Selected herbal hazards.
One of the most important considerations in treating herbal ingestions is product quality assurance. Although most herbal companies are reputable, there are numerous reports of adulterated products (addition of substances not noted on the label). This has been particularly true of Chinese herbal products, which frequently contain pharmaceutical agents. Plant identification errors occur, and entire batches of product have been mixed using the wrong herb. In some cases, labels are written in a foreign language or only contain directions for mixing, making interpretation difficult. In cases where a known ingestion produces unexpected clinical signs, the potential for adulteration or other errors should be considered. When a product is not standardized, a consumer cannot be sure what dose of active constituents has been used or how bioavailable the product may be. Standardization also provides assurance that the actual herb is in the product [26]. Clients who use herbal products should be advised to treat them as a medication and to keep them away from pets. Specifically, ask clients if they take or use any natural or herbal products. Many people do not consider these substances drugs or assume, "If natural, it is harmless." Clients should be encouraged to learn about the herbal and neutraceutical products they are taking or giving their pets. Owners need to discuss the proper use of herbal products in pets with their veterinarian. Clients can be encouraged to discuss alternative therapies by discussing a pet's diagnosis and suggested treatments thoroughly. Discuss the client's expectations and opinions of alternative and conventional medicine. Issues of safety and efficacy must be fully explained to clients. Clients should be encouraged to report potential adverse reactions or to discuss different routes of therapy if a pet's medical condition is not improving. Clients who want to use alternative medical treatments should obtain a thorough medical workup so as to make a correct diagnosis and be referred to a veterinarian trained in alternative medicine. In choosing an alternative medicine practitioner, the same criteria would be used as for any other specialist: education, training, and professionalism [14].


Exome sequencing reveals novel rare variants in Iranian familial multiple sclerosis: The importance of POLD2 in the disease pathogenesis.
The prevalence of familial multiple sclerosis (FMS) is increasing worldwide which endorses the heritability of the disease. Given that many genome variations are ethnicity-specific and consanguineous marriage could affect genetic diseases, hereditary disease gene analysis among FMS patients from Iran, a country with high rates of parental consanguinity, could be highly effective in finding mutations underlying disease pathogenesis. To examine rare genetic mutations, we selected three Iranian FMS cases with ≥3 MS patients in more than one generation and performed whole exome sequencing. We identified a homozygous rare missense variant in POLD2 (p. Arg141Cys; rs372336011). Molecular dynamics analysis showed reduced polar dehydration energy and conformational changes in POLD2 mutant. Further, we found a heterozygote rare missense variant in NBFP1 (p. Gly487Asp; rs778806175). Our study revealed the possible role of novel rare variants in FMS. Molecular dynamic simulation provided the initial evidence of the structural changes behind POLD2 mutant.


[Peculiarities of juvenile vertebral fractures and dislocations of the cervical vertebrae].
In addition to diagnostic and therapeutic problems of the bony spine injuries in childhood, questions of the participation of the growth plate arise and indicate the following treatment. In the last decade we treated 23 spine injuries, resulting after fall from height. Most of the cases showed single to multiple compression fractures of the anterior spine followed in a descending frequence by the lateral compression fractures, the disconnection ot the epiphyseal plate of the axis and the actual luxation fractures with injury of the stratum germinativum. In contrast to the prognostic favourable impression fractures with a spontaneous correction, luxation fractures with or without paraplegia must be repositionned and stabilized.


The neuropsychology of post-polio fatigue.
To test the hypothesis that post-polio fatigue and its concomitant cognitive deficits are associated with an impairment of attention and not of higher-level cognitive processes, six carefully screened polio survivors were administered a battery of neuropsychological tests. Only subjects reporting severe fatigue, and not those with mild fatigue, demonstrated clinically significant deficits on all tests of attention, concentration, and information processing speed while showing no impairments of cognitive ability or verbal memory. These findings suggest that an impaired ability to maintain attention and rapidly process complex information appears to be a characteristic in polio survivors reporting severe fatigue, because these deficits were documented even when their subjective rating of fatigue was low. This finding supports the hypothesis that a polio-related impairment of selective attention underlies polio survivors' subjective experience of fatigue and cognitive problems.


Clinical correlation between the consumption of nicotine and cotinine concentrations in urine and serum by competitive enzyme-linked immunosorbent assay.
Different negative effects of smoking are known (e.g. postoperative complications), which lead, especially in plastic surgery, to unsatisfactory results. The aim of this study was to examine the appropriateness of a cotinine enzyme-linked immunosorbent assay (ELISA) for routine usage in operative disciplines. By correlation of smoking habits and concentration of cotinine in serum and urine, we tried to ascertain reference values for smokers, passive smokers and non-smokers. The reliability and sensitivity of the cotinine ELISA concerning nicotine exposure need to be proven. 165 (108 men, 57 women) test persons were examined by detecting cotinine in serum and urine by ELISA. The study shows a very good sensitivity, precision and reproducibility of the cotinine ELISA according to the laboratory criteria. The test shows significance of a good differentiation between smokers, passive smokers and non-smokers in urine. In serum, cotinines are excellent to differentiate between smokers and non-smokers/passive smokers. Urine and serum tests demonstrate valid and comparable results.


Beneficial effects of polyunsaturated fatty acids in partially nephrectomized rats.
Evening primrose oil, safflower oil, and salmon oil, all with high polyunsaturated fatty acid content, were fed to partially nephrectomized rats; the effects were compared to those of feeding beef tallow. All three oils had favorable effects on progression of renal failure, salmon oil on kidney histology as well. The changes induced in platelet production of thromboxane A2, and in the renal production of various eicosanoids may explain the protective role of these oils.


Quality by Design as a risk-based strategy in pharmaceutical analysis: Development of a liquid chromatography-tandem mass spectrometry method for the determination of nintedanib and its impurities.
Nintedanib (NIN) is a tyrosine kinase inhibitor recently approved for the treatment of idiopathic pulmonary fibrosis. As a new drug, no monograph is available so far in official compendia. A liquid chromatography-tandem mass spectrometry method is presented for the simultaneous determination of NIN and its seven potential impurities. The risk-based approach of Analytical Quality by Design was applied in method development. The critical method parameters (CMPs) were the type of organic solvent in the mobile phase, formic acid percentage, column flow rate, oven temperature, gradient slope of organic eluent. The critical method attributes (CMAs) were selected as analysis time and selectivity between the main compound NIN and the adjacent peaks. Design of Experiments methodology was effectively employed for establishing the relationship between the CMPs and the CMAs. In the scouting step, a Restek Ultra AQ C18 (100 × 2.1 mm, 2.7 µm) core-shell column was selected, and then the effects of different levels of the five CMPs on the CMAs were evaluated by means of a 35//16 symmetric screening matrix. A Box-Behnken Design made it possible to obtain detailed maps of predicted CMAs throughout the investigated experimental domain, pointing out the presence of interaction and quadratic effects. The probability of meeting the specifications for the CMAs was calculated by Monte-Carlo simulations, performing a risk analysis and drawing risk of failure maps, which were used to visualize and define the method operable design region (MODR) with a probability π ≥ 90%. The final working conditions (enclosing the MODR interval) were as follows: methanol as organic solvent; formic acid percentage, 0.15% v/v; flow rate, 0.40 mL min-1 (0.37-0.43 mL min-1); oven temperature, 40 °C (38-40 °C); gradient slope of organic eluent, 14.00% eluent B min-1 (12.85-15.15% eluent B min-1). The resulting analysis time was about 10 min. Validation was carried out according to International Council for Harmonisation guidelines and the optimized method was applied to the analysis of NIN soft capsules for quality control purposes.


Updates for Cardio-Kidney Protective Effects by Angiotensin Receptor-Neprilysin Inhibitor: Requirement for Additional Evidence of Kidney Protection.
The incidence of heart failure and chronic kidney disease is increasing, and many patients develop both diseases. Angiotensin receptor-neprilysin inhibitor (ARNI) is a promising therapeutic candidate for both diseases. ARNI has demonstrated superior cardioprotective effects compared with renin-angiotensin system inhibitors (RAS-Is) in large clinical trials such as the PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. It has also been suggested that ARNI can provide renoprotective effects beyond those of RAS-Is in patients with HF. ARNI might have beneficial effects on the kidneys because of its ability to improve cardiac function in patients with heart failure and affect renal hemodynamics by enhancing the effects of hormones such as natriuretic peptide. In contrast, in the PARADIGM-HF trial, ARNI was associated with more albuminuria compared with RAS-I; thus, it is unclear whether long-term ARNI therapy has renoprotective effects. Additionally, ARNI did not provide renoprotective effects beyond RAS-I in patients with chronic kidney disease in the UK HARP-III (United Kingdom Heart and Renal Protection-III) trial. In other words, the patient population in which ARNI is more renoprotective than RAS-I might be limited. Collectively, ARNI may have renoprotective effects in addition to cardioprotective effects, but the evidence to date is applicable only to heart failure. Theoretically, given the molecular mechanism of ARNI, it could also be renoprotective in conditions such as nephrosclerosis, which has low risks of albuminuria and reduced kidney perfusion, but the evidence for such effects is lacking. Further research is needed to clarify whether ARNI therapy is an acceptable treatment strategy for renal protection.


Computed tomography of xanthogranulomatous pyelonephritis presenting as a flank mass.
Xanthogranulomatous pyelonephritis should be part of the differential diagnosis when extensive soft tissue involvement is associated with renal disease. As a diagnosis of neoplasm may be rendered even on microscopy, it is particularly important that this entity be considered.


Host modification of chlamydiae: presence of an egg antigen on the surface of chlamydiae grown in the chick embryo.
Egg-grown chlamydiae (EGO) have a yolk sac antigen assoicated with their surface which is absent from cell monolayer-grown organisms (CGO). EGO infectivity was specifically neutralized by rabbit antiserum to normal yolk sac; CGO infectivity, before or after incubation with normal yolk sac material, was not neutralized. Treatment of EGO with Clostridium welchii culture filtrate, containing phospholipase C, abolished spontaneous infectivity for monolayers and neutralization by anti-yolk sac antiserum but did not affect centrifuge-assisted infectivity. The possible significance of host antigen on the chlamydial surface is considered.


Psychoses of Epilepsy in Pregnancy: A Case Report.
To discuss the unique relationship between psychosis and seizures in a young individual, who is also pregnant. Psychosis of epilepsy can present in multitude of ways, including pre-ictal, ictal, post-ictal, chronic interictal, and forced normalization psychosis.


