[Behavior of various enzyme activities during high blood lactate and pyruvate levels in albino rats reared in a normobaric hypoxic atmosphere for 1 or 2 generations].
Albino rats Wistar family raised in normobaric hypoxic environment (10% O2 in N2) since one or two generations showed an increase in arterial blood creatine-kinase, glutamate-dehydrogenase, lactic-dehydrogenase, lactate and pyruvate when compared with normoxic controls. Moreover the values found in hypoxic rats of second generation were intermediate between those found in hypoxic rats of first generation and normoxic controls. These differences are probably due to an improved efficiency of the processes of cellular adaptation to the hypoxic environment when named species remain in hypoxic environment for more than one generation.


[A clinical analysis of glucagonoma syndrome (four cases reported)].
To study the clinical features, diagnosis, and treatment of glucagonoma syndrome (GS) for providing clues for the recognition of this disorder in clinical practice. The clinical and laboratory findings of four confirmed patients with GS were analyzed retrospectively. All four patients had typical clinical manifestations of necrolytic migratory erythema (NME), elevated glucagon level in serum and hepatic metastasis. The skin rashes disappeared gradually and serum glucagon level decreased after operation and somatostatin treatment. NME is the most specific clinical finding of GS. Biopsy of the lesions, glucagon level in serum and various radiological examinations should be done in order to confirm the diagnosis. Surgical resection, chemotherapy, and somatostatin are the main therapies of GS.


Rethinking glutamine addiction.
Tumours reprogram their metabolism to maximize macromolecule biosynthesis for growth. However, which of the common tumour-associated metabolic activities are critical for proliferation remains unclear. Glutamate-derived glutamine is now shown to satisfy the glutamine needs of glioblastoma, indicating that glutamine anaplerosis is dispensable for growth.


Stimulation of fat storage by prostacyclin and selective agonists of prostanoid IP receptor during the maturation phase of cultured adipocytes.
We have previously shown that cultured adipocytes have the ability to biosynthesize prostaglandin (PG) I2 called alternatively as prostacyclin during the maturation phase by the positive regulation of gene expression of PGI synthase and the prostanoid IP receptor. To clarify how prostacyclin regulates adipogenesis, we investigated the effects of prostacyclin and the specific agonists or antagonists for the IP receptor on the storage of fats during the maturation phase of cultured adipocytes. Exogenous PGI2 and the related selective agonists for the IP receptor including MRE-269 and treprostinil rescued the storage of fats attenuated by aspirin, a cyclooxygenase inhibitor. On the other hand, selective antagonists for IP such as CAY10441 and CAY10449 were effective to suppress the accumulation of fats as GW9662, a specific antagonist for peroxisome proliferator-activated receptor (PPAR)γ. Thus, pro-adipogenic action of prostacyclin can be explained by the action mediated through the IP receptor expressed at the maturation stage of adipocytes. Cultured adipocytes incubated with each of PGI2 and MRE-269 together with troglitazone, an activator for PPARγ, exhibited additively higher stimulation of fats storage than with either compound alone. The combined effect of MRE-269 and troglitazone was almost abolished by co-incubation with GW9662, but not with CAY10441. Increasing concentrations of troglitazone were found to reverse the inhibitory effect of CAY10441 in a dose-dependent manner while those of MRE-269 failed to rescue adipogenesis suppressed by GW9662, indicating the critical role of the PPARγ activation as a downstream factor for the stimulated adipogenesis through the IP receptor. Treatment of cultured adipocytes with cell permeable stable cAMP analogues or forskolin as a cAMP elevating agent partly restored the inhibitory effect of aspirin. However, excess levels of cAMP stimulated by forskolin attenuated adipogenesis. Supplementation with H-89, a cell permeable inhibitor for protein kinase A (PKA), had no effect on the promoting action of PGI2 or MRE-269 along with aspirin on the storage of fats, suggesting that the promotion of adipogenesis mediated by the IP receptor does not require the PKA activity.


