Desmoplastic infantile ganglioglioma: novel aspects in clinical presentation and genetics.
Desmoplastic infantile ganglioglioma is a rare tumor occurring mainly in infants and young children. Both radiological and histopathological appearances may resemble malignancy, although its clinical course is mainly benign. Altogether, 5 cases of DIG have been operated on in our hospital since the first diagnosis of DIG in Finland in 1993. We evaluated their presenting symptoms, radiological and surgical findings, histologic characteristics, and follow-up. All patients were male. Three were less than 18 months old, and 2 were 35 and 79 months old. The most common presenting symptoms were epileptic seizures (4 cases). In 4 cases, there was a histopathologically verified single cystic tumor. In 1 case, DIG was operatively diagnosed in 2 separate locations. This patient, moreover, had 2 other lesions suspected of being DIG, including a mass originating from the ophthalmic nerve. None of the patients received adjuvant therapies. All our patients are alive after 7 to 120 months of follow-up. There were no recurrences in any of the patients after tumor resection. For the first time, we describe EGFR and MYCN amplifications in tumors which are, respectively, of their mixed glial and neuronal origin. The clinical presentation of DIG may be more often associated with epileptic seizures than previously thought. The radiological appearance of DIG may vary from cystic to solid and from contrast-enhancing to nonenhancing. Even multiple locations of DIG have been encountered. Increasing evidence supports surgery as the treatment of choice for DIG, although oncogene amplifications have been described.


Role of primary healthcare providers in supporting a gifted child.
'Giftedness' in children relates to high potential, whereas 'talent' relates to high achievement. The concept of giftedness can be perplexing for those involved in caring for and supporting a gifted child. This article provides a starting point for primary healthcare providers in supporting gifted children by outlining a range of issues that may impact on these children. Gifted children are a heterogeneous population; giftedness occurs on a continuum. Giftedness can also co-occur with disabilities. Evidence-informed strategies to provide support to gifted children need to be considered.


Step-by-Step Arthroscopic Assessment of the Anterolateral Ligament of the Knee Using Anatomic Landmarks.
New insights into the existence and function of the anterolateral ligament (ALL) of the knee have redirected and refocused attention on the secondary restraints of rotational stability of the knee. The importance of assessing the ALL is increasing, especially in anterior cruciate ligament reconstruction surgery, to decide on the need for an adjunctive extra-articular reconstruction of the ALL to control rotational instability of the knee. However, preoperative assessment of this ligament is difficult. Clinical assessment of rotatory instability has poor reproducibility. Moreover, it is difficult to assess by current imaging techniques. We describe an easy, simple, practical, safe, and reproducible arthroscopic technique to fully assess the ALL of the knee.


How far are we from a medication use process aiming at well-informed adherent patients with long-term medications in Finland? Qualitative study.
Finland is one of the few countries that has established a national Medicines Information (MI) Strategy. The ultimate goal of the strategy is a well-implemented medication use process resulting in well-informed adherent patients. This study aimed at evaluating the implementation of the strategy 3 years after its launch. The evaluation applied a pragmatic approach and was conducted by interviewing stakeholders involved in the National MI Network enhancing the MI Strategy's implementation. The network comprises national key stakeholders producing and using MI. Data were deductively analysed according to the medication use process of the MI Strategy using the framework method, complemented with inductively derived categories. National implementation of the MI Strategy throughout the healthcare system after the first operational period (2012-2014) in 2015. The members of the National MI Network (n=79/111, participation rate 71%, representing 42/53 stakeholder organisations). A new conceptual framework was developed based on stakeholders' views on well-implemented actions and actions needing development in the medication use process at (1) infrastructure (macro), (2) healthcare professionals (meso) and (3) patient (micro) levels. Medication counselling by community pharmacists was the primary implemented action, followed by physicians' actions while starting a new medication, and advice given by nurses. The major development needs concerned (1) poor access to patient information and its transfer in healthcare, particularly the lack of reconciled medication lists and electronic health records (macro); (2) poorly functioning medication use process in home care and social care units, such as nursing homes (meso); and (3) limited patient involvement in their care (micro). Far more actions for development than well-established practices in the medication use process were identified. Major challenges found in this evaluation are considered in the ongoing Rational Pharmacotherapy Action Plan 2018-2022 by the Ministry of Social Affairs and Health.


[The central regulation of pain sensitivity in rats after irradiation with high doses of ionizing radiation].
It was shown that during 24 h following whole-body exposure of male rats to gamma-quanta (150 Gy) the latent period of their response to the thermal effect increased a "tail-flick" test) and the threshold of the nociceptive response to an electric stimulus (the vocalization threshold) decreased. A correlation was found between the initial response to the nociceptive effects and variation of these values in irradiated animals.


Feline alimentary lymphoma: 1. Classification, risk factors, clinical signs and non-invasive diagnostics.
Alimentary lymphoma (AL) occurs commonly in cats and exists as distinct subtypes that differ in their clinical course, response to treatment and prognosis. Accurate diagnosis is important to guide appropriate treatment. Differentiation of low-grade alimentary lymphoma from lymphoplasmacytic enteritis can be challenging, especially where endoscopic intestinal biopsies, which sample only the mucosa and submucosa, are used. The major differentials for intermediate- and high-grade alimentary lymphoma are other neoplastic and non-neoplastic intestinal mass lesions. The diagnosis of large granular lymphocyte lymphoma requires vigilance as it may be missed with routine diagnostics. AL affects predominantly middle- to old-aged domestic crossbred cats (median age 10-13 years). The evidence supporting this review is grade II, III and IV, derived from prospective studies, retrospective case series, reviews, extrapolation from other species, pathophysiological justification and the combined clinical experience of those working in the field.


Ring-testing and field-validation of a terrestrial model ecosystem (TME)--an instrument for testing potentially harmful substances: effects of carbendazim on enchytraeids.
The effects of the fungicide carbendazim (applied in the formulation Derosal) on enchytraeids were determined in Terrestrial Model Ecosystem (TME) tests and field-validation studies. TMEs consisted of intact soil columns (diameter 17.5 cm; length 40 cm) taken from a grassland or, in one case, from an arable site. The TMEs were taken from the same site where the respective field study was performed. The tests were performed in Amsterdam (The Netherlands), Bangor (Wales, England), Coimbra (Portugal) and Flörsheim (Germany). Concerning the enchytraeid overall abundance and the number of species, differences between sampling points and differences between the TME tests and the respective field-validation studies were not found in the controls. Generally, a high variability of data which reduced the probability of determining statistically significant differences was determined. Effects of the model chemical carbendazim were determined for the overall abundance of enchytraeids and the number of enchytraeid species. The clearest dose-response relationship was found for the abundance of the genus Fridericia. The abundance of the genera Achaeta and Enchytraeus was not affected. Effects were most pronounced 8 and 16 weeks after application of the test chemical. The observed effects appeared not to differ between the TME tests and the respective field-validation studies. Due to the high variability of data NOEC-values could often not be determined. The EC50-values derived from the TME pre-test, TME ring-test and field-validation study indicate that the reproducibility (i.e. the variation between the partners) of the EC50-values was reasonable, although different soils were used at the different sites. The EC50-values for effects of carbendazim on enchytraeid abundance ranged between 0.5 and 28.4 kg a.i./ha (corresponding to 0.7-37.8 mg/kg), on the number of species between 7.2 and 87.4 kg a.i./ha (9.5-116.2 mg/kg) and on the abundance of Fridericia between 0.7 and 18.6 kg a.i./ha (0.9-24.7 mg/kg). Since one specific taxon has the potential to be more sensitive for a chemical stressor than other taxa, it is recommended to include investigations on the species level in the assessment of TME or field studies.


Premature antibodies with rapid reaction kinetics and their characterization for diagnostic applications.
In this study, rapidly reversible antibodies were produced and the binding kinetics, stability, and utility as an analytical binder were evaluated. The number of times the animals were immunized with the antigen (myoglobin as marker for acute myocardial infarction [AMI]) was limited to two, increasing the chances of producing premature antibodies that rapidly reacted with the binding partner in both association and dissociation. The rate constants were higher than 1×10(6)M(-1)s(-1) and 1×10(-3)s(-1), respectively, and the affinity exceeded 10(8)M(-1). They responded to an abrupt environmental change (acidic pH in this study) where the reaction kinetics was changed to slow binding, particularly for dissociation, resulting in a 10-fold increase in affinity. The binding characteristic before and after the transition were stable at 37°C for longer than 1 month, suggesting that the rapidly reversible antibody was the intermediate of the slow binder. The rapid kinetic antibody was used as the primary binder in the conventional competitive immunoassay, which displayed a lower sensitivity than the transformed antibody due to its lower affinity. We further demonstrated that, on combination with a microfluidic label-free sensor, the reaction could be continuously monitored in serum medium by recycling the same antibody without employing the regeneration step.


[Effects of cystamine on the state of peripheral blood neutrophilic granulocytes in vivo in rats].
It has been found experimentally, that decay of the intercellular energy exchange, intensification of the secretory degranulation, activation of the oxygen-dependent enzyme system and increasing the functional potential of the male-rats neutrophils took place on the height of the protective action of cystamine. On the 1-st day the tendency to restoration was noted and the normalisation of the functional and metabolical status of the neutrophils could be seen on the 5-th day after injection.


Evaluation of the preventative effects exerted by Lactobacillus fermentum in an experimental model of septic shock induced in mice.
The preventative effects of the probiotic Lactobacillus fermentum CECT5716 were evaluated in the lipopolysaccharide (LPS) model of septic shock in mice. The probiotic was administered suspended in drinking water at the final concentration of 108 colony-forming units/ml for 2 weeks before the induction of an endotoxic shock by an intraperitoneal injection of LPS (400 microg/200 microl per mouse). Blood and different organs were collected after 24 h to evaluate the severity of the endotoxic shock and the preventative effects of the probiotic. L. fermentum reduced TNF-alpha levels in blood, which promotes the major alterations observed during septic shock, as well as the infiltration of activated neutrophils into the lungs. Furthermore, free radical overproduction and oxidative stress were associated with a significant decrease in hepatic glutathione levels in septic mice, and with an excessive NO production attributed to the induction of the inducible isoform of NO synthase (iNOS). In fact, hepatic glutathione levels were significantly increased in the group of mice receiving the probiotic, and the increased iNOS expression both in the colon and lungs was down-regulated in those mice treated with L. fermentum. Finally, pre-treatment with L. fermentum may also exert its protective action modulating the expression of different cytokines in splenocyte-derived T cells such us IL-2, IL-5, IL-6 or IL-10. In conclusion, pre-treatment with L. fermentum may exert its protective action against LPS-induced organ damage in mice by a combination of several actions including its antioxidant properties and by reduction of the synthesis of the pro-inflammatory TNF-alpha and IL-6.