Brazil and cashew nuts intake improve body composition and endothelial health in women at cardiometabolic risk (Brazilian Nuts Study): a randomized controlled trial.
Several mechanisms have been proposed for the beneficial effect of nuts on health. However, Brazil and cashew nuts remain the least studied. We aim to evaluate the effect of these nuts within an energy-restricted diet on body weight, body composition, cardiometabolic markers, and endothelial function in cardiometabolic risk women. Brazilian nuts study is a randomized controlled parallel 8-week dietary intervention trial. Forty women were randomly allocated to 1) Control group: Energy-restricted diet without nuts, n= 19 or, 2) Brazil and cashew nuts group (BN-Group): Energy-restricted diet containing daily 45 g of nuts (15 g of Brazil nuts + 30g of cashew nuts), n= 21. At the beginning and final intervention, anthropometry, body composition, and blood pressure were measured. Fasting blood sampling was obtained to evaluate lipid profile, glucose homeostasis, and endothelial function markers. After 8-week, plasma selenium concentration increased in BN-group (∆ = + 31.5 ± 7.8 μg/L; p= 0.001). Brazil and cashew nuts intake reduced total body fat (-1.3 ± 0.4 %) parallel to improvement of lean mass percentage in BN-group compared to the control. Besides, the soluble adhesion molecule VCAM-1 decreased (24.03 ± 15.7 pg/mL vs. -22.2 ± 10.3 pg/mL; p= 0.019) after Brazil and cashew nuts intake compared to the control. However, lipid and glucose profile markers, apolipoproteins, and blood pressure remained unchanged after the intervention. Thus, the addition of Brazil and cashew nuts to an energy-restricted diet can be a healthy strategy to improve body composition, selenium status, and endothelial inflammation in cardiometabolic risk women.


The outcome of conventional open reduction approach vs endoscopic approach for orbital floor repair.
Blunt trauma to the orbital rim is a frequent cause of both orbital fractures and damage to the surrounding facial bones and soft tissues. The inception of endoscopy and minimal invasive intervention has revolutionized the surgical treatment of blow out fracture of orbital walls. Thus, the present study was conducted to compare the outcome of conventional open reduction approach with endoscopic approach for orbital floor repair. The study included 10 patients with clinical and radiographic evidence of orbital floor fracture, divided randomly into two groups: Group I-operated using endoscopic approach; and Group II- operated using conventional external approach. All the patients were evaluated clinically preoperatively, immediate post-operative and after 1 month for Diplopia, Extrinsic ocular motility, Enophthalmos and Hypoglobus. The study consisted of 40% females and 60% males, with mean age of Endoscopic and Conventional group being 27.20 ± 6.14 years and 27.60 ± 7.23 years respectively. In relation to diplopia, an insignificant difference was observed statistically. The mean change in enophthalmos and hypoglobus in endoscopic and conventional group showed a significant difference statistically (p < 0.001). Unrestricted ocular motility was present only in one case of each group and significantly increased to 5 cases in both the groups (p = 0.048). The mean duration of surgery in endoscopic and conventional group showed a significant difference statistically. Diplopia, hypoglobus and Enophthalmos correction was better achieved in endoscopic group as compared to conventional group. But duration of surgery was more in endoscopic group as compared to conventional group.


The effectiveness of orthopaedic trauma theatres in decreasing morbidity and mortality: a study of 701 displaced subcapital hip fractures in two trauma centres.
In countries with universal health care systems patients frequently wait days for their "emergency" surgery. A general trend in orthopaedic traumatology is the advent of daily, dedicated orthopaedic trauma theatres. Availability of trauma theatres is believed to decrease morbidity and mortality, but this remains unproven. A retrospective review comparing morbidity and mortality outcomes between two similar level-one trauma centres (one without a dedicated trauma room system) was undertaken. We reviewed 701 elderly patients receiving hemiarthroplasties for displaced subcapital hip fractures over a 76-month period. Patients were similar between centres in terms of age, gender ratio and comorbidities. Statistically significant differences were found favouring the dedicated trauma room system with approximately half the operative delay and post-operative morbidity. A trend towards decreased mortality was also seen. This study supports the use of regular orthopaedic trauma theatres in tertiary care institutions.


Effect of nifedipine on gastric acid secretion and gastrin release in healthy man.
Nifedipine, a calcium-channel antagonist widely used in cardiovascular disease, has recently been reported to be effective in the treatment of oesophageal motor disorders. The effect of a single therapeutic dose of nifedipine (20 mg p.o.) has been evaluated on basal and submaximal pentagastrin-stimulated gastric secretion and meal-stimulated gastrin release in healthy man. In comparison with placebo, nifedipine significantly decreased both basal and stimulated gastric acidity and juice volume, whereas only a slight but insignificant reduction in meal-stimulated gastrin levels was observed after drug administration. The results are in agreement with previous reports that calcium is involved in stimulus-secretion coupling in the human parietal cell. They do not confirm the effect of calcium on G-cells, although it is likely that doses of nifedipine higher than those commonly used might be effective in the reduction of gastrin secretion.


Epidemiology of the UK population of hearing-impaired children, including characteristics of those with and without cochlear implants--audiology, aetiology, comorbidity and affluence.
This study reports epidemiological data for 17,160 children with permanent bilateral hearing impairment >40 dB in the UK in the birth cohorts 1980-95 inclusive. Children were uniquely ascertained from notifications from professionals in health and education. Results indicate a changing aetiological profile over birth cohort. The percentage of unknown aetiologies and those of prenatal or postnatal origin have decreased, while syndromal and perinatal aetiologies have increased, with no change in genetic aetiologies. Nearly 30% of hearing-impaired children have another disability in addition to their hearing impairment. Children with cochlear implants are more likely than other profoundly impaired children to have a postnatal aetiology and less likely to have disabilities concerned with learning or cognition. A proxy measure of affluence indicates that significantly more profoundly impaired children in more affluent families receive cochlear implants than do those in less affluent families. These findings provide baseline data for the UK population and raise questions of widespread relevance for future research.


Clinical evaluation of nuclear matrix protein 22 (NMP22) in urine as a novel marker for urothelial cancer.
This study was undertaken to determine the clinical usefulness of nuclear matrix protein 22 (NMP22) as a novel urine marker for urothelial cancer, particularly, to substitute for voided-urine cytology. NMP22 values were determined for 280 patients and 20 healthy volunteers by NMP22 Test Kit based on an enzyme-linked immunosorbent assay. When the cut-off value was set at 10 U/ml, the positive rate of urinary NMP22 for urothelial cancer was 80.9% (38/47), whereas that for posttreatment cases and benign diseases was 35.7% (74/207). When urinary NMP22 and voided-urine cytology were compared, the test for urinary NMP22 showed higher sensitivity than cytology in patients with urothelial cancer. When urinary NMP22 values were determined pre- and postoperatively in patients with urothelial cancer, the postoperative value decreased in all patients, and were below the cut-off value in all except one patient. Urinary NMP22 is a useful diagnostic marker as a substitute for voided-urine cytology for the surveillance of urothelial cancer.


Cervicography. Does it improve cervical cancer screening?
To compare the reliability of cytology with that of cervicography and with the use of both tests when screening for neoplasia of the cervix and to analyze the causes of false positive and false negative results with both methods. The results of cytology and cervicography in 1,709 patients (1,447 seen for routine screening, 82 for follow-up after treatment for cervical neoplasia and 180 referred because of cytologic anomalies) were correlated with colpohistologic findings. Cervicography entailed more defective examinations than did cytology (8.9% vs. 0.2%, P < .0001). It was less sensitive (51% vs. 59%, P = .320) and less specific (96% vs. 98%, P = .004). Whatever the clinical criteria (patient's age, parity, pregnancy or history of cervical treatment), the rate of false positives with cervicography was always higher than with cytology, as was the rate of false negatives, except in pregnant women. Cervicography does not seem to offer a worthwhile alternative to cytology for cervical screening.


Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus.
Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5- CD11c+ cells (DN2) representing pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased Toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naive cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells, and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naive B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B cell activation in SLE, and identifies therapeutic targets.


Thrice weekly azacitidine does not improve hematological responses in lower-risk myelodysplastic syndromes: a study of the Hoosier Oncology Group.
Prolonged administration of methyl transferase inhibitors may increase response rates in myelodysplastic syndromes (MDS). Fourteen MDS patients with anemia and less than 10% marrow blasts received azacitidine 50 mg/m(2) thrice weekly for 2 weeks every 4 weeks; 7 also received weekly erythropoietin. The response rate of 43% did not improve the rates reported with other azacitidine administration schedules, so the study was closed. A decreased apoptosis of primitive erythroid progenitors and increased expression of BclX(L) was observed with treatment in responding patients compared to non-responders. Azacitidine may modulate BclX(L) and improve erythropoiesis through reduction of apoptosis in primitive erythroid progenitor population in MDS.


Intracellular sorting and polarized cell surface delivery of (Na+,K+)ATPase, an endogenous component of MDCK cell basolateral plasma membranes.
Madin Darby Canine Kidney (MDCK) cells grown on polycarbonate filters in a two-chamber culture system were used to study the postsynthetic sorting of the alpha-subunit of the (Na+,K+)ATPase, an important native protein of the MDCK cell basolateral plasmalemmal domains. The N-azidobenzoyl derivative of ouabain (NAB-ouabain) and anti-ouabain antibodies were used in pulse labeling experiments to monitor the arrival of newly synthesized molecules of (Na+,K+)ATPase at the apical and basolateral cell surfaces. The results show that newly synthesized alpha-subunits bind NAB-ouabain and become substrates for immunoprecipitation only when this compound is present in the basolateral chamber. No more than 10% of the (Na+,K+)ATPase synthesized during the pulse period could appear at the apical surface without being detected by our assay. Thus, sorting of this native protein is effected intracellularly prior to its direct insertion into the basolateral plasmalemmal domain. Passage through an acidic compartment is not required for proper sorting.


