complementation of 'inductive' descriptors with conventional QSAR parameters does not generally improve the quality of resulting solutions, conforming high predictive ability of 'inductive' variables. The conducted comparative QSAR analysis based on a novel linear optimization approach has helped to identify the extent of overlapping between the studied groups of compounds, such as cross-recognition of bacterial metabolites and antimicrobial compounds reflecting their immanent resemblance and similar origin. Human metabolites have been characterized as a very distinctive class of substances, separated from all other groups in the descriptors space and exhibiting different QSAR behavior. The analysis of unique structural fragments and substituents revealed inhomogeneous scale-free organization of human metabolites illustrating the fact that certain molecular scaffolds (such as sugars and nucleotides) may be strongly favored by natural evolution. The established scale-free organization of human metabolites has been contemplated as a factor of their unique positioning in the descriptors space and their distinctive QSAR properties. It is anticipated that the study may bring additional insight into QSAR determinants for conventional drugs, inactive chemicals, and metabolic substances and may help in rationalizing design and discovery of novel antimicrobials and human therapeutics with improved, metabolite-like properties.


Management of locally advanced primary mediastinal synovial sarcoma.
Primary mediastinal synovial sarcoma (PMSS) is a relatively rare disease, and patients are treated predominantly with surgery for resectable disease. Management of locally advanced borderline resectable and unresectable PMSS is not only challenging but also lacks standard guidelines. We present three patients with PMSS, who were unresectable or borderline resectable at presentation and were treated with neoadjuvant chemotherapy followed by surgery and postoperative radiotherapy.


Muscarinic receptor mediated signaling pathways in hepatocytes from CCL4 - induced liver fibrotic rat.
The pathological changes of parasympathetic nerves are considered as an independent prognostic factor of the survival rate for patients with chronic liver disease. The non-selective muscarinic acetylcholine receptors (mAchR) agonists and antagonists can affect the proliferation of hepatocytes, but little is known about the role of mAChR in hepatocytes and hepatic fibrosis and the signaling pathway of this receptor in regulation of hepatocytes remains elusive. Here, 3ml/kg 40% carbon tetrachloride (CCL4) was given to induce hepatic fibrosis in rats and the hepatocytes were isolated to investigate the expression of mAchR and the cell signaling pathways which were involved in. Compared with the normal state, the expression levels of m1, 3, 5 in fibrotic hepatocytes (FHC) and the cells treated with 10μM pilocarpine (Pi) were obviously increased, while decreased in m2,4. Pi could increase the value of alanine aminotransferase (ALT), hydroxyproline (Hyp), decrease albumin (ALB) and cell viability, while atropine could ameliorate fibrotic hepatocytes fuction. The p-AKT, p-ERK, p- JNK and p-P38 increased in Pi group or FHC group, but the inhibitors of PI3K, MAPK and PKC could reverse the Pi action and improve the FHC fuction. In this study we found that mAchR played an important role in the regulation of hepatic fibrosis process and the PKC, ERK, P38 and PI3K/AKT signaling pathways involved in the parasympathetic excitation mediated by mAchR.


Modification of lipid peroxidation by some known substituted imidazole derivatives. An attempt to correlate their antioxidant activity with lipophilicity.
The antioxidant activity of two antiallergic agents, oxatomide, astemizole and two neuroleptic drugs, penfluridol, pimozide, structurally related, was tested, using heat-inactivated rat hepatic microsomal fraction and linoleic acid. Lipid peroxidation was induced by Fe2+/ascorbic acid and Fe2+, respectively, and evaluated spectrophotometrically as 2-thiobarbituric acid reactive material. It was found that these compounds inhibited significantly the peroxidation of microsomal membranes in a concentration-dependent manner, as well as the peroxidation of linoleic acid. The lipophilicity of the tested compounds, expressed as RM values derived from reversed phase thin layer chromatography (RPTLC), was determined and the relationship between antioxidant activity and lipophilicity was discussed.


IL-1 induces intracisternal type A virus and retrovirus type C in pancreatic beta-cells of NOD mice.
Recent observations have suggested a role for interleukin 1 (IL-1), a macrophage-derived cytokine, in the autoimmune beta-cell destruction, that is associated with type 1 diabetes. In this study, we investigated the effects of human recombinant IL-1 beta on pancreatic beta-cells from NOD and NON mice (diabetes-resistant NOD-related strain), focussing upon the appearance of intracisternal type A virus (IAP) and retrovirus type C. NOD mice pancreatic islets were incubated with or without IL-1 (0.1, 1, 10, 100 U/ml) for 10 days. Thereafter, the islets were examined using an electron microscope. When the islets of NOD mice were incubated with the IL-1 (10, 100 U/ml) under condition of high glucose, IAP and endogenous retrovirus type C frequently appeared in the beta-cells. Retrovirus type C was present as a cluster. In contrast, IAP and retrovirus type C were rarely found in beta-cells from the control group. When the islets of NON mice were incubated with or without IL-1 (10 U/ml) in the presence of high glucose, IAP was rarely found in beta-cells and retrovirus type C was undetectable in beta-cells. This study indicated that IL-1 is an important effector that leads to insulitis or aggravates insulitis in NOD mice.


Dreams deferred: Contextualizing the health and psychosocial needs of undocumented Asian and Pacific Islander young adults in Northern California.
There are currently 1.5 million undocumented Asians and Pacific Islanders (APIs) in the US. Undocumented API young adults, in particular, come of age in a challenging political and social climate, but little is known about their health outcomes. To our knowledge, this is the first study to assess the psychosocial needs and health status of API undocumented young adults. Guided by social capital theory, this qualitative study describes the social context of API undocumented young adults (ages 18-31), including community and government perceptions, and how social relationships influence health. This study was conducted in Northern California and included four focus group discussions (FGDs) and 24 in-depth interviews (IDIs), with 32 unique participants total. FGDs used purposeful sampling by gender (two male and two female discussions) and education status (in school and out-of-school). Findings suggest low bonding and bridging social capital. Results indicate that community distrust is high, even within the API community, due to high levels of exploitation, discrimination, and threats of deportation. Participants described how documentation status is a barrier in accessing health services, particularly mental health and sexual and reproductive health services. This study identifies trusted community groups and discusses recommendations for future research, programs, and policies.


Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.
In controlled clinical trials there are usually several prognostic factors known or thought to influence the patient's ability to respond to treatment. Therefore, the method of sequential treatment assignment needs to be designed so that treatment balance is simultaneously achieved across all such patients factor. Traditional methods of restricted randomization such as "permuted blocks within strata" prove inadequate once the number of strata, or combinations of factor levels, approaches the sample size. A new general procedure for treatment assignment is described which concentrates on minimizing imbalance in the distributions of treatment numbers within the levels of each individual prognostic factor. The improved treatment balance obtained by this approach is explored using simulation for a simple model of a clinical trial. Further discussion centers on the selection, predictability and practicability of such a procedure.


