Clinical implications for pro-GRP in small cell lung cancer. A single center experience.
Recently, pro-gastrin-releasing peptide (pro-GRP) became available as an alternative sensitive, specific and reliable tumor marker for patients with small cell lung cancer (SCLC), both in limited (LD) and diffuse disease (DD). We retrospectively analyzed pro-GRP, neuron-specific enolase (NSE) and CEA in patients with SCLC and non-small cell lung cancer (NSCLC). Serum pro-GRP level was measured with electrochemiluminescence at our laboratory (cutoff 77.8 pg/mL). Continuous variables were analyzed with the Mann-Whitney test, contingency data with Fisher's exact test. Receiver operator characteristic (ROC) curve analysis was performed to identify threshold values to set the highest sensitivity (Sn) and specificity (Sp) values. A total of 65 patients were studied (49 men, median age 67 years, range 27-79). Thirty-seven patients had SCLC (29 DD, 8 LD) and 28 advanced NSCLC. Median pro-GRP level was 919 pg/mL (range 22-147,350) in SCLC and 32 pg/mL (range 10-119.2) in NSCLC (p<0.0001). NSE was 4.38-fold higher in SCLC patients (p = 0.0005); CEA did not reveal significant differences between groups. Pro-GRP Sn and Sp were 86.4% and 96.4%, respectively. With ROC curve analysis, a cutoff value of 329.3 pg/mL showed a Sn of 75.8% and Sp of 87.5% in discriminating DD from LD. Pro-GRP was not influenced by either liver metastases or renal impairment. Pro-GRP is sensitive for SCLC diagnosis. Since high marker levels are related to high disease burden, pro-GRP may have a negative prognostic significance. Follow-up studies are required to define its role in clinical practice in monitoring responses to treatment and early relapses.


Eating behavior and thyroid disease in female obese patients.
It has been suggested that preexisting thyroid disease (TD) could be a risk factor for the development of eating disorders. The aim of this study was to compare eating attitudes and behavior in female obese patients with and without TD. Thyrotropin (TSH) was determined in 256 patients aged 44.9+/-14.7 years with body mass index (BMI) >30 kg/m(2); eating attitudes and behavior were assessed with the Eating Disorder Examination (EDE). EDE Shape Concern score was significantly higher in patients with previous or current hypothyroidism (N=30) than in the rest of the sample. Among patients without known TD, no difference in eating attitudes was observed between patients with elevated TSH (N=24; 11%) and those with normal thyroid function. The prevalence of binge eating disorder (BED) in the total sample was 9.7%; no difference in prevalence was observed between patients with and without a history of hypothyroidism, and between those with and without previously unknown hypothyroidism. In conclusion, known hypothyroidism is associated with increased shape concern; this does not appear to be related to differences in current levels of thyroid hormones or related hormones.


Comparison of the cytotoxicity of the MEIC reference chemicals measured in protein free and in complete culture medium.
In order to investigate if a protein free cytotoxicity assay could improve the prediction of human acute toxicity, the cytotoxicity of 40 MEIC reference chemicals was measured by the neutral red uptake inhibition after 24h in protein free culture medium on rat hepatoma-derived Fa32 cells. The results were compared with the corresponding values obtained in complete culture medium, including 10% fetal calf serum. Potassium cyanide, arsenic trioxide, mercuric chloride, hexachlorophene and pentachlorophenol were much more cytotoxic in PF medium, as was the case to a lower extent for 16 other chemicals. The cytotoxicity of 8 chemicals was only changed to a limited extent when tested in PF medium, suggesting that serum proteins do not strongly interact with their cytotoxicity. Eleven other chemicals were less cytotoxic in PF medium, maybe because of too poor physiological conditions. Although a large number of differences in cytotoxicity were observed in function of the medium used for the assay, a good correlation was observed between both series of data (r(2)=0.946). The correlation between the cytotoxicity in PF medium and the human acute toxicity is lower (r(2)=0.647) than that in complete medium (r(2)=0.746). The results show that further research is necessary in order to improve the in vitro/in vivo correlations by introducing protein-dependent considerations.


Integration of IgG and IgA autoantibodies for early diagnosis of hepatocellular carcinoma.
Autoantibodes against tumor-associated antigens (TAAs) have been recommended for the early diagnosis of malignancies. In this study, we intend to comprehensively evaluate the performances of four autoantibodies including anti-p53, CTAG1A, TIF1γ-IgG and anti-TIF1γ-IgA for the early diagnosis of hepatocellular carcinoma (HCC), and then determine an optimal panel of autoantibodies for early HCC diagnosis. The performances of four autoantibodies were evaluated by enzyme-linked immunosorbent assay (ELISA) for the early diagnosis of HCC with 380 retrospective serum samples. A training set comprised of 92 patients with early HCC, 72 patients with hepatic benign lesions (HBL), and 86 healthy controls (HC) was used to develop the predictive model for early HCC. And then, data obtained from an independent validation set was applied to evaluate and validate the predictive model to distinguish the early HCC from the controls (HBL + HC). The results of the training set showed the levels and positive rates of four autoantibodies in early HCC group were significantly higher than that in HBL group/HC group (P < 0.01), of which anti-p53-IgG exhibited the highest AUC of 0.679, with 33.7% sensitivity at 93.7% specificity; the panel comprised of four autoantibodies showed the highest AUC for the patients with early HCC, up to 0.814 (95%CI 0.760-0.860), with 72.8% sensitivity at 84.2% specificity among all possible combinations of four autoantibodies. Additionally, this four-autoantibody panel showed the AUC of 0.824, 70.8% sensitivity at 84.2% specificity in the validation set. Serum IgG autoantibodies against p53, CTAG1A and TIF1γ, and IgA autoantibody against TIF1γ present the diagnostic value for early HCC, of which anti-p53-IgG is a preferable biomarker. The panel comprised of four autoantibodies might contribute to early HCC diagnosis.


Triptolide nanoemulsion gel as a transdermal drug delivery system: preparation, pharmacokinetics, and rheumatoid arthritis evaluation.
This study aimed to develop and evaluate triptolide nanoemulsion gels (TP-NE gels) as a transdermal drug delivery system. TP-NE was prepared and optimized via emulsification and the central composite design response surface method. The optimized TP-NE gel was evaluated in vitro and in vivo. TP-NE gel microstructure, in vitro and in vivo pharmacokinetics, and anti-rheumatoid arthritis effects were studied to evaluate the feasibility of its percutaneous administration. The Optimized TP-NE was observed using a Malvern Autosizer Nano ZS 90 inspection system and a transmission electron microscope (TEM). The nanoemulsion had an average size of 162.9 ± 0.281 nm, a polydispersity index of 0.272 ± 0.024, a zeta potential of -30.03 ± 2.01 mV, and mostly spherical and uniform morphology. In addition, the TP-NE gel pharmacokinetics, assessed via a skin-blood two-site synchronous microdialysis, revealed that TP was higher in the skin than in the blood. TP-NE gel is crucial in reducing knee edema, inhibiting inflammation, and treating rheumatoid arthritis by regulating tumor necrosis factor-alpha, interleukin-1β, and -6 levels. The TP-NE gel is a promising local delivery method for rheumatoid arthritis (RA)-associated edema and inflammation and can serve as a prospective platform for percutaneous TP administration.


Recurrent divergence-insufficiency esotropia in Machado-Joseph disease (spinocerebellar ataxia type 3).
To describe a case of incomitant divergence insufficiency esotropia in the setting of Machado-Joseph disease (spinocerebellar ataxia type 3) that recurred completely within one week after augmented bilateral medial rectus recession. A 53-year-old female with a history of Machado-Joseph disease presented with horizontal diplopia primarily at distance consistent with divergence insufficiency esotropia. Augmented bilateral medial rectus recessions were performed which initially produced orthotropia, but recurrence of the esodeviation to the full preoperative amount occurred by post-operative week one. The patient subsequently underwent bilateral lateral rectus resections with excellent result. Divergence insufficiency is common in the spinocerebellar ataxia variants and is thought to be secondary to atrophy of brainstem structures involved in the control of ocular vergence. Strabismus surgery in these patients may be complicated by limited response or even rapid regression despite augmented surgery as suggested for divergence insufficiency in the setting of neurologic disease. Patients should be counseled on these risks as well as the potential for multiple procedures in order to achieve surgical success.


Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes.
Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS, but also distinguish RA FLS isolated from knees and hips. Using genome-wide methods, we show differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as IL-6 signalling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee and hip FLS using RNA-sequencing. Double-evidenced genes that are both differentially methylated and expressed include multiple HOX genes. Joint-specific DNA signatures suggest that RA disease mechanisms might vary from joint to joint, thus potentially explaining some of the diversity of drug responses in RA patients.


Quantification of cyanuric acid residue in human urine using high performance liquid chromatography-tandem mass spectrometry.
Concern has increased about the resulting health effects of exposure to melamine and its metabolic contaminant, cyanuric acid, after infants in China were fed baby formula milk products contaminated with these compounds. We have developed a selective and sensitive analytical method to quantify the amount of cyanuric acid in human urine. The sample preparation involved extracting free-form cyanuric acid in human urine using anion exchange solid phase extraction. Cyanuric acid was separated from its urinary matrix components on the polymeric strong anion exchange analytical column; the analysis was performed by high performance liquid chromatography-tandem mass spectrometry using negative mode electrospray ionization interface. Quantification was performed using isotope dilution calibration covering the concentration range of 1.00-200ng/mL. The limit of detection was 0.60ng/mL and the relative standard deviations were 2.8-10.5% across the calibration range. The relative recovery of cyanuric acid was 100-104%. Our method is suitable to detect urinary concentrations of cyanuric acid caused by either environmental exposures or emerging poisoning events.


[Automating the solid phase extraction for the determination of ochratoxin A].
For some foodstuffs, determination of the mycotoxin ochratoxin A (OTA) requires time consuming clean up by means of solid phase extraction (SPE). Therefore a system for automated SPE was tested for cleaning up roasted coffee as a possible way of shortening preparation time. Validation of the method in accordance to the so called "Concept '98" led to a LOD of 0.2 μg/kg and a recovery rate of 92%. By using the described procedure with samples of roasted coffee the OTA contents varied between the LOD and 3.4 μg/kg. This method was also used to determine ochratoxin A in liquorice roots, ginger and valerian.