Multi-modal multi-resolution atlas of the human neonatal cerebral cortex based on microstructural similarity.
The neonatal period is a critical window for the development of the human brain and may hold implications for the long-term development of cognition and disorders. Multi-modal connectome studies have revealed many important findings underlying the adult brain but related studies were rare in the early human brain. One potential challenge is the lack of an appropriate and unbiased parcellation that combines structural and functional information in this population. Using 348 multi-modal MRI datasets from the developing human connectome project, we found that the information fused from the structural, diffusion, and functional MRI was relatively stable across MRI features and showed high reproducibility at the group level. Therefore, we generated automated multi-resolution parcellations (300 - 500 parcels) based on the similarity across multi-modal features using a gradient-based parcellation algorithm. In addition, to acquire a parcellation with high interpretability, we provided a manually delineated parcellation (210 parcels), which was approximately symmetric, and the adjacent areas around each boundary were statistically different in terms of the integrated similarity metric and at least one kind of original features. Overall, the present study provided multi-resolution and neonate-specific parcellations of the cerebral cortex based on multi-modal MRI properties, which may facilitate future studies of the human connectome in the early development period.


New insights into pradimicin biosynthesis revealed by two O-methyltransferases.
Pradimicins are a group of antiviral and antifungal natural products from Actinomadura hibisca. Two putative O-methyltransferase genes, pdmF and pdmT, are present in the pradimicin biosynthetic gene cluster. However, there is only one methoxy group (11-OCH3) in pradimicins. Through heterologous expression and in vitro reactions with various substrates, PdmF was characterized as the C-11 O-methyltransferase with a relatively broad substrate specificity. To probe the role of PdmT in pradimicin biosynthesis, the corresponding gene was disrupted through homologous recombination, leading to the production of pradimicinone II. This enzyme was then expressed in Escherichia coli with an N-terminal His6 tag and purified by Ni-NTA chromatography. Reaction of pradimicinone II with PdmT generated 7-O-methylpradimicinone II, confirming that this enzyme is a C-7 O-methyltransferase. Characterization of PdmT suggests a novel pathway that leads to the "flip" of 7-OH to C-14 in pradimicin biosynthesis.


Morphological changes and smooth muscle cell proliferation after experimental excimer laser treatment.
Little is known about the mechanism(s) in the development of restenosis after excimer laser angioplasty. Thus, the rationale of this study was to determine the time course of intimal and medial smooth muscle cell (SMC) proliferation and histomorphological changes after experimental excimer laser treatment. Laser ablation was performed in the right carotid artery of 34 New Zealand White rabbits after development of a fibromuscular plaque by repeated weak electrical stimulations. The vessels were excised 3, 7, 14, 21, 28, and 42 days after excimer laser treatment. Staining of alpha-actin was used to identify SMCs. In five rabbits (15%), a stenosis of more than 50% of luminal area was due to intimal proliferation of SMCs, and in four other rabbits, a total occlusion was due to organized thrombi. After the initial ablation of the performed plaque (13 +/- 6 intimal SMC layers) a continuous increase of intimal wall thickness was found from 7 +/- 6 SMC layers at 7 days to 28 +/- 5 intimal SMC layers at 28 days after excimer laser ablation (p less than 0.01). After 42 days, no additional increase of intimal thickening occurred. After bromodeoxyuridine labeling, the extent of cell proliferation (percent of cells undergoing DNA synthesis) in the intima and media was determined using a monoclonal antibody against bromodeoxyuridine. Immunohistological quantification of SMC proliferation in the intima revealed a significant increase of cells undergoing DNA synthesis at 3 (p less than 0.05) and 14 (p less than 0.01) days after laser treatment. Medial proliferation of SMCs was delayed and had a significant increase 7 days (p less than 0.05) after intervention. Twenty-one days after laser treatment, SMC proliferation in the intima as well as in the media was normalized. The proliferative response of SMCs after experimental excimer laser treatment will occur as a dynamic process with a maximum of SMCs undergoing DNA synthesis during 14 days after laser ablation, resulting in an increase of intimal thickening within 4 weeks after laser treatment. The extent of intimal hyperplasia due to SMC proliferation after excimer laser treatment is comparable with the effect of transluminal balloon angioplasty in this experimental model.


Efficiency scale for scattering luminescent particles linked to fundamental and measurable spectroscopic properties.
Comparing the performance of molecular and nanoscale luminophores and luminescent micro- and nanoparticles and estimating achievable signal amplitudes and limits of detection requires a standardizable intensity scale. This initiated the development of the relative MESF (number of molecules of equivalent soluble fluorochromes) and ERF (equivalent reference fluorophores) scales for flow cytometry and fluorescence microscopy. Both intensity scales rely on fluorescence intensity values assigned to fluorescent calibration beads by an intensity comparison to spectrally closely matching fluorophore solutions of known concentration using a spectrofluorometer. Alternatively, the luminophore or bead brightness (B) can be determined that equals the product of the absorption cross section (σa) at the excitation wavelength (σa(λex)) and the photoluminescence quantum yield (Φpl). Thereby, an absolute scale based on fundamental and measurable spectroscopic properties can be realized which is independent of particle size, material, and luminophore staining or labeling density and considers the sensitivity of the optical properties of luminophores to their environment. Aiming for establishing such a brightness scale for light-scattering dispersions of luminescent particles with sizes exceeding a few ten nanometers, we demonstrate how the brightness of quasi-monodisperse 25 nm, 100 nm, and 1 µm sized polystyrene particles (PSP), loaded with two different dyes in varying concentrations, can be obtained with a single custom-designed integrating sphere setup that enables the absolute determination of Φpl and transmittance and diffuse reflectance measurements. The resulting Φpl, σa(λex), imaginary parts of the refractive index, and calculated B values of these samples are given in dependence of the number of incorporated dye molecule per particle. Finally, a unitless luminescence efficiency (LE) is defined allowing for the direct comparison of luminescence efficiencies of particles with different sizes.


Prediction of maturity in first trimester of pregnancy by ultrasonic measurement of fetal crown-rump length.
Three hundred ninety fetal crown-rump measurements by ultrasound echography were performed in order to correlate the crown-rump length with gestational age between the sixth and fourteenth weeks of gestation. A blind trial in 58 patients showed a good correlation of ultrasonically determined age and menstrual age. A graph of normal values was designed and is currently being used in routine work.


Correlation of specific platelet activation markers with carotid arterial wall thickness.
Many studies have shown increased platelet activation in patients with coronary artery, cerebrovascular and peripheral vascular diseases. However, the temporal relationship between platelet activation and arterial atherosclerosis is unclear. To answer this basic question, we measured the plasma concentrations of two specific platelet activation markers, beta-thromboglobulin (beta TG) and platelet factor 4 (PF4) in 459 cases with increased carotid arterial wall thickness and 459 age-, sex-and race-matched controls selected from a cohort of 15,800 men and women, aged 45-64 who participated in the Atherosclerosis Risk in Communities Study. These participants had no acute vascular symptoms or known cardiovascular disease. The mean values of beta TG and PF4 were significantly higher in cases than in controls. However, when analyzed by quartiles using conditional logistic regression, only beta TG exhibited a significant association with carotid wall thickness, while PF4 did not. The odds ratio (OR) determined by multivariate logistic regression analysis was significantly higher for the uppermost quartile of beta TG (OR=1.7, 95% CI 1.1-2.5) compared to the lower 3 quartiles. This OR was 2.3 in white men (95% CI 1.2-4.2), 1.4 in white women (95% CI 0.6-3.0) and 1.0 in blacks (95% CI 0.4-2.5). This study indicates that plasma beta TG may be useful as a marker for early atherosclerosis in middle aged adults, particularly in white men. It also suggests that platelet activation has an independent role in the pathogenesis of atherosclerosis, although the possibility that this may be a response to carotid atherosclerosis cannot be excluded.


The polymorphisms of C-reactive protein gene modify the association between central obesity and lung function in taiwan asthmatics.
High-sensitivity C-reactive protein (hs-CRP) concentrations and obesity are proposed to have a significant relationship with impairment of lung function, but little has been reported to date on the association between CRP gene and lung function. We studied the association of three tagSNPs (tag single nucleotide polymorphisms) of CRP gene and their interactions with central obesity on lung function. A total of 384 asthmatic adults and 384 controls who were 1:1 matched by sex and age were recruited for this study. Three tagSNPs polymorphisms for CRP rs1417938, rs1800947 and rs1205 were selected from HapMap data and genotyping by using TaqMan allelic discrimination assay. A questionnaire interview, body composition and pulmonary function tests were performed. CRP single nucleotide polymorphisms (SNPs) did not increase the risk of asthma, but CRP rs1205 CC genotype significantly decreased the predictive value of forced vital capacity (FVC) in the asthma group (adjusted mean change = -7.54%, 95% CI = -13.82 to -1.25%). Waist-to-hip ratio, not body mass index, also decreased the predictive value of FVC in asthmatics. The subjects with central obesity who carried CRP SNPs have a significant reduction effect in lung function. The current results suggest that central obesity may play a major role in lung function, and these effects were modified significantly by the polymorphisms for CRP gene.


Refined non-steady-state gas-liquid chromatography for accurate determination of limiting activity coefficients of volatile organic compounds in water: application to C(1)-C(5) alkanols.
This work presents a new refined method of non-steady-state gas-liquid chromatography (NSGLC) suitable for determination of limiting activity coefficients of VOCs in water. The modifications done to the original NSGLC theory address its elements (as the solvent elution rate from the column) as well as other new aspects. The experimental procedure is modified accordingly, taking advantage of current technical innovations. The refined method is used systematically to determine limiting activity coefficients (Henry's law constants, limiting relative volatilities) of isomeric C(1)-C(5) alkanols in water at 328.15K. Applied to retention data measured in this work the refined NSGLC theory gives values 15-20% higher than those from the original approach. The values obtained by the refined NSGLC method agree very well (typically within 3%) with the most reliable literature data determined by other experimental techniques, this result verifying thus the correct performance of the refined method and demonstrating an improved accuracy of the new results.


Dyslipidemia as a long-term marker for survival in pulmonary embolism.
To analyse survival rate after 24 months in consecutive patients with a diagnosis of PE as well as associated factors. Prospective cohort study during a follow-up period of two years in a series of consecutive patients with PE. During the follow-up period, 34 out of 148 patients died (23%). Factors independently associated with reduced survival rate were: creatinine levels > 2 (OR, 8.8; 95% CI, 1.1 - 70.87), previous neoplasm (OR, 8.8; 95% CI, 3.69 - 20.98), dementia (OR, 6.85; 95% CI, 2.1 - 22.33) and dyslipidemia (OR, 5.07; 95% CI, 1.92 - 13.44). Forty four percent of the patients with dyslipidemia died vs. 20.8% of patients without this condition. In our study dyslipidemia shows as a long-term negative prognostic marker for survival in patients with EP.