Genetic Alteration, Prognostic and Immunological Role of Acyl-CoA Synthetase Long-Chain Family Member 4 in a Pan-Cancer Analysis.
Acyl-CoA Synthetase long-chain family member 4 (ACSL4) is a member of acyl-CoA synthetase protein long-chain family, which is associated with amino acid synthesis, lipid synthesis and lipid peroxidation dependent iron death. However, the role of ACSL4 in generalized carcinoma remains unclear. We aim to analyze the expression and prognostic value of ACSL4 in pan-cancer, and further explore the correlation between ACSL4 and immune infiltration. Through ONCOMINE, TIMER (Tumor Immune Estimation Resource), GEPIA (Gene expression Profiling Interactive), UALCAN and HPA, ACSL4 expression patterns of in pan-cancer were analyzed. The prognostic value of ACSL4 was analyzed using PrognoScan and Kaplan-Meier Plotter databases. Furthermore, gene variation and epigenetic modification of ACSL4 were analyzed by cBioPortal and GSCA databases. Meanwhile, GEPIA and TIMER databases applied to evaluate the relationship between ACSL4 expression and immune infiltration. These results indicate that ACSL4 expression is down-regulated and associated with prognosis in most tumors. In general, lower ACSL4 expression shows more beneficial prognosis. The most common genetic alteration of ACSL4 is point mutation. ACSL4 is negatively correlated with DNA methylation levels in most cancers. ACSL4 mutations or hypomethylation are associated with poor prognosis. In addition, ACSL4 is positively correlated with immune infiltration in cancers. ACSL4 and immune infiltration are strongly associated with prognosis in BRCA (Breast invasive carcinoma) and SKCM (Skin Cutaneous Melanoma). ACSL4 mutation caused significant changes of immune infiltration in UCEC (Uterine Corpus Endometrial Carcinoma) and SARC (Sarcoma). ACSL4 may be a promising prognostic biomarker for pan-cancer and is closely associated with immune infiltration in the tumor microenvironment.


[Neuroimaging and neurochemical studies of Rett syndrome].
We review here the current status of neuroimaging and neurochemical research on Rett syndrome (RTT), with reference to neurophysiological, neuropathological, and immuno-histochemical changes previously described. Abnormalities have been reported in the intermediates of the biogenic amine neurotransmitters/receptor systems, and of beta-phenylethylamine (PEA), an endogenous amine synthesized by the decarboxylation of phenylalanine in dopaminergic neurons of the nigrostratal system. We also discuss the roles of other neurotransmitters including beta-endrophin, substance P and neurotrophic factors including nerve growth factors. Recently, mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2), mapped to Xq28, have been identified in patients with RTT. Multiple abnormalities in various neurotransmitter/receptor systems may accounts for the pervasive defects in RTT.


Self-Assembly of Semiconducting-Plasmonic Gold Nanoparticles with Enhanced Optical Property for Photoacoustic Imaging and Photothermal Therapy.
Although various noble metal and semiconducting molecules have been developed as photoacoustic (PA) agents, the use of semiconducting polymer-metal nanoparticle hybrid materials to enhance PA signal has not been explored. A novel semiconducting-plasmonic nanovesicle was fabricated by self-assembly of semiconducting poly(perylene diimide) (PPDI) and poly(ethylene glycol (PEG) tethered gold nanoparticles (Au@PPDI/PEG). A highly localized and strongly enhanced electromagnetic (EM) field is distributed between adjacent gold nanoparticles in the vesicular shell, where the absorbing collapsed PPDI is present. Significantly, the EM field in turn enhances the light absorption efficiency of PPDI, leading to a much greater photothermal effect and a stronger photoacoustic signal compared to PDI nanoparticle or gold nanovesicle alone. The optical property of the hybrid vesicle can be further tailored by controlling the ratio of PPDI and gold nanoparticle as well as the adjustable interparticle distance of gold nanoparticles localized in the vesicular shell. In vivo imaging and therapeutic evaluation demonstrated that the hybrid vesicle is an excellent probe for cancer theranostics.


Amino acid changes in the amino terminus of the Na,K-adenosine triphosphatase alpha-2 subunit associated to familial and sporadic hemiplegic migraine.
Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura inherited with an autosomal dominant pattern. Here, we report the genetic analysis of four families and one sporadic case with hemiplegic migraine (HM) in whom we searched for mutations in the three genes associated with the disease CACNA1A, ATP1A2 and SCN1A. Two novel amino acid changes p.Arg65Trp and p.Tyr9Asn, in the Na,K-adenosine triphosphatase (ATPase) alpha-2 subunit encoded by the ATP1A2 gene, were found in one FHM family and in the sporadic case, respectively. These mutations are peculiar for their location in the extreme N-terminus, an uncommon mutation target in this protein. Low frequency of migraine attacks in all our mutant patients with low complexity of the associated aura symptoms in the sporadic case is also observed. Besides the two novel mutations, the data here reported confirm the involvement of ATP1A2 gene in the sporadic form of HM, while the negative results on the other families tested for all genes known in HM strengthen the hypothesis of the existence of at least another locus involved in FHM.


Jaspine B induces nonapoptotic cell death in gastric cancer cells independently of its inhibition of ceramide synthase.
Sphingolipids (SLs) have been extensively investigated in biomedical research due to their role as bioactive molecules in cells. Here, we describe the effect of a SL analog, jaspine B (JB), a cyclic anhydrophytosphingosine found in marine sponges, on the gastric cancer cell line, HGC-27. JB induced alterations in the sphingolipidome, mainly the accumulation of dihydrosphingosine, sphingosine, and their phosphorylated forms due to inhibition of ceramide synthases. Moreover, JB provoked atypical cell death in HGC-27 cells, characterized by the formation of cytoplasmic vacuoles in a time and dose-dependent manner. Vacuoles appeared to originate from macropinocytosis and triggered cytoplasmic disruption. The pan-caspase inhibitor, z-VAD, did not alter either cytotoxicity or vacuole formation, suggesting that JB activates a caspase-independent cell death mechanism. The autophagy inhibitor, wortmannin, did not decrease JB-stimulated LC3-II accumulation. In addition, cell vacuolation induced by JB was characterized by single-membrane vacuoles, which are different from double-membrane autophagosomes. These findings suggest that JB-induced cell vacuolation is not related to autophagy and it is also independent of its action on SL metabolism.


The genes BnSCT1 and BnSCT2 from Brassica napus encoding the final enzyme of sinapine biosynthesis: molecular characterization and suppression.
This study describes the molecular characterization of the genes BnSCT1 and BnSCT2 from oilseed rape (Brassica napus) encoding the enzyme 1-O-sinapoyl-beta-glucose:choline sinapoyltransferase (SCT; EC 188.8.131.52). SCT catalyzes the 1-O-beta-acetal ester-dependent biosynthesis of sinapoylcholine (sinapine), the most abundant phenolic compound in seeds of B. napus. GUS fusion experiments indicated that seed specificity of BnSCT1 expression is caused by an inducible promoter confining transcription to embryo tissues and the aleurone layer. A dsRNAi construct designed to silence seed-specifically the BnSCT1 gene was effective in reducing the sinapine content of Arabidopsis seeds thus defining SCT genes as targets for molecular breeding of low sinapine cultivars of B. napus. Sequence analyses revealed that in the allotetraploid genome of B. napus the gene BnSCT1 represents the C genome homologue from the B. oleracea progenitor whereas BnSCT2 was derived from the Brassica A genome of B. rapa. The BnSCT1 and BnSCT2 loci showed colinearity with the homologous Arabidopsis SNG2 gene locus although the genomic microstructure revealed the deletion of a cluster of three genes and several coding regions in the B. napus genome.