Fractional-order modeling of lithium-ion batteries using additive noise assisted modeling and correlative information criterion.
In this paper, the fractional-order modeling of multiple groups of lithium-ion batteries with different states is discussed referring to electrochemical impedance spectroscopy (EIS) analysis and iterative learning identification method. The structure and parameters of the presented fractional-order equivalent circuit model (FO-ECM) are determined by EIS from electrochemical test. Based on the working condition test, a P-type iterative learning algorithm is applied to optimize certain selected model parameters in FO-ECM affected by polarization effect. What's more, considering the reliability of structure and adaptiveness of parameters in FO-ECM, a pre-tested nondestructive 1 / f noise is superimposed to the input current, and the correlative information criterion (CIC) is proposed by means of multiple correlations of each parameter and confidence eigen-voltages from weighted co-expression network analysis method. The tested batteries with different state of health (SOH) can be successfully simulated by FO-ECM with rarely need of calibration when excluding polarization effect. Particularly, the small value of CIC α indicates that the fractional-order α is constant over time for the purpose of SOH estimation. Meanwhile, the time-varying ohmic resistance R 0 in FO-ECM can be regarded as a wind vane of SOH due to the large value of CIC R 0 . The above analytically found parameter-state relations are highly consistent with the existing literature and empirical conclusions, which indicates the broad application prospects of this paper.


Airbag induced corneal ectasia.
To report a case of airbag induced corneal ectasia. Case report. A patient 3 years post-LASIK developed bilateral corneal ectasia worse in the right eye following airbag deployment in a road traffic accident. At last follow up, best corrected vision was 20/40 with -4.00/-4.00 x 25 in the right eye and 20/25 with -1.25/-0.50 x 135 in the left eye. This is a rare presentation of trauma induced ectasia in a patient post-LASIK. It is possible that reduction in biomechanical integrity of the cornea from prior refractive surgery contributed to this presentation.


Disparities in access for melanoma screening by region, specialty, and insurance: A cross-sectional audit study.
Early detection of melanoma is critical for positive outcomes. However, access for the diagnosis of melanoma remains problematic for segments of the general population. To compare the rates of dermatology and family medicine practitioner acceptances for a public insurance (Medicaid) versus private insurance (Anthem Blue Cross) and clinic wait times for an appointment for a changing pigmented skin lesion concerning melanoma in rural and urban regions in California. Cross-sectional audit study between June 2017 and March 2019; scripted phone calls were made to dermatology and family medicine practices (FMPs). Family medicine and dermatology practices in both regions had significantly decreased acceptance of Medicaid. Dermatology practices had 11.3% to 13.0% Medicaid acceptance rates that were less than FMP rates of 28% to 36%. In both regions, FMP wait times were 2.4- to 3.2-fold longer for public versus private insurance; there were little differences in wait times for the 2 insurance types in dermatology practices, in both regions. Assessment of only 2 regions in the state of California. Delays at FMPs and insurance types limit access to melanoma screening in California for underserved segments of the general population, which has implications for melanoma outcomes and health policy.


Topographic mapping of the EEG: an examination of accuracy and precision.
The accuracy and precision of topographic maps depicting scalp potentials and scalp potentials squared have been examined. Electrode placement was that specified by the International 10-20 System and the methods of interpolation bilinear and bicubic spines. The results indicate that, for these interpolation methods, the maximum error expected between the measured scalp quantities and those predicted by interpolation is positively correlated to the root-mean-square value of the measured quantity. Both interpolation methods produce accurate estimates of the interelectrode quantities. Both methods produce precise estimates of the scalp potential in the delta, theta and alpha frequency bands but only poor estimates in the beta band. The precision of the estimates of the scalp potentials squared is poor in all frequency bands. This result indicates that another look at the now common practice of topographically mapping the power-spectral components of the EEG is in order. In general, the bilinear and bicubic spline methods of interpolation perform about equally. This result is used to suggest that because of its additional computational complexity, use of the bicubic method for potential mapping may not be warranted. Advantages of the bicubic method, particularly in radial-current mapping, are however discussed.


Taxing sugar-sweetened beverages: the fight against obesity.
Increased consumption of sugar-sweetened beverages has been identified as a key contributor in the obesity epidemic. Taxing these beverages is currently a hot topic for healthcare providers, manufacturers, and legislators. Whether a tax will help trim American waist lines remains questionable.


Determinants of caregivers' awareness of Universal Newborn Hearing Screening in Malaysia.
This paper aims to investigate the effects of perceived attitude and anxiety on awareness of UNHS among caregivers in Malaysia. Using cross sectional research approach, data were collected and some 46 out of 87 questionnaires distributed to caregivers attending UNHS programs at selected public hospitals were usable for analysis (response rate of 52.8%). Partial Least Squares Method (PLS) algorithm and bootstrapping technique were employed to test the hypotheses of the study. R square value is 0.205, and it implies that exogenous latent variables explained 21% of the variance of the endogenous latent variable. This value indicates moderate and acceptable level of R-squared values. Findings from PLS structural model evaluation revealed that anxiety has no significant influence (β = -0.091, t = 0.753, p > 0.10) on caregivers' awareness; but perceived attitude has significant effect (β = -0.444, t = 3.434, p < 0.01) on caregivers' awareness. Caregivers' awareness of UNHS is influenced by their perceived attitude while anxiety is not associated with caregivers' awareness. This implies that caregivers may not believe in early detection of hearing impairment in children, thinking that their babies are too young to be tested for hearing loss. Moreover, socio-economic situation of the caregivers may have contributed to their failure to honor UNHS screening appointments as some of them may need to work to earn a living while some may perceive it a waste of time honoring such appointments. Non-significant relationship between anxiety and caregivers' awareness may be due to religious beliefs of caregivers. Limitations and suggestions were discussed.


Radiation gonad doses received by children in intravenous urography and micturition cysto-urethrography.
Measurements of gonad doses in intravenous urography (IVU) was performed on 47 children and in micturition cysto-urethrography (MCU) on 57 children. Ionization chamber dosimeters were placed rectally in girls and fixed on the scrotum in boys. Gonad dose ranged from 27 mrad to 201 mrad in girls and from 7 mrad to 112 mrad in boys during IVU; during MCU doses ranged from 53 mrad to 1900 mrad in girls and form 24 mrad to 309 mrad in boys. Risk of leukemia and genetic risk were calculated.


Aesthetic considerations in the reconstruction of the anophthalmic orbit.
Twenty-four patients with severe anophthalmic orbit syndrome were treated with a combination of techniques utilizing autogenous tissue. Autogenous corticocancellous bone grafts were used in the orbit as a volume filler. The temporalis muscle and a fasciae flap with a pericranial flap were used as a curtain to cover the bone grafts and to give a softening effect. The prosthesis used was a regular eye shell. With this method it can be smaller, thinner, and lighter to produce less deformation of the lower lid, particularly when used for a long period of time. In children who have this deformity compounded by small orbits after oncologic treatment, three-wall orbital enlargement is done to achieve a larger orbit, so as to match the normal unaffected socket and produce symmetry.


Suction-Cup-Inspired Adhesive Micromotors for Drug Delivery.
Micromotors have opened novel avenues for drug delivery due to their capacity for self-propelling. Attempts in this field trend towards ameliorating their functions to promote their clinical applications. In this paper, an ingenious suction-cup-inspired micromotor is presented with adhesive properties for drug delivery in the stomach. The micromotors are fabricated by using hydrogel replicating the structure of suction-cup-like microparticles, which derive from self-assembly of colloidal crystals under rapid solvent extraction, followed by loading magnesium (Mg) in the bottom spherical surface. The Mg-loaded micromotors can realize spontaneous movement due to the continual generation of hydrogen bubbles in gastric juice. The combination of unique suction-cup-like structure with excellent motion performance makes the micromotor an ideal carrier for drug delivery as they can efficiently adhere to the tissue. Moreover, benefiting from the porous structure, the hydrogel micromotors exhibit a high volume-surface ratio, which enables efficient drug loading. It is demonstrated that the suction-cup-inspired micromotors can adhere efficiently to the ulcer-region in the stomach and release drugs due to their distinctive architecture and spontaneous motion, exhibiting desirable curative effect of gastric ulcer. Thus, the suction-cup-inspired micromotors with adhesive properties are expected to advance the development of micromotor in clinical applications.


Map from one-dimensional quantum field theory to quantum chaos on a two-dimensional torus.
Dynamics of a class of quantum field models on a one-dimensional (1D) lattice in a Heisenberg picture is mapped onto a class of quantum chaotic one-body systems on a configurational 2D torus (or 2D lattice) in the Schrödinger picture. The continuum field limit of the former corresponds to the quasiclassical limit of the latter.


Antipsychotic drug action: antagonism, inverse agonism or partial agonism.
The positive, psychotic symptoms of schizophrenia can be treated by antipsychotic drugs and it has been assumed that these are antagonists at the D(2) and D(3) dopamine receptors in the brain. Recently, the D(2)/D(3) partial agonist aripiprazole has been introduced as an antipsychotic drug. It has also been realized that, using in vitro assays, the other antipsychotic drugs are in fact inverse agonists at D(2)/D(3) dopamine receptors. This raises questions about how these disparate drugs can achieve a similar clinical outcome. In this review, I shall consider the efficacies of these drugs in signalling assays and how these efficacies might affect treatment outcomes. It seems that the treatment outcome might depend on the overall level of cell stimulation, which is in turn dependent on the level of residual dopamine and the efficacy of the drug in signalling assays.