Cross polarization, radio frequency field homogeneity, and circuit balancing in high field solid state NMR probes.
Homogeneous radio frequency (RF) fields are important for sensitivity and efficiency of magnetization transfer in solid state NMR experiments. If the fields are inhomogeneous the cross polarization (CP) experiment transfers magnetization in only a thin slice of sample rather than throughout the entire volume. Asymmetric patterns have been observed in plots of the CP signal versus RF field mismatch for an 800 MHz solid-state NMR probe where each channel is resonated in a single-ended mode. A simple model of CP shows these patterns can be reproduced if the RF fields for the two nuclei are centered at different places in the coil. Experimental measurements using B1 field imaging, nutation arrays on extremely short NMR samples, and de-tuning experiments involving disks of copper incrementally moved through the coil support this model of spatially offset RF fields. We have found that resonating the high frequency channel in a double-ended or "balanced" mode can alleviate this field offset problem, and have implemented this in a three-channel solid state NMR probe of our own design.


Effects of bilateral Pecto-intercostal Fascial Block for perioperative pain management in patients undergoing open cardiac surgery: a prospective randomized study.
Open cardiac surgical patients may experience severe acute poststernotomy pain. The ultrasound-guided Pecto-intercostal Fascial Block (PIFB) can cover anterior branches of intercostal nerves from T2 to T6. The aim of this study was to investigate the effect of bilateral PIFB in patients undergoing open cardiac surgery. A group of 108 patients were randomly allocated to either receive bilateral PIFB (PIFB group) or no nerve block (SALI group). The primary endpoint was postoperative pain. The secondary outcome measures included intraoperative and postoperative sufentanil and parecoxib consumption, time to extubation, time to first feces, length of stay in the ICU and the length of hospital stay. Insulin, glucose, insulin resistance and interleukin (IL)-6 at 1, 2, 3 days after surgery were mearsured. The homeostasis model assessment (HOMA-IR) was used to measure perioperative insulin resistance. The PIFB group reported significantly less sufentanil and parecoxib consumption than the SALI group. Compared to the PIFB group, the SALI group had higher Numerical Rating Scale (NRS) pain scores at 24 h after operation both at rest and during coughing. The time to extubation, length of stay in the ICU and length of hospital stay were significantly decreased in the PIFB group compared with the SALI group. The PIFB group had a lower insulin, glucose, IL-6, HOMA-IR level than the SALI group 3 days after surgery. Bilateral PIFB provides effective analgesia and accelerates recovery in patients undergoing open cardiac surgery. This study was registered in the Chinese Clinical Trial Registry ( ChiCTR 2000030609 ) on 08/03/2020.


WNT10A and isolated hypodontia.
WNT10A has been associated with various syndromes with ectodermal dysplasia from severe autosomal recessive SchO?pf-Schulz-Passarge syndrome to odonto-onycho-dermal dysplasia and autosomal dominant hypodontia. We report WNT10A mutations in an American family of which four members are affected with isolated hypodontia or microdontia. Here we demonstrate that in addition to MSX1, PAX9, AXIN2, and EDA, mutations in WNT10A can cause isolated hypodontia.


Locomotor damage and brain oxidative stress induced by lead exposure are attenuated by gallic acid treatment.
We investigated the antioxidant potential of gallic acid (GA), a natural compound found in vegetal sources, on the motor and oxidative damages induced by lead. Rats exposed to lead (50 mg/kg, i.p., once a day, 5 days) were treated with GA (13.5mg/kg, p.o.) or EDTA (110 mg/kg, i.p.) daily, for 3 days. Lead exposure decreased the locomotor and exploratory activities, reduced blood ALA-D activity, and increased brain catalase (CAT) activity without altering other antioxidant defenses. Brain oxidative stress (OS) estimated by lipid peroxidation (TBARS) and protein carbonyl were increased by lead. GA reversed the motor behavior parameters, the ALA-D activity, as well as the markers of OS changed by lead exposure. CAT activity remained high, possibly as a compensatory mechanism to eliminate hydroperoxides during lead poisoning. EDTA, a conventional chelating agent, was not beneficial on the lead-induced motor behavior and oxidative damages. Both GA (less) and EDTA (more) reduced the lead accumulation in brain tissue. Negative correlations were observed between the behavioral parameters and lipid peroxidation and the lead levels in brain tissue. In conclusion, GA may be an adjuvant in lead exposure, mainly by its antioxidant properties against the motor and oxidative damages resulting from such poisoning.


Increased production of thyroxine and inappropriately elevated serum thyrotropin in levels in endogenous depression.
The increased serum thyroxine (T4) levels in endogenous depression (ED) might be due to an increased production or a reduced degradation of T4. We therefore performed turnover studies of radiolabeled T4 and 3,5,3'-triiodothyronine (T3) in 6 patients with ED and 8 age-matched healthy controls. In ED, the median daily production of T4 was 130 nmol/day/70 kg, (range 100-186 nmol/day/70 kg) and elevated compared to control values which were 99 nmol/day/70 kg (range 85-142 nmol/day/70 kg) (p less than 0.05), whereas that of T3 was similar in the two groups. Serum thyrotropin (TSH) levels (0.90 mU/liter, 0.18-2.15 mU/liter) were elevated in ED compared to a group of 7 L-T4-treated hypothyroid subjects with similar production and serum levels of T4 and T3 (0.11 mU/liter, 0.07-1.10 mU/liter) (p less than 0.02). The data show that increased serum T4 levels in ED are secondary to an increased thyroidal production of T4, which is at least partly due to inappropriately high serum TSH levels.


Effects of insulin degludec and insulin glargine U300 on glycaemic stability in individuals with type 1 diabetes: A multicentre, randomized controlled crossover study.
To compare the effects of insulin degludec (IDeg) and insulin glargine U300 (IGlarU300) on glycaemic stability in subjects with type 1 diabetes. In this multicentre, crossover trial, 46 individuals with type 1 diabetes and essentially undetectable circulating C-peptide were randomly assigned to either the IDeg-first/IGlarU300-second group or the IGlarU300-first/IDeg-second group, and were treated with the respective basal insulins for 4-week periods. Data were collected in the last week of each treatment period. The primary aim was to examine the potential non-inferiority of IDeg relative to IGlarU300 with regard to day-to-day variability, as evaluated by the standard deviation (SD) of fasting blood glucose (FBG) levels. Intra-day glycaemic variability and other variables were also determined by continuous glucose monitoring (CGM). The SD of FBG for IDeg was non-inferior to that for IGlarU300. The mean of FBG, coefficient of variation of FBG, and various glycaemic variability indexes determined by CGM did not differ between the two insulins. Whereas the administered doses of the insulins also did not differ, the mean glycaemic value was lower for IDeg than IGlarU300; the time above the target range (>180 mg/dL [10.0 mmol/L]) and the time below the target range (<70 mg/dL [3.9 mmol/L]) were shorter and longer, respectively, for IDeg than IGlarU300. Our data suggest that IDeg and IGlarU300 have comparable glucose-stabilizing effects in individuals with type 1 diabetes. However, the glucose-lowering effect of IDeg may be greater than that of IGlarU300 when titrated with a unit-based protocol.


Factors Linked to Injection Interval Extension in Eyes with Wet Age-Related Macular Degeneration Switched to Brolucizumab.
To evaluate factors associated with anti-vascular endothelial growth factor (VEGF) injection interval extension in patients with neovascular age-related macular degeneration (nAMD) switched to brolucizumab treatment. Retrospective, observational cohort study. Adults in the United States-based IRIS® Registry (Intelligent Research in Sight) with nAMD who switched from another anti-VEGF agent to brolucizumab-only treatment for ≥ 12 months from October 8, 2019, through November 26, 2021. Univariable and multivariable analyses examined associations of demographic and clinical characteristics with the likelihood of interval extension after switching to brolucizumab therapy. Eyes were classified as either extenders or nonextenders at 12 months. Extenders were eyes that achieved (1) an extension of ≥ 2 weeks in the brolucizumab injection interval at 12 months versus the interval before switching (time between the last known prior anti-VEGF injection and first [index] brolucizumab injection) and (2) stable (< 10 letters gained or lost) or improved (≥ 10 letters gained) visual acuity (VA) at 12 months versus VA at index injection. Of 2015 eyes among 1890 patients who switched to brolucizumab treatment, 1186 (58.9%) were extenders. In univariable analyses, demographic and clinical characteristics were comparable between extenders and nonextenders, except that extenders had shorter intervals before switching versus nonextenders (mean, 5.9 ± 2.1 weeks vs. 10.1 ± 7.6 weeks, respectively). In multivariable logistic regression modeling, a shorter interval before switching was associated significantly and positively with interval extension with brolucizumab therapy (adjusted odds ratio, 5.6 for interval before switching of < 8 weeks versus ≥ 8 weeks; 95% confidence interval, 4.5-6.9; P < 0.001), and eyes with an index VA of 40 to 65 letters were significantly less likely to be extenders than eyes in the higher (better) index VA categories. Length of the treatment interval before switching was the characteristic associated most strongly with successful interval extension with brolucizumab. Treatment-experienced patients who required more frequent injections (i.e., shorter intervals before switching) showed the greatest extensions when switching to brolucizumab. With careful consideration of benefits and risks, brolucizumab may be a valuable option for patients with higher treatment burdens because of the need for frequent injections. Proprietary or commercial disclosure may be found after the references.


Hepatitis B, C and D virus infections and risk of hepatocellular carcinoma in Africa: A meta-analysis including sensitivity analyses for studies comparable for confounders.
Africa denotes unique facies for hepatocellular carcinoma (HCC) characterized by a conjunction of low sensitization, restricted access to diagnosis and treatment and associated with the highest incidence and mortality in the world. We investigated whether hepatitis B (HBV), C (HCV) and D (VHD) viruses were etiological agents of HCC in Africa. Relevant articles were searched in PubMed, Web of Science, African Index Medicus, and African Journal Online databases, as well as manual searches in relevant reviews and included articles. Analytical studies from Africa evaluating the association between HCC development and HBV, HCV, and HDV were included. Relevant studies were selected, data extracted, and the risk of bias assessed independently by at least 2 investigators. The association was estimated using odds ratios (OR) and their 95% confidence interval (95% CI) determined by a random-effects model. Sources of heterogeneity were determined by subgroup analyses. A total of 36 case-control studies were included. With controls having non-hepatic disease, the overall results suggested a significantly increased risk of HCC in patients with HBV (HBeAg (OR = 19.9; 95% CI = [3.7-105.2]), HBsAg (OR = 9.9; 95%) CI = [6.2-15.6]) and DNA (OR = 8.9; 95% CI = [5.9-13.4]); HCV (Anti-HCV (OR = 9.4; 95% CI = [6.3-14.0]) and RNA (OR = 16.5; 95% CI = [7.8-34.6]); HDV (Anti-VHD, (OR = 25.8; 95% CI = [5.9-112.2]); and HBV/HCV coinfections (HBV DNA/HCV RNA (OR = 22.5; 95% CI = [1.3-387.8]). With apparently healthy controls, the overall results suggested a significantly increased risk of HCC in patients with HBV (HBsAg, (OR = 8.9; 95% CI = [6.0-13.0]); HCV (Anti-HCV, (OR = 7.7; 95% CI = [5.6-10.6]); and HBV/HCV coinfections (HBsAg/Anti-HCV (OR = 7.8; 95% CI = [4.4-13.6]) Substantial heterogeneity and the absence of publication bias were recorded for these results. In Africa, HBV/HCV coinfections and HBV, HCV, and HDV infections are associated with an increased risk of developing HCC. The implementation of large-scale longitudinal and prospective studies including healthy participants to search for early biomarkers of the risk of progression to HCC is urgently needed.