Impact and outcomes of routine microstaging of sentinel lymph nodes in breast cancer: significance of the pN0(i+) and pN1mi categories.
In 2003, the American Joint Committee on Cancer (AJCC) initiated the 6th edition staging criteria, including pN0(i+) and pN1mi categories for breast cancer. However, the clinical significance of these categories is debated in the literature. A prospective registry was used to identify patients staged with sentinel lymph node (SLN) biopsy. SLN evaluation included routine serial sectioning and immunohistochemical stains. SLN biopsies performed before January 2003 were restaged according to the AJCC's 6th edition criteria. Of 954 SLN biopsies identified, on review, 491 N0i-, 86 N0i+, 73 N1mi, 146 N1a, 29 N2a, and 11 N3a patients were available for analysis with a median follow-up of 45.4 months. Significant prognostic and therapeutic differences existed between the groups. Differences in overall survival (OS) and recurrence-free survival (RFS) were only noted when the size of the metastases reached the N1a level. There were no statistically significant differences in OS or RFS between N0(i-) and N0(i+) or N1mi disease. Cases that were N0(i+) or N1mi were more likely to have other poor prognostic factors and to receive more aggressive therapy. SLN biopsy allows a more sensitive evaluation of lymph nodes for metastatic cells. This has led to the increased identification of very small axillary metastases. While the new microstaging categories are not yet clearly associated with a significantly decreased OS or DFS in this series, they are associated with other poor prognostic factors and more local/regional and systemic therapy. Further analysis of the microstaging categories is needed.


Intraperitoneal radioimmunotherapy for ovarian cancer.
Twenty-eight patients with assessable residual ovarian cancer after cytoreductive surgery and chemotherapy received intraperitoneal I-131 labelled monoclonal antibodies. There was no response in eight patients with tumour nodules greater than 2 cm, a partial response in two of the 15 patients with tumour nodules less than 2 cm, and a complete response in three of the other five patients with positive peritoneal washings. A further six patients received Y-90 labelled monoclonal antibodies for residual ovarian cancer. There was no response in one patient with nodules greater than 2 cm, and a partial response in one of the other five patients with tumour nodules less than 2 cm. The non-specific radiation dose in the peritoneal cavity from the infused isotope was measured by lithium fluoride thermoluminescent dosimetry (TLD). The radiation dose received by the peritoneal serosa was less than 500 cGy and was not sufficient to account for the observed tumour response. Significant bone marrow suppression was observed with I-131 activities greater than 120 mCi and with Y-90 activities greater than 13 mCi. The haemopoietic bone marrow is the dose-limiting organ in patients receiving radioimmunotherapy.


Novel endoscopic therapeutics for early gastric cancer.
Gastrointestinal cancers are among the commonest cancers worldwide. Treatment of these cancers at an early stage will result in a significantly better prognosis. Endoscopic submucosal dissection (ESD) is a new method of endoscopic resection that can achieve higher rates of en bloc resection for early gastrointestinal neoplasia. Three retrospective case-control studies showed that ESD achieved significantly higher en bloc resection with lower recurrence rates than endoscopic mucosal resection for treatment of early gastric cancers. Most of the reports on clinical outcomes of ESD were from countries with a high incidence of gastric cancers, including Japan and Korea. The development of ESD has been slow for countries outside Japan and Korea because ESD requires a high level of endoscopic skills, and the dissection was performed single-handedly without assistance. A newly developed robotic endoscopic platform will enhance the performance of ESD through the use of 2 robotic arms: one arm for retraction of the mucosa and the other arm for dissection.


[Changes at the liver cell level in rats subjected to protein-calorie malnutrition].
The effect of a low protein-calorie diet (restricted diet) on cellular growth and on RNA metabolism in Wistar rat liver has been studied. Experimentation was carried out over 30 days and the comparisons were made against well-nourished group (10% protein, controls). Liver weight and hepatic proteins dropped significantly in malnourished rats. Both rate of DNA and number of nuclei were unchanged. However, protein/DNA and liver weight/number of nuclei ratios decreased, which led to an atrophy phenomenon. DNase specific activity however, was not modified. Liver RNA content together with RNase activity dropped in deficient rats. Protein synthesis capacity (RNA/protein) did not change. These results suggest that restricted diet leads to a lower hepatocyte size with a decreased rat of RNA turnover.


Fabrication of near infrared light responsive photoelectrochemical immunosensor for in vivo detection of melanoma cells.
Effective and convenient detection of melanoma cells with high sensitivity is essential to identify malignant melanoma in its early stage. However, the existing detection methods, such as immunohistochemical analysis, are too complicated and time-consuming to realize the convenient in vivo and in situ detection. Herein, a near infrared responsive photoelectrochemical (PEC) immunosensor is proposed with plasmonic Au nanoparticles-photonic TiO2 nanocaves (Au/TiO2 NCs) as photon harvest and conversion transducer and antibody as cell recognition unit. The micro-antibody/Au/TiO2 NCs photoelectrode can easily in vivo distinguish melanoma cells and can realize sensitive detection of melanoma cells in short time of 1 min with a lowest limit of detection of 2 cell mL-1. The PEC immunosensor strategy not only allows us to pioneeringly implement sensitive in vivo bio-detection, but also opens up a new avenue for rational design of cell recognition units and micro-electrode for universal and reliable bio-detections.


Activation of the STING pathway induces peripheral sensitization via neuroinflammation in a rat model of bone cancer pain.
Neuroinflammation in the peripheral nervous system has been linked to cancer metastasis-induced bone pain. The stimulator of interferon genes (STING), an innate immune sensor for cytosolic DNA, plays an important role in inflammation and cancer metastasis and is reported to be a critical regulator of nociception. Here, we examined the role of STING in primary nociceptive neurons and chronic pain to determine if it could be a new target for treating bone cancer pain (BCP). Walker 256 cancer cells were injected intratibially to induce bone cancer pain in rats. STING and its downstream inflammatory factors in dorsal root ganglia (DRG) were detected using western blotting and immunofluorescent staining. Transmission electron microscopy and the BCL2-associated X (Bax) expression were used to detect the mitochondrial stress in DRG neurons. C-176, a specific inhibitor of STING, was used to block STING activation and to test the pain behavior. Mechanical hyperalgesia and spontaneous pain were observed in BCP rats, accompanied by the upregulation of the STING expression in the ipsilateral L4-5 DRG neurons which showed significant mitochondrion stress. The STING/TANK-binding kinase 1 (TBK1)/nuclear factor-kappa B (NF-κB) pathway activation was observed in the DRGs of BCP rats as well as increased IL-1β, IL-6, and TNF-α expression. C-176 alleviated bone cancer pain and reduced the STING and its downstream inflammatory pathway. We provide evidence that STING pathway activation leads to neuroinflammation and peripheral sensitization. Pharmacological blockade of STING may be a promising novel strategy for preventing BCP.


[Comedocarcinoma of the breast: mammographic and thermographic evaluation of 52 cases (author's transl)].
A series of 52 patients with comedocarcinoma of the breast was studied by means of mammography and thermography. All the patients underwent surgery and histologic examination. The results stress the importance of these investigations which reach a diagnostic accuracy in 98% of the cases.


Angina bullosa haemorrhagica-like lesions in pemphigus vulgaris.
The aim of this study was to describe a previously unreported association of oral pemphigus vulgaris with short-lived blood-filled painless blisters resembling angina bullosa haemorrhagica (ABH). A cross-sectional study of consecutive patients with Pemphigus vulgaris. All patients were examined for the presence of ABH-like lesions, and demographic, clinical and histopathological data were collected. Histopathological examination was performed when feasible. A total of 318 with pemphigus vulgaris were included (63.5% female, mean age: 46 years). ABH-like lesions were present in 82 (25.8%) patients, commonly observed in the buccal mucosa (47, 57.3%) followed by the palate (15, 18.3%). All patients had normal platelet counts with no evidence of bleeding diathesis. Biopsies of the ABH-like lesions showed suprabasal clefts in four of six samples. ABH-like lesions were significantly associated with partial remission of pemphigus vulgaris (47.5%, P = 0.002) and the use of intraoral steroids (P = 0.001, odds ratio: 5.9 [95% confidence interval: 2.5-13.6]). ABH-like lesions may represent a transient or abortive form of oral pemphigus vulgaris and tend to have a benign and self-limiting nature.


The Changing Epidemiology of Meningococcal Disease.
The incidence of meningococcal disease is at an historic low in the United States, but prevention remains a priority because of the devastating outcomes and risk for outbreaks. Available vaccines are recommended routinely for persons at increased risk for disease to protect against all major serogroups of Neisseria meningitidis circulating in the United States. Although vaccination has virtually eliminated serogroup A meningococcal outbreaks from the Meningitis Belt of Africa and reduced the incidence of serogroup C disease worldwide, eradication of N meningitidis will unlikely be achieved by currently available vaccines because of the continued carriage and transmission of nonencapsulated organisms.


Protection of isolated cardiomyocytes against reoxygenation-induced hypercontracture by SIN-1C.
Previous studies have shown that SIN-1C (N-morpholinoiminoacetonitrile) can protect ischemic-reperfused myocardium. The aim of the present study was to analyse on the cellular level the mechanism by which SIN-1C may exert this effect. To simulate ischemia-reperfusion, isolated adult rat cardiomyocytes were incubated at pH 6.4 under anoxia and reoxygenated at pH 7.4 in presence or absence of SIN-1C. Reoxygenation was started when intracellular Ca2+ (measured with fura-2) had increased to > or = 10(-5) mol/L and pHi (BCECF) decreased to 6.6. Development of hypercontracture was determined microscopically. In the control group reoxygenation provoked oscillations of cytosolic Ca2+ (60.9 +/- 9.6 min-1 at 5 min of reoxygenation) accompanied by development of hypercontracture (to 77.2 +/- 3.8% of end-ischemic cell length). When SIN-1C was added upon reoxygenation, Ca2+ oscillations were markedly reduced (27.0 +/- 4.5 min-1, p < 0.001) and hypercontracture virtually abolished (90.6 +/- 2.0% of end-ischemic cell length, p < 0.001). SIN-1C did not influence the recovery of pHi during reoxygenation. The results indicate that SIN-1C protects cardiomyocytes against reoxygenation-induced hypercontracture by its ability to suppress oscillations of intracellular Ca2+ during the early phase of reoxygenation.