Topographical organization in the nucleus accumbens of afferents from the basolateral amygdala and efferents to the lateral hypothalamus.
The basolateral region of the amygdala and the lateral hypothalamic area are involved in cardiovascular regulation. The aim of the present investigation was to determine if the terminal field of afferent projections from the basolateral nucleus of the amygdala to the nucleus accumbens overlap with the origin of the efferent projections from the nucleus accumbens to the lateral hypothalamic area. Neurons projecting from the nucleus accumbens to the lateral hypothalamic area were labeled by injecting the retrograde tracer Fluoro-Gold in the lateral hypothalamus of rats. In the same rats, fiber terminals from the amygdala to the nucleus accumbens were labeled by injecting the anterograde tracer Fluoro-Ruby in the basolateral region of the amygdala. Injections of Fluoro-Gold in the lateral hypothalamus labeled neurons in the posteromedial portion of the nucleus accumbens. Injections of Fluoro-Ruby in the basolateral amygdala labeled fibers and terminals in all parts of the nucleus accumbens with the highest density being found in the posteromedial part of the nucleus accumbens where Fluoro-Gold-labeled neurons were located. When regions of the posteromedial nucleus accumbens were examined under high-magnification, Fluoro-Ruby-labeled terminals appeared to make contact on Fluoro-Gold-labeled dendrites and cell bodies. This investigation demonstrates that there is a distinct overlap in the posteromedial region of the nucleus accumbens between the terminal field from neurons originating in the amygdala and neurons which project to the lateral hypothalamus. In addition, neurons in the basolateral amygdala appear to make synaptic contact with neurons in the nucleus accumbens that project to the lateral hypothalamic area.(ABSTRACT TRUNCATED AT 250 WORDS)


Modified laparoscopic splenectomy: a beneficial technique for ABO-incompatible living donor renal transplantation candidates on hemodialysis.
Advances in laparoscopy have enabled minimally invasive surgical treatment of splenic diseases. Even with these advances, laparoscopic splenectomy in patients on dialysis can be difficult because of tissue fragility due to the underlying renal disease. We report a safe surgical technique for laparoscopic splenectomy in patients on maintenance dialysis that is suitable for use before ABO-incompatible living donor renal transplantation (LDRTx). Between June 1972 and December 2006, a total of 800 patients underwent LDRTx in our department, including 82 patients who underwent ABO-incompatible LDRTx. Between April 2001 and December 2006 we performed laparoscopic splenectomy in 48 hemodialysis patients as a pretreatment before ABO-incompatible LDRTx. Under general anesthesia the operation was performed using a new technique, referred to as the "splenic hilum lump method." We evaluated the surgical outcomes, such as the operative time, amount of blood loss, efficacy, and complications. The mean operative time was 131.6 +/- 38.4 min and mean blood loss was 126 +/- 395 mL. Blood transfusion was required in three patients. All cases had satisfactory kidney function after LDRTx and none developed kidney graft failure due to acute rejection. Almost all patients could walk the day after laparoscopic splenectomy and were satisfied with the cosmetic appearance of the scar after wound healing. The surgical technique we report here can be safely performed on patients with renal failure who require caution because of tissue fragility. Laparoscopic splenectomy is a safe, effective and less invasive operative procedure as a pretreatment for ABO-incompatible LDRTx.


Place Cell Networks in Pre-weanling Rats Show Associative Memory Properties from the Onset of Exploratory Behavior.
Place cells are hippocampal pyramidal cells that are active when an animal visits a restricted area of the environment, and collectively their activity constitutes a neural representation of space. Place cell populations in the adult rat hippocampus display fundamental properties consistent with an associative memory network: the ability to 1) generate new and distinct spatial firing patterns when encountering novel spatial contexts or changes in sensory input ("remapping") and 2) reinstate previously stored firing patterns when encountering a familiar context, including on the basis of an incomplete/degraded set of sensory cues ("pattern completion"). To date, it is unknown when these spatial memory responses emerge during brain development. Here, we show that, from the age of first exploration (postnatal day 16) onwards, place cell populations already exhibit these key features: they generate new representations upon exposure to a novel context and can reactivate familiar representations on the basis of an incomplete set of sensory cues. These results demonstrate that, as early as exploratory behaviors emerge, and despite the absence of an adult-like grid cell network, the developing hippocampus processes incoming sensory information as an associative memory network.


Memory impairment after convulsive therapy. Influence of age and number of treatments.
The influence of age and number of treatments on memory impairment was studied in depressed patients after a series of convulsive treatments: bilateral ECT, unilateral ECT on the nondominant hemisphere, and fluorothyl convulsive therapy. Before and after the completed convulsive therapy course the patients were tested with a memory test battery and the symptoms rated with a depression scale. Before treatment older age-groups had decreased ability to learn, but their post-treatment forgetting score was not significantly higher than in other age-groups. An increase in the number of ECTs did not seem to correlate with the degree of memory impairment. The conclusion of the present study is that age (up to 65) and the number of ECTs (up to 10) have no apparent influence on memory impairment after electroconvulsive therapy.


Comparison of intraperitoneal antithrombin III and heparin in experimental peritonitis.
The antifibrotic effect of heparin, an anticoagulant used routinely in the treatment of peritonitis, is unknown, whereas antithrombin III (AT-III) has both anticoagulant and anti-inflammatory actions. The aim of this study was to compare the antifibrotic and anti-inflammatory effects of AT-III and heparin in rats with experimentally developed peritonitis while on peritoneal dialysis (PD). Sixty-four Wistar albino rats (in four groups of 16) were used in the study. Group 1 received PD solution only, group 2 had experimentally developed peritonitis in addition to PD solution; group 3 received heparin intraperitoneally for 3 days, in addition to group 2; and group 4 received AT-III intraperitoneally for 3 days, in addition to group 2. Plasma and dialysate levels of tissue-plasminogen activator were similar in heparin and AT-III groups on both day 3 and day 14. The inflammation scores of heparin and AT-III groups were also similar in both early and late phases. The fibrosis score of the AT-III group was low compared with both peritonitis and heparin groups in the early phase (p = 0.03), though it was similar in the late phase. The effects of AT-III are comparable with that of heparin in PD peritonitis in rats with experimentally developed peritonitis while on PD.


A pre-operatively diagnosed advanced abdominal pregnancy with a surviving neonate: a case report.
Abdominal pregnancy is a rare form of ectopic pregnancy with a high rate of maternal and fetal complications. Most of the reported cases are diagnosed in early trimesters, usually after presenting with complications. Advanced abdominal pregnancy poses a huge diagnostic and management challenge, particularly in low-income countries. A term abdominal pregnancy diagnosed pre-operatively and resulting in a surviving neonate is quite rare. A 35-year-old, para 2, unbooked, Ethiopian Somali woman presented with amenorrhea of 9 months' duration, abdominal pain, and painful fetal movements of 4 months' duration. Her physical examination revealed a uterus sized 36 weeks' gestation with easily palpable fetal parts. Her laboratory test results were unremarkable except for mild anemia. Her ultrasound findings were suggestive of abdominal pregnancy. Laparotomy was done to salvage an alive healthy neonate from the peritoneum with removal of placenta implanted on the right broad ligament. The mother had a smooth post-operative course. An advanced abdominal pregnancy diagnosed pre-operatively with delivery of a surviving neonate is rare. A high index of suspicion and thorough clinical and ultrasound evaluation are crucial to making an early diagnosis. This is particularly important in areas where advanced imaging technologies are not readily available. Timely surgical intervention is imperative to avert maternal and fetal complications.


Extraosseous Ewing's sarcoma. Computed tomography evaluation before and after chemotherapy.
Fourteen patients with extraosseous Ewing's sarcoma were evaluated by computed tomography (CT) and conventional radiography. The sites of involvement were in the lower extremities (six cases), the chest wall (four), pelvis (two), and the paravertebral region (two). In seven cases, the initial contrast-enhanced CT disclosed a necrotic soft tissue mass in four, two of them with peripheral enhancement. In three cases, the mass was homogeneous and did not enhance. CT enabled us to detect the size of the mass, the integrity of adjacent bone and medullary cavity, and to determine the presence or absence of metastases. CT was useful for evaluation of the patients' tumor response to treatment. In three of four patients treated with chemotherapy, CT showed evidence of a dramatic initial response. In one patient who was resistant to chemotherapy, surgical methods were required.


Reversal of antigen-induced resistance to collagen arthritis by cyclophosphamide.
Treatment of rats with intravenous injection of 1 mg of soluble native type II collagen induced resistance against the subsequent induction of active arthritis by type II collagen immunization. This resistant state was accompanied by suppressed antibody response and delayed-type hypersensitivity (DTH) skin reaction to type II collagen. However, pretreatment of rats with 20 mg/kg of cyclophosphamide (CY), an agent reputed to damage suppressor T-cell function, 2 days before intravenous injection of soluble type II collagen abrogated the antigen-induced resistance against the subsequent induction of active arthritis. The DTH skin reaction to type II collagen was completely restored and the antibody response to type II collagen was significantly though not completely restored by CY pretreatment. These results provide evidence that antigen-induced resistance to collagen arthritis is mediated, at least in part, under the control of CY-sensitive events.


Growth at elevated CO(2) delays the adverse effects of drought stress on leaf photosynthesis of the C(4) sugarcane.
Sugarcane (Saccharum officinarum L. cv. CP72-2086) was grown in sunlit greenhouses at daytime [CO(2)] of 360 (ambient) and 720 (elevated)mumolmol(-1). Drought stress was imposed for 13d when plants were 4 months old, and various photosynthetic parameters and levels of nonstructural carbohydrates were determined for uppermost fully expanded leaves of well-watered (control) and drought stress plants. Control plants at elevated [CO(2)] were 34% and 25% lower in leaf stomatal conductance (g(s)) and transpiration rate (E) and 35% greater in leaf water-use efficiency (WUE) than their counterparts at ambient [CO(2)]. Leaf CO(2) exchange rate (CER) and activities of Rubisco, NADP-malate dehydrogenase, NADP-malic enzyme and pyruvate P(i) dikinase were marginally affected by elevated [CO(2)], but were reduced by drought, whereas activity of PEP carboxylase was reduced by elevated [CO(2)], but not by drought. At severe drought developed at day 12, leaf g(s) and WUE of ambient-[CO(2)] stress plants declined to 5% and 7%, while elevated-[CO(2)] stress plants still maintained g(s) and WUE at 20% and 74% of their controls. In control plants, elevated [CO(2)] did not enhance the midday levels of starch, sucrose, or reducing sugars. For both ambient- and elevated-[CO(2)] stress plants, severe drought did not affect the midday level of sucrose but substantially reduced that of starch. Nighttime starch decomposition in control plants was 55% for ambient [CO(2)] and 59% for elevated [CO(2)], but was negligible for stress plants of both [CO(2)] treatments. For both ambient-[CO(2)] control and stress plants, midday sucrose level at day 12 was similar to the predawn value at day 13. In contrast, sucrose levels of elevated-[CO(2)] control and stress plants at predawn of day 13 were 61-65% of the midday values of day 12. Levels of reducing sugars were much greater for both ambient- and elevated-[CO(2)] stress plants, implying an adaptation to drought stress. Sugarcane grown at elevated [CO(2)] had lower leaf g(s) and E and greater leaf WUE, which helped to delay the adverse effects of drought and, thus, allowed the stress plants to continue photosynthesis for at least an extra day during episodic drought cycles.


New advances of DNA/RNA methylation modification in liver fibrosis.
Liver fibrosis is a complex pathological process caused by multiple pathogenic factors,such as ethanol, viruses, toxins, drugs or cholestasis, and it can eventually develop into liver cirrhosis without effective treatment. Activation of hepatic stellate cells (HSCs) is a pivotal cellular event in the pathogenesis of liver fibrosis. However, the pathogenesis of liver fibrosis has not been fully elucidated. DNA/RNA methylation can regulate gene expression without alteration in its sequence, and numerous studies have shown the involvement of DNA methylation in the activation of HSCs and then promote the progression of liver fibrosis. In addition, RNA methylation has recently been reported to play a regulatory role in this process. In this review, we focus on the aberrant DNA/RNA methylation of selected genes and explore their functional mechanism in regulating HSCs activation and liver fibrogenesis. All of these findings will enhance our understanding of DNA/RNA methylation and their roles in liver fibrosis and provide the basis to identify effective therapeutic targets.