Optimal disintegration strategy in spatial networks with disintegration circle model.
The problem of network disintegration, such as suppression of an epidemic spread and destabilization of terrorist networks, has broad applications and recently has received increasing attention. In this study, we concentrate on the problem of network disintegration in the spatial network in which the nodes and edges are embedded in space. For such a network, it is crucial to include spatial information in the search for an optimal disintegration strategy. We first carry out an optimization model with multiple disintegration circles in the spatial network and introduce a tabu search to seek the optimal disintegration strategy. We demonstrate that the "best" disintegration strategy can be identified through global searches in the spatial network. The optimal disintegration strategy of the spatial network tends to place the disintegration circles so that they cover more nodes which are closer to the average degree to achieve a more destructive effect. Our understanding of the optimal disintegration strategy in spatial networks may also provide insight into network protection, e.g., identification of the weakest part, which deserves further study.


Future directions for monitoring treatment responses in breast cancer.
In the prior review, we outlined the current standard of care for monitoring treatment responses in breast cancer and discussed the many challenges associated with these strategies. We described the challenges faced in common clinical settings such as the adjuvant setting, neoadjuvant setting, and the metastatic setting. In this review, we will expand upon future directions meant to overcome several of these current challenges. We will also explore several new and promising methods under investigation to enhance how we monitor treatment responses in breast cancer. Furthermore, we will highlight several new technologies and techniques for monitoring breast cancer treatment in the adjuvant, neoadjuvant and metastatic setting.


OnabotulinumtoxinA injections in chronic migraine, targeted to sites of pericranial myofascial pain: an observational, open label, real-life cohort study.
OnabotulinumtoxinA has proven its efficacy in reducing the number of headache days in chronic migraine (CM) patients. The usual paradigm includes 31 pericranial injection sites with low dose (5 U) per site. The aim of this study is to present the results obtained using a simpler injection protocol of onabotulinumtoxinA, with injection sites targeted to pericranial myofascial sites of pain. Observational, open label, real-life, cohort study. We enrolled 63 consecutive patients fulfilling the diagnostic criteria of CM, and refractory to conventional treatments. The patients were injected using a "follow-the-pain" pattern into the corrugator and/or temporalis and/or trapezius muscles. The doses per muscle were fixed. According to the number of muscles injected, the total dose could vary from 70 to 150 U per session. Patients were considered responders if they had a ≥ 50% decrease in number of headache days in at least two consecutive injection cycles. Forty one patients (65.1% in intention to treat analysis) responded to treatment. In 70.7% of responders, the effect size was even higher, with a reduction ≥70% in the number of headache days. The associated cervical pain and muscle tenderness, present in 33 patients, was reduced by ≥50% in 31 patients (94%). Triptan consumption dramatically decreased (81%) in responders. The trapezius was the most frequently injected muscle. We observed no serious adverse event. The mean patient satisfaction rate was 8.5/10. This study provides additional robust evidence supporting the efficacy of onabotulinumtoxinA injections in CM. Furthermore, the paradigm we used, with reduced number of injection sites targeted to pericranial myofascial sites of pain, may provide evidence in favor of the implication of myofascial trigger points in migraine chronicization. ClinicalTrials.gov Protocol Record I17022 ClinicalTrials.gov Identifier: NCT03175263 . Date of registration: June 7, 2017. Retrospectively registered.


Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly.
Inhibition of programmed cell death pathways of mammalian cells often facilitates the sustained survival of intracellular microorganisms. The apicomplexan parasite Toxoplasma gondii is a master regulator of host cell apoptotic pathways. Here, we have characterized a novel anti-apoptotic activity of T. gondii. Using a cell-free cytosolic extract model, we show that T. gondii interferes with the activities of caspase 9 and caspase 3/7 which have been induced by exogenous cytochrome c and dATP. Proteolytic cleavage of caspases 9 and 3 is also diminished suggesting inhibition of holo-apoptosome function. Parasite infection of Jurkat T cells and subsequent triggering of apoptosome formation by exogenous cytochrome cin vitro and in vivo indicated that T. gondii also interferes with caspase activation in infected cells. Importantly, parasite inhibition of cytochrome c-induced caspase activation considerably contributes to the overall anti-apoptotic activity of T. gondii as observed in staurosporine-treated cells. Co-immunoprecipitation showed that T. gondii abolishes binding of caspase 9 to Apaf-1 whereas the interaction of cytochrome c with Apaf-1 remains unchanged. Finally, T. gondii lysate mimics the effect of viable parasites and prevents holo-apoptosome functionality in a reconstituted in vitro system comprising recombinant Apaf-1 and caspase 9. Beside inhibition of cytochrome c release from host cell mitochondria, T. gondii thus also targets the holo-apoptosome assembly as a second mean to efficiently inhibit the caspase-dependent intrinsic cell death pathway.


Influence of caloric density on energy intake by dairy cows.
Twenty-four Holstein cows were fed mixed diets of alfalfa hay and concentrate in a series of periods to determine the relationship between caloric density (mcal digestible energy/liter) of the diet and energy intake. Five diets with caloric densities of .58, .63, .68, .84, and 1.17 (as-fed form) were used. Steers were fed the diets in digestion trials to determine maintenance digestibility. Intake of digestible energy was adjusted for intake. Means of digestible energy intakes (kcal/day per kg. 75) were: 291.7, 324.0, 370.0, 371.4, and 369.1 for diets with caloric densities of .58, .63, .68, .68, .84, and 1.17. Physical fill was limiting for the two most dilute diets. The diet with caloric density of .68 represented the point above which physiological regulation was employed by the animals. The relationship between digestible energy intake (kcal/day per kg-75) body weight (Y) and caloric density (mcal/liter dry matter, as fed form) (X) was Y = 759.2X-148.4, simple correlation .99, for diets with caloric densities of .58, .63, and .68. Potential uses of this relationship in maximizing forage utilization and formulating diets to meet specific energy requirements are cited.


Ancient maya mercury.
Discovery of mercury in an ancient Maya offering at Lamanai, Belize, has stimulated examination of possible sources of the material in the Maya area. Two zones of cinnabar and native mercury deposits can be defined in the Maya highlands, and the presence of the native metal suggests that the ancient Maya collected rather than extracted the mercury from ore.


DIOGENES.
This paper describes the DIOGENES database available though BRS Information Technologies. The database focuses on drug and medical device regulatory information from the Food and Drug Administration. The specific strengths of DIOGENES are mentioned as well as some plans for further development of the database.


Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock.
Severity of multiple organ failure is significantly impacted by age and gender in patients with hemorrhagic shock. However, the molecular mechanisms underlying the enhanced organ injury are not fully understood. AMP-activated protein kinase (AMPK) is a pivotal orchestrator of metabolic responses during stress. We investigated whether hemorrhage-induced myocardial injury is age and gender dependent and whether treatment with metformin, an AMPK activator, affords cardioprotective effects. C57/BL6 young (3-5months) and mature (9-12months) male and female mice were subjected to hemorrhagic shock by blood withdrawing followed by resuscitation with blood and Lactated Ringer's solution. Vehicle-treated young and mature mice of both genders had a similar elevation of plasma inflammatory cytokines at 3h after resuscitation. However, vehicle-treated male mature mice experienced hemodynamic instability and higher myocardial damage than young male mice, as evaluated by echocardiography, histology and cardiovascular injury biomarkers. There was also a gender-dependent difference in cardiovascular injury in the mature group as vehicle-treated male mice exhibited more severe organ injury than female mice. At molecular analysis, vehicle-treated mature mice of both genders exhibited a marked downregulation of AMPKα activation and nuclear translocation of peroxisome proliferator-activated receptor γ co-activator α when compared with young mice. Treatment with metformin improved cardiovascular function and survival in mature animals of both genders. However, specific cardioprotective effects of metformin were gender-dependent. Metformin did not affect hemodynamic or inflammatory responses in young animals. Thus, our data suggest that targeting metabolic recovery with metformin may be a potential treatment approach in severe hemorrhage in adult population.