When a Differential Diagnosis Is Fundamental: Choriocarcinoma Mimicking Lung Carcinoma.
Background: Choriocarcinoma is a rare malignant disease that is usually associated with a gestational event. Lung metastasis with no evident primary origin and choriocarcinoma, which mimics features of non-small-cell lung cancer, might be misdiagnosed as adenocarcinoma or large-cell carcinoma. This is a pivotal clinical concern since the tumor can lead to various symptoms, seriously affecting the quality of life and can escalate rapidly, with a high mortality rate, compared to lung cancer. Methods: We reported a case of a 37-year-old woman with a history of one-year enhancement of beta-human chorionic gonadotropin levels and only a single nodule in the right upper lobe, with no abnormal findings on the gynecological investigation. Then we retrospectively examined all cases treated in the Division of Thoracic Surgery at the European Institute of Oncology in the last twenty years (from 1998 to 2018). Results: This was the first time in our experience that choriocarcinoma presentation was with a single nodule without a gynecological finding. Moreover, the differential diagnosis between lung carcinoma and choriocarcinoma was achieved only after surgical removal. Conclusions: As confirmed by our literature search, precise and expedited differential diagnosis is essential in choriocarcinoma care (both with single or multiple metastases), to successfully remove the tumor and increase the patient's chances of survival.


Anoikis resistance conferred by tenascin-C-derived peptide TNIIIA2 and its disruption by integrin inactivation.
Glioblastoma multiforme (GBM), the most common brain tumor in adults, has an extremely poor prognosis, which is attributed to the aggressive properties of GBM cells, such as dysregulated proliferation and disseminative migration. We recently found that peptide TNIIIA2, derived from tenascin-C (TNC), which is highly expressed in GBM, contributes to the acquisition of these aggressive properties through β1-integrin activation. In general, cancer cells often acquire an additional malignant property that confers resistance to apoptosis due to loss of adhesion to the extracellular matrix, termed anoikis resistance. Our present results show that regulation of β1-integrin activation also plays a key role in both the development and loss of anoikis resistance in GBM cells. Despite being derived from a GBM with an extremely poor prognosis, the human GBM cell line T98G was susceptible to anoikis but became anoikis resistant via treatment with peptide TNIIIA2, which is able to activate β1-integrin. The TNIIIA2-conferred anoikis resistance of T98G cells was disrupted by further addition of peptide FNIII14, which has the ability to inactivate β1-integrin. Moreover, anchorage-independent survival of GBM cells in suspension culture was abrogated by peptide FNIII14, but not by RGD and CS-1 peptides, which are antagonistic for integrins α5β1, αvβ3, and α4β1. These results suggest that GBM cells develop anoikis resistance through activation of β1-integrin by TNC-derived peptide TNIIIA2, which is abundantly released into the tumor microenvironment of GBM. Inactivation of β1-integrin may provide a promising strategy to overcome the apoptosis resistance of cancer cells, including GBM.


Intraoperative indocyanine green fluorescence cholangiography can rule out biliary atresia: A preliminary report.
The prognosis of BA is known to be poor if definitive surgery is performed too late. Therefore, excluding BA as a diagnosis at an early stage is crucial. Conventional cholangiography requiring cannulation through the gallbladder may be unnecessarily invasive for patients, especially when ruling out BA. Therefore, a less invasive alternative such as indocyanine green (ICG) cholangiography, which does not require cannulation, should be established. In this study, we focused on excluding BA and confirmed the usefulness of intravenous ICG fluorescence cholangiography. To the best of our knowledge, this is the first preliminary study to report the use of intravenous ICG cholangiography for BA exclusion. The study participants were patients who underwent liver biopsy and intraoperative cholangiography after they were suspected to have BA, between 2013 and 2022. ICG fluorescence cholangiography was performed on all patients who provided informed consent. During the study period, 88 patients underwent a laparoscopic liver biopsy and cholangiography. Among them, 65 (74%) were diagnosed with BA and underwent a subsequent laparoscopic Kasai portoenterostomy. BA was ruled out intraoperatively in 23 patients. Of the 23 patients in whom BA was ruled out, 14 underwent ICG cholangiography, 11 had gallbladder (GB) fluorescence, and 9 had both GB and common bile duct (CBD) fluorescence. Conventional cholangiography was very difficult in 2 of 23 cases: in 1 case, cannulation of the atrophic gallbladder was impossible, and cholecystectomy was indicated after multiple attempts; in 1 case, upstream cholangiography was not possible. In both cases, ICG fluorescence cholangiography successfully imaged the CBD and the GB. In conclusion, intravenous ICG fluorescence cholangiography might be a useful and less invasive diagnostic procedure that can rule out BA in infants.