Thymic precursor cells generate acute myeloid leukemia in NUP98-PHF23/NUP98-HOXD13 double transgenic mice.
Transgenic mice that express either a NUP98-PHF23 (NP23) or NUP98-HOXD13 (NHD13) fusion in the hematopoietic compartment develop a wide spectrum of leukemias, including myeloid, erythroid, megakaryocytic and lymphoid, at age 9-14 months. NP23-NHD13 double transgenic mice were generated by interbreeding NP23 and NHD13 mice. Remarkably, 100% of the NP23-NHD13 double transgenic mice developed acute myeloid leukemia (AML) within three months, characterized by replacement of the thymus with leukemic myeloblasts. The marked infiltration of thymus led to the intriguing hypothesis that AML generated in NP23-NHD13 mice arose in the thymus, as opposed to the bone marrow (BM). Transplantation of CD4-CD8- double negative (DN) thymocytes (which were also negative for Mac1 and Gr1) from leukemic NHD13/NP23 mice demonstrated that DN thymocytes could transmit AML, and limiting dilution studies showed that leukemia initiating cells were increased 14-fold in the thymus compared to BM. Further thymocyte fractionation demonstrated that DN1 and DN2, but not DN3 or DN4 fractions transmitted AML, and a marked expansion (100-fold) of Lineage-Sca1 + Kit + (LSK) cells in the thymus of the NP23-NHD13 mice. Taken together, these results show that the thymus of NP23-NHD13 mice acts as a reservoir for AML initiating cells and that thymic progenitors can transmit AML.


RAGE and ICAM-1 differentially control leukocyte recruitment during acute inflammation in a stimulus-dependent manner.
The receptor for advanced glycation endproducts, RAGE, is involved in the pathogenesis of many inflammatory conditions, which is mostly related to its strong activation of NF-κB but also due to its function as ligand for the β2-integrin Mac-1. To further dissect the stimulus-dependent role of RAGE on leukocyte recruitment during inflammation, we investigated β2-integrin-dependent leukocyte adhesion in RAGE-/- and Icam1-/- mice in different cremaster muscle models of inflammation using intravital microscopy. We demonstrate that RAGE, but not ICAM-1 substantially contributes to N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced leukocyte adhesion in TNF-α-pretreated cremaster muscle venules in a Mac-1-dependent manner. In contrast, fMLP-stimulated leukocyte adhesion in unstimulated cremaster muscle venules is independent of RAGE, but dependent on ICAM-1 and its interaction with LFA-1. Furthermore, chemokine CXCL1-stimulated leukocyte adhesion in surgically prepared cremaster muscle venules was independent of RAGE but strongly dependent on ICAM-1 and LFA-1 suggesting a differential and stimulus-dependent regulation of leukocyte adhesion during inflammation in vivo. Our results demonstrate that RAGE and ICAM-1 differentially regulate leukocyte adhesion in vivo in a stimulus-dependent manner.


Functional characterization of a putative aquaporin from Encephalitozoon cuniculi, a microsporidia pathogenic to humans.
The microsporidia are a group of obligate intracellular parasitic protists that have been implicated as both human and veterinary pathogens. The infectious process of these organisms is believed to be dependent upon the rapid influx of water into spores, presumably via aquaporins (AQPs), transmembrane channels that facilitate osmosis. An AQP-like sequence of the microsporidium Encephalitozoon cuniculi (EcAQP), when cloned and expressed in oocytes of Xenopus laevis, rendered these oocytes highly permeable to water. No permeability to the solutes glycerol or urea was observed. Pre-treatment of EcAQP-expressing oocytes with HgCl(2) failed to inhibit their osmotic permeability, as predicted from EcAQP's lack of mercury-sensitive cysteine residues near the NPA motifs which line the AQP aqueous pore. EcAQP exhibits sequence identity to AQP A of Dictyostelium discoideum (26%) and human AQP 2 (24%). Further study of AQPs in microsporidia and their potential inhibitors may yield novel therapeutic agents for microsporidian infections.


A nationwide cohort study on incidence and mortality associated with extracranial vascular malformations.
Extracranial vascular malformations are abnormal formations of blood vessels located outside the brain (extracranial) that develop during fetal development. They are caused by errors in the formation of blood vessels in the embryo and can affect various parts of the body, such as the head, neck, face, and other regions. Some malformations may be asymptomatic and only require monitoring, while others may cause significant health issues or cosmetic concerns and may need medical intervention. There are very few studies have investigated the nationwide incidence and quantitative mortality of vascular malformations in terms of their subtypes. Thus, this study aimed to determine the nationwide incidence and mortality associated with vascular malformations. This nationwide population-based study evaluated 70,517 patients with vascular malformations from 2008 to 2021. We evaluated the incidence and mortality associated with each subtype of vascular malformation. Furthermore, Cox regression analysis was used to evaluate the association between vascular malformation and mortality. The annual incidence (per 100,000 population) of overall vascular, venous, capillary, arteriovenous, and lymphatic malformations was 9.85, 1.48, 2.31, 0.24, and 5.82 cases, respectively. Patients with vascular malformations, except those with venous malformations, had higher mortality than the matched controls. Moreover, among the vascular malformation subgroups, the adjusted hazard ratio of mortality was the highest for arteriovenous malformations. This study revealed that the overall annual incidence of vascular malformations was 9.85 cases per 100,000 population in Korea from 2008 to 2021. The mortality of the matched general population was lower than that of patients with vascular malformations, except for those with venous malformations. Additionally, the adjusted hazard ratio for mortality associated with arteriovenous malformations was the highest among the vascular malformation subgroups.


Cervical disc prolapse in the elderly: an easily overlooked, reversible cause of spinal cord compression.
It is important to distinguish cord compression due to cervical disc prolapse, which has a very favourable prognosis following surgery, from that due to cervical spondylosis. In the elderly the occurrence of cervical disc prolapse as a cause of spinal compression may be under-recognised because symptoms are too readily attributed to long standing degenerative changes on plain cervical X-rays. The difficulty of making an accurate diagnosis is complicated further in the elderly by the prevalence of other diseases which may mask the symptoms of cord compression. We report our experience with 19 patients over 60 who underwent anterior cervical discectomy for myelopathy due to intervertebral disc prolapse. There was generally a short history of walking difficulty, but the presence of 'numb clumsy hands', perhaps due to selective posterior column impairment, was often a more disabling complaint. Neck pain and disturbances of micturition were unusual. The prognosis after disc excision can be excellent. In this series all the severely disabled patients returned to an independent existence. Overall 16/19 patients made an excellent or good recovery.


Phe(208) and Ile(199) in human monoamine oxidase A and B do not determine substrate and inhibitor specificities as in rat.
It has been reported previously that reciprocally switching Phe(208) and Ile(199) in rat monoamine oxidase (MAO) A and B, respectively, was sufficient to switch their substrate and inhibitor preferences. In this study, the same mutants were made in the human forms of MAO. When compared with MAO A, MAO A-F208I showed a sixfold decrease in the specificity constant k(cat)/K(m) for both the MAO A- and the MAO B-preferring substrates 5-hydroxytryptamine and beta-phenylethylamine, respectively. The reciprocal point mutant MAO B-I199F had no effect on substrate affinity. To investigate if the region neighboring these two residues is responsible for conferring preferences, we have also made chimeric constructs by reciprocally switching the corresponding amino acid segments 159-214 in MAO A and 150-205 in MAO B. Chimerics MAO AB(159-214)A and MAO BA(150-205)B had small changes in K(m) and IC(50) values when compared with MAO A and B, respectively, but did not exhibit a preference switch. The results suggest that Phe(208) in MAO A and amino acid segments 159-214 and 150-205 in MAO A and B, respectively, influence the enzyme active site. However, substrate and inhibitor preferences of human MAO A and B are not determined by the respective residues Phe(108) and Ile(199) as in rat MAO nor by their neighboring regions.


Pelvic fracture-specific scales versus general patient reported scales for pelvic fracture outcomes: a systematic review.
Multiple scoring systems are used in the assessment of post-injury outcomes in pelvic fracture patients. Although commonly used, there is scarce evidence as to their validity. We performed a systematic review of the current literature to compare a well validated generic outcome tool (Short Form-36 (SF-36)) and three commonly used pelvic-specific outcome tools, the Iowa Pelvic Score, Majeed Pelvic Score and Orlando Pelvic Score. Eleven papers were found that used both the SF-36 and one or more of the pelvic-specific outcome tools. The data demonstrate great variability in both the method of application and form of reporting. The pelvic-specific tools produce similar results to the SF-36 and are potentially more sensitive in examining specific areas related to pelvic injuries and easier to perform and calculate than the SF-36.


Associated co-morbidities in a retrospective cohort of orthostatic tremor.
Orthostatic tremor (OT) is characterized by tremor in orthostatism. Primary OT is characterized by a high-frequency tremor at surface EMG recording and assumed to be idiopathic, whereas slow-frequency OT is classically associated with neurological pathologies. We report here a retrospective monocentric cohort study of primary (fast OT) and pseudo-OT (slow OT) patients to describe associated neurological and non-neurological co-morbidities. Between November 2014 and October 2019, 27 patients with OT were selected from the EMG database of the Department of Clinical Physiology in Lariboisière' s hospital. Patients were classified in primary OT if tremor frequency was ≥ 13 Hz and in pseudo-OT if tremor frequency was < 13 Hz. Leg tremor on standing represented 10.2% of all tremor recordings. Ten patients were included in the primary and 17 in the pseudo-OT group. Females were predominant (62.9%) (p = 0.04). Mean age at diagnosis was 64.8 ± 1.1 years. At the first visit, a movement disorder was associated with 30% of primary OT, among them one CADASIL patient, whereas extrapyramidal or cerebellar disorders were reported in 100% of pseudo-OT, among them three Wilson's disease patients. These pathologies all preceded primary OT and occurred concomitantly with pseudo-OT. Frequency remained unchanged during evolution, except pseudo-OT in two patients that completely resolved following the introduction of antiParkinsonian drugs. Treatment of primary OT was partially effective in 28% and in 50% of pseudo-OT patients. In this monocentric study, movement disorders were present in 30% of primary OT patients. This result questions the term "idiopathic" or "primary" OT, but the small number of patients does not allow answering this issue.