Circling mouse, a spontaneous mutant in the inner ear.
A spontaneous mutant was established in the ICR mouse strain. The affected mice became hyperactive at about 7 days of age, and then showed circling behavior. The body weight decreased significantly 2 weeks after birth, and developmental defects were revealed in the middle ear, cochlea, cochlear nerve, and semicircular canal areas. The mutation was inherited by an autosomal single recessive gene and is referred to as cir.


Brushlike interactions between thermoresponsive microgel particles.
Using a simplified microstructural picture we show that interactions between thermosensitive microgel particles can be described by a polymer brushlike corona decorating the dense core. The softness of the potential is set by the relative thickness L0 of the compliant corona with respect to the overall size of the swollen particle R. The elastic modulus in quenched solid phases derived from the potential is found to be in excellent agreement with diffusing wave spectroscopy data and mechanical rheometry. Our model thus provides design rules for the microgel architecture and opens a route to tailor rheological properties of pasty materials.


Development process in Africa: Poverty, politics and indigenous knowledge.
Persons with disability run the danger of not profiting from the development process due to exclusion from basic services and opportunities. Still, the knowledge base on exclusion mechanisms is relatively weak and there is a danger that important aspects are not addressed as they are hidden behind established understandings that are not critically scrutinised. The main purpose of this article was to highlight critical thoughts on prevailing knowledge of the relationship between disability and poverty, the policy base for addressing the rights of persons with disability, and culture as a key component in continued discrimination. This article aimed at integrating three papers on the above topics presented at the 2011 African Network for Evidence-to-Action on Disability (AfriNEAD) Symposium. The researchers have therefore thoroughly examined and questioned the relationship between disability and poverty, the influence of policy on action, and the role of culture in reproducing injustice. The article firstly claims that there are limitations in current data collection practice with regards to analysing the relationship between poverty and disability. Secondly, ambitions regarding inclusion of persons with disability in policy processes as well as in implementation of policies are not necessarily implemented in an optimal way. Thirdly, negative aspects of culture in discrimination and bad treatment of disabled need to be highlighted to balance the discussion on disability and culture. A critical view of prevailing understandings of disability and development is key to producing the knowledge necessary to eradicate poverty amongst persons with disability and other vulnerable groups. Not only do we need research that is actually designed to reveal the mechanisms behind the disability-poverty relationship, we need research that is less tied up with broad political agreements that is not necessarily reflecting the realities at ground level.


Heterocyclic Analogues as Kinase Inhibitors: A Focus Review.
Role of kinase inhibitors in various diseases is well established and discovery of imatinib opens up new paradigms in kinase inhibition. Furthermore, presence of heterocyclic moiety in a kinase inhibitor seems to be essential now. However, the potential of a single heterocyclic moiety was discussed in variety of reviews but a focus review considering the potential of different heterocyclic moieties is unavailable. Based on this, we classify prospective kinase inhibitors on the basis of number of heterocyclic moieties present and summarize the prospective kinase inhibitors. Finally, important key points, current challenges and future prospects of kinase inhibitors are also discussed.


Application of cell growth analysis to the quality assessment of human cell-processed therapeutic products as a testing method for immortalized cellular impurities.
In human cell-processed therapeutic products (hCTPs) for clinical application, tumorigenic cellular impurities in the manufacturing process are a major concern. Because cellular immortalization is one of the prerequisite steps in tumorigenesis, we tested whether cell growth analysis can be employed to check for immortalized (and potentially tumorigenic) cellular impurities in hCTPs. We monitored the growth of human bone marrow-derived mesenchymal stem cells (BMSCs) mixed with HeLa cells at a ratio of 1/106 or more and compared their growth rates with that of BMSCs alone. The cell growth analysis detected a significant increase in the growth rate of the BMSCs spiked with 0.0001% HeLa within 30 days at a probability of 47%. When human adipose-derived stem cells (ADSCs) were spiked with ASC52telo cells, a human telomerase reverse transcriptase (hTERT)-immortalized adipose-derived mesenchymal stem cell line, at a ratio of 0.001% or more, their growth rates were significantly increased within 15 passages, compared with that of ADSCs alone. These results indicate that cell growth analysis for the detection of immortalized cellular impurities in human somatic stem cells is simple and can be useful for the quality assessment of hCTPs in the manufacturing process.


Recent advances of gold nanoparticles as biomaterial in dentistry.
Major goal of dental treatment is to eradicate the existing diseases of the oral cavity and implement preventive measures to control the spread of the diseases. Various interventions are being used to cure the dental diseases. Due to the nanostructures, high surface volume and biocompatibility, Gold nanoparticles (GNPs) have been experimented in the treatment of gum diseases, dental caries, tissue engineering, dental implantology and diagnosis of cancers. GNPs possess antifungal and antibacterial activity, hence are incorporated in various biomaterials to potentiate the effect. They also enhance the mechanical properties of materials leading to improved outcomes. They are available in different sizes and concentrations to exhibits its beneficial outcomes. These properties of GNPs make these materials as choice of fillers in biomaterials. This review aims to discuss the effect of incorporation of GNPs in several biomaterials used for dental and medical applications.


[Three-dimensional analysis of craniofacial growth in adolescents with normal occlusion in Beijing].
To analyze craniofacial growth three-dimensionally for adolescents with normal occlusion in Beijing. One hundred and twenty-six adolescents with normal occlusion were selected according to the criteria. The sample was divided into four age groups (53 within 4 years, 30 within 7 years, 27 within 10 years and 16 within 13 years). Information of growth was collected. Three-dimensional cephalometric system based on cone-bean CT was established. From 4 to 13 years Co-A increased (14.55 ± 1.15) mm on average on the left and (13.66 ± 1.14) mm on the right, and Co-Gn increased (22.89 ± 1.40) mm on the left and (22.82 ± 1.38) mm on the right; and U1-NA increased (2.20 ± 0.44) mm on the left and (1.60 ± 0.46) mm on the right; and CoL-CoR and GoL-GoR increased (13.31 ± 1.21) mm and (18.59 ± 1.40) mm, and N-Me increased (18.03 ± 1.32) mm.SN-PP and SN-MPL basically remained unchanged. Adolescents with normal occlusion in Beijing grew obviously in three-dimensions and developed harmoniously.