Biological and immunological properties of tritiated salmon calcitonin.
Tritiated salmon calcitonin was prepared by methylation of the free amino groups using tritiated sodium borohydride as precursor. Specific radioactivity was measured in competitive inhibition studies with specific anticalcitonin antibodies or tubular membranes as binding sites for calcitonin. The value observed, approx. 4 Ci/mmol, corresponded to methylation of one third of the available N-H bonds. Tritiated calcitonin prepared in this way retained full biological activity as assessed in vitro by stimulation of adenylate cyclase and in vivo by rat bioassay. Tritiated calcitonin specifically bound to isolated renal cells and nonspecific binding did not exceed 10% of total binding. Equilibrium was obtained after 15 min incubation. The hormone-receptor complex could be dissociated in the presence of an excess of unlabelled calcitonin. This data shows that tritiated calcitonin can be used in metabolic and receptor studies.


Skip segment Hirschsprung's disease: diagnostic clues and surgical management.
It is challenging to establish a definitive diagnosis and initiate timely management for skip segment Hirschsprung's disease (SSHD). Herein, we report three cases of SSHD at our institution between December 2008 and March 2018. Patient #1 was misdiagnosed and underwent three successive operations within 2 years. Patient #2 and #3 were diagnosed timely based on previous experience. A segmental narrowing detected by barium enema may raise the possibility of SSHD. Laparoscopic-guided multipoint biopsy is regarded as a mini-invasive and purposeful way to take representative samples after locating the segmental narrowing intraoperatively and accurate the final diagnosis. The laparoscopic-assisted pull-through procedure with radical resection from the distal rectum to the most proximal margin of the diseased skip segment is safe and effective in treating patients with SSHD.Level of evidence: Level III.


Acute injury to the immature brain with hypoxia with or without hypoperfusion.
This article reviews the imaging features and evolution of immature brain injury caused by hypoxia with or without hypoperfusion in the neonate and young child. Clinical presentations and available literature on mechanisms and clinical outcomes are discussed. In many of these cases, diffusion-weighted imaging does not show the full extent of the injury but detects a pattern of injury that is important in guiding clinical care. Awareness of the delayed cell death mechanisms is essential to understand diffusion-weighted imaging sensitivity and evolution and to provide the most accurate clinical interpretation, especially in cases of hypoxia with or without hypoperfusion.


[Still's disease in children and acute lymphoblastic leukemia, an exceptional association: a case report].
Still's disease, also known as systemic juvenile idiopathic arthritis (SJIA), and acute lymphoblastic leukemia have similar clinical and biological features posing diagnostic and treatment challenges. Indeed, while Still's disease is a diagnosis of exclusion in rheumatology, polyarthritis associated with hyperleukocytosis and fever, which is characteristic of this disease, are often detected in early stages of acute lymphocytic leukaemias. We here report the case of a 4-year-old girl, treated for Still's disease, in whom the diagnosis of acute lymphoblastic leukemia was made after 2 months, based on bone marrow biopsy.


Visual and Refractive Status of Children With Down's Syndrome and Nystagmus.
Children with Down's syndrome (DS) are known to have poorer visual acuity than neurotypical children. One report has shown that children with DS and nystagmus also have poor acuity when compared to typical children with nystagmus. What has not been established is the extent of any acuity deficit due to nystagmus and whether nystagmus affects refractive error within a population with DS. Clinical records from the Cardiff University Down's Syndrome Vision Research Unit were examined retrospectively. Binocular visual acuity and refraction data were available for 50 children who had DS and nystagmus and 176 children who had DS but no nystagmus. Data were compared between the two groups and with published data for neurotypical children with nystagmus. The study confirms the deficit in acuity in DS, compared to neurotypical children, of approximately 0.2 logMAR and shows a deficit attributable to nystagmus of a further 0.2 logMAR beyond the first year of life. Children with both DS and nystagmus clearly have a significant additional impairment. Children with DS have a wide range of refractive errors, but nystagmus increases the likelihood of myopia. Prevalence and axis direction of astigmatism, on the other hand, appear unaffected by nystagmus. Nystagmus confers an additional visual impairment on children with DS and must be recognized as such by families and educators. Children with both DS and nystagmus clearly need targeted support.


A Multicentre, Randomised Clinical Trial to Compare a Topical Nitrizinc® Complex Solution Versus Cryotherapy for the Treatment of Anogenital Warts.
Anogenital warts (AGW) are a relevant clinical issue in the field of sexually transmitted disease, and to date no treatment provides a satisfactory clearance rate. Treatment can be both medical and surgical, and be provided by a healthcare provider or by the patient. Cryotherapy (CRYO) is among the most common treatments for AGW. Nitrizinc® Complex solution (NZCS) is a solution containing organic acids, nitric acid and zinc and copper salts that is applied topically to warts, producing mummification of the damaged tissue. It is considered to be an effective and well-tolerated treatment for genital and common warts. The aim of our study was to compare NZCS to CRYO in the treatment of AGW. We performed a prospective, multicentre, single-blind, randomised, superiority clinical study involving 120 patients, aged 18-55 years, diagnosed with a first episode of AGW, with each patient having from three to ten AGW. The patients were treated either with NZCS or CRYO for a maximum of four treatments. Primary endpoints were: (1) comparison of the clinical efficacy of CRYO and NZCS, based on response to treatment (clearance of AGW) within four treatment sessions; and (2) tolerability, assessed via a short questionnaire at the end of each treatment session. Secondary endpoints were: (1) number of treatments needed for clearance; and (2) recurrence at 1 and 3e months after confirmed clearance. The results were analysed on an intention-to-treat basis. A complete response was achieved in 89.7% of the NZCS group and in 75.4% of the CRYO group (p = 0.0443). NZCS was found to be better tolerated. There was no difference between the NZCS and CRYO treatment arms in the number of sessions needed to clear the lesions. Recurrence occurred after 1 month in 18.4% of the NZCS group and 38.1% of the CRYO group (p = 0.0356), and after 3 months in 25 and 40.6% of these groups, respectively (p = 0.1479). Nitrizinc® Complex solution can be considered to be as effective as CRYO for the treatment of small (< 5 mm) external AGW, with a better tolerability profile and lower rate of recurrence. ISRCTN identifier, ISRCTN36102369.


Density regulation of amino acid transport in cultured, androgen-responsive tumour cells.
In androgen-responsive cells, activity of a sodium-dependent transport system for neutral amino acids is shown to be density-dependent, whereas activity of a sodium-independent system is not. Transport of the non-metabolizable amino acid, alpha-aminoisobutyric acid (alpha-aib) was largely sodium-dependent, whereas transport of cycloleucine (cyleu) was by both sodium-dependent and sodium-independent systems. The Km for cyleu transport changed with density because only the sodium-dependent portion of this transport was density-dependent. By contrast, the Vmax for alpha-aib transport changed with density, indicating that either the amount of functional membrane carrier or the activity of the sodium pump was affected.


Synthesis and preclinical evaluation of rhenium and technetium-99m "4 + 1" mixed-ligand complexes bearing quinazoline derivatives as potential EGFR imaging agents.
Epidermal growth factor receptors (EGFR) of tyrosine kinase (TK) have shown high expression levels in most cancers and are considered a promising target for cancer diagnosis and therapy. Expanding the investigation for novel targeted radiopharmaceuticals, an EGFR inhibitor such as 4-aminoquinazoline derivatives along with a radionuclide such as technetium-99m (99mTc) could be ideal. Thus, we report herein the synthesis, characterization, and biological evaluation of new "4 + 1" mixed-ligand ReIII- and 99mTcIII-complexes of the general formula [99mTc][Tc(NS3)(CN-R)] bearing tris(2-mercaptoethyl)-amine (NS3) as the tetradentate tripodal ligand and a series of isocyanide derivatives (CN-R) of tyrosine kinase inhibitor (3-bromophenyl)quinazoline-4,6-diamine as the monodentate ligand. The quinazoline isocyanide derivatives 4a-d were prepared in two steps and reacted with the [Re(NS3)PMe2Ph] precursor leading to the final complexes 5a-d in high yield. All compounds were characterized by elemental analysis, IR, and NMR spectroscopies. In vitro studies, for their potency to inhibit the cell growth, using intact A431 cells indicate that the quinazoline derivatives 4a-d and the Re complexes 5a-d significantly inhibit the A431 cell growth. In addition, the EGFR autophosphorylation study of complex 5b shows an IC50 value in the nanomolar range. The corresponding "4 + 1" 99mTc-complexes 6a-d were prepared by employing the [99mTc]TcEDTA intermediate and the appropriate monodentate 4a-d in a two-step synthetic procedure with a radiochemical yield (RCY) from 63 to 77 % and a radiochemical purity (RCP) > 99 % after HPLC purification. Their structures have been established by HPLC comparative studies using the well-characterized Re-complexes 5a-d as reference. All 99mTc-complexes remain stable for at least 6 h, and their logD7.4 values confirmed their anticipated lipophilic character. Biodistribution studies in healthy Swiss albino mice of 99mTc-complexes showed hepatobiliary excretion and initial fast blood clearance. Complex 6b was also tested in Albino SCID mice bearing A431 tumors and showed rapid tumor uptake at 5 min (2.80 % ID/g) with a moderate tumor/muscle ratio (2.06) at 4 h p.i. The results encourage further investigation for this type of 99mTc-complexes as single-photon emission computed tomography (SPECT) radio agents for imaging tumors overexpressing EGFR.


Intraphrenic esophageal leiomyoma associated with diverticula preoperatively diagnosed by angiography.
Two cases of esophageal leiomyoma associated with diverticulum are described. Angiography demonstrated an intraphrenic location.


Efficacy and tolerability of quinidine as salvage therapy for monomorphic ventricular tachycardia in patients with structural heart disease.
Quinidine is an effective therapy for a subset of polymorphic ventricular tachycardia and ventricular fibrillation (VF) syndromes; however, the efficacy of quinidine in scar-related monomorphic ventricular tachycardia (MMVT) is unclear. Between 2009 and 2020 a single VT referral center, a total of 23 patients with MMVT and structural heart disease (age 66.7 ± 10.9, 20 males, 15 with ischemic cardiomyopathy, mean LVEF 22.2 ± 12.3%, 9 with left ventricular assist device [LVAD]) were treated with quinidine (14 quinidine gluconate; 996 ± 321 mg, 8 quinidine sulfate; 1062 ± 588 mg). Quinidine was used in combination with other antiarrhythmics (AAD) in 19 (13 also on amiodarone). All patients previously failed >1 AAD (amiodarone 100%, mexiletine 73%, sotalol 32%, other 32%) and eight had prior ablations (median of 1.5). Quinidine was initiated in the setting of VT storm despite AADs (6), inability to tolerate other AADs (4), or recurrent VT(12). Ventricular arrhythmias recurred despite quinidine in 13 (59%) patients at a median of 26 (4-240) days after quinidine initiation. In patients with recurrent MMVT, VT cycle length increased from 359 to 434 ms (p = .02). Six (27.3%) patients remained on quinidine at 1 year with recurrence of ventricular arrhythmias in all. The following adverse effects were seen: gastrointestinal side effects (6), QT prolongation (2), rash (1), thrombocytopenia (1), neurologic side effects (1). One patient discontinued due to cost. Quinidine therapy has limited tolerability and long-term efficacy when used in the management of amiodarone-refractory scar-related MMVT.


Multifunctional materials for implantable and wearable photonic healthcare devices.
Numerous light-based diagnostic and therapeutic devices are routinely used in the clinic. These devices have a familiar look as items plugged in the wall or placed at patients' bedsides, but recently, many new ideas have been proposed for the realization of implantable or wearable functional devices. Many advances are being fuelled by the development of multifunctional materials for photonic healthcare devices. However, the finite depth of light penetration in the body is still a serious constraint for their clinical applications. In this Review, we discuss the basic concepts and some examples of state-of-the-art implantable and wearable photonic healthcare devices for diagnostic and therapeutic applications. First, we describe emerging multifunctional materials critical to the advent of next-generation implantable and wearable photonic healthcare devices and discuss the path for their clinical translation. Then, we examine implantable photonic healthcare devices in terms of their properties and diagnostic and therapeutic functions. We next describe exemplary cases of noninvasive, wearable photonic healthcare devices across different anatomical applications. Finally, we discuss the future research directions for the field, in particular regarding mobile healthcare and personalized medicine.


Nafamostat mesilate induces production of interleukin-12 and -18 in human peripheral blood mononuclear cells.
Little has been reported on the drugs inducing production of monocyte-derived cytokines like interleukin (IL)-18 and IL-12. We found that nafamostat mesilate elicits IL-12, IL-18, tumor necrosis factor-alpha and interferon-gamma production, and the expression of intercellular adhesion molecules-1, B7.1, B7.2, CD40, and CD40 ligand in human peripheral blood mononuclear cells. The cytokine production and adhesion molecule expression were abolished by anti-IL-12 and IL-18 antibodies. Therefore, IL-18 and IL-12 may play roles in the significant and immediate effects of nafamostat mesilate.


Role of Death Receptors-associated Lipid Rafts in Oxaliplatin-induced Death Mode Regulation of HepG2 Cells.
We previously showed that oxaliplatin induces necrotic-like cell death in hepatocarcinomas, and combination with ursodexoycholic acid (UDCA) significantly shifts the necrotic-like death to apoptosis. Since cell death mode is crucial on inflammatory responses and chemotherapeutic efficacy, the mechanism underlying determination of cell death mode by UDCA was investigated in this study. Apoptosis or necrosis was determined by apoptotic body formation, caspase-8 activity, LDH release and PI inclusion. The involvement of lipid rafts and death receptors was examined by rafts fractionation, confocal microscopy and gene silencing assays. UDCA combination enhanced recruitment of death receptors and adaptors into cholesterol-enriched lipid rafts, and induced a stronger raft clustering. Lipid raft disruption decreased the UDCA/oxaliplatin-mediated apoptosis and increased necrotic-like death. UDCA promotes lipid raft localization of multiple death receptors, thereby contributing to a shift of cell death mode from oxaliplatin-induced necrotic death to apoptosis in HepG2 cells.


Proton NMR studies of 5'-d-(TC)(3) (CT)(3) (AG)(3)-3'--a paperclip triplex: the structural relevance of turns.
In this study, we present the results of structural analysis of an 18-mer DNA 5'-T(1)C(2)T(3)C(4)T(5)C(6)C(7)T(8)C(9)T(10)C(11)T(12)A(13)G(14)A(15)G(16)A(17)G(18)-3' by proton nuclear magnetic resonance (NMR) spectroscopy and molecular modeling. The NMR data are consistent with characteristics for triple helical structures of DNA: downfield shifting of resonance signals, typical for the H3(+) resonances of Hoogsteen-paired cytosines; pH dependence of these H3(+) resonance; and observed nuclear Overhauser effects consistent with Hoogsteen and Watson-Crick basepairing. A three-dimensional model for the triplex is developed based on data obtained from two-dimensional NMR studies and molecular modeling. We find that this DNA forms an intramolecular "paperclip" pyrimidine-purine-pyrimidine triple helix. The central triads resemble typical Hoogsteen and Watson-Crick basepairing. The triads at each end region can be viewed as hairpin turns stabilized by a third base. One of these turns is comprised of a hairpin turn in the Watson-Crick basepairing portion of the 18-mer with the third base coming from the Hoogsteen pairing strand. The other turn is comprised of two bases from the continuous pyrimidine portion of the 18-mer, stabilized by a hydrogen-bond from a purine. This "triad" has well defined structure as indicated by the number of nuclear Overhauser effects and is shown to play a critical role in stabilizing triplex formation of the internal triads.


Detection of laser-associated heating in the brain during simultaneous fMRI and optogenetic stimulation.
To calculate temperatures from T2 *-weighted images collected during optogenetic fMRI based on proton resonance frequency (PRF) shift thermometry, to monitor confounding heating effects and determine appropriate light parameters for optogenetic stimulation. fMRI is mainly based on long-TE gradient-recalled echo acquisitions that are also suitable for measuring small temperature changes via the PRF shift. A motion- and respiration-robust processing pipeline was developed to calculate temperature changes based on the PRF shift directly from the T2 *-weighted images collected for fMRI with a two-shot 2D gradient-recalled echo-EPI sequence at 9.4T. Optogenetic fMRI protocols which differed in stimulation durations (3, 6 and 9 s) within a total block duration of 30 s were applied in a squirrel monkey to validate the methods with blue and green light (20 Hz, 30 mW) delivery interleaved between periods. General linear modeling was performed on the resulting time series temperature maps to verify if light delivery with each protocol resulted in significant heating in the brain around the optical fiber. The temperature SD was 0.05°C with the proposed imaging protocol and processing. Statistical analysis showed that the optogenetic stimulation protocol with a 3 s stimulation duration did not result in significant temperature rises. Significant temperature rises up to 0.13°C (p < 0. 05) were observed with 6 and 9 s stimulation durations for blue and green light. The proposed processing pipeline can be useful for the design of optogenetic stimulation protocols and for monitoring confounding heating effects.


Synergistic Effects on the Co-pyrolysis of Agricultural Wastes and Sewage Sludge at Various Ratios.
This study investigated the co-pyrolysis of blends of sewage sludge (SS) with rice husk (RH) and with hemp straw (HS) at different ratios by using thermogravimetry (TG) and its rate (DTG, derivative TG) analysis at heating rates of 10, 20, and 30 K/min. The resulting kinetic parameters of activation energy (E a) were calculated by both Flynn-Wall-Ozawa and Kissinger-Akahira-Sunose models, followed by comparison of experimental values with calculated values to reveal the synergistic effects of SS/RH and SS/HS. With increasing additions of RH or HS to SS, a gradual decreasing trend in the experimental pyrolysis temperature range was evident, ranging from 144.5 to 95.2 °C for SS/RH and from 144.5 to 88.8 °C for SS/RH. Moreover, such temperature ranges were 6.7-20.4 °C less than the calculated values at the same blending ratio. The fitting results of the two kinetic models showed that with the same SS mass ratio, the experimental E a * (average activation energy) of both SS/RH and SS/HS were less than the calculated E a *. Especially, the experimental E a * of 7SS-3RH was lower around 43.8% than the calculated E a *, whereas the experimental E a * of 3SS-7HS was lower by about 39.4% than the calculated E a *. Synergistic analysis demonstrated that the co-pyrolysis of RH or HS with SS at various mass ratios presented obvious synergistic effects and then the decrease of E a. The mechanism experiment showed that the co-pyrolysis of SS/HS may promote the decrease of E a by changing the co-pyrolysis gas products or by increasing the overflow of volatile matter and then forming intermediate transition products, while SS/RH may accelerate the decrease of the E a by using an appropriate K addition ratio from RH as a metal catalyst.


Clinical Characteristics and Laboratory Abnormalities of Hospitalized and Critically Ill Children with Coronavirus Disease 2019: A Retrospective Study from Saudi Arabia.
COVID-19 was reported in several studies characterized by milder clinical course, benign disease, and peculiar epidemiologic patterns among pediatric patients compared to adults' disease. However, other studies indicated that critical cases also exist and are associated with preexisting cardiopulmonary comorbidities and concurrent multisystem inflammatory syndrome in children. The study period was six months, May-October 2020. Data on demographics, clinical manifestations, laboratory abnormalities were extracted from the patients' hospital records. During the study period, 644 pediatric patients attended the hospital. They were all screened for SARS-CoV-2 using RT-PCR. Only the confirmed positive patients were included in the subsequent study analysis. They were hospitalized either in the general pediatric wards (GPW) or pediatric intensive care unit (PICU). Out of the total patients screened, 79 (12.3%) children were confirmed to have COVID-19 infection. All the confirmed COVID-19 patients were either admitted to the general pediatric wards (58; 73.4%) or PICU (21; 26.6%). The admission diagnoses for these children were acute gastroenteritis (22.85%), acute pneumonia (19%), clinical sepsis (17.7%), and multisystem inflammatory syndrome in children (10.1%). A significantly higher percentage of the PICU admitted patients showed shortness of breath (SOB) (P= 0.016). Respiratory insufficiencies, prematurity, and congenital heart diseases are the most reported comorbid conditions among the admitted children. The oxygen saturation was significantly lower among PICU patients than those in GPW (P=0.001). The total hospital stays differ significantly between the two groups, which were ten days for the PICU group compared to 4.5 days for the GPW group with a statistical significance noted (P= 0.001). Despite the observable variations in the clinical and laboratory findings among the hospitalized pediatric COVID-19 patients, no serious consequences among all patients were observed. The history of SOB and the initial oxygen saturation level were significantly associated with PICU admissions.


Combining repurposed drugs to treat colorectal cancer.
The drug development process, especially of antineoplastic agents, has become increasingly costly and ineffective. Drug repurposing and drug combination are alternatives to de novo drug development, being low cost, rapid, and easy to apply. These strategies allow higher efficacy, decreased toxicity, and overcoming of drug resistance. The combination of antineoplastic agents is already being applied in cancer therapy, but the combination of repurposed drugs is still under-explored in pre- and clinical development. In this review, we provide a set of pharmacological concepts focusing on drug repurposing for treating colorectal cancer (CRC) and that are relevant for the application of new drug combinations against this disease.


Long-term defects of nasal epithelium barrier functions in patients with nasopharyngeal carcinoma post chemo-radiotherapy.
Chronic and recurrent upper respiratory tract infection and inflammation is common in patients with nasopharyngeal carcinoma (NPC) post chemo-radiotherapy (CRT). Whether it is due to intrinsic (e.g., host-defense mechanisms of the epithelium), epigenetic or extrinsic factors is not fully understood. Tissue biopsies of the middle turbinate (MT) and inferior turbinate (IT) from NPC patients after CRT (mean of 3 years, n = 39) were compared with the IT biopsies from healthy subjects (n = 44). The epithelial ultrastructure was examined by transmission electron microscope (TEM). mRNA and protein expressions of epithelial stem/progenitor cells markers, as well markers of cell proliferation and differentiation markers was analyzed. Abnormal epithelial architecture was observed in all tissue samples of NPC patients. Significantly decreased expression levels of mRNA and protein levels for p63 (basal cells), Ki67 (cell proliferation), p63+/KRT5+ (epithelial stem/progenitor cells), MUC5AC and MUC5B (secretary proteins from goblet cells), alpha-tubulin, beta-tubulin and TAp73 (ciliated cells), DNAH5 and DNAI1 and RSPH4A (microtubule assemblies of motile cilia), FOXJ1 and CP110 (ciliogenesis-associated markers) were evident in MT and IT biopsies from NPC patients when compared to healthy controls. CRT causes long-term defects of epithelial barrier functions and increases the susceptibility of these patients to upper respiratory tract infection and inflammation.


Autoradiographic study of the nuclear transfer of the antiglucocorticoid compound RU38486 in mouse tissues.
In order to investigate the mode of action of RU38486, a recently described antiglucocorticoid molecule, we have studied by autoradiography the localization of [3H]RU38486 in various glucocorticoid target tissues 30 and 60 min following in vivo injection. The results obtained in brain, liver and kidney sections clearly demonstrate that [3H]RU38486 is specifically translocated in target cell nuclei. Indeed, the nuclear labelling observed after injection of the tracer was significantly decreased after injection of [3H]RU38486 in the presence of a 100-fold excess of unlabelled RU38486. The distribution of the specific labelling of RU38486 within the central nervous system was very similar to that previously described for dexamethasone with an accumulation of radioactivity in the cell nuclei of the hypothalamic area of the nucleus arcuatus. Our results thus provide additional evidence for an action of this antiglucocorticoid molecule at the nuclear level.


Effects of cold acclimation on the energetic metabolism of the staggerer mutant mouse.
Staggerer mutant mice are lean despite their hyperphagia. Brown adipose tissue activity may be implicated in this phenomenon. The aim of this work is to determine the energetic metabolism and to detail some characteristics of the brown adipose tissue of Staggerer mutant mice born and reared either at 28 degrees C (within the thermoneutral zone) or 22 degrees C (cold temperature) compared to nonmutant control mice. In mutant mice reared at thermoneutrality the resting metabolism was found to be higher than that of controls, and further the activity of the brown adipose tissue increased as indicated in relative mass, composition and cytochrome oxydase activity. A stimulatory effect of cold exposure was observed in both mutant and nonmutant mice. It is suggested that Staggerer mice may provide a good model for the study of the cold-induced or diet-induced mechanisms of brown fat stimulation.


Narrow-band imaging as an alternative to chromoendoscopy for the detection of dysplasia in long-standing inflammatory bowel disease: a prospective, randomized, crossover study.
Narrow-band imaging (NBI) is a novel technique that may represent an alternative method to chromoendoscopy (CE) for the detection of colitis-associated intraepithelial neoplasia (IN) in patients with long-standing inflammatory bowel disease (IBD). To compare NBI with CE for the detection of IN. Prospective, randomized, crossover study. Academic hospital. Patients with clinically inactive colonic IBD (≥8 years). Patients underwent both CE and NBI in randomized order. Targeted biopsy specimens from abnormal areas were obtained. Pathological examination was regarded as the reference standard. Number of false-positive and true-positive lesions in patients undergoing CE and NBI were compared as well as the proportion of patients with missed IN lesions. Eighty patients were screened, of whom 20 were excluded. Mean ± standard deviation withdrawal time for CE was significantly longer than that for NBI (26.87 ± 9.89 minutes vs 15.74 ± 5.62 minutes, P < .01). Thirteen patients had at least 1 IN lesion on 1 of the examinations. In the per-lesion analysis, NBI resulted in a significantly inferior false-positive biopsy rate (P = .001) and a similar true-positive rate. The percentage of missed IN lesions and patients was superior with NBI, albeit without reaching statistical significance. Lesions were sampled immediately after detection, which precluded the possibility of paired analysis. NBI appears to be a less time-consuming and equally effective alternative to CE for the detection of IN. However, given the NBI lesion and patient miss rates, it cannot be recommended as the standard technique.


Complex dystonia of Parkinson's disease: clinical features and relation to plasma levodopa profile.
We studied the clinical characteristics and plasma levodopa (LD) profile of complex, LD-associated dystonia in 33 patients with Parkinson's disease (PD). Generalized, abdominal, respiratory, and myoclonic, but not facial or foot, dystonia could be related to specific phases of the plasma LD cycle. Simultaneous clinical observation and determinations of plasma LD concentrations were often necessary to find the most efficacious dosing schedule for these patients. Maintenance of steady plasma LD concentrations within a dystonia-free window of benefit was the best treatment.


The morphology of the rostral notochord in embryos of Ichthyophis kohtaoensis (Amphibia, Gymnophiona) is comparable to that of higher vertebrates.
The rostral notochord plays an important role in the head development of vertebrates. Yet, in contrast to trunk notochord, the course and behavior of the head notochord shows species-specific variations. To analyze normal and abnormal development in the head region, knowledge of the normal behavior of the rostral notochord is a prerequisite. Therefore, we studied the rostral notochord of Ichthyophis kohtaoensis, not only in anatomical view a relatively unknown order of Gymnophiona, in embryos of the stages B, C, D, E according to Himstedt (1996) or stages 21, 22, 26, 31 according to Dünker et al. (2000). We described the course, form, and structure of this part of the notochord and compared it with morphological features and variations of the notochord in existing studies of higher vertebrates (Barteczko and Jacob 1999). We found that the rostral notochord of this oviparous Gymnophiona from Thailand is quite similar to that of higher vertebrates: its tendency to elongate directly in a rostral direction is prevented by the adenohypophysis as a barrier; at stage B the neurohypophysis/infundibulum takes the role of a hindrance. Light microscopic results, laser scanning micrographs, and plastic reconstructions based on serial sections showed unequivocally in stages B-E the effects resulting from this hindrance: buckling, variations in volume, screw-like torsions, undulations, deviations, and splintering. The notochord was found to lie dorsal to the developing cartilaginous basicranium. The tendency to press the dura towards the brain was conspicuous. The formation of a bursa pharyngea was likewise observed; the predisposition of several such structures exist. We suggest that the vertebrate phenotype with the appearance of preaxial structures, in contrast to the chordata phenotype, correlate with the formation of a hypophysis. Experiments have yet to prove this hypothesis.


The experience of pregnancy and early motherhood in women diagnosed with gestational breast cancer.
To explore the psychosocial experiences of pregnancy in women diagnosed with breast cancer during or shortly after pregnancy. A retrospective qualitative design was employed. Fifteen women who had received a gestational breast cancer (GBC) diagnosis participated in semi- structured interviews. The interviews sought to identify the emotional and social issues related to the experiences of pregnancy and motherhood in women diagnosed with gestational breast cancer. Women diagnosed with GBC experience difficulties in adjusting to two different and conflicting life events; the threat of their breast cancer alongside the news of their pregnancy. They have to make difficult decisions that impact on their own life, the life of their foetus/new baby and that of their existing family. Women who received a GBC diagnosis reported high levels of anxiety and stress, which pervaded their whole GBC experience. Women reported their anxiety was linked to the conflict between the concern for their baby's health and the concern for their own health and wellbeing. Women diagnosed with GBC attributed different meanings to their experience of pregnancy and motherhood and made choices based on their own beliefs, values and how complete they believed their family was.


Assessment of marine litter through remote sensing: recent approaches and future goals.
This bibliographic review provides an overview of techniques used to detect marine litter using remote sensing. The review classified studies in terms of platform (satellite, aircrafts, drones), sensors (passive or active), spectral (visible, infrared, microwaves), spatial resolution (<1 to >30 m), type and size (macroplastics, microplastics), or classification methodology (sighting, photointerpretation, supervised). Most studies applied satellite information to address marine litter using multi- and hyper- spectral optical sensors. The correspondence analysis on analyzed variables exhibited that aircrafts with high spatial resolution (<3 m) with optical sensors (λ = 400 to 2500 nm) seem to be the most optimum combination to target marine litter, while satellites carrying Synthetic Aperture Radar (SAR) sensors (λ = 3.1 to 5.6 cm) may detect sea-slicks associated to surfactants that might contain high concentration of microplastics. Gaps indicate that future goals in marine litter detection should be addressed with platforms including optical and SAR sensors.


Skeletal injuries after cesarean section - a rare differential diagnosis of child abuse.
Birth-related fractures are an important differential diagnosis of child abuse in early infancy. While fractures associated to vaginal deliveries are well known, cesarean section is not necessarily known to cause such injuries. Nevertheless neonatal fractures have been described after cesarean sections. To give an overview over the frequency and typical locations of such fractures, the appearance of symptoms and the timespan until diagnosis, a literature research was conducted via Google scholar and Pubmed, using the key words "cesarean section" and "fractures". Birth-related fractures after cesarean sections are rare but can occur, with the long bones being particularly affected. Therefore, birth injuries should always be considered in the forensic medical assessment of fractures in early infancy, even after cesarean section. To enable a differentiation between birth trauma and physical abuse, birth and operation records should be checked for surgical manoeuvres, possible difficulties during the procedure or other risk factors. Birth-related fractures are usually detected early; in rare cases, the diagnosis is made only weeks after birth.


Safety and efficacy of switching from branded to generic imatinib in chronic phase chronic myeloid leukemia patients treated in Italy.
The use of generic drugs after patent expiration of their originators is a relative novelty in the treatment of chronic cancer patients in Western countries. In this observational study we analyzed a cohort of 294 Italian chronic phase chronic myeloid leukemia patients treated frontline with branded imatinib (Glivec®) for at least 6 months and then uniformly switched to generic imatinib upon requirement of health authorities in early 2017. Median age at diagnosis was 57 years (range 19-87). Sokal risk was low/intermediate/high in 55%, 32% and 8% of cases, respectively. Median duration of branded imatinib treatment was 7.4 years (range 0.5-16.7). At a median follow-up of 7.5 months after switch to generic imatinib, 17% of patients reported new or worsening side effects, but grade 3-4 non-hematological adverse events were rare. Six patients switched back to branded imatinib, with improvement in the side effect profile, and 4 pts moved to bosutinib or nilotinib for resistance/intolerance. The majority of patients were in major (26%) or deep molecular response (66%) at the time of switch. Molecular responses remained stable, improved or worsened in 61%, 25% and 14% of patients, respectively. We conclude that switch to generic imatinib for patients who have been receiving branded imatinib appears to be effective and safe. Molecular responses may continue to improve over time. Some patients experienced new or worsened side effects but less than 5% of the whole cohort needed to switch back to branded imatinib or move to other treatments. Savings were around 3 million Euros.


Sex-specific differences in risk factors of lymph node metastasis in patients with early gastric cancer.
Accurate prediction of lymph node status is of crucial importance in the appropriate treatment planning for patients with early gastric cancer (EGC). Some studies have examined factors predicting lymph node metastasis (LNM) in EGC; however, these studies did not consider sex-specific differences. This study aimed to investigate sex-specific differences in predictive risk factors of LNM in EGC based on surgical specimens. Patients who underwent surgical treatment for EGC between January 2003 and February 2016 were retrospectively evaluated. Patients who underwent previous gastric surgery or treatment for gastric neoplasms were excluded. Finally, 1076 patients treated for EGC were included in the analysis. We analyzed risk factors of LNM by dividing patients into male and female groups. Of 1076 patients (mean age 59.6 years), 69% were men. The overall LNM rate was 9.4%. The LNM rate was lower in men (7.8%) than in women (12.9%). Multivariate analysis showed that elevated type (odds ratio [OR], 2.084; 95% confidence interval [CI]: 1.053-4.125; P = 0.035), submucosal invasion (OR, 2.162; 95% CI: 1.018-4.595; P = 0.045), undifferentiated type (OR, 2.044; 95% CI: 1.107-3.772; P = 0.022), and lymphovascular invasion (LVI) (OR, 7.210; 95% CI: 3.835-13.554; P<0.001) were independent predictive risk factors of LNM in EGC in men. However, only submucosal invasion (OR, 8.772; 95% CI: 2.823-27.259; P<0.001) and LVI (OR, 8.877; 95% CI: 3.861-20.410; P<0.001) were independent predictive risk factors of LNM in EGC in women. Submucosal invasion and LVI were risk factors of LNM in both men and women. However, elevated and undifferentiated types were risk factors in men but not in women. Clinicians should consider these sex-specific differences with regard to individualized management.


[Comparison of MGMT and ERCC₂ expression in temozolomide for the treatment of malignant glioma drug resistance and their genetic relationship].
To study the impact of two human glioma tissue resistance genes MGMT and ERCC(2) on the temozolomide-based treatment of malignant gliomas and detect the relationship of their expressions. A total of 58 malignant glioma patients aged 19 - 68 years old receiving a chemotherapy of temozolomide were followed up and classified as non-sensitive group (n = 30) and sensitive group (n = 28). Immunohistochemistry was employed to detect the expression rates of MGMT and ERCC(2). And the correlation between the expressions of two genes was analyzed by immunohistochemistry and RT-PCR (reverse transcription-polymerase chain reaction). The expression rates of MGMT and ERCC(2) were 10.71% and 3.57% in the sensitive group and 63.33% and 56.67% in the non-sensitive group. It had an obvious correlation with the expressions of MEGT and ERCC(2) through an analysis of immunohistochemistry and RT-PCR (both P < 0.01). The expressions of MGMT and ERCC(2) in the sensitive group are markedly lower than those in the non-sensitive group. The expression of two genes may be related to tumor prognosis. Maybe these two genes have an intrinsic link between their expressions. Both participate in the repair of cellular DNA damage and the formation of tumor drug resistance. And the prognosis has obvious relevance.


[Multidisciplinary treatment program on chronic low back pain, part 4. Prognosis of treatment outcome and final conclusions].
Studies using a multimodal approach in order to prognose therapeutic success in patients suffering from back pain were seen to have highly diverse results. However, in spite of various independent health care systems, a common interest prevails in identifying determinants of therapeutic success in order to improve therapy. Ninety disabled patients with chronic low back pain were admitted to an 8-week out-patient program of functional restoration and behavioral support. The program consisted of a pre-program (education, stretching and calisthenic exercises 4 h a day, three times a week for 3 weeks) and an intensive treatment period (physical exercises, back school education, cognitive behavioral group therapy, relaxation training, occupational therapy, socioeconomic and vocational counseling) which took place for 5 weeks, 7 h a day as an outpatient program. The program's philosophy encourages active effort on the patients' part in order to improve their functional status within a therapeutic environment. This reinforces behavior conducive to getting well, enhances the patients' sense of self-control over their pain and the resulting disability. The main therapeutic target was to facilitate the patients' return to work. Apart from medical examination and personal interview, the patients' physical impairment, pain descriptions, and psychological distress were also measured. This included variables such as depression, psychovegetative complaints, quality of life and workplace satisfaction, disability, and coping with disease. Measurements were repeated at the end of the 8-week program, and following 6 and 12 month intervals. The reliability of prognostic factors in predicting treatment outcome (return to work, reduction of pain intensity, self-assessment of success by the patients) was tested by analyses of variance and discriminant function analyses. Patients' return to the workplace could be predicted in 85% of cases based on whether an application for pension had been made, on the length of duration of work disability, and on "fixed" assumptions on the part of the patient concerning his work situation. Pre-treatment somatic findings (for example, diagnosis, degree of physical impairment, and functional debilities), together with depressive and psychovegetative reactions, were shown to have no connection with the patient's ability to return to the workplace. Similar findings were demonstrated for the prediction of pain reduction and patient satisfaction with treatment. Predicting successful treatment is hardly possible without analyzing individual circumstances, focusing on sociodemographic variables, workplace-related conditions, and aspects of individual motivation. With regard to objective therapeutic success, subjective perceptions proved highly influential. Treatment proved successful only when the patient's perception of functional disability was minimized. Hence, individual perceptions and experiences were more important than physical capabilities.


Mentoring urban Black Middle-School Male Students: Implications for Academic Achievement.
Researchers have called for innovative and culturally responsive intervention programs to enhance male, African American middle school students' academic achievement. Mentoring has received considerable attention as a novel remedy. Although anecdotal evidence supports the positive role of mentoring on academic achievement, these results are not consistent. The Benjamin E. Mays Institute (BEMI) builds on the ideals of mentoring to counter the effects academic underachievement among adolescent Black males by building a model that is Afro-centric, uses pro-social modeling, and emphasizes cultural strengths and pride, and single-sex instruction in a dual-sex educational environment. Sixty-one middle-school Black males were enrolled (BEMI: n=29; Comparison: n=32) in this study. Results revealed that students in the BEMI program had significantly greater academic attachment scores and academic success than their non-mentored peers. Additionally, racial identity attitudes of immersion/emersion and internalization and identification with academics were also significantly associated with standardized achievement tests and GPA. Policy and practice implications are discussed.


Hemocyte responses to implanted tissues inDrosophila melanogaster larvae.
At 26° C temperature-sensitivetu(1) Sz ts larvae ofDrosophila melanogaster develop melanotic tumors consisting of aberrant caudal adipose tissue encapsulated by precociously differentiated hemocytes (lamellocytes). Whentu-Sz ts larvae are grown at 18° C, lamellocytes are present but the caudal fat body surfaces remain normal and melanotic tumors do not develop (Rizki and Rizki, preceding paper). In this paper we demonstrate that the lamellocytes intu-Sz ts larvae at 18° C encapsulate implants of mechanically-damaged fat bodies and adipose cells devoid of basement membrane, while leaving host fat bodies or implanted fat bodies with intact basement membrane unencapsulated. Therefore, low temperature blocks melanotic tumor formation by normalizing the surfaces of the prospective tumor-forming sites intu-Sz ts.The discriminatory ability oftu-Sz ts lamellocytes was examined by challenging them with undamaged heterospecific tissues. Tissues from sibling species ofD. melanogaster were not encapsulated whereas tissues fromDrosophila species outside theD. melanogaster species subgroup were. Ultrastructural examination of encapsulated heterospecific tissues showed intact basement membrane, so we propose that distinction between "self" and "not self" by lamellocytes depends upon the molecular architecture of the basement membrane. In similar series of experiments usingD. virilis donor tissues inOre-R wild type larval hosts, fat bodies remained unencapsulated and imaginal disks metamorphosed. These studies suggest that continued presence of lamellocytes in the larval host is a prerequisite for encapsulation.