Antenatal corticosteroids in the management of preterm birth: are we back where we started?
Though the preterm birth rate in the United States has finally begun to decline, preterm birth remains a critical public health problem. The administration of antenatal corticosteroids to improve outcomes after preterm birth is one of the most important interventions in obstetrics. This article summarizes the evidence for antenatal corticosteroid efficacy and safety that has accumulated since Graham Liggins and Ross Howie first introduced this therapy. Although antenatal corticosteroids have proven effective for singleton pregnancies at risk for preterm birth between 26 and 34 weeks' gestation, questions remain about the utility in specific patient populations such as multiple gestations, very early preterm gestations, and pregnancies complicated by IUGR. In addition, there is still uncertainty about the length of corticosteroid effectiveness and the need for repeat or rescue courses. Though a significant amount of data has accumulated on antenatal corticosteroids over the past 40 years, more information is still needed to refine the use of this therapy and improve outcomes for these at-risk patients.


Glycoform analysis of intact erythropoietin by MALDI FT-ICR mass spectrometry.
Recombinant human erythropoietin (EPO) is a complex therapeutic glycoprotein with three N- and one O-glycosylation sites. Glycosylation of EPO influences its safety and efficacy and is defined as a critical quality attribute. Thus, analytical methods for profiling EPO glycosylation are highly demanded. Owing to the complexity of the intact protein, information about EPO glycosylation is commonly derived from released glycan and glycopeptide analysis using mass spectrometry (MS). Alternatively, comprehensive insights into the glycoform heterogeneity of intact EPO are obtained using ESI MS-based methods with or without upfront separation of EPO glycoforms. MALDI MS, typically performed with TOF mass analyzers, has been also used for the analysis of intact EPO but, due to the poor glycoform resolution, has only provided limited glycoform information. Here, we present a MALDI FT-ICR MS method for the glycosylation profiling of intact EPO with improved glycoform resolution and without loss of sialic acid residues commonly observed in MALDI analysis. Three EPO variants were characterized in-depth and up to 199 glycoform compositions were assigned from the evaluation of doubly-charged ions, without any deconvolution of the mass spectra. Key glycosylation features such as sialylation, acetylation, and N-acetyllactosamine repeats were determined and found to agree with previously reported data obtained from orthogonal analyses. The developed method allowed for a fast and straightforward data acquisition and evaluation and can be potentially used for the high-throughput comparison of EPO samples throughout its manufacturing process.


Evidence for a central postsynaptic action of clonidine.
Intravenous administration of clonidine (1--100 micrograms/kg) produces a dose-dependent mydriasis in cats by inhibition of parasympathetic tone to the iris. The magnitude of CNS-induced pupillary dilation was similar in both normal anaesthetized cats and in anaesthetized preparations pretreated with reserpine (5 mg/kg i.p.) and alpha-methyl-p-tyrosine (2 x 300 mg/kg i.p.). Pretreatment reduced the concentrations of noradrenaline, dopamine and serotonin to less than 3% of that control levels in most parts of the CNS in which these amines were measured. Clonidine produced bradycardia in control animals but not in pretreated cats. In amine depleted animals in which only one eye was innervated by the ciliary nerves (parasympathetic), clonidine produced mydriasis only on the innervated side. These experiments confirm our previous observations that clonidine produces mydriasis in the cat by means of inhibition of parasympathetic tone to the iris. It is concluded that if clonidine produces this effect by stimulating noradrenergic, dopaminergic or serotonergic receptors, then clonidine exerts its centrally-induced mydriatic effect by acting on post-synaptic mechanisms.


The place of symmetry in the study of biological macromolecules.
The various aspects of symmetry involved in discussions of biological macromolecules are analysed. Among these are geometrical symmetry of the macromolecule itself, the symmetry of its binding isotherms and the underlying thermodynamic and mathematical relations, the role of symmetry in different allosteric models, and the effect of symmetry on the number of relaxation times shown by a macromolecule in its approach to equilibrium or a steady state. Finally there is the symmetry of the group of potentials and the resulting linkage relations which govern the response of the macromolecule to its ligands and embody the grammar of a macromolecular language.


Paternal origin of new mutations in von Recklinghausen neurofibromatosis.
Von Recklinghausen neurofibromatosis (NF-1) is a common autosomal dominant disorder. The estimated new mutation rate (1 x 10(-4] is one of the highest for a human disorder. Here we report that in 12 of 14 families we have analysed, the new mutation is of paternal origin. This result is similar to that recently obtained for retinoblastoma. In other genetic disorders that show a bias towards paternal origin of new mutations, there is a marked increase in the incidence of mutations with paternal age, consistent with the mutations arising from replication errors in mitosis of spermatogonial stem cells. In retinoblastoma and NF-1, however, such paternal age effects are slight or absent. The mechanism or timing of germline mutation could therefore be different in the two cases.


Comparison of competitive protein binding analysis and radioimmunoassay for the determination of cortisol in serum and urine.
The determination of serum and urinary free cortisol by competitive protein binding and radioimmunoassay were compared on patient samples using two commercially available kits. In addition, the Beckman RIA kit reagents were examined for precision and accuracy through the performance of reproducibility, recovery, cross reactivity and parallelism studies on serum and urine. Analytical recovery experiments with cortisol added to urine and serum showed 90% and 97% recovery respectively with the RIA reagents. Good reproducibility and parallelism criteria were also obtained using Beckman kit reagents. Antiserum specificity was documented and demonstrated no cross reactivity with structurally related steroids at clinically normal serum concentrations.


Effect of GnRH analogs in postnatal domestic cats.
The aim of this study was to reproductively assess the clinical and hormonal effects of a GnRH agonist (AG) and an antagonist (AN) administered during the postnatal period in domestic cats. Forty-eight male and female postnatal kittens were randomly assigned to deslorelin acetate 1.6 mg subcutaneous (AG; n = 16), acyline 33 μg/100 g subcutaneous weekly for 3 months (AN; n = 16), or control (CO; n = 16) which remained untreated. The cats were followed up (behavioral observation, physical examination, fecal sexual steroid determinations, mating test, and pregnancy diagnosis) up to puberty. Puberty was delayed (weeks) in the AG animals (62.9 ± 3.5; P < 0.01) but not in the AN (15.5 ± 1.7; P > 0.05) when they were compared with CO kittens (13.4 ± 0.4). Fifteen (15/16) of the AN and CO animals, and only 11 of 16 cats of the AG group were fertile (P > 0.1). No differences were found in body weight (P > 0.1) and measurements (P > 0.1), libido (P > 0.1) and in the appearance of side effects (P > 0.1; except a pyometra in an AG female) among groups. In both AG- and AN-treated males (testosterone; P < 0.01) and females (estradiol-17β; P < 0.01) fecal hormone concentrations were lower than in CO group during the first five postnatal weeks but not later. It is concluded that the neonatal administration of these AG and AN decreased fecal sexual steroids during the first postnatal weeks causing, the agonists but not the antagonist, a significant, reversible delay in puberty appearance.


"What Have We Done for Us Lately?"--Defining Performance and Value at the Individual Clinician Level.
Consolidation in anesthesiology practice and the rest of health care creates pressure to improve the product offered by anesthesia professionals. Anesthesia professionals must offer more than a reliable stream of anesthetized, operated, and recovered patients to remain competitive. By pooling resources and application of leadership effort, large departments and group practices can conduct individual-level value assessments of clinicians. Individual clinicians can be incentivized to improve their personal value proposition. By creating an interlocking program of ongoing assessment, career development coaching and opportunities, as well as compensation, departments and group practices can return value to individual clinicians by curating and accelerating their career and capability development.


A call to reconceptualize lichen symbioses.
Several decades of research across disciplines have overturned historical perspectives of symbioses dominated by binary characterizations of highly specific species-species interactions. This paradigm shift has unlocked the previously underappreciated and overlooked dynamism of fungal mutualisms such as mycorrhizae. Lichens are another example of important fungal mutualisms where reconceptualization is urgently needed to realize their potential as model systems. This reconceptualization requires both an objective synthesis of new data and envisioning a revised integrative approach that unifies the spectrum of ecology and evolution. We propose a ten-theme framework that if pursued would propel lichens to the vanguard of symbiotic theory.


Accreditation as a quality-improving policy tool: family planning, maternal health, and child health in Egypt.
Accreditation of healthcare providers has been established in many high-income countries and some low- and middle-income countries as a tool to improve the quality of health care. However, the available evidence on the effectiveness of this approach is limited and of questionable quality, especially in low- and middle-income countries. We exploit the interventions introduced under Egypt's health sector reform program between 2000 and 2014 to estimate the effect of health facility accreditation on family planning, maternal health, and child health outcomes. We use difference-in-differences fixed-effects and propensity score matching difference-in-differences models. To do so, we spatially link women to their nearest mapped health facilities using their global positioning system coordinates. We find that accreditation had multiple positive effects, especially on delivery care and child morbidity prevalence. The effects appear to weaken over time though. Our findings suggest that facility accreditation can be effective in improving family planning, antenatal care, delivery care, and child health, but stress the need to study how the effects can be sustained.


How to assess visual function in acquired brain injury-Asking is not enough.
Acquired brain injury affects many brain areas and causes a range of dysfunctions including vision-related issues. These issues can have negative impacts on rehabilitation progress and activities of daily life but may easily be overlooked. There is no common recommendation about how to assess visual impairments after ABI. The purpose of this study was to estimate the frequency of objectively measures oculomotor dysfunctions, and also how these findings are related to two inventories intended to support detection of visual impairment. The study was cross-sectional and included 73 outpatients. In addition to the standard evaluation program, the patients went through a comprehensive optometric examination. The inventories used were the Vision Interview (VI) and the Convergence Insufficiency Symptom Survey (CISS). All three types of examinations showed a high proportion vision-related symptoms. Fusion vergence was the most common objectively measured finding, 83%. There were seven statistically significant associations between five VI items and five visual deficits. The strength of associations was moderate (Phi 0.261-0.487, p < .05). The sensitivity and specificity of the CISS were moderate. We found high percentages of the patients with visual symptoms and dysfunctions. Due to the complexity of visual symptoms and functional deficits in ABI, we find it necessary to combine both symptom assessment and vision examination in order to capture visual function issues.