Detection of bacteriophage VSH-1 svp38 gene in Brachyspira spirochetes.
VSH-1 is a mitomycin C-inducible, non-lytic, phage-like agent that packages random 7.5-kb fragments of the Brachyspira hyodysenteriae genome. VSH-1 is the first recognized mechanism for gene transfer between B. hyodysenteriae cells. To analyze the distribution of VSH-1 among spirochetes, a 344-bp probe for gene svp38, encoding the VSH-1 major head protein, was amplified by polymerase chain reaction and used in Southern blot hybridizations with genomic DNA from various spirochete genera. The svp38 probe hybridized to a 40-kb SalI-SmaI fragment of the B. hyodysenteriae B78(T) chromosome, indicating VSH-1 DNA insertion into the chromosome at a unique site. Restriction endonuclease digested DNAs of 27 spirochete strains representing six Brachyspira species (B. hyodysenteriae, B. innocens, B. pilosicoli, B. murdochii, B. intermedia, B. alvinipulli) contained a single fragment hybridizing with the svp38 probe. DNAs from spirochete species of the genera Treponema, Spirochaeta, Borrelia, and Leptospira did not hybridize with the probe. VSH-1-like agents appear to be widely distributed among Brachyspira species and, as has been demonstrated for B. hyodysenteriae, may serve as useful gene transfer agents for those other species.


Metabolic Bone Disease in Primary Biliary Cirrhosis.
Primary biliary cirrhosis (PBC) is a liver-specific autoimmune disease that primarily affects women (female-to-male ratio, 10:1) between 40 and 60 years of age. Metabolic bone disease is a common complication of PBC, affecting 14% to 52% of patients, depending on the duration and severity of liver disease. The osteoporosis seen in PBC seems mainly due to low bone formation, although increased bone resorption may contribute. Treatment of osteoporosis consists primarily of antiresorptive agents. Additional large prospective, long-term studies in patients with PBC are needed to determine efficacy in improving bone density as well as reducing fracture risk.


Outcomes of acute type A aortic dissection repair during pregnancy.
To evaluate the efficacy and safety of performing cesarean section surgery before aortic repair after acute type A aortic dissection (ATAAD) during pregnancy. A total of six patients who received ATAAD repair during their pregnancies were retrospectively identified in the hospital database from January 2002 to December 2021. The mean gestational period at the time of aortic repair was 35.3 ± 2.7 weeks, and the aortic root diameter ranged from 40 to 60 mm. The mean time from disease onset to arrival at the operation room was 20.3 ± 10.8 h (range 10-36 h). All patients successfully received aortic repair operations following cesarean section and survived the peri-surgery period without developing major complications. All fetuses were successfully delivered. After an average follow up of 25.8 months, all patients and their children had survived without developing major complications except for one mother who committed suicide 6 months after discharge as a result of postpartum depression. The present study suggested that ATAAD repair can be safely performed in the third-trimester.


Neural correlates of temporal auditory processing in developmental dyslexia during German vowel length discrimination: an fMRI study.
This fMRI study investigated phonological vs. auditory temporal processing in developmental dyslexia by means of a German vowel length discrimination paradigm (Groth, Lachmann, Riecker, Muthmann, & Steinbrink, 2011). Behavioral and fMRI data were collected from dyslexics and controls while performing same-different judgments of vowel duration in two experimental conditions. In the temporal, but not in the phonological condition, hemodynamic brain activation was observed bilaterally within the anterior insular cortices in both groups and within the left inferior frontal gyrus (IFG) in controls, indicating that the left IFG and the anterior insular cortices are part of a neural network involved in temporal auditory processing. Group subtraction analyses did not demonstrate significant effects. However, in a subgroup analysis, participants performing low in the temporal condition (all dyslexic) showed decreased activation of the insular cortices and the left IFG, suggesting that this processing network might form the neural basis of temporal auditory processing deficits in dyslexia.


Pulse wave analysis to assess vascular compliance changes in stable renal transplant recipients.
Calcineurin inhibitor drugs (cyclosporine and tacrolimus) given to renal transplant recipients to prevent rejection are associated with an increased incidence of hypertension. Reduced arterial compliance, which is a consequence of hypertension, is associated with an increased risk of cardiovascular disease and can be measured noninvasively using pulse wave analysis technology. The purpose of the study was to determine whether calcineurin inhibitor drugs have any effect on arterial compliance. A total of 36 stable renal transplant recipients were evaluated using pulse wave analysis to determine large and small vessel compliance. Of the patients, 18 were receiving cyclosporine and 18 tacrolimus. Patients were matched for age and sex. No significant differences in systolic blood pressure, diastolic blood pressure, heart rate, or small vessel compliance were observed. There was a significant decrease in large vessel compliance in patients receiving tacrolimus versus those receiving cyclosporine, respectively (13.5 +/- 4.0 mL/mm Hg x 10 v 9.9 +/- 3.3 mL/mm Hg x 10; P =.005). Differences in large vessel compliance in renal transplant subjects may depend on the choice of calcineurin inhibitor. Specifically, decreased large vessel compliance in tacrolimus-treated subjects may be associated with an increased cardiovascular risk. This may be due to a difference in vascular collagen accumulation or to elastin loss in large elastic arteries.


Progression to end-stage glaucoma after laser in situ keratomileusis.
We describe 2 patients, one a glaucoma suspect because of family history and the other with juvenile glaucoma. Both patients developed complications after laser in situ keratomileusis that required frequent topical steroids, leading to steroid-induced glaucoma. In both cases, corneal edema from the acute rise in intraocular pressure (IOP) caused inaccurate IOP measurement by standard methods. The inability to recognize glaucoma early may have resulted in significant irreversible vision loss.


Designing clinical trials with arbitrary specification of survival functions and for the log rank or generalized Wilcoxon test.
This article describes a computer program that allows interactive determination of the length of accrual period and follow-up period sufficient to assure desired level of significance and power. The program allows for arbitrary specification of the hypothesized survival curves and the alternative survival curve. It allows use of either the generalized Wilcoxon test or the log rank test. The program can be run on an IBM personal computer.


Somatization in primary care: patients with unexplained and vexing medical complaints.
Somatizing patients experience or express emotional discomfort and psychosocial distress as physical symptoms. Somatization occurs in a broad spectrum of illnesses, in association with a wide variety of mental disorders, including depression, anxiety, and the somatoform disorders. Primary care providers must detect and treat these patients. Diagnosis is based on positive criteria. Care rests upon conservative medical management and evaluation; a physician-patient relationship based on acceptance, caring, and trust; reinforcement of positive behaviors and elimination of destructive ones; and the gradual use of the relationship to promote healthy relating in the patient.


Physical exercise alleviates oxidative stress in brown adipose tissue and causes changes in body composition and nutritional behavior in rats with polycystic ovary syndrome.
Polycystic Ovary Syndrome (PCOS) is a very common endocrine disorder in women. We investigate the effect of physical exercise on body composition, nutritional parameters, and oxidative stress in rats with PCOS. Female rats were into three groups: Control, PCOS, and PCOS + Exercise. PCOS was induced by letrozole (1 mg/kg via p.o.) for 21 days consecutively. Physical exercise was swimming, for 21 consecutive days, 1 h/day with 5 % load. In all groups, we assessed the nutritional and murinometric parameters, body composition, thermography, and oxidative stress in brown adipose tissue (BAT) and peri-ovarian adipose tissue (POAT). In PCOS we observed an increase (P < 0.05) in body weight vs. the Control group. But, the PCOS + Exercise group prevent this weight gain (P < 0.05). The temperature in BAT, decrease (P < 0.05) in the PCOS group vs. Control group. PCOS + Exercise prevented this reduction (P < 0.05) in BAT temperature vs. PCOS groups. We observed decreases (P < 0.05) in Lee Index and BMI in POS + Exercise vs. PCOS group. In PCOS rats, we observed an increase (P < 0.05) in murinometric (SRWG, EI, and FE) and body composition parameters (TWB, ECF, ICF, and FFM) vs. the Control group. The PCOS + Exercise prevents (P < 0.05) these changes in all groups, compared with PCOS. Regarding the BAT, we observe an increase (P < 0.05) in MPO and MDA levels in the PCOS vs. Control group. PCOS + Exercise prevents (P < 0.05) these increases vs. the PCOS group. PCOS modifies body composition, and nutritional parameters, and induces changes in oxidative stress in BAT. Physical exercise prevented these alterations.


Methodology of premature chromosome condensation and its potential for relapse prediction in acute leukemia of children and adolescents.
Premature chromosome condensation has been examined as a method for measuring the proliferative potential of bone marrow cells derived from children with acute leukemia with the intention of finding a predictor of relapse. A proliferative potential index (PPI) has been determined for patients with active disease at diagnosis and relapse, as well as at onset of remission and at extramedullary relapse. A modification of the technique established by Hittelman is described, which can be easily performed by the leukemia cytogeneticist. A PPI of 35% or greater is usually obtained for patients at diagnosis or in relapse. At the onset of remission, the PPI declines to values significantly below 35% and during extramedullary relapse the value of the PPI is near normal (12%). The method for the determination of the PPI is given in detail.


Hypoxia in prostate cancer: a powerful shield against tumour destruction?
Tumour hypoxia is progressively emerging as a common feature of prostate tumours associated with poor prognosis. While the molecular basis of disease progression is increasingly well documented, the potential role of hypoxia in these processes remains poorly evaluated. By dissecting the impact of hypoxia-inducible factor 1 alpha on molecular responses, this review provides evidence for a powerful protecting role of oxygen deprivation against oxidative stress injury, androgen deprivation, chemotherapeutic and radiation cytotoxicity. We propose hypoxia as a potent tumour-induced shield against destruction and suggest its targeting may need to be routinely addressed in the management of prostate cancer.