Biotransformation of drugs in rats treated with a synthetic muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP).
Natural immunoadjuvant mixtures like BCG and FCA are known to produce gross alterations of drug-metabolizing systems in the rat. Since it has been shown that the smallest structure of various bacterial peptidoglycans, possessing adjuvant activity, is muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), the possibility has been tested whether this substance is involved in production of the observed metabolic changes. Synthetic compound was applied subcutaneously for the period of 21 days, and the in vitro activity of 7-ethoxycoumarin-O-de-ethylase, aminopyrine-N-demethylase, together with the microsomal content of cytochrome P-450 and b5, and the in vivo acetylation of sulphadimidine, were investigated. No effect of MDP on any of these tests was noted in both the Lewis arthritic strain and the AVN disease-free strain. It is suggested that MDP is metabolically inactive and that the defects in metabolism of drugs, following bacterial-adjuvant treatment, are likely to be due to some additional cell-wall components, other than peptidoglycans. Furthermore, our data support the view of no relationship between the development of metabolic changes and the established arthritic lesions in rats.


The effects of three cold plasma treatments on the osteogenic activity and antibacterial property of PEEK.
This study examines the differences in osteogenic activity and antibacterial property among polyetheretherketone (PEEK) treated by three types of cold plasma. Standard PEEK specimens were randomly assigned to four groups, which were named according to the treatment: PEEK-C (untreated), PEEK-A (Ar cold plasma treatment), PEEK-N (N2 cold plasma treatment), and PEEK-AN (90% Ar and 10% N2 mixed cold plasma treatment). Physical and chemical properties of the specimen surfaces were determined by scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and drop shape analyzer (DSA). MC3T3 osteoblasts were used in vitro to determine the osteogenic activity by cell adhesion morphology observation, cell counting-kit 8 (CCK-8) assay, and alkaline phosphatase (ALP) activity assay. Streptococcus mutans and Staphylococcus aureus were used in vitro to determine the antibacterial property by a plate colony-counting method and bacterial adhesion morphology observation. SEM and AFM analysis showed that the PEEK-C surface was smooth, whereas matrix-arranged nanoprotrusions appeared on the surface of the experimental groups: scaly nano-protrusions appeared on the PEEK-A and PEEK-AN surfaces, while dendritic nanoprotrusions appeared on the PEEK-N surface. Among the experimental groups, PEEK-AN had the finest surface nanoprotrusions. The roughness of the experimental groups increased compared with the PEEK-C group: the PEEK-N group was the roughest with a Ra of 192.60 ± 5.89 nm and PEEK-A was the smoothest with a Ra of 99.60 ± 5.43 nm. The hydrophilicity of the experimental groups was significantly enhanced compared with the PEEK-C group, among which, PEEK-N was the strongest and PEEK-A the weakest. The osteogenic activity and antibacterial property of the experimental groups displayed a remarkable increase compared with the PEEK-C group. Among the experimental groups, PEEK-N displayed the best osteogenic activity while PEEK-AN possessed the strongest antibacterial property. The osteogenic activity and antibacterial performance of PEEK-A were the weakest. Among these treatments, the N2 cold plasma treatment was the most suitable modification method for PEEK application in dental implant. Cold plasma treatment is a promising method to improve PEEK osteogenic activity and antibacterial properties. This study provides a theoretical basis for future research on PEEK cold plasma treatment.


[Renal resistance index in patients with obstructive sleep apnea].
Previous studies have demonstrated renal dysfunction in patients with obstructive sleep apnea (OSA). The renal resistance index (RI) measured by renal duplexsonography (RI = 1-[enddiastolic velocity/peak systolic velocity]) is at the same time a marker of parenchymal renal damage and predictor of the progression of renal dysfunction. It was the aim of this study to test the influence of OSA on RI. RI was compared between patients with (n = 97) and those without OSA (n = 61). The impact of OSA on the RI was analysed by adjusting for age. Thus, the difference between the measured RI and