MiR-146b-5p regulates the scavenging effect of GPx-3 on peroxide in papillary thyroid cancer cells.
Glutathione peroxidase (GPx) is an important antioxidant enzyme in thyroid follicular cells. Reduced levels of glutathione peroxidase 3 (GPx-3) expression in papillary thyroid cancer (PTC) are associated with poor prognosis. However, the reason for the decreased expression level of GPx-3 in PTC is unclear. The expression of GPx-3 in papillary thyroid carcinoma and adjacent normal tissue (n = 18) was detected by Western blotting. Bioinformatics was used to predict the relationship between the level of GPx-3 and gender, age, lymph node metastasis, stage, BRAFV600E mutation, and recurrence-free survival of patients. The possible upstream microRNAs of GPx-3 were analyzed by bioinformatics tools also. We verified the relationship between GPx-3 and upstream microRNA by dual luciferase reporter assay and enzyme-linked immunosorbent assay (ELISA). The protein level of GPx-3 decreased in PTC, and analysis of public database datasets suggests that its decreased expression may be associated with the BRAFV600E mutation. MiR-146b-5p was significantly overexpressed in PTC. The dual luciferase reporter assay verified the effect of miR-146b-5p on 3'-UTR of GPx-3 mRNA. Knockdown of miR-146b-5p in thyroid cancer cell lines TPC-1 and BCPAP increased GPx-3 expression levels, accompanied by an increase in the conversion of glutathione (GSH) to oxidized glutathione (GSSG). In conclusion, the level of GPx-3 decreases in papillary thyroid carcinoma and impairs intracellular peroxide clearance, due to the inhibitory effect of miR-146b-5p. The accumulation of intracellular peroxides may contribute to the poor prognosis of thyroid cancer.


SARS-CoV-2 targets the liver and manipulates glucose metabolism.
A recent publication by Barreto and colleagues showed that SARS-CoV-2 directly triggers hyperglycemia by infecting hepatocytes and inducing phosphoenolpyruvate carboxykinase (PEPCK)-dependent gluconeogenesis. Here, we discuss the biological importance of these findings, including the hepatic tropism of SARS-CoV-2. We also comment on the clinical implications of the bidirectional connection between COVID-19 and noncommunicable diseases.


Surgery for ulcerative colitis.
Ileal pouch-anal anastomosis is a relatively new surgical alternative to conventional ileostomy in patients with chronic ulcerative colitis. The rationale for the operation is that the disease is cured by the colectomy, proximal proctectomy, and distal endorectal mucosal resection, but enteric continence is maintained because the anal sphincters are preserved and the reservoir capacity is restored by incorporating an ileal pouch. This article describes the criteria for selecting appropriate patients, the surgical technique, the short- and long-term clinical results, and the physiologic consequences of the operation. The possible implications of this new procedure on the future management of patients with chronic ulcerative colitis are also presented.


Diagnosis of prostatic carcinoma: value of random transrectal sonographically guided biopsies.
We studied the efficacy of random, transrectal sonographically guided biopsies in the diagnosis of prostatic carcinoma in a high-risk population. During a 2-year period, 570 transrectal sonographically guided prostatic biopsies were done because of clinical findings suggestive of prostatic carcinoma. Biopsies of hypoechoic lesions that were suggestive of carcinoma and segmental random biopsies of normal-appearing lobes of the prostate were performed. Transrectal sonographic findings were correlated with results of pathologic examination of the biopsy specimen and with surgical results, when available. Of the 202 patients found to have carcinoma, the carcinoma was detected with directed biopsy in 145 patients (72%). One hundred twenty (71%) of 169 carcinomas were detected with random biopsy when that procedure was performed. Random biopsies were the only method of diagnosing 57 (28%) of the 202 carcinomas, increasing the yield by 39%. Yield of carcinoma on transrectal sonographically guided biopsies increases significantly when segmental random biopsies are performed. Transrectal sonographically guided biopsies should include cores through hypoechoic lesions that are suggestive of carcinoma and bilateral segmental random biopsies.


Depot medroxyprogesterone acetate and norethisterone enanthate differentially impact T-cell responses and expression of immunosuppressive markers.
Injectable contraceptive use may impact immune cell responsiveness and susceptibility to infection. We measured responsiveness of T-cells from women before and after initiating depot medroxyprogesterone acetate (DMPA) or norethisterone enanthate (Net-En). Peripheral blood mononuclear cells collected from women aged 18-34 years prior to, at steady state, and nadir concentrations after initiating DMPA (n = 30) or Net-En (n = 36) and from women initiating copper intrauterine device (CU-IUD; n = 32) were stimulated with phorbol myristate acetate and analyzed using flow cytometry. We evaluated percentage change in T-cells expressing programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4). Compared to baseline, there were decreased numbers of CD4+CTLA4+ (P < .001) and CD8+CTLA4+ (P < .01) T-cells following ex vivo stimulation challenge at steady state DMPA concentrations and no differences at nadir concentrations (P = .781 and P = .463, respectively). In Net-En users, no differences in CD4+CTLA4+ T-cells at steady state (P = .087) and nadir concentrations (P = .217) were observed. DMPA users had fewer CD4+PD-1+ (P < .001) and CD8+PD-1+ (P < .001) T-cells at nadir concentrations. Number of CD4+PD-1+ and CD8+PD-1+ T-cells decreased at steady state concentration (P = .002 and P = .001, respectively) and at nadir concentrations after Net-En initiation (P < .001 and P < .001). In CU-IUD users, there were no changes in number of CD4+CTLA4+ (P = .426) and CD8+CTLA4+ (P = .169) and no changes in CD4+PD-1+ (P = .083) and CD8+PD-1+ (P = .936) compared to baseline. Activation of T-cells in response to ex vivo stimulation is suppressed at steady state DMPA concentration and resolves at nadir concentration, suggesting DMPA immunosuppressive effects may be transient.


Effect of different terpene-containing essential oils on permeation of estradiol through hairless mouse skin.
Purpose of the present investigation was to evaluate six terpene-containing essential oils for their capacity to promote permeation of estradiol (ES) through hairless mouse skin in vitro. Tests on cajuput, cardamom, melissa, myrtle, niaouli and orange oil, all used at the 10% w/w concentration in propylene glycol (PG), evidenced niaouli oil (NIA) as the best permeation promoter for ES. Tests on the main terpene components of NIA (1,8 cineole, alpha-pinene, alpha-terpineol and D-limonene), evaluated neat (10% w/w in PG) or in admixture, confirmed the better promoting activity of whole NIA. The present data point to the validity of complex terpene mixtures, such as that composing NIA, as transdermal penetration enhancers for moderately lipophilic drugs like ES.


Extreme eccentric canal type pectus excavatum: morphological study and repair techniques.
Extreme eccentric canal type pectus excavatum (Grand Canyon type, GC, Type 2A3), is a distinct morphological variation, characterized by an eccentric longitudinal canal. Due to the extent of depression and asymmetry, repair is often challenging with the minimally invasive technique. Following, we present its morphologic characteristics and evaluate repair techniques according to morphology type. Extreme eccentric canal type pectus excavatum is an eccentric, long canal-like chest wall depression from the infra-clavicle to lower chest. Among 851 patients who underwent pectus excavatum repair from 1999 to 2007, 112 patients (13.2%) had the eccentric canal type. Morphologic type and repair techniques were evaluated; results were assessed by pectus indices (depression index (DI), asymmetry index (AI), and eccentricity index (EI)). Of the asymmetric cases, 31% (112/361) were the eccentric canal type. Female proportion (male to female ratio=2.3) was higher than in general pectus excavatum (4.1, p<0.05). Young female adults were more frequently affected (8/17, 47%, p<0.05). Repair techniques included asymmetric bar (n=97, 86.6%), seagull bar (n=53, 47.3%), crest compression (n=13, 11.6%), and parallel bar (n=79, 70.5 %) techniques. Pectus indices changes were: DI (pre 2.89 to post 1, p<0.01), AI (pre 1.11 to post 1.03, p<0.01), and EI (pre 1.69 to post 1, p<0.01). AI change represented asymmetric to symmetric correction. Extreme eccentric canal type pectus excavatum represents a distinctive morphology and requires special techniques for repair. Post-repair symmetry can be achieved by an asymmetric bar technique. Upper chest wall depression can be corrected by a parallel bar technique. Protruding ridge was relieved by a seagull bar or crest compression technique.


Development of plasmid-mediated resistance in Vibrio cholerae during treatment with trimethoprim-sulfamethoxazole.
The persistence of Vibrio cholerae, biotype el tor, in a patient treated with trimethoprim-sulfamethoxazole was due to the acquisition of a conjugative resistance plasmid. The plasmid, with a molecular size of 72 megadaltons, belonged to incompatibility group 6-C and conferred resistance to ampicillin, chloramphenicol, sulfonamide, and trimethoprim.


Fast-LC determination of 1-methyl-1H-tetrazole-5-thiol in human plasma with column-switching sample clean-up.
A simple, fast and sensitive method for the quantitative determination of 1-methyl-1H-tetrazole-5-thiol using HPLC is reported. Samples are deproteinated by plasma water filtration and injected into a HPLC system capable of column switching and backflushing the analytical column. The limit of quantitation was determined to be 70 ng ml-1 and the limit of detection 22 ng ml-1. Between-day precision (expressed as percent coefficient of variation) of standard curve slopes was +/- 3.5% with a range of within-day percent coefficient of variations from 0.28 to 1.4%. Recovery and precision of spiked control samples was 96 +/- 7% over a concentration range of 630-6300 ng ml-1.


Comparison between fluorescence in situ hybridization (FISH) and quantitative-fluorescent polymerase chain reaction (QF-PCR) for the detection of aneuploidies in single blastomeres.
The aim of our investigation was to compare the efficiencies of the fluorescence in situ hybridization (FISH) and the quantitative-fluorescent PCR (QF-PCR) methods for the detection of sexing and numerical chromosome disorders in single blastomeres collected from the same preimplantation human embryos. FISH analysis was carried out on 145 blastomeres from the 79 surplus embryos with probes specific for chromosomes 13, 18, 21, X, and Y. QF-PCR was performed with each one or two of the primers specific for the same chromosomes on 151 blastomeres from the same embryos obtained from patients undergoing IVF treatment. Analyses were possible on 135 blastomeres (93%) by FISH and on 117 blastomeres (77%) by QF-PCR. Of 65 embryos, which could be analyzed by both methods, 20 embryos (31%) were diagnosed as abnormal. The present study shows that FISH tests are more accurate than QF-PCR assays for the detection of numerical chromosome disorders when performed on single blastomeres.