A Kettle of Fish: A Review of the Scientific Literature for Evidence of Fish Sentience.
Fish are traded, caught, farmed, and killed in their trillions every year around the world, yet their welfare is often neglected and their sentience regularly disregarded. In this review, we have sought to (1) catalogue the extent to which fish sentience has featured over the past 31 years in the scientific literature and (2) discuss the importance of fish sentience in relation to their commercial uses. We searched the journal database Science Direct using 42 keywords that describe traits or elements of sentience to find articles that were referring to or exploring fish sentience. Our review returned 470 results for fish sentience in 142 different species and subspecies of fish, and featured 19 different sentience keywords. The top four keywords were; 'stress' (psychological) (n = 216, 45.9% of total results), 'anxiety' (n = 144, 30.6%), 'fear' (n = 46, 9.7%), and 'pain' (n = 27, 5.7%). Our findings highlight an abundance of evidence for fish sentience in the published scientific literature. We conclude that legislation governing the treatment of fish and attitudes towards their welfare require scrutiny so that their welfare can be safeguarded across the globe.


The role of midazolam and flumazenil in urology.
The effects of midazolam (3-10 mg i.m.) and their reversal by flumazenil were studied in transurethral endoscopic procedures performed using topical analgesia. In one randomised study, patients (n = 84) received either no medication or flumazenil (0.5 mg i.v.) on completion of endoscopy. Recovery was assessed subjectively. Within 15 min, 83% of those receiving flumazenil were considered ready for discharge compared with only 24% of the control group (P less than 0.001). In a second randomised, double-blind, placebo-controlled trial of 44 patients, post-operative recovery was assessed using five objective psychomotor tests. Whereas the placebo group took up to 2 h to recover, those receiving flumazenil recovered fully or returned to near control values within 15 min. Sedoanalgesia--a technique combining adequate local anaesthesia with sedation (using midazolam)--has wide application in urology, and the introduction of flumazenil has major implications for the practice of day-case surgery.


Returning to work after a stroke: a retrospective study at the Physical and Rehabilitation Medicine Center La Tour de Gassies.
To study work re-entry by patients having suffered a stroke at least 3 years previously. This was a retrospective survey in which a questionnaire was administered to all patients admitted after a first stroke to the "La Tour de Gassies" Centre for Physical and Rehabilitation Medicine (CPRM) in France between January 2005 and June 2007 and who were in work at the time of the incident. Fifty-six of the 72 included patients (78%) completed and returned the survey questionnaire. The mean age at the time of the stroke was 48.3±10.1. Eighteen (32.1%) of the 56 patients returned to work after their stroke (mean post-stroke time interval: 19.2±13.4 months). Negative prognostic factors for a return to work were living alone, the presence of severe functional impairment and the presence of speech disorders. Positive prognostic factors included specific, professional support and early involvement of the occupational physician. Patients who resumed driving were more likely to return to work and there was a positive correlation between the time to work re-entry and the time to resumption of driving. Close cooperation between occupational health services and CPRM appears to be necessary to speed the return to work by stroke patients.


Chronic outcome of proximal gastrectomy with jejunal pouch interposition in dogs.
To prevent or minimize postgastrectomy complications, proximal gastrectomy with an interposed jejunal pouch has been advocated as an organ-preserving surgical strategy to improve quality of life for the patients. However, the utility of this surgical method has only been evaluated clinically and no reports have been published concerning animal studies. Therefore, we carried out an experiment in beagle dogs to investigate the utility of proximal gastrectomy with an interposed jejunal pouch. Female beagle dogs weighting 8.0-10.0 kg were divided into two groups that underwent proximal gastrectomy with jejunal pouch interposition (JP group) and esophagogastrostomy (EG group). The time course of the electrophysiological changes on electromyograms were compared between the JP and EG groups. Electrophysiologically, a significant difference was noted between the two groups on the number of action potentials per unit time, the mean amplitude, and the length of the resting period in the preprandial state. All parameters tended to be normalized sooner after surgery in the JP group. The clinical superiority of jejunal pouch interposition was suggested experimentally to the same extent on electromyograms.


The lumazine synthase-riboflavin synthase complex of Bacillus subtilis. Crystallization of reconstituted icosahedral beta-subunit capsids.
The lumazine synthase-riboflavin synthase complex (heavy riboflavin synthase) of Bacillus subtilis consists of an icosahedral capsid of 60 beta-subunits containing a core of three alpha-subunits. The enzyme has been purified from the derepressed mutant H 94 of B. subtilis by a novel efficient procedure using column chromatography and preparative crystallization. Beta-Subunits were isolated after dissociation of the enzyme at pH 8.0. Ligand-driven renaturation of beta-subunits yields hollow icosahedral beta 60 capsids which could be crystallized in 1.55 M phosphate, pH 8.7, in three different modifications. A monoclinic modification belongs to space group C2 with unit cell dimensions of a = 235.5, b = 191.2, and c = 165.4 A and alpha = gamma = 90 degrees and beta = 134.4 degrees. The crystals contain two hollow beta 60 particles/unit cell and diffract to approximately 2.8-A resolution. A hexagonal modification has the space group P6(3)22 with unit cell dimensions of a = b = 157.2 and c = 300.8 A and alpha = beta = 90 degrees and gamma = 120 degrees. These cell parameters are similar to the dimensions of hexagonal crystals of native heavy riboflavin synthase (alpha 3 beta 60). A second hexagonal modification shows unit cell parameters of a = b = 156.3 and c = 622.6 A and alpha = beta = 90 degrees and gamma = 120 degrees. The space group of this modification could not be determined unambiguously.


Analysing Time to Event Data in Dementia Prevention Trials: The Example of the GuidAge Study of EGb761.
Time-to-event analysis is frequently used in medical research to investigate potential disease-modifying treatments in neurodegenerative diseases. Potential treatment effects are generally evaluated using the logrank test, which has optimal power and sensitivity when the treatment effect (hazard ratio) is constant over time. However, there is generally no prior information as to how the hazard ratio for the event of interest actually evolves. In these cases, the logrank test is not necessarily the most appropriate to use. When the hazard ratio is expected to decrease or increase over time, alternative statistical tests such as the Fleming-Harrington test, provide a better sensitivity. An example of this comes from a large, five-year randomised, placebo-controlled prevention trial (GuidAge) in 2854 community-based subjects making spontaneous memory complaints to their family physicians, which evaluated whether treatment with EGb761 can modify the risk of developing AD. The primary outcome measure was the time to conversion from memory complaint to Alzheimer's type dementia. Although there was no significant difference in the hazard function of conversion between the two treatment groups according to the preplanned logrank test, a significant treatment-by-time interaction for the incidence of AD was observed in a protocol-specified subgroup analysis, suggesting that the hazard ratio is not constant over time. For this reason, additional post hoc analyses were performed using the Fleming-Harrington test to evaluate whether there was a signal of a late effect of EGb761. Applying the Fleming-Harrington test, the hazard function for conversion to dementia in the placebo group was significantly different from that in the EGb761 treatment group (p = 0.0054), suggesting a late effect of EGb761. Since this was a post hoc analysis, no definitive conclusions can be drawn as to the effectiveness of the treatment. This post hoc analysis illustrates the interest of performing another randomised clinical trial of EGb761 explicitly testing the hypothesis of a late treatment effect, as well as of using of better adapted statistical approaches for long term preventive trials when it is expected that prevention cannot have an immediate effect but rather a delayed effect that increases over time.


Blocking S1P interaction with S1P₁ receptor by a novel competitive S1P₁-selective antagonist inhibits angiogenesis.
Sphingosine 1-phosphate receptor type 1 (S1P(1)) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P(1) and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P(1)-selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P(1) antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P(1) is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.


Community mental health centers and the "seed money" concept: effects of terminating federal funds.
What happens to community mental health centers when federal funding ends? Analysis of the funding patterns of a cohort of "graduate" community mental health centers indicates that these centers remained fiscally viable subsequent to termination of basic federal grants. However, further analysis revealed two distinct funding patterns within the cohort. One group relied primarily on increased third-party reimbursements to offset the end of basic federal grants. The other sought more state funds and additional federal grants available through the Community Mental Health Center Amendments of 1975. As more centers "graduate," federal "floor funding" may be necessary to insure the survival of some of them.


Leukemia derived from intermediately differentiated lymphocytic lymphoma.
The availability of monoclonal antibodies has facilitated the immunophenotypic characterization of malignant lymphocytes from patients with lymphoma and leukemia. The chronic lymphocytic leukemias are diseases of both clinical and morphological diversity and the application of monoclonal antibodies can prove helpful in their classification. Enzyme cytochemistry, surface markers, mouse rosetting, and electron microscopy were used to determine the phenotype of cells from an atypical case of B-CLL. The use of monoclonals Leu-1, CALLA and BA-2 on bone marrow and peripheral blood provided the opportunity to diagnose this patient's disease as intermediately differentiated lymphoma. Leu-1 was found to be a useful alternative to mouse rosetting, a technique not easily performed in a routine setting. Ultrastructural studies helped to prove the prolymphocytic component of this patient's disease. It was concluded that phenotypic characterization of lymphoid cells using monoclonal antibodies directed against membrane antigens facilitated the assessment of this patient's disease.


Identification of a PIG-A related processed gene on chromosome 12.
PIG-A, the gene encoding the glycoinositol phospholipid anchor synthetic element that is defective in paroxysmal nocturnal hemoglobinuria (PNH), resides on the X chromosome. In the course of analyses of PIG-A genetic alterations in PNH patients, polymerase chain reaction (PCR) amplification of reverse-transcribed RNA from affected leukocytes of a patient with diminished PIG-A mRNA expression yielded a PIG-A related sequence with 126 nucleotide substitutions and five deletions. In the present study, the origin of this product was investigated. Selective reverse transcription (RT)/PCR amplifications with primers specific for PIG-A and this variant sequence, analyses of RNA from unaffected cells, and differential endonuclease digestions showed that mRNA with this sequence is coexpressed with PIG-A mRNA in a wide range of cell types. Mapping of genomic DNA from human/rodent hybrids showed that the sequence derives from a processed gene, designated PIG-A-II, that is encoded on chromosome 12.