Physicochemical characterization of chemotatic lymphokines produced by human T and B lymphocytes.
Ostensibly pure populations of T and B lymphocytes were separated from peripheral human blood by a sequential rosetting method. These cells, and mononuclear leukocyte (MNL) cell preparations (60 to 85% T cells), were cultured in vitro and the supernatants of these cultures were assayed for chemotactic lymphokine (CTX) activity. B lymphocytes were activated to produce CTX by binding erythrocytes sensitized with antibody and complement (EAC) to their C3 receptors and phytohemagglutinin (PHA) stimulation of isolated T cells was used to produce T cell-derived CTX. Sephadex G-100 gel filtration chromatography of supernatants obtained from T and B cell cultures showed that both cell types produce a CTX of approximate molecular weight 12,500 daltons. This result is identical to that previously obtained in characterizing the CTX produced by buffy coat leukocytes. Isoelectric focusing of lymphocyte supernatants and chemotactically active Sephadex G-100 fractions showed that the CTX produced by B cells and PHA-stimulated MNL contained two peaks of lymphokine activity, a major peak at pH 10.1 and a minor peak at pH 5.6. Additionally, these studies show that the chemotactic complement peptide C5a has an isoelectric point of pH 8.7 and is antigenically distinct from T and B cell-derived CTX, although relatively homogenous by gel filtration, contain two isoelectrically distinct species. In addition, these findings suggest that T and B cells although possessing different membrane receptors and requiring different mechanisms of activation to initiate lymphokine synthesis, produce lymphokines with identical physiocochemical properties.


A trend analysis of breast cancer incidence rates in the United States from 2000 to 2009 shows a recent increase.
Recent reports have shown that the breast cancer incidence rate in the US stabilized after a sharp reduction in 2002 and 2003. It is important to continue monitoring breast cancer incidence rates according to age group, race/ethnicity, estrogen receptor (ER) status, and tumor stage. Age-standardized breast cancer incidence rates were calculated using data from the surveillance, epidemiology, and end results 18 registries from 2000 to 2009, for 677,774 female breast cancer patients aged 20 and above. Jointpoint regression models were used to fit a series of joined straight lines on a log scale to annual age-standardized rates. The incidence rates of all breast cancer significantly increased for non-Hispanic blacks from 2005 to 2009 (annual percentage change, APC = 2.0 %, p = 0.01) and Asian/Pacific Islanders from 2000 to 2009 (APC = 1.2 %, p = 0.02). Since 2004, incidence rates in women aged 40-49 years significantly increased for most racial/ethnic groups (overall APC = 1.1 %, p = 0.001). The incidence rate of carcinoma in situ significantly increased in all racial/ethnic groups, with an APC range from 2.3 to 3.0 % (p < 0.005). The localized breast cancer incidence significantly increased in non-Hispanic blacks (APC = 1.3 %, p = 0.004) and Asians (APC = 1.2 %, p = 0.03). ER-positive breast cancer significantly increased in almost all age/race sub-groups after 2005 (APC by race: non-Hispanic whites 1.5 %, non-Hispanic blacks 4.3 %, Asian/Pacific Islanders 1.7 %, and Hispanics 1.8 %; all p values <0.05), while ER-negative breast cancer decreased in most sub-groups (APC by race: non-Hispanic whites-3.9 %, non-Hispanic blacks-3.7 %, Asian/Pacific Islanders-1.5 %, and Hispanics-4.3 %; all p values <0.05). Recently the incidence of breast cancer appears to be increasing in certain subgroups, including ER-positive, early-stage breast cancers, in particular among non-Hispanic blacks and Asian/Pacific Islanders. Further studies are warranted to examine possible reasons for these changes, such as changes in mammography screening methods and risk factors prevalence.


Combination of Nicks' and Konno's procedures for surgical treatment of severe congenital aortic stenosis.
This 11-year-old girl with Down's syndrome had severe aortic valvular stenosis with a pressure gradient of 95 mmHg. Balloon valvotomy failed to reduce the pressure gradient. Surgical correction was performed. The aortic valve was bicuspid with fibrotic change and the anulus was about 10 mm in diameter. The aortic valve was resected, and the anulus was enlarged by a combination of the Nicks and Konno procedures. Then, a St. Jude 19 mm mechanical prosthesis was implanted, and the right ventricular outflow tract was repaired with a baked woven Dacron patch. The postoperative course was very uneventful. She was discharged in good condition on the 10th postoperative day. A combination of the Nicks and Konno procedures is recommended to correct very small aortic anuli requiring extensive enlargement of the aortic root.


Physical achirality in geometrically chiral rotamers of hydrazine and boranylborane molecules.
The diagonal components and the trace of tensors which account for chiroptical response of the hydrazine molecule N2 H4 , that is, static anapole magnetizability and frequency-dependent electric dipole-magnetic dipole polarisability, are a function of the ϕ ≡ ∠ H─N─N─H dihedral angle. They vanish for symmetry reasons at ϕ = 0° and ϕ = 180°, corresponding respectively to C2v and C2h point group symmetries, that is, cis and trans conformers characterized by the presence of molecular symmetry planes. Nonetheless, vanishing diagonal components have been observed also in the proximity of ∠ H─N─N─H = 90°, in which the point group symmetry is C2 and hydrazine is unquestionably chiral. In the boranylborane molecule B2 H4 , assuming the B─B bond in the y direction, the ayy component of the anapole magnetizability tensor approximately vanishes for dihedral angles ∠ H─B─B─H corresponding to chiral rotamers which belong to D2 symmetry. Such anomalous effects have been ascribed to physical achirality of these conformers, that is, to their inability to sustain electronic current densities inducing either anapole moments, or electric and magnetic dipole moments, about the chiral axis connecting heavier atoms, as well as perpendicular directions. In other terms, the structure of certain geometrically chiral rotamers may be such that neither toroidal nor helical flow, which determine chiroptical phenomenology, can take place in the presence of perturbing fields parallel or orthogonal to the chiral axis.


Control of Staphylococcus aureus biofilms by the application of single and combined treatments based in plant essential oils.
Effective and environmentally-friendly alternatives to traditional disinfectants are necessary to reduce the pollution and the emergence of antimicrobial-resistant bacterial strains in food-related environments. In the present study, treatments based in single and combined applications of plant essential oils (EOs) were evaluated for control Staphylococcus aureus biofilms. EOs of Lippia sidoides, Thymus vulgaris and Pimenta pseudochariophyllus showed a higher efficacy than peracetic acid and sodium hypochlorite against S. aureus planktonic cells and 24-h-old biofilms formed on polystyrene and stainless steel under food-related conditions. High concentrations of thymol and chavibetol were detected in these EOs, as well as the presence of other antimicrobial compounds such as carvacrol, eugenol, p-cymene, limonene, α-pinene, α-terpineol, terpinen-4-oil and linalool. L. sidoides oil were particularly effective against S. aureus, but doses higher than 2.75% (v/v) were required to completely eradicate 24-h-old biofilms. Binary combinations of L. sidoides, T. vulgaris and P. pseudochariophyllus allowed decrease significantly doses required to reduce 99.99% the number of biofilm cells. Furthermore, peracetic acid increased its efficacy against S. aureus biofilms by the combined application with these EOs. The most effective treatments against S. aureus biofilms were those combining L. sidoides with T. vulgaris or peracetic acid. Therefore, these EO-based treatments can be considered as an effective and environmentally-friendly alternative to control S. aureus biofilms in food-contact surfaces.


Aortoesophageal Fistula Occurring during Lung Cancer Treatment: A Case Treated by Thoracic Endovascular Aortic Repair.
A 63-year-old man had received chemoradiotherapy 7 years ago for stage IIIA pulmonary adenocarcinoma of the left lower lobe and stereotactic irradiation 3 years ago for stage IA pulmonary squamous cell carcinoma of the left upper lobe. An esophageal stent was placed because of esophageal narrowing caused by tumor invasion. Five months later, he was diagnosed with an aortoesophageal fistula. Because invasive surgery posed challenges, thoracic endovascular aortic repair (TEVAR) was performed. We report this rare case of aortoesophageal fistula treated using TEVAR. However, the therapeutic effect was temporary. Further studies investigating the indications for TEVAR are warranted.