Amphetamine abuse in emergency department patients undergoing psychiatric evaluation.
Amphetamine abuse accounts for numerous Emergency Department (ED) visits and is often associated with psychiatric disease, with many patients requiring involuntary psychiatric hold placement. It is a common practice in EDs to obtain a urine drug screen (UDS) as part of the "medical clearance" process for psychiatric patients. However, the prevalence of amphetamine-positive UDS in ED patients with psychiatric disease is unknown, as is the relationship of the UDS test to the final patient disposition. The objectives of this study were to determine the prevalence of amphetamine-positive UDS in ED patients undergoing psychiatric evaluation, and whether amphetamine-positive UDS is associated with involuntary psychiatric hold placement. This was a retrospective study of adult patients seen in a single urban university ED who had a psychiatric evaluation and a UDS over a 1-year period. Eligible patients had results of the UDS, placement of involuntary holds, past psychiatric history, chief complaint, insurance status, and demographic information recorded. Regression analysis was performed, adjusting for the listed covariates, to evaluate the independent association of amphetamine-positive UDS and involuntary psychiatric hold placement. A total of 1207 patients were included for analysis. Amphetamine-positive UDS were found in 14.8% of patients. Multivariate analysis showed no association of a psychiatric hold due to presence of amphetamines on UDS (adjusted odds ratio [OR] 0.76, 95% confidence interval [CI] 0.55-1.05, p=0.1). The only significant factor in placement of an involuntary hold was a past psychiatric history (adjusted OR 1.8, 95% CI 1.2-2.7, p=0.005). The prevalence of amphetamine-positive UDS was high in the study population; however, there was no independent association of amphetamine-positive UDS with involuntary psychiatric hospitalization.


A naphthylamide based fluorescent probe for detection of Al3+, Fe3+, and CN- with high sensitivity and selectivity.
A naphthylamide based fluorescent chemosensor, N,N'-(1,2-phenylene)bis(1-hydroxy-2-naphthamide) (H4L), for detection of Fe3+ and Al3+ cations as well as CN- anion is reported. This compound has been synthesized by a novel and facile synthetic method with high yield and characterized by FT-IR, 1H NMR, elemental analysis, and UV-Vis spectroscopy. It could detect Fe3+ and Al3+ ions in different media with different excitation and emission wavelengths. In DMSO solution, H4L showed selective ON-OFF quenching of its 451 nm emission in the presence of Fe3+. On the other hand, in DMF solution, H4L exhibited selective OFF-ON fluorescence upon the addition of Al3+, the intensity at 429 nm increases drastically by 24-fold. Also, among the anions, the probe can selectively distinguish CN- by deprotonation of OH and NH groups, as proved by 1H NMR titration. TD-DFT calculation supports the UV-Vis and fluorescence measurements of the chemosensor.


Impaired nitrergic relaxation in pyloric sphincter of the 6-OHDA Parkinson's disease rat.
Patients with Parkinson's disease (PD) often suffer from delayed gastric emptying, but the underlying mechanism remains unclear. We have shown previously that a PD rat model comprising bilateral substantia nigra destruction by 6-hydroxydopamine (6-OHDA rats) exhibits gastroparesis with alteration of neural nitric oxide synthase (nNOS) and acetylcholine in gastric corpus. However, changes in pyloric motility in the 6-OHDA rats have not been characterized. Solid gastric emptying test, immunofluorescence, Western blot, and in vitro pyloric motility recordings were used to assess pyloric motor function in the 6-OHDA rats. The 6-OHDA-treated rats displayed delayed solid gastric emptying and a lower basal pyloric motility index. In the 6-OHDA rats, high K+-induced transient contractions were weaker in pyloric sphincters. Electric field stimulation (EFS)-induced pyloric sphincter relaxation was lower in the 6-OHDA rats. NG-nitro-l-arginine methyl ester (l-NAME), a nonselective inhibitor of NOS, markedly inhibited the EFS-induced relaxation in both control and 6-OHDA rats. Pretreatment of tetrodotoxin abolished the effect of EFS on the pyloric motility. In addition, nNOS-positive neurons were extensively distributed in the pyloric myenteric plexus, whereas the number of nNOS-immunoreactive neurons and the protein expression of nNOS were significantly decreased in the pyloric muscularis of 6-OHDA rats. However, sodium nitroprusside-induced pyloric relaxations were similar between the control and 6-OHDA rats. These results indicate that the pyloric sphincters of 6-OHDA rats exhibit both weakened contraction and relaxation. The latter may be due to reduced nNOS in the pyloric myenteric plexus. The dysfunction of the pyloric sphincter might be involved in the delayed gastric emptying.NEW & NOTEWORTHY Reduced nitrergic neurons in pyloric myenteric plexus potently contributed to the attenuated relaxation in 6-hydroxydopamine (6-OHDA) rats, subsequently affecting gastric emptying. SNP could well improve the relaxation of pylori in 6-OHDA rats. The present study provides new insight into the diagnosis and treatment of delayed gastric emptying in patients with PD.


Autographa californica MNPV nucleocapsid assembly: inhibition by cytochalasin D.
Autographa californica nuclear polyhedrosis virus (AcMNPV) is a large, double-stranded DNA virus of lepidopteran insects. It replicates in the nucleus of host cells and produces two different infectious forms. One of them buds from the plasma membrane and is responsible for systemic infection in insects and for the spread of infection in cell culture. Earlier we reported that cytochalasin D (CD) inhibited the production of this form of the virus in infected IPLB-SF-21 cells by a mechanism other than the prevention of budding [L. E. Volkman, P. A. Goldsmith, and R. T. Hess (1987). Virology 156, 32-39]. Herein we present evidence that CD interferes with proper nucleocapsid assembly which indicates that microfilaments are involved in this nuclear process. The observation that phalloidin localizes in the nuclei of 24-hr infected cells in the absence, but not in the presence, of CD supports this hypothesis. Viral DNA replication and synthesis of the major capsid antigen and its transport to the nucleus are not inhibited by CD.


Gram staining of gallbladder bile samples is useful for predicting surgical site infection in acute cholecystitis patients undergoing an early cholecystectomy.
Microbiological assessment of gallbladder bile is important for postoperative management in cholecystectomy for acute cholecystitis (AC). Gram staining is used as the first step in the assessment, in order to preliminarily detect bacteria in the bile sample. This study was conducted to evaluate the clinical significance of Gram staining results in the development of postoperative surgical site infection (SSI) in AC patients. A total of 428 AC patients, who underwent an early cholecystectomy with microbiological assessment of gallbladder bile, were enrolled in this retrospective study. The clinical usefulness of the Gram staining results was evaluated by univariate and multivariate regression analyses. Of the 428 patients, 298 patients (69.6%) were diagnosed with bile infection by the Gram staining method. The rate of SSI was higher in patients with bile infection (9.7%) than in those without the infection (0.8%). The multivariate analysis indicated that the bile infection diagnosed by Gram staining (odds ratio: 9.091; P = .033) was an independent factor to predict SSI development, along with open surgery. Gram staining diagnosis of bile infection in an early cholecystectomy for AC is useful for predicting postoperative SSI development, which should benefit postoperative management.


Development of UPLC-MS/MS method for the determination of colistin in plasma and kidney and its application in pharmacokinetics.
Recently, the frequent emergence of multidrug-resistant gram-negative bacterial infections has forced colistin to be used as one of the last-line options for the treatment of these infections. This study aimed to establish and validate a simple, rapid, and reliable method for the quantitative determination of colistin in plasma and kidney homogenates by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The pharmacokinetic parameters of colistin sulfate in rats and the relationship between renal accumulation and time of administration in rats were estimated by measuring plasma and renal colistin concentrations. The colistin in the sample was precipitated by acetonitrile, followed by extraction with nitrogen blow-drying and reconstitution. The chromatographic separation of analytes was conducted on an C18 column using a mobile phase consisting of 0.1% aqueous formic acid and acetonitrile. Polymyxin B was used as an internal standard (IS). Colistin and IS were monitored in positive ion mode with the following mass transition pairs: m/z 585.6→m/z 101.4 for colistin A,m/z 578.6→m/z 101.4 for colistin B and m/z 595.6→m/z 227.2 for IS, respectively. The established method expressed good linearity in 50 - 20000 ng·mL-1 of colistin, with the lower limit of quantification (LLOQ) of 50 ng·mL-1. Methodology validations, including accuracy, precision, matrix effect, recovery, stability, and dilution integrity met the US Food and Drug Administration (FDA) acceptance criteria for bioanalytical method validation. Noncompartmental pharmacokinetic parameters were obtained by the statistical moment theory. The estimates for the terminal half-life (t1/2), the peak time (Tmax), the peak concentration (Cmax), the area under the plasma concentration-time curve (AUC0-t), the volume of distribution (V), the total body clearance (CL) and the mean residence time (MRT0-t) were calculated to be 2.53 ± 1.6 h, 2.17 ± 1.57 h, 2913.01 ± 644.89 ng·mL-1, 15153.46 ± 3599.81 h·ng·mL-1, 0.98 ± 0.56 L·kg-1, 0.28 ± 0.09 L·h-1·kg-1 and 4.07 ± 1.13 h, respectively. And the concentrations of colistin in rat kidney tissue after continuous administration for 1, 3, 5, 7 days were 1.49 ± 0.35 μg·g-1, 2.88 ± 0.74 μg·g-1, 3.40 ± 0.25 μg·g-1 and 4.33 ± 0.63 μg·g-1, respectively. The established method provided a convenient, rapid, stable, sensitive, accurate way for the determination of colistin concentration, which has been successfully used for the pharmacokinetic analysis of colistin sulfate in rat and to explore the relationship between the renal accumulation of colistin and the duration of dosing.


Spatial Characterization of Tumor-Infiltrating Lymphocytes and Breast Cancer Progression.
Tumor-infiltrating lymphocytes (TILs) have been established as a robust prognostic biomarker in breast cancer, with emerging utility in predicting treatment response in the adjuvant and neoadjuvant settings. In this study, the role of TILs in predicting overall survival and progression-free interval was evaluated in two independent cohorts of breast cancer from the Cancer Genome Atlas (TCGA BRCA) and the Carolina Breast Cancer Study (UNC CBCS). We utilized machine learning and computer vision algorithms to characterize TIL infiltrates in digital whole-slide images (WSIs) of breast cancer stained with hematoxylin and eosin (H&E). Multiple parameters were used to characterize the global abundance and spatial features of TIL infiltrates. Univariate and multivariate analyses show that large aggregates of peritumoral and intratumoral TILs (forests) were associated with longer survival, whereas the absence of intratumoral TILs (deserts) is associated with increased risk of recurrence. Patients with two or more high-risk spatial features were associated with significantly shorter progression-free interval (PFI). This study demonstrates the practical utility of Pathomics in evaluating the clinical significance of the abundance and spatial patterns of distribution of TIL infiltrates as important biomarkers in breast cancer.