Eight weeks of inorganic nitrate/nitrite supplementation improves aerobic exercise capacity and the gas exchange threshold in patients with type 2 diabetes.
Patients with type 2 diabetes mellitus (T2DM) have reduced exercise capacity, indexed by lower maximal oxygen consumption (V̇o2max) and achievement of the gas exchange threshold (GET) at a lower % V̇o2max. The ubiquitous signaling molecule nitric oxide (NO) plays a multifaceted role during exercise and, as patients with T2DM have poor endogenous NO production, we investigated if inorganic nitrate/nitrite supplementation (an exogenous source of NO) improves exercise capacity in patients with T2DM. Thirty-six patients with T2DM (10F, 59 ± 9 yr, 32.0 ± 5.1 kg/m2, HbA1c = 7.4 ± 1.4%) consumed beetroot juice containing either inorganic nitrate/nitrite (4.03 mmol/0.29 mmol) or a placebo (0.8 mmol/0.00 mmol) for 8 wk. A maximal exercise test was completed before and after both interventions. V̇o2max was determined by averaging 15-s data, whereas the GET was identified using the V-slope method and breath-by-breath data. Inorganic nitrate/nitrite increased both absolute (1.96 ± 0.67 to 2.07 ± 0.75 L/min) and relative (20.7 ± 7.0 to 21.9 ± 7.4 mL/kg/min, P < 0.05 for both) V̇o2max, whereas no changes were observed following placebo (1.94 ± 0.40 to 1.90 ± 0.39 L/min, P = 0.33; 20.0 ± 4.2 to 19.7 ± 4.6 mL/kg/min, P = 0.39). Maximal workload was also increased following inorganic nitrate/nitrite supplementation (134 ± 47 to 140 ± 51 W, P < 0.05) but not placebo (138 ± 32 to 138 ± 32 W, P = 0.98). V̇o2 at the GET (1.11 ± 0.27 to 1.27 ± 0.38L/min) and the %V̇o2max in which GET occurred (56 ± 8 to 61 ± 7%, P < 0.05 for both) increased following inorganic nitrate/nitrite supplementation but not placebo (1.10 ± 0.23 to 1.08 ± 0.21 L/min, P = 0.60; 57 ± 9 to 57 ± 8%, P = 0.90) although the workload at GET did not achieve statistical significance (group-by-time P = 0.06). Combined inorganic nitrate/nitrite consumption improves exercise capacity, maximal workload, and promotes a rightward shift in the GET in patients with T2DM. This manuscript reports data from a registered Clinical Trial at ClinicalTrials.gov ID: NCT02804932.NEW & NOTEWORTHY We report that increasing nitric oxide bioavailability via 8 wk of inorganic nitrate/nitrite supplementation improves maximal aerobic exercise capacity in patients with type 2 diabetes mellitus. Similarly, we observed a rightward shift in the gas exchange threshold. Taken together, these data indicate inorganic nitrate/nitrite may serve as a means to improve fitness in patients with type 2 diabetes mellitus.


Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut.
Mucosal surfaces such as the intestinal tract are continuously exposed to both potential pathogens and beneficial commensal microorganisms. This creates a requirement for a homeostatic balance between tolerance and immunity that represents a unique regulatory challenge to the mucosal immune system. Recent findings suggest that intestinal epithelial cells, although once considered a simple physical barrier, are a crucial cell lineage for maintaining intestinal immune homeostasis. This Review discusses recent findings that identify a cardinal role for epithelial cells in sampling the intestinal microenvironment, discriminating pathogenic and commensal microorganisms and influencing the function of antigen-presenting cells and lymphocytes.


Fusion and endocytosis of anionic liposomes with Ehrlich ascitic carcinoma cells.
Polyethylene glycol 300 and low pH of the incubation medium initiate fusion of anionic lipid liposome membranes with Ehrlich ascitic carcinoma cell membranes. Some liposomes are endocytosed in cells and are distributed near the inner surface of the membrane. Liposome membranes spontaneously fuse with the cells under certain conditions.


Impact of stroke on anterior-posterior force generation prior to seat-off during sit-to-walk.
Force generation during sit-to-walk (STW) post-stroke is a poorly studied area, although STW is a common daily transfer giving rise to a risk of falling in persons with disability. The purpose of this study was to describe and compare strategies for anterior-posterior (AP) force generation prior to seat-off during the STW transfer in both subjects with stroke and in matched controls. During STW at self-selected speed, AP force data were collected by 4 force plates, beneath the buttocks and feet from eight subjects with stroke (>6 months after onset) and 8 matched controls. Subjects with post-stroke hemiparesis and matched controls generated a similar magnitude of total AP force impulses (F(1,71)=0.67; p=0.42) beneath buttocks and feet prior to seat-off during STW. However, there were significant group differences in AP force impulse generation beneath the stance buttock (i.e. the non-paretic buttock in the stroke group), with longer duration (F(1,71)=8.78; p<0.005), larger net AP impulse (F(1,71)=6.76; p<0.05) and larger braking impulse (F(1,71)=7.24; p<0.05) in the stroke group. The total braking impulse beneath buttocks and feet was about 4.5 times larger in the stroke group than in the control group (F(1,71)=8.84; p<0.005). An intra- and inter-limb dys-coordination with substantial use of braking impulses was demonstrated in the stroke group. This motor strategy differed markedly from the smooth force interaction in the control group. These results might be important in the development of treatment models related to locomotion post-stroke.


Effects of age, education, and gender on verbal fluency in healthy adult Arabic-speakers in Egypt.
The objective of this study is to establish the effects of age, gender, and education and to provide preliminary normative data for letter and category fluency tasks in the Egyptian Arabic-speaking population. We evaluated 139 cognitively healthy volunteers aged 20-93 by adapting the letter and category verbal fluency tasks for the Egyptian population. On the letter fluency task, mean number of words generated in one-minute beginning with the Arabic letter "Sheen" (pronounced "sh") was 8.14 words per minute (SD = 3.25). Letter fluency was significantly influenced by education. On category fluency tasks, mean number of animal names generated in one minute was 14.63 words (SD = 5.28). Category fluency was significantly influenced by age and education. We were able identify that age significantly affects category fluency while education significantly affected both letter and category fluency. We were also able to provide preliminary normative data for both tasks in the Egyptian population.


Presentation and Management of Food Allergy in Breastfed Infants and Risks of Maternal Elimination Diets.
Breastfeeding is currently recommended as the optimal source of nutrition to infants. However, there are several studies that have shown clinical IgE- and non-IgE-mediated reactions to foods in exclusively breastfeeding infants, specifically to cow's milk, egg, peanut, and fish. Literature suggests that antigenic food proteins present in human milk can be found in substantial enough amounts to elicit clinical reactions in some, already-sensitized infants, including anaphylaxis, eczema exacerbation, and non-IgE-mediated gastrointestinal food-allergic syndromes. Diagnosis of food allergy in a breastfed infant and identification of the trigger foods in the mother's diet can be especially challenging in infants with delayed symptoms, such as eczema and gastrointestinal symptoms. Management is further complicated in infants with atopic dermatitis, who have increased caloric needs and therefore in whom nutrition is an extremely important factor for growth and development. One needs to balance possible benefits with risks of further food sensitization through the skin when foods are eliminated from their diets. We review here the literature on clinical presentation and evidence for food allergy in exclusively breastfed infants, including the presence of food antigens in human milk. Incorporating clinical experience and the available data, which largely come from case reports and small, nonrandomized studies performed in referral centers with several limitations, we propose a novel algorithm to diagnosis and management, with emphasis on nutritional considerations.


Combined modality therapy of early stage nonsmall cell lung cancer.
Therapy for locally advanced NSCLC has evolved into a multidisciplinary effort. Patients who are considered for this approach should undergo rigorous testing to accurately stage their disease. Patients with pleural effusions (with rare exception) are not candidates for intensive combined modality therapy. Appropriate patients for combined modality therapy should have a good performance status (generally Zubrod 0 or 1), adequate pulmonary function, absence of significant heart, lung, or other medical diseases, and be appropriate candidates for combination chemotherapy and thoracic surgery or thoracic radiotherapy. Several lessons can be learned from looking broadly at the phase II and phase III combined modality experience. The available data do not support the routine use of postoperative therapy in patients with completely resected disease. Treatment with chemotherapy before surgery or radiation has demonstrated survival benefit in patients with stage III disease. The French phase III trial of induction chemotherapy in patients with early stage disease found an 11-month improvement in overall survival (P = 0.15) and a significant increase in the risk of death for patients with stage I and II disease. The ongoing U.S. intergroup trial (SWOG 9900) and European trials will help to further define the role of chemotherapy in patients with clinical stage IB, II and IIIA NSCLC. Clinical trials should be conducted to compare preoperative chemoradiotherapy with preoperative chemotherapy. The recently completed intergroup 0139 trial (chemoradiation followed by surgery or not) should help to define whether surgery and radiation are required in the management of stage IIIA NSCLC. Finally, further improvement in survival with the use of "newer" cytotoxic agents seems unlikely as phase III trials in metastatic NSCLC have not demonstrated marked superiority over cispiatin-based regimens. Ongoing trials are assessing the incorporation of newer, biologic-based "targeted" therapies. Despite the dismal findings of trials of postoperative therapy, many patients continue to have surgery as their initial treatment followed by postoperative therapy. In contrast, trials with induction treatment seem to offer improved survival. It is time for a true multidisciplinary approach to the treatment of locally advanced NSCLC. Pulmonary physicians, thoracic surgeons, medical oncologists, and radiation oncologists should meet before the initiation of treatment to plan the most appropriate therapy for the individual patient.


Problems of drug surveillance--an international view.
The importance of Post Marketing Surveillance (PMS) is stressed, both to determine the therapeutic value of the drug and its adverse effects revealed in a large population of patients. A survey of such adverse effects of anti-epileptic drugs is provided: metabolic, dose-related and idiosyncratic. Problems of monotherapy and of drug interactions are discussed, as well as questions of central nervous system toxicity and of teratogenicity.


Lack of interlimb transfer following visuomotor adaptation in a person with congenital mirror movements.
Congenital mirror movements (CMMs) have been traditionally thought to occur due to the corticospinal tracts that project abnormally to both sides of the body. More recently, it has been suggested that both brain hemispheres are activated during intended unilateral movements due to deficient transcallosal inhibition, leading to mirror movements on the unintended side as well. To further understand the mechanisms underlying CMMs, we examined the pattern of interlimb transfer following visuomotor adaptation in 'DB', an individual with CMMs. DB's CMMs were confirmed by detecting EMG signals in both arms during intended unilateral movements, and also when transcranial magnetic stimulation (TMS) was applied to the motor cortex. Following that, DB performed reaching movements with the left arm under a visuomotor condition in which the visual display was rotated 30° counterclockwise about the start circle, and then with the right arm under the same (experiment 1) or opposing (experiment 2) rotation condition. DB's performances were compared with the data from control subjects. In both experiments, DB was able to adapt to the rotation with either arm; however, movement errors at the beginning of right-arm adaptation did not differ from those at the beginning of left-arm adaptation, indicating no transfer. These transfer patterns differ from those observed in controls, who demonstrated substantial transfer when the rotation directions were the same between the arms, but no transfer when they were opposite. These findings suggest that in DB, both hemispheres are activated during unilateral movements, but interhemispheric communication is impaired, thus resulting in mirror movements on the involuntary side.