Identification of obstacles for chronic pain patients to return to work: evaluation of a questionnaire.
The Obstacles to Return-to-Work Questionnaire (ORQ) was developed and evaluated. A total of 154 patients with chronic musculoskeletal pain and prolonged work disability participated in the study. Factor analyses reduced the ORQ to 55 items grouped into 9 subscales. The subscales were named "Depression," "Pain intensity," "Difficulties at work return," "Physical workload and harmfulness," "Social support at work," "Worry due to sick leave," "Work satisfaction," "Family situation and support," and "Perceived prognosis of work return." The subscales showed satisfactory reliability. In order to determine predictive validity a discriminant analysis was conducted with sick leave 9 months after assessment as the outcome. This analysis indicated that the scales "Perceived prognosis of work return," "Social support at work," "Physical workload and harmfulness," "Depression," and "Pain intensity" could significantly predict sick leave and correctly classified 79% of the patients. The Multidimensional Pain Inventory and the Disability Rating Index could also significantly predict sick leave in this sample and correctly classified as many patients as the ORQ. However, these questionnaires do not include any work-oriented items and they had a lower specificity than the ORQ. This study suggests that patients' perceptions and beliefs about work and returning to work may be a significant hindrance for actual recovery.


Impact of Non-Automobile Rollover Accidents on Patient Outcomes at an Appalachian Level I Trauma Center.
The objective of this study was to evaluate outcomes of patients involved in rollover accidents in non-automobile vehicles in a rural level I trauma center. This was a retrospective study including a total of 127 patients over 5 years who were admitted to our level I trauma center following rollover accidents in either of the following: ATV, lawnmower, or tractor. Patients were significantly older in the tractor and lawnmower rollover groups, and patients less than 65 years old were significantly more likely to sustain an injury in a rollover accident when compared to those greater than 65. Patients with extremity fractures secondary to tractor rollovers were more likely to be older, and patients who sustained spinal injuries secondary to tractor rollovers were more likely to be younger. Non-automobile rollovers have the potential to cause traumatic injuries; however, there does not appear to be 1 vehicle type that is more prone to injury.


High-Throughput Algorithm for Discovering New Drug Indications by Utilizing Large-Scale Electronic Medical Record Data.
Drug repositioning is an effective way to mitigate the production problem in the pharmaceutical industry. Electronic medical record (EMR) databases harbor a large amount of data on drug prescriptions and laboratory test results and may thus be useful for finding new indications for existing drugs. Here, we present a novel high-throughput data-driven algorithm that identifies and prioritizes drug candidates that show significant effects on specific clinical indicators by utilizing large-scale EMR data. We chose four laboratory tests as clinical indicators: hemoglobin A1c (HbA1c), low-density lipoprotein (LDL) cholesterol, triglycerides (TGs), and high-density lipoprotein (HDL) cholesterol. From a 5-year EMR database, we generated datasets consisting of paired data with averaged measurement values during on and off each drug in each patient, adjusted for co-administered drug effects at each timepoint, and applied one sample t-test with the Bonferroni correction for statistical analysis. Among 1,774 drugs, 45 were associated with increases in HDL cholesterol, and 41, 146, and 65 were associated with reductions in HbA1c, LDL cholesterol, and TGs, respectively. We compared the list of candidate drugs with that of drugs indicated for relevant clinical conditions and found that the algorithm had high values for both sensitivity (range 0.95-1.00) and negative predictive value (range 0.95-1.00). Our algorithm was able to rediscover well-known drugs that are used for diabetes and dyslipidemia while revealing potential candidates without current indications but have shown promising results in the literature. Our algorithm may facilitate the repositioning of drugs with proven safety profiles.


Connections and performances of Green's function methods for charged and neutral excitations.
In recent years, Green's function methods have garnered considerable interest due to their ability to target both charged and neutral excitations. Among them, the well-established GW approximation provides accurate ionization potentials and electron affinities and can be extended to neutral excitations using the Bethe-Salpeter equation (BSE) formalism. Here, we investigate the connections between various Green's function methods and evaluate their performance for charged and neutral excitations. Comparisons with other widely known second-order wave function methods are also reported. Additionally, we calculate the singlet-triplet gap of cycl[3,3,3]azine, a model molecular emitter for thermally activated delayed fluorescence, which has the particularity of having an inverted gap thanks to a substantial contribution from the double excitations. We demonstrate that, within the GW approximation, a second-order BSE kernel with dynamical correction is required to predict this distinctive characteristic.


The impact of maternal electrolyte and albumin levels on the efficacy of single-dose methotrexate treatment for ectopic pregnancies.
This study aims to investigate the impact of maternal albumin and serum electrolyte levels on the efficacy of single-dose methotrexate (SDMtx) therapy for ectopic pregnancies. Building on previous research, recommendations are provided to enhance the success of SD-Mtx therapy in the management of ectopic pregnancy. Conducted at a tertiary center gynecology clinic, the study included 353 patients diagnosed with ectopic pregnancy and treated with SD-Mtx from 2012 to 2023. Patients who responded positively to SD-Mtx treatment comprised Group 1 (n=313), while those requiring surgical intervention due to failed SD-Mtx therapy constituted Group 2 (n=40). Through the hospital's digital database, patient data including complete blood count, biochemistry, and hormone test results were retrospectively examined. The mean β-hCG value was 1996 IU/mL for Group 1 in contrast to 2058 IU/mL for Group 2. There was no statistically significant difference in β-hCG levels between the two groups. Notably, Group 1 patients exhibited lower serum magnesium levels but higher potassium levels compared to Group 2 patients, with statistically significant differences. Furthermore, Group 1 patients had higher albumin levels than those in Group 2, with a statistically significant difference. Successful SD-Mtx treatment was associated with lower maternal serum magnesium levels and higher potassium and albumin levels. Considering electrolyte levels before administering SD-Mtx and addressing any imbalances could potentially enhance treatment success. Additionally, restoring low albumin levels might improve the efficacy of SD-Mtx treatment for ectopic pregnancies. While this study suggests these trends, further extensive studies with a larger sample size are necessary to establish more definitive evidence.


Shift work and colorectal cancer risk in the MCC-Spain case-control study.
Objectives Shift work that involves circadian disruption has been associated with a higher cancer risk. Most epidemiological studies to date have focused on breast cancer risk and evidence for other common tumors is limited. We evaluated the risk for colorectal cancer (CRC) in relation to shift work history in a population-based case-control study in Spain. Methods This analysis included 1626 incident CRC cases and 3378 randomly selected population controls of both sexes, enrolled in 11 regions of Spain. Sociodemographic and lifestyle information was assessed in face-to-face interviews. Shift work was assessed in detail throughout lifetime occupational history. We estimated the risk of colon and rectal cancer associated with rotating and permanent shift work (ever, cumulative duration, age of first exposure) using unconditional logistic regression analysis adjusting for potential confounders. Results Having ever performed rotating shift work (morning, evening and/or night) was associated with an increased risk for CRC [odds ratio (OR) 1.22, 95% confidence interval (95% CI) 1.04-1.43], as compared to day workers. Having ever worked permanent night shifts (≥3 nights/month) was not associated with CRC risk (OR 0.79, 95% CI 0.62-1.00). OR increased with increasing lifetime cumulative duration of rotating shift work (P-value for trend 0.005) and were highest among subjects in the top quartiles of exposure (3 rdquartile, 20-34 years, OR 1.38, 95%CI 1.06-1.81; 4 thquartile, ≥35 years, OR 1.36, 95% CI 1.02-1.79). Conclusions These data suggest that rotating shift work may increase the risk of CRC especially after long-term exposures.