Filling the gap: Cloze probability and sentence constraint norms for 807 European Portuguese sentences.
Sentence processing is affected by the sentence context and word expectancy. To investigate sentence comprehension experimentally, it is useful to have sentence completion norms with both context constraint and word expectancy measures. In this study, two experiments were conducted to collect norms for completion of 807 European Portuguese sentences. Context constraint was measured through type-token ratio and proportion idiosyncratic responses, while word expectancy was assessed by cloze probability. Besides establishing norms for a large sample of sentences, the study investigated the impact of the production procedure and method of analysis. In Experiment 1, a single-production procedure was used, i.e., participants completed each sentence fragment with only a single response, whereas in Experiment 2, a multiple-production procedure was used, i.e., participants have to provide up to three completion words for each sentence fragment. In Experiment 2, the analyses were obtained using two distinct methods: first-response analysis and combined-response analysis. The results showed that cloze and context measures are comparable between production paradigms and that the results from both analysis methods were correlated. The advantages of each production procedure and analysis method are discussed.


Modulation of the amino acid control of hepatic protein degradation by caloric deprivation. Two modes of alanine co-regulation.
Intracellular protein degradation in perfused livers of fed rats has been shown to be directly regulated by 7 amino acids (Leu, Tyr, Gln, Pro, Met, His, and Trp) and co-regulated by alanine. Responses to graded increases of regulatory amino acids (individually or combined) are multiphasic and include (a) an initial inhibition at 0.5 times normal plasma concentrations, (b) a localized, zonal loss of inhibition at normal levels, and (c) suppression to basal rates at 4 times normal concentrations or greater; the zonal loss of inhibition is prevented by 0.5 mM (normal) alanine. In further perfusion studies carried out at the usual time (1100 h), we have occasionally observed a sharp decrease in proteolytic responsiveness at normal amino acid concentrations. The decrease, which occurred spontaneously in normal fed rats, was attributed to a nearly 90% loss in the sensitivity of alanine co-regulation. In all instances, alanine sensitivity was restored after 4 to 24 h of starvation. The cause of the insensitivity and the mechanism of its reversal by caloric deprivation are not presently known. Starvation for 24 h also appeared to alter the individual inhibitory effectiveness of Leu, Tyr, and Gln. On the other hand, inhibition by the full regulatory group at 4 times normal plasma levels was unchanged when compared with the complete plasma mixture except for a concentration shift in the peak zonal loss of proteolytic inhibition from 1.25 to 0.6 times plasma levels. Since the shift paralleled known changes in portal vein regulatory amino acids, it may have been adaptive in nature. As with fed animals, the zonal loss in starvation was abolished by 0.5 mM alanine, but not with high levels of lactate and pyruvate (10 mM), a finding consistent with the view that co-regulation is mediated by the recognition of alanine per se rather than its metabolism.


Effectiveness of virtual reality on functional mobility during treadmill training in children with cerebral palsy: a single-blind, two-arm parallel group randomised clinical trial (VirtWalkCP Project).
Treadmill training and virtual reality have been investigated in children with cerebral palsy. However, few studies have assessed the effectiveness of the combination of both treatments on children's functional and balance activities. The project aims to compare the effects of treadmill training with and without virtual reality on walking endurance and speed, static and dynamic balance, gross motor function, functional independence, quality of life and occupational participation in children with spastic cerebral palsy between the ages of 4 and 12 years classified at levels I, II and III of the Gross Motor Function Classification System. This study is a single-blind, two-arm parallel group, randomised, controlled clinical trial. Participants will be recruited at the Pediatric Department of the Vic Hospital Consortium, and the research will be conducted at the University of Vic - Central University of Catalonia. The participants will be randomly allocated into two groups: (1) the experimental group, which will receive the treadmill training at the same time as the virtual reality; and (2) the control group, which will undertake treadmill gait training alone. The training will be provided in 10 sessions over 2 weeks with 30 min for each session. Assessments will be performed on three occasions: 1 week before the intervention, 1 week following the intervention and 1 month after the end of the intervention. The evaluations will involve the 6 min walk test, stabilometry, the Berg Balance Scale, the 10 m walk test, the Gross Motor Function Measure, the Functional Independence Measure, the paediatric quality of life inventory and the Children Participation Questionnaire. For between-within group comparison, a mixed-effect linear model will be used. The study has been approved by the Clinical Research Ethics Committee of the Osona Foundation for Health Research and Education (2021061). Results will be published in peer-reviewed journals and presented at international conferences. NCT05131724.


Heteroatom- and carbon-linked biphenyl analogs of Brequinar as immunosuppressive agents.
Structure-activity relationships were explored for some analogs of Brequinar having a linking atom between the 2-biphenyl substituent and the quinoline ring. Activities as inhibitors of dihydroorotate dehydrogenase and the mixed lymphocyte reaction were related to the overall shape and lipophilicity of the 2-substituent.


A case of human cystic echinococcosis acquired in Ireland.
Cystic echinococcosis (CE) is caused by the cestodes of the Echinococcus granulosus sensu lato complex and, in the majority of cases, is associated with hepatic or pulmonary involvement. Human CE is not thought to be endemic in Ireland. We describe the first reported case of human CE possibly acquired in Ireland.


Chronic Chlamydia pneumoniae infection increases the risk of occlusion of lumbar segmental arteries of patients with sciatica: a 3-year follow-up study.
A magnetic resonance imaging follow-up study of lumbar arteries among patients with sciatica with chronic Chlamydia pneumoniae infection. To determine whether chronic infection causes occlusion of lumbar arteries. C. pneumoniae infection is associated with coronary heart disease, and the infectious pathogen has also been detected in abdominal aortic aneurysms and in atherosclerotic plaques. No studies are available on the effect of this infectious agent on lumbar arteries. Chronic infection was defined as persistent high positive immunoglobulin G and/or immunoglobulin A antibodies and/or the presence of immune complexes. The lumbar arteries, evaluated with two-dimensional time-of-flight magnetic resonance angiography, were scored as normal, narrowed, or occluded. The differences in the segmental and whole lumbar spine (segments L1-L4) sum of arterial occlusion at baseline and at 3 years, and the incidence of new arterial stenosis were compared in patients with and without chronic infection using the Kolmogorov-Smirnov test. Patients with chronic infection were more likely to be persistent smokers (P = 0.006), male (P = 0.04), and more obese (P = 0.02) compared to patients with normal antibody levels. They had significantly higher degree of arterial stenosis at L4 segment at baseline and at 3 years (P = 0.001 and 0.002, respectively), in the whole lumbar spine at baseline and at 3 years (P < 0.001 for both), and at L1 and L3 segments at 3 years (P = 0.013 for both). The incidence of new arterial stenosis was similar in both patient groups. Patients with chronic infection also had significantly higher grade of endplate degeneration at L4-L5 (P = 0.008). The results of this study suggest that chronic C. pneumoniae infection may induce stenosis of lumbar arteries.


Estrogen replacement therapy: current recommendations.
Estrogen replacement therapy is effective for the prevention and treatment of postmenopausal osteoporosis and should be offered to all women at high risk for osteoporosis. Such therapy is particularly beneficial for prevention of spinal compression fractures; in addition, it alleviates menopausal symptoms (hot flushes, genitourinary symptoms, and changes in mood). In each patient, these benefits must be weighted against the potential risks of endometrial hyperplasia and carcinoma, breast tenderness, hypertension, vascular headaches, and the inconvenience of menstrual bleeding if the uterus is intact. The risk of endometrial cancer associated with estrogen replacement therapy can be considerably reduced by the addition of a progestin, and other side effects can be diminished or eliminated by use of the new transdermal estrogen preparations. Thus, estrogen replacement therapy should be considered in all women who have experienced natural or surgically induced menopause, and it is advisable in women who have osteoporosis or an increased risk for this disorder and no contra-indications to its use. Estrogen replacement therapy should be instituted as soon after menopause as possible and seems to be well tolerated until at least 75 years of age.


Secular Trends in the Cost of Immunosuppressants after Solid Organ Transplantation in the United States.
Immunosuppressive medications are critical for maintenance of graft function in transplant recipients but can represent a substantial financial burden to patients and their insurance carriers. To determine whether availability of generic immunosuppressive medications starting in 2009 may have alleviated some of that burden, we used Medicare Part D prescription drug events between 2008 and 2013 to estimate the average annualized per-patient payments made by patients and Medicare in a large national sample of kidney, liver, and heart transplant recipients. Repeated measures linear regression was used to determine changes in payments over the study period. Medicare Part D payments for two commonly used immunosuppressive medications, tacrolimus and mycophenolic acid (including mycophenolate mofetil and mycophenolate sodium), decreased overall by 48%-67% across organs and drugs from 2008 to 2013, reflecting decreasing payments for brand and generic tacrolimus (21%-54%), and generic mycophenolate (72%-74%). Low-income subsidy payments, which are additional payments made under Medicare Part D, also decreased during the study period. Out-of-pocket payments by patients who did not receive the low-income subsidy decreased by more than those who did receive the low-income subsidy (63%-79% versus 24%-44%). The decline in payments by Medicare Part D and by transplant recipients for tacrolimus and mycophenolate between 2008 and 2013 suggests that the introduction of generic immunosuppressants during this period has resulted in substantial cost savings to Medicare and to patients, largely reflecting the transition from brand to generic products.


[The value of 3 dimensional-fat suppression-spoiled gradient-recalled acquisition sequence on single compartment osteoarthritis for unicompartmental arthroplasty preoperative assessment].
To analyze the 3 dimensional-fat suppression-spoiled gradient-recalled acquisition (3D-FS-SPGR) sequence in the diagnosis of knee articular cartilage injury. A total of 56 knee osteoarthritis patients (26 males, 30 females, ages 52-73 years, mean 61.8 years) treated in Department of Orthopedics, Chinese People's Liberation Army General Hospital between June 2013 and May 2014 were involved in this study. All patients underwent knee MRI, plus 3D-FS-SPGR sequence, arthroscopic exploration, and in contrast to the results of MRI results analysis, evaluation 3D-FS-SPGR and conventional sequence of cartilage damage consistent with the arthroscopic accuracy. Divided 56 knee joints into 336 cartilage articular surface, included 55.1% normal articular surface, 21.4% early osteoarthritis and 23.5% advanced osteoarthritis. The accordance of 3D-FS-SPGR sequence grading and arthroscopic was 90.2%. The sensitivity of 3D-FS-SPGR sequence was 93.1%, specificity was 98.3%, and Kappa value was 0.849. The sensitivity of T2WI sequence was 84.4%, specificity was 96.9%, and the Kappa value was 0.671. For unicompartment osteoarthritis , MRI 3D-FS-SPGR sequence is effective in sensitivity and specificity of cartilage damage.