Behavioral testing of antidepressant compounds: an analysis of crossover design for correlated binary data.
The differential reinforcement of low-rate 72 seconds schedule (DRL-72) is a standard behavioral test procedure for screening potential antidepressant compounds. The protocol for the DRL-72 experiment, proposed by Evenden et al. (1993), consists of using a crossover design for the experiment and one-way ANOVA for the statistical analysis. In this paper we discuss the choice of several crossover designs for the DRL-72 experiment and propose to estimate the treatment effects using either generalized linear mixed models (GLMM) or generalized estimating equation (GEE) models for clustered binary data.


The effects of food and of antacid on the single oral dose pharmacokinetics of tenoxicam.
A single oral dose (40 mg) of tenoxicam (Ro12-0068) was administered to six normal male volunteers pre- and post-prandially and to a further six volunteers with and without antacid to determine the effect of food and and of antacid on absorption. The rate of absorption was slower with post-prandial than with pre-prandial administration, resulting in a significantly later time for peak plasma drug levels (4.1 h compared to 1.3 h). No effect was evident on the extent of absorption or other pharmacokinetic parameters. Similarly, the rate of absorption was significantly slower after concurrent antacid than without antacid (t1/2 0.47 h compared to 0.18 h) resulting in a later peak time (4.7 h compared to 2.3 h) and significantly lower peak level (4.2 micrograms X ml-1 compared to 5.1 micrograms X ml-1) of parent drug in plasma. Again, no effect was evident on the extent of absorption or other pharmacokinetic parameters. It is concluded that food and antacids both tend to reduce the rate of absorption of tenoxicam, but that the extent of absorption is essentially unchanged. The influence on the overall kinetic profile is relatively minor, and thus unlikely to affect the therapeutic response.


Preclinical Characterization and In Vivo Imaging of 111In-Labeled Mesenchymal Stem Cell-Derived Extracellular Vesicles.
Mesenchymal stem cell-derived EVs (MSC-EVs) are demonstrated to have similar therapeutic effect as their cells of origin and represent an attractive cell-free stem cell therapy. With the potential to be the future medical regimen, the information of fate and behavior of MSC-EVs in the living subject should be urgently gathered. This study aimed to track MSC-EVs by 111In-labeling and μSPECT/CT imaging. Wharton's jelly-MSC-EVs (WJ-MSC-EVs) were isolated using Exo-Prep kit followed by characterization of expressing markers and size. After labeled by 111In-oxine, 111In-EVs were injected into C57BL/6 mice followed by μSPECT/CT imaging. Organs were then taken out for ex vivo biodistribution analysis. The radiochemical purity of 111In-EVs was > 90 % and remained stable up to 24 h. The image results showed that with injection of 111In-EVs, the signal mainly accumulated in the liver, spleen, and kidney, compared to that in lung and kidney after 111In-oxine injection. The ex vivo biodistribution showed the similar pattern to that of imaging. Chelation of free 111In with EDTA was found necessary to reduce the nonspecific accumulation of signal. This study demonstrated the feasibility of radiolabeling WJ-MSC-EVs with 111In-oxine for in vivo imaging and quantitative analysis in a mouse model. This simple and quick labeling method preserves the characteristics of WJ-MSC-EVs. The results in this study provide a thorough and objective basis for future clinical study.


Metallo therapeutics for COVID-19. Exploiting metal-based compounds for the discovery of new antiviral drugs.
The COVID-19 pandemic poses an unprecedented challenge for the rapid discovery of drugs against this life-threatening disease. Owing to the peculiar features of the metal centers that are currently used in medicinal chemistry, metallodrugs might offer an excellent opportunity to achieve this goal. Two main strategies for developing metal-based drugs against the SARS-CoV-2 are herein illustrated. Firstly, a few clinically approved metallodrugs could be evaluated in patients according to a 'drug repurposing' approach. To this respect, the gold drug auranofin seems a promising candidate, but some other clinically established metal compounds are worthy of a careful evaluation as well. On the other hand, libraries of inorganic compounds, featuring a large chemical diversity, should be screened to identify the most effective molecules. This second strategy might be assisted by a pathway-driven discovery approach arising from a preliminary knowledge of the mode of action, exploitable to inhibit the functional activities of the key viral proteins. Also, attention must be paid to selectivity and toxicity issues. The medicinal inorganic chemistry community may offer a valuable contribution against COVID-19. The screening of metallodrugs' libraries can expand the explored 'chemical space' and increase the chance of finding effective anti-COVID agents.


Segmental release of Met-enkephalin-like material from the spinal cord of rats, elicited by noxious thermal stimuli.
In order to investigate possible changes induced by noxious thermal stimuli in the activity of enkephalinergic neurones at various levels of the spinal cord, either the whole cord, the cervicotrigeminal area or the lumbar area were perifused with artificial CSF at a rate of 0.1 ml/min in halothane anaesthetized rats, and Met-enkephalin-like material (MELM) was measured in 0.5 ml fractions collected from the perifusates. Immersing the muzzle of intact rats in water at 52 degrees C produced a significant enhancement of MELM content in perifusates from both the whole spinal cord and the cervicotrigeminal area but not from the lumbar area. Heating the tail resulted in an increase in MELM release from the whole spinal cord of intact as well as of cervically transected rats. It is concluded that noxious thermal stimuli can induce a segmental release of MELM, i.e., only within spinal zones receiving the nociceptive inputs.


A mechanistic investigation of the effect of keratin-based hemostatic agents on coagulation.
Uncontrolled bleeding continues to be one of the leading causes of death in individuals following traumatic injury. Prognosis is worsened with the onset of acute coagulopathy characterized by metabolic acidosis, hypothermia and hemodilution, which consequently perpetuates blood loss and increases mortality. While there are several limitations to biomaterials employed as hemostatic agents, keratin biomaterials have demonstrated efficacy in mitigating blood loss in an animal model of hemorrhage in prior studies. Here we investigate the hypothesis that keratins actively participate in coagulation and that a potential mechanism of action is independent of temperature and dilution of clotting factors. Data from this study show that keratins appear to contribute to hemostasis by significantly decreasing plasma clotting lag times and are able to maintain activity under simulated conditions of coagulopathy. Moreover, a system of isolated fibrin polymerization provided evidence of increased fibril lateral assembly in the presence of keratin. The data provided here provides a platform for further development of keratin biomaterials as hemostatic agents.


[Corticotrophic adenomas with melanoderma (Nelson's syndrome). Two cases clinical and laboratory studies before and after spontaneous intercurrent necrosis (author's transl)].
Two cases of Nelson's syndrome (macroscopic cortico-melanotropic pituitary adenoma developing after bilateral total adrenalectomy for Cushing's disease) are reported. The unusual feature was spontaneous necrosis of the adenoma, as indicated by the rapid disappearance of melanoderma, the normalisation or decrease in plasma ACTH level, retraction in the diaphragm of the sella at air encephalography and autopsy findings in one case.


Clinical pharmacokinetics of the salicylates.
The use of salicylates in rheumatic diseases has been established for over 100 years. The more recent recognition of their modification of platelet and endothelial cell function has lead to their use in other areas of medicine. Aspirin (acetylsalicylic acid) is still the most commonly used salicylate. After oral administration as an aqueous solution aspirin is rapidly absorbed at the low pH of the stomach millieu. Less rapid absorption is observed with other formulations due to the rate limiting step of tablet disintegration - this latter factor being maximal in alkaline pH. The rate of aspirin absorption is dependent not only on the formulation but also on the rate of gastric emptying. Aspirin absorption follows first-order kinetics with an absorption half-life ranging from 5 to 16 minutes. Hydrolysis of aspirin to salicylic acid by nonspecific esterases occurs in the liver and, to a lesser extent, the stomach so that only 68% of the dose reaches the systemic circulation as aspirin. Both aspirin and salicylic acid are bound to serum albumin (aspirin being capable of irreversibly acetylating many proteins), and both are distributed in the synovial cavity, central nervous system, and saliva. The serum half-life of aspirin is approximately 20 minutes. The fall in aspirin concentration is associated with a rapid rise in salicylic acid concentration. Salicylic acid is renally excreted in part unchanged and the rate of elimination is influenced by urinary pH, the presence of organic acids, and the urinary flow rate. Metabolism of salicylic acid occurs through glucuronide formation (to produce salicyluric acid), and salicyl phenolic glucoronide), conjugation with glycine (to produce salicyluric acid), and oxidation to gentisic acid. The rate of formation of salicyl phenolic glucuronide and salicyluric acid are easily saturated at low salicylic acid concentrations and their formation is described by Michaelis-Menten kinetics. The other metabolic products follow first-order kinetics. The serum half-life of salicylic acid is dose-dependent; thus, the larger the dose employed, the longer it will take to reach steady-state. There is also evidence that enzyme induction of salicyluric acid formation occurs. No significant differences exist between the pharmacokinetics of the salicylates in the elderly or in children when compared with young adults. Apart from differences in free versus albumin-bound salicylate in various disease states and physiological conditions associated with low serum albumin, pharmacokinetic parameters in patients with rheumatoid arthritis, osteoarthritis, chronic renal failure or liver disease are essentially the same.(ABSTRACT TRUNCATED AT 400 WORDS)


Eomesodermin is a localized maternal determinant required for endoderm induction in zebrafish.
In zebrafish, endoderm induction occurs in marginal blastomeres and requires Casanova (Cas), the first endoderm-specific factor expressed in the embryo. Whereas the transcription factors Gata5 and Bon are necessary and sufficient for cas expression in marginal blastomeres, Bon and Gata5 are unable to induce cas in animal pole cells, suggesting that cas expression requires an additional, unidentified factor(s). Here, we show that cas expression depends upon the T box transcription factor Eomesodermin (Eomes), a maternal determinant that is localized to marginal blastomeres. Eomes synergizes potently with Bon and Gata5 to induce cas, even in animal pole blastomeres. We show that Eomes is required for endogenous endoderm induction, acting via an essential binding site in the cas promoter. Direct physical interactions between Eomes, Bon, and Gata5 suggest that Eomes promotes endoderm induction in marginal blastomeres by facilitating the assembly of a transcriptional activating complex on the cas promoter.