Human versus non-human sex steroid use in hormone replacement therapies part 1: Preclinical data.
Prior to 2002, hormone replacement therapy (HRT) was considered to be an important component of postmenopausal healthcare. This was based on a plethora of basic, epidemiological and clinical studies demonstrating the health benefits of supplementation with human sex steroids. However, adverse findings from the Women's Health Initiative (WHI) studies that examined the 2 major forms of HRT in use in the US at that time - Premarin (conjugated equine estrogens; CEE) and Prempro (CEE + medroxyprogesterone acetate; MPA), cast a shadow over the use of any form of HRT. Here we review the biochemical and physiological differences between the non-human WHI study hormones - CEE and MPA, and their respective human counterparts 17β-estradiol (E2) and progesterone (P4). Preclinical data from the last 30 years demonstrate clear differences between human and non-human sex steroids on numerous molecular, physiological and functional parameters in brain, heart and reproductive tissue. In contrast to CEE supplementation, which is not always detrimental although certainly not as optimal as E2 supplementation, MPA is clearly not equivalent to P4, having detrimental effects on cognitive, cardiac and reproductive function. Moreover, unlike P4, MPA is clearly antagonistic of the positive effects of E2 and CEE on tissue function. These data indicate that minor chemical changes to human sex steroids result in physiologically distinct actions that are not optimal for tissue health and functioning.


Intraluminal thrombus, intraplaque hemorrhage, plaque thickness, and current smoking optimally predict carotid stroke.
Intraplaque hemorrhage (IPH) is associated with acute and future stroke. IPH is also associated with lumen markers of stroke risk including stenosis, plaque thickness, and ulceration. Whether IPH adds further predictive value to these other variables is unknown. The purpose of this study was to determine whether IPH improves carotid-source stroke prediction. In this retrospective cross-sectional study, patients undergoing stroke workup were imaged with MRI and IPH detection. Seven hundred twenty-six carotid-brain image pairs were analyzed after excluding vessels with noncarotid plaque stroke sources (420) and occlusions (7) or near-occlusions (3). Carotid imaging characteristics were recorded, including percent diameter and mm stenosis, plaque thickness, ulceration, intraluminal thrombus, and IPH. Clinical confounders were recorded, and a multivariable logistic regression model was fitted. Backward elimination was used to determine essential carotid-source stroke predictors with a threshold 2-sided P<0.10. Receiver operating characteristic analysis was performed to determine discriminatory value. Significant predictors of carotid-source stroke included intraluminal thrombus (odds ratio=103.6; P<0.001), IPH (odds ratio=25.2; P<0.001), current smoking (odds ratio=2.78; P=0.004), and thickness (odds ratio=1.24; P=0.020). The final model discriminatory value was excellent (area under the curve=0.862). This was significantly higher than the final model without IPH (area under the curve=0.814), or models using only stenosis as a continuous variable (area under the curve=0.770) or cutoffs of 50% and 70% (area under the curve=0.669), P<0.001. After excluding patients with noncarotid plaque stroke sources, optimal discrimination of carotid-source stroke was obtained with intraluminal thrombus, IPH, plaque thickness, and smoking history but not ulceration and stenosis.


Effects of infection and endotoxin on rat hepatic RNA production and distribution.
Rat liver was quantitatively subfractionated into free ribosomal, bound ribosomal, nuclear, and soluble fractions to determine the effects of infection and endotoxin treatment on hepatic RNA production and distribution. A 4-h pulse label of [14C]orotic acid was used to monitor newly transcribed RNA; distribution was determined by measuring RNA content at various times after infection or endotoxin treatment. A significant increase in the rate of RNA synthesis was seen by 12 h and continued through 20 h in response to Streptococcus pneumoniae infection. During the peak hours of the RNA response, redistribution of RNA into the bound ribosomal fraction takes place at the expense of the free ribosomes. However, in Salmonella typhimurium and its endotoxin, more involvement of the free ribosoma fraction during the early stages of the infection was apparent. These data suggest that the hepatic RNA response takes place in two stages, an early "endotoxin" response, resulting in redistribution of cytoplasmic RNA into free ribosomes, and a later "infection" response, involving the mobilization of the bound ribosomes.


Mutation in lamin A/C sensitizes the myocardium to exercise-induced mechanical stress but has no effect on skeletal muscles in mouse.
LMNA gene encodes lamin A/C, ubiquitous proteins of the nuclear envelope. They play crucial role in maintaining nuclear shape and stiffness. When mutated, they essentially lead to dilated cardiomyopathy with conduction defects, associated or not with muscular diseases. Excessive mechanical stress sensitivity has been involved in the pathophysiology. We have previously reported the phenotype of Lmna(delK32) mice, reproducing a mutation found in LMNA-related congenital muscular dystrophy patients. Heterozygous Lmna(delK32/+) (Het) mice develop a progressive dilated cardiomyopathy leading to death between 35 and 70 weeks of age. To investigate the sensitivity of the skeletal muscles and myocardium to chronic exercise-induced stress, Het and wild-type (Wt) mice were subjected to strenuous running treadmill exercise for 5 weeks. Before exercise, the cardiac function of Het mice was similar to Wt-littermates. After the exercise-period, Het mice showed cardiac dysfunction and dilation without visible changes in cardiac morphology, molecular remodelling or nuclear structure compared to Wt exercised and Het sedentary mice. Contrary to myocardium, skeletal muscle ex vivo contractile function remained unaffected in Het exercised mice. In conclusion, the expression of the Lmna(delK32) mutation increased the susceptibility of the myocardium to cardiac stress and led to an earlier onset of the cardiac phenotype in Het mice.


Exhaustive Suzuki-Miyaura reactions of polyhalogenated heteroarenes with alkyl boronic pinacol esters.
A novel Suzuki-Miyaura protocol is described that enables the exhaustive alkylation of polychlorinated pyridines. This method facilitates a formal synthesis of normuscopyridine and the rapid assembly of a dumbbell shaped portion of a [2]rotaxane.


Intestinal absorption of dietary carotenoids.
The assessment of carotenoid bioavailability has long been hampered by the limited knowledge of their absorption mechanisms. However, recent reports have elucidated important aspects of carotenoid digestion and absorption. Disruption of food matrix and increasing amounts of fat seem to enhance the absorption of carotenes to a larger extent than that of xanthophylls. Comparing different carotenoid species, xanthophylls seem to be more easily released from the food matrix and more efficiently micellized than the carotenes. On the other hand, carotenes are more efficiently taken up by the enterocytes. However, carotenoid emulsification and micellization steps are largely affected by the food matrix and dietary components, being the main determinant of carotenoid bioavailability from foodstuffs. Although the intestinal uptake of carotenoids has been thought to occur by simple diffusion, recent studies reported the existence of receptor-mediated transport of carotenoids in enterocytes. Comparisons between the intestinal absorption of a wide array of carotenoids would be useful to elucidate the absorption mechanism of each carotenoid species, in view of the recent indications that intestinal carotenoid uptake may involve the scavenger receptor class B type I and possibly other epithelial transporters. The unraveling of the whole mechanism underlying the absorption of carotenoids will be the challenge for future studies.