Varicella zoster antibodies in healthcare workers from two neonatal units in São Paulo, Brazil--assessment of a staff varicella policy.
Although frequently reported in the literature, a staff varicella policy is not standard in many hospitals even in developed countries. In the present study, we assessed varicella zoster immunity in staff from two neonatal units from hospitals in São Paulo, Brazil. Ninety-seven percent of all staff working in both units agreed to participate. A simple and cost-effective varicella policy was subsequently set up, based on costs and data from serology and a history of previous varicella infection. Our results confirm that a varicella vaccination programme can be implemented in a healthcare facility, even in developing countries.


Sulfate radical-based removal of chloride ion from strongly acidic wastewater: Kinetics and mechanism.
Specific to strongly acidic wastewater, the traditional lime neutralization produces massive hazardous waste and present serious environmental risks. Thus, the recycling of purified wastewater after the contained contaminants being removed has been proposed. However, among these contaminants, chloride ion (Cl(-I)) is rather difficult to remove. This study proposes a new method to remove Cl(-I) using thermal activated persulfate (PS). Under optimized conditions, above 96% of initial Cl(-I) was removed from the actual wastewater, and the residual Cl(-I) was below 158 mg/L, which satisfies the requirement of Cl(-I) concentration for wastewater recycling. Furthermore, the mechanism was investigated. In the strongly acidic wastewater, the high concentration of H+ prompted the thermal activation process of PS through two pathways. (1) H+ prompted the transformation of S2O82- into HSO4- and SO4, and then into HSO5- that was finally transformed into ·OH and ·SO4- at above 70 ℃. (2) H+ prompted the production of ·OH through the transformation of ·SO4- into ·HSO4 and the cleavage of ·HSO4. The key step for Cl(-I) removal was identified as the formation of ·Cl or ·Cl2- from the oxidation of Cl(-I) by ·SO4- and ·OH, and their contribution ratios were estimated to be 67.4% and 32.6%, respectively.


Psychiatrists in community mental health centers.
A study of 20 community memtal health centers indicates that of all staff, psychiatrists are least identified with the ideology of community mental health.


A method for recovering a lost retrieval line under direct vision in children with esophageal strictures.
Loss of a retrieval line for repeated esophageal dilations for caustic esophageal stricture may result in inability to dilate these strictures. We describe a simple means for retrieving such a line once it has been removed.


Timely Care is Patient-Centered Care for Patients with Acute Cholecystitis at a Safety-Net Hospital.
Multiple strategies exist to improve the timeliness and efficiency of surgical care at safety-net hospitals (SNH), such as acute care surgery models and nighttime surgery. However, the patient-centeredness of such approaches is unknown. Adults ( ≥18 years) with acute cholecystitis were interviewed upon admission to a SNH. Interviews were semi-structured and designed to obtain both exploratory qualitative data and ratings of patient-centered outcomes, ranked by importance to the patient. Outcomes included for rating were general health, symptom status, quality of life, and return to prior functional status. Latent content analysis applying inductive coding methods were used to code and condense raw qualitative data from interview transcripts. Thematic saturation was reached with a sample size of 15 patients. Most participants were female (87%), Hispanic (87%), and had prior diagnosis of benign biliary disease (60%). Patients identified symptom resolution as the highest-ranked outcome in their treatment. Themes expressed by patients during the exploratory segments of the interview included: desire for pain alleviation, frustration with delays to both symptom resolution and surgical intervention, lack of perceived control over their health care, and reticence in discussing preferences with physicians. All patients preferred to have surgical treatment as soon as possible, even if that meant having nighttime surgery. Effective and timely resolution of symptoms is of utmost importance to patients with acute cholecystitis at a SNH. Efforts to improve timeliness of surgical care are also perceived as patient-centered.


Endophthalmitis after cataract surgery: risk factors relating to technique and events of the operation and patient history: a retrospective case-control study.
This study aimed to investigate the relationship between postoperative endophthalmitis and current changes in the cataract operative technique. A retrospective case-control study. The 22,091 cataract operations performed from 1990 through 1993 at St Eriks Hospital formed the basis for this investigation. In a random fashion, 220 control subjects were selected to be compared with the endophthalmitis cases. Numerous variables pertaining to the cataract extraction procedure and to the ocular and general health of patients with cataracts were analyzed regarding the development of postoperative intraocular infection. Patient age, presence of diabetes or immunosuppression, type of cataract extraction and intraocular lens (IOL), and intraoperative or postoperative complications were the principal variables assessed. Fifty-seven patients with endophthalmitis were diagnosed, resulting in an overall frequency of 0.26%. Immunosuppressive treatment (P = 0.019), wound abnormality (P = 0.03), and the use of IOLs without a heparinized surface (P = 0.0023) were the only significant risk factors found in a logistic regression model. The results suggest that cataract operating practice may alter the risk for endophthalmitis in that implanting a heparinized IOL and creating a tight section both seem to provide protection against this dreaded complication. Regarding patient history, an increased susceptibility was found among subjects treated with immunosuppressants. Designing a prophylactic protocol that protects against endophthalmitis more efficiently than did the study prophylaxis of 20 mg of subconjunctival gentamicin, is important not only for this patient subgroup but also for the cataract operated population at large.


Burns in school-age children: demographics and burn prevention.
Epidemiologic and demographic study of burn center patients and admission patterns can be useful in tailoring burn prevention programs. Such studies can pinpoint specific high-risk areas and seasons, thus allowing more efficient expenditure of resources.


Radioimaging of human ovarian carcinoma xenograft in nude mice.
Human ovarian carcinomas in nude mice were radioimaged using a well-characterized antibody against a tumor-associated antigen (CA 125) and three transplantable human ovarian carcinoma tumor lines: NIH:OVCAR 3, NIH:OVCAR 5, and NIH:OVCAR 9. Radioiodinated monoclonal antibody OC125 was used in these studies. In order to establish the optimal conditions for imaging, tumor/blood ratios were determined. Gamma scintigraphy of nude mice bearing subcutaneous transplants of human ovarian carcinomas 3-4 days after 131I-OC125 administration demonstrated selective localization of the radiolabeled monoclonal antibody by these tumors without need for any background subtraction techniques.


Diversification rates and chromosome evolution in the most diverse angiosperm genus of the temperate zone (Carex, Cyperaceae).
The sedge family (Cyperaceae: Poales; ca. 5600 spp.) is a hyperdiverse cosmopolitan group with centres of species diversity in Africa, Australia, eastern Asia, North America, and the Neotropics. Carex, with ca. 40% of the species in the family, is one of the most species-rich angiosperm genera and the most diverse in temperate regions of the Northern Hemisphere, making it atypical among plants in that it inverts the latitudinal gradient of species richness. Moreover, Carex exhibits high rates of chromosome rearrangement via fission, fusion, and translocation, which distinguishes it from the rest of the Cyperaceae. Here, we use a phylogenetic framework to examine how the onset of contemporary temperate climates and the processes of chromosome evolution have influenced the diversification dynamics of Carex. We provide estimates of diversification rates and map chromosome transitions across the evolutionary history of the main four clades of Carex. We demonstrate that Carex underwent a shift in diversification rates sometime between the Late Eocene and the Oligocene, during a global cooling period, which fits with a transition in diploid chromosome number. We suggest that adaptive radiation to novel temperate climates, aided by a shift in the mode of chromosome evolution, may explain the large-scale radiation of Carex and its latitudinal pattern of species richness.


Validation of an autotaxin enzyme immunoassay in human serum samples and its application to hypoalbuminemia differentiation.
Autotaxin (ATX), a tumor cell motility-stimulating factor, regulates the blood concentrations of lysophosphatidic acid (LPA), an important and multi-functional bioactive lipid, through its lysophospholipase D activity (lysoPLD). The introduction of ATX measurements into clinical laboratory testing is urgently needed. Anti-human ATX monoclonal antibodies were produced by immunization of recombinant human ATX expressed in a baculovirus system. An immunoassay for the quantitative determination of ATX was established, and human serum samples were assayed. The within-run and between-run precision, interference, detection limit, and linearity studies were satisfactory. The central 95 percentile reference interval for the serum ATX antigen concentration in healthy subjects was 0.468-1.134 mg/l (n=120) and was strongly correlated with the serum lysoPLD activity. The ATX concentration was significantly (p<0.001) higher in women (0.625-1.323 mg/l) than in men (0.438-0.914 mg/l). The serum ATX concentrations were increased in patients with chronic liver diseases and decreased in postoperative prostate cancer patients but were not altered in nephrosis patients. Thus, serum ATX antigen concentrations could be used to discriminate these hypoalbuminemia conditions. The present ATX antigen assay may be useful for clinical laboratory testing.


Maximum likelihood estimators for scaled mutation rates in an equilibrium mutation-drift model.
The stationary sampling distribution of a neutral decoupled Moran or Wright-Fisher diffusion with neutral mutations is known to first order for a general rate matrix with small but otherwise unconstrained mutation rates. Using this distribution as a starting point we derive results for maximum likelihood estimates of scaled mutation rates from site frequency data under three model assumptions: a twelve-parameter general rate matrix, a nine-parameter reversible rate matrix, and a six-parameter strand-symmetric rate matrix. The site frequency spectrum is assumed to be sampled from a fixed size population in equilibrium, and to consist of allele frequency data at a large number of unlinked sites evolving with a common mutation rate matrix without selective bias. We correct an error in a previous treatment of the same problem (Burden and Tang, 2017) affecting the estimators for the general and strand-symmetric rate matrices. The method is applied to a biological dataset consisting of a site frequency spectrum extracted from short autosomal introns in a sample of Drosophila melanogaster individuals.


Thoracic CT-scanning follow-up of residual mediastinal masses after treatment of Hodgkin's disease.
Sequential thoracic CT-scanning was performed for 14 patients presenting with residual mediastinal masses on chest X-ray after treatment of stage I and II Hodgkin's disease (HD). Eleven patients initially presented with bulky mediastinal involvement. No mediastinal biopsy was performed. No local recurrence was detected at a 48 month median follow-up. Early evaluation by CT-scanning showed cystic degeneration in three cases. Sequential CT-scans on longer follow-up demonstrated continuous regression of residual masses in six cases and no or limited volume reduction in six other cases. In two patients, part of the residual mass remained stable and the other part showed reduction in size. In addition, late calcifications developed in four cases. The results of sequential CT-scanning suggest that residual mediastinal masses do not generally represent active disease. Hence additional, potentially toxic, therapy can be avoided.


The effects of noise levels on nurses in intensive care units.
Intensive care units (ICUs) are noisy environments, which may have negative psychological effects on nurses. To investigate the effects of the noise level of ICUs on nurses' burnout, job satisfaction, anxiety, psychological symptoms and general psychopathology level. A descriptive and correlational study. The study was conducted with 150 intensive care nurses. A Type 2250-L Brüel & Kjaer hand-held sound level meter was used for noise measurement. A Nurse Information Form, the Maslach Burnout Inventory, Minnesora Satisfaction Questionnaire, Self-Report Inventory and Symptom Checklist-90 Revised were used for data collection. The highest levels of noise (71 dB(A) and above) were measured in the neonatal, neurology and cardiovascular surgery ICUs. It was observed that noise level affected extrinsic satisfaction (F = 3·704; p = 0·027) and trait anxiety (F = 3·868; p = 0·023) of nurses. Noise levels in ICUs are well above the recommended levels, and this affects nurses' job satisfaction and anxiety levels. More studies on the effects of noise levels on the physical and mental states of nurses working in ICUs are needed. Increased quality of patient care can be achieved by providing healthy working conditions for nurses working in special units such as ICUs.


Systematic considerations for a multicomponent pharmacokinetic study of Epimedii wushanensis herba: From method establishment to pharmacokinetic marker selection.
Prenylflavonoids are major active components of Epimedii wushanensis herba (EWH). The global pharmacokinetics of prenylflavonoids are unclear, as these compounds yield multiple, often unidentified metabolites. This study successfully elucidated the pharmacokinetic profiles of EWH extract and five EWH-derived prenylflavonoid monomers in rats. The study was a comprehensive analysis of metabolic pathways and pharmacokinetic markers. Major plasma compounds identified after oral administration of EWH-derived prototypes or extract included: (1) prenylflavonoid prototypes, (2) deglycosylated products, and (3) glucuronide conjugates. To select appropriate EWH-derived pharmacokinetic markers, a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was established to simultaneously monitor 14 major compounds in unhydrolyzed plasma and 10 potential pharmacokinetic markers in hydrolyzed plasma. The pharmacokinetic profiles indicated that the glucuronide conjugates of icaritin were the principle circulating metabolites and that total icaritin accounted for ∼99% of prenylflavonoid exposure after administration of EWH-derived materials to rats. To further investigate icaritin as a prospective pharmacokinetic marker, correlation analysis was performed between total icaritin and its glucuronide conjugates, and a strong correlation (r > 0.5) was found, indicating that total icaritin content accurately reflected changes in the exposure levels of the glucuronide conjugates over time. Therefore, icaritin is a sufficient pharmacokinetic marker for evaluating dynamic prenylflavonoid exposure levels. Next, a mathematical model was developed based on the prenylflavonoid content of EWH and the exposure levels in rats, using icaritin as the pharmacokinetic marker. This model accurately predicted exposure levels in vivo, with similar predicted vs. experimental area under the curve (AUC)(0-96 h) values for total icaritin (24.1 vs. 32.0 mg/L h). Icaritin in hydrolyzed plasma can be used as a pharmacokinetic marker to reflect prenylflavonoid exposure levels, as well as the changes over time of its glucuronide conjugates.


Screening for Comorbid Cardiovascular Risk Factors in Pediatric Psoriasis Among Iraqi Patients: A Case-Control Study.
Psoriasis is a polygenic multifactorial immune-mediated skin disease associated with comorbidities. As one-third of adult psoriasis starts during childhood, early detection of these comorbidities might help to mitigate their impact on future health. To investigate the risk for cardiovascular events and their relationship with psoriasis severity among Iraqi children and adolescents. A prospective, case-control, cross-sectional study on 150 patients with psoriasis and 150 age and sex-matched individuals. The study was carried out at the Department of Dermatology/Basra Teaching Hospital from December 2018 to December 2020. Psoriasis severity was assessed by PASI (psoriasis area severity index) score, and in both groups, blood pressure and body mass index (BMI) were measured. Laboratory tests including fasting blood sugar (FBS) and lipid profile were also done. More patients were overweight and obese in the psoriatic group compared to the control group (26.7% and 40% versus 11% and 8%), 5.3% of psoriatic patients who had stage 2 hypertension (defined as any blood pressure [BP] measurement higher than 99th plus 5 mm of mercury applied to BP levels for boys and girls by age and height percentile charts), none of the control group was hypertensive, and the difference was statistically significant (p-value<0.05). A significantly higher proportion of the psoriatic patients had abnormal lipid profiles compared with the control group, 62% versus 30% (p<0.05), 15.3% versus 6.7% had elevated cholesterol (p<0.05), 24.7% versus 8% had raised low-density lipoprotein (LDL, p<0.05), 18% versus 8.6% had low high-density lipoprotein (HDL, p<0.05), and 12.6% versus 6% had elevated very-low-density lipoprotein (VLDL) and triglyceride (TG, p<0.05), 8% patients had elevated FBS (more than 100 mg per deciliter) versus 2.6% (p<0.05), and metabolic syndrome in 65 versus 2% (p<0.05). These changes were related to the severity of psoriasis. Pediatric psoriatic patients in our population may have an atherogenic lipid profile with an increased prevalence of risk factors for cardiovascular diseases, especially those with moderate to severe psoriasis.


Enhanced efficacy in anti-tumour activity by combined therapy of recombinant FGFR-1 related angiogenesis and low-dose cytotoxic agent.
Fibroblast growth factor receptor-1 (FGFR-1) has been used as a target for anti-angiogeneic therapy of cancer. The strategies of combining anti-angiogenic biotherapy with chemotherapeutic drugs show potential and promise for cancer therapy. In this study, we evaluated the anti-tumour efficacy of chicken FGFR-1 (cFR-1) vaccine combined with low-dose gemcitabine in two mice tumour models. We found that both the cFR-1 vaccine and low-dose gemcitabine can suppress tumour growth to some extent. Remarkably, the combination strategy produces an apparent decrease in tumour volume, microvessel density and tumour cell proliferation, and an increase of apoptosis without obvious side-effects compared with either therapy alone. Moreover, the combination strategy also demonstrated synergistic indices against tumour growth and angiogenesis. Furthermore, auto-antibodies against mouse FGFR-1 were identified. These findings support the idea that the combination strategy synergistically strengthens anti-tumour activity via suppression of tumour angiogenesis without overt toxicity in tumour-bearing mice.


Vocal expression of emotional arousal across two call types in young rhesus macaques.
As Darwin first recognized, the study of emotional communication has the potential to improve scientific understanding of the mechanisms of signal production as well as how signals evolve. We examined the relationships between emotional arousal and selected acoustic characteristics of coo and scream vocalizations produced by female rhesus macaques, Macaca mulatta, during development. For coos, arousal was assessed through measures of stress-induced elevations of plasma cortisol exhibited in response to the human intruder test. In the analysis of screams, arousal was evaluated from the intensity of aggression experienced by the vocalizer during natural social interactions. Both call types showed a positive relationship between arousal and overall fundamental frequency (F0, perceived as pitch in humans). In coos, this association was dampened over development from infancy (6 months) to the juvenile, prepubertal period (16 months) and further to menarche (21.3-31.3 months), perhaps reflecting developmental changes in physiology, anatomy and/or call function. Heightened arousal was also associated in coos with increases in an acoustic dimension related to F0 modulation and noisiness. As monkeys matured, coos showed decreases in overall F0 as well as increased noisiness and F0 modulation, likely reflecting growth of the vocal apparatus and changes in vocal fold oscillation. Within screams, only one acoustic dimension (related to F0 modulation) showed developmental change, and only within one subclass of screams within one behavioural context. Our results regarding the acoustic correlates of arousal in both call types are broadly consistent with findings in other species, supporting the hypothesis of evolutionary continuity in emotion expression. We discuss implications for broader theories of how vocal acoustics respond to selection pressures.


Diffraction quality crystals of lysin from spermatozoa of the red abalone (Haliotis rufescens).
Single crystals of the protein lysin (Mr = 16,070) from the spermatozoa of the red abalone (Haliotis rufescens) have been obtained by the vapor diffusion technique, using as precipitants a 32.5% saturated solution of (NH4)2SO4 (incubation at 18 degrees C) or a 5% w/v polyethyleneglycol 8000 solution (incubation at 29 degrees C), both in Bis-Tris-iminodiacetic acid buffers of pH 7.0. The addition to the droplets of EDTA, other carboxylate-containing polyanions, and/or organic solvents improved the size and quality of the crystals and, especially with (NH4)2SO4, addition of EDTA, and/or organic solvents produced a change in crystal habit which resulted in crystals more elongated in the b direction. The crystals belong to the orthorhombic space group P2(1)2(1)2(1) with a = 52.3 A, b = 46.0 A, and c = 81.5 A and one molecule per asymmetric unit. The crystals diffract to 2.3 A resolution. The molecular structure of lysin is relevant to the nonenzymatic mechanism by which the protein dissolves a hole in the egg vitelline layer during fertilization.


[Cost-analysis of treating patients with multiple injuries in a reference hospital in Spain].
The aim of this study is to analyse the costs of the treatment of a group of patients with severe injuries. The distribution of the costs between the different departments involved in the management of these patients is also investigated. The data from patients who suffered severe injuries, and recorded in the Traumasur data base, were prospectively gathered to be used in the study. The data from a total of 131 patients treated in the year 2008 were collected. Data obtained from the hospital finance office were also used, providing the overall cost as well as the separate costs of each of the departments involved in the treatment. The injury severity score (ISS) and the new injury severity score (NISS) mean values were 31.8 and 39.4, respectively. The mortality rate was 17.5%. The overall costs of the patients was 3,791,879.3 €, with a mean cost per patient of 28,945 €. The mean percentage of the overall costs of the treatment incurred by the ICU and the ward was 62% and 12.7%, respectively. The cost of the ICU admission increased up to 68.4% in patients with an ISS>40. Although the patients who died had more serious injuries, they had a lower cost in all areas. Patients with multiple injuries represent a significant health cost, with the greater percentage being due to the hospital stay, particularly that in ICU. Other cost areas involve a lower percentage of the cost.


The host response in secondary hydatidosis of mice. II. Cell mediated immunity.
The presence of cell mediated immunity to Echinococcus granulosus antigen was detected in syngeneic mice with secondary hydatidosis. Significant increases of thymidine uptake were observed in spleen cells from infected animals exposed to protoscolex or hydatid fluid antigens. A definite decrease in the number and size of cysts occurred in mice following the simultaneous intraperitoneal injection of viable protoscolices and a suspension of 1 x 10(7) sensitized spleen cells.