Successful bailout stenting strategy against lethal coronary dissection involving left main bifurcation.
Catheter-induced coronary dissection involving left main bifurcation is a rare complication during cardiac catheterization but can become lethal unless it is treated appropriately. Interventional cardiologists always have to pay attention to the risk of complications related to cardiac catheterization and prepare for determining the best bailout strategy for the situation.


Delineating anatomy and function with multimodality imaging: a case report of giant right coronary artery aneurysms.
Giant coronary artery aneurysms (CAAs) are rare and have been reported in patients with connective tissue diseases, arteritides, and atherosclerosis. Given the rarity of the condition, multimodality imaging is essential for comprehensive evaluation of coronary aneurysms and determination of their haemodynamic significance. A 58-year-old Filipino female was evaluated for dyspnoea on exertion of one month. Chest computed tomography (CT) showed right coronary artery (RCA) aneurysms. Invasive coronary angiogram (ICA) confirmed two giant aneurysms of the RCA. Distal RCA could not be opacified due to contrast stagnation in the proximal aneurysms. Coronary CT angiography (CCTA) depicted an additional giant distal RCA aneurysm not visualized on ICA with intraluminal thrombosis. Contrast-enhanced cardiac magnetic resonance imaging (CMR) revealed delayed time to peak perfusion in the mid to apical inferior walls, on first-pass imaging, without myocardial scarring. Late gadolinium images revealed aneurysmal wall inflammation. This case highlights the anatomical findings of giant CAA and the application of multimodality imaging for their accurate characterization. While ICA confirmed the presence of the aneurysms, CCTA enabled the assessment of their full extent and depict intraluminal thrombosis. Contrast-enhanced CMR delineated aneurysm wall characteristics, with first-pass images demonstrating reduced inferior wall perfusion at rest, which was likely the cause of patient's exertional symptoms. Management of giant coronary aneurysms involves surgical resection with bypass grafting.


Current prevalence of hepatitis delta virus (HDV) infection and the range of HDV genotypes in Lebanon.
Recently the prevalence of hepatitis B virus (HBV) genotypes and the association between these genotypes and the clinical status of HBV-infected patients were recently investigated in the Lebanese population. The aim of the additional study reported here was to determine the current prevalence of hepatitis delta virus (HDV) infection and the range of HDV genotypes in this Lebanese population. Two hundred and fifty-eight HBsAg-positive patients (107 asymptomatic blood donors, 92 with chronic hepatitis, 24 with cirrhosis, 15 with hepatocellular carcinoma, 20 patients on haemodialysis) from ten medical centers in Lebanon were tested for antibody to hepatitis D virus (anti-HDV). Those testing positive were analysed further for HDV-RNA and for genotyping by reverse transcriptase-polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP). Three samples (1.2%) were anti-HDV positive and out of these, only one was HDV-RNA positive (0.6%) and was analysed as HDV genotype I. Our results point to a low endemicity of HDV in the Lebanese population which is in sharp contrast to data reported from Lebanon 20 years ago and to the situation in neighbouring Arab and non-Arab countries in the Mediterranean region. HDV genotype I seems to be the predominant genotype in Lebanon and the Middle East.


Cytotoxic activity and subset populations of peripheral blood natural killer cells in patients with chronic pain.
Chronic pain reportedly exerts complex effects on immune function. Natural killer (NK) cells are lymphocytes that play a critical role in cellular and innate immunity. This study examined changes in the subset populations and cytotoxic activity of peripheral blood NK cells in patients with chronic pain. Thirty patients with chronic moderate-to-severe pain (group P) and age-matched pain-free subjects (group NoP) were enrolled. Peripheral whole blood was analyzed for the percentage and expression of NK cell surface markers (CD56 and CD16) by flow cytometry. Cytotoxic activity was assayed by evaluating CD69 expression on CD3-/CD56+NK cells. The percentage of NK cells among total lymphocytes was not significantly different between groups P and NoP (16.3 ± 9.3 vs. 20.2 ± 10.5%). Likewise, the percentages of two major NK cell subsets, CD56bright and CD56dim, were also not significantly different between the two groups. However, the percentage of CD56bright/CD16+ subset, was slightly but significantly increased in group P (1.0 ± 0.9%; P < 0.01) compared with group NoP (0.5 ± 0.6%). The cytotoxicity of NK cells was not different between the two groups, showing similar CD69 expression (P vs. NoP = 29.2 ± 15.2 vs. 32.0 ± 15.0%). These findings were not influenced by pain intensity, opioid use, or disease causing pain in group P. NK cell cytotoxic activity and major subset populations, with the exception of an increased percentage of the CD56bright/CD16+ subset, are not significantly altered in patients with chronic severe pain.


Introducing forensic health services research.
Financial fraud and abuse are rampant within our healthcare system. Recent estimates suggest that $68 to $234 billion is lost to fraud annually. Despite numerous efforts, current strategies have met with limited success in preventing and remediating this practice. Why have we not been better able to tackle this problem? Current strategies aimed at preventing healthcare fraud and abuse fail to appreciate the spectrum that lies between clinically appropriate care and fraudulent practice. This oversight is critical, as what may be fitting treatment in one setting may just as easily be fraudulent in another. Therefore, in order to untangle the web of fraud and abuse, novel techniques and engagement of physicians who best understand these nuances are necessary. In this commentary, we introduce "forensic health services research," an extension of this scientific discipline that can best identify wasteful and fraudulent expenditure. The use of health services research in this fashion is not only synergistic with ongoing efforts, but greatly enhances current approaches. Despite the promise of this endeavor, important policy changes are needed to nurture this novel niche. We review these challenges and outline a path to move forward using this platform.


Exploring the Anticancer Potential of Premna resinosa (Hochst.) Leaf Surface Extract: Discovering New Diterpenes as Heat Shock Protein 70 (Hsp70) Binding Agents.
Premna, a genus consisting of approximately 200 species, predominantly thrives in tropical and subtropical areas. Many of these species have been utilized in ethnopharmacology for diverse medicinal applications. In Saudi Arabia, Premna resinosa (Hochst.) Schauer (Lamiaceae) grows wildly, and its slightly viscid leaves are attributed to the production of leaf accession. In this study, we aimed to extract the surface accession from fresh leaves using dichloromethane to evaluate the anticancer potential. The plant exudate yielded two previously unknown labdane diterpenes, Premnaresone A and B, in addition to three already described congeners and four known flavonoids. The isolation process was accomplished using a combination of silica gel column chromatography and semi-preparative HPLC, the structures of which were identified by NMR and HRESIMS analyses and a comparison with the literature data of associated compounds. Furthermore, we employed a density functional theory (DFT)/NMR approach to suggest the relative configuration of different compounds. Consequently, we investigated the possibility of developing new chaperone inhibitors by subjecting diterpenes 1-5 to a Surface Plasmon Resonance-screening, based on the knowledge that oridonin, a diterpene, interacts with Heat Shock Protein 70 (Hsp70) 1A in cancer cells. Additionally, we studied the anti-proliferative activity of compounds 1-5 on human Jurkat (human T-cell lymphoma) and HeLa (epithelial carcinoma) cell lines, where diterpene 3 exhibited activity in Jurkat cell lines after 48 h, with an IC50 of 15.21 ± 1.0 µM. Molecular docking and dynamic simulations revealed a robust interaction between compound 3 and Hsp70 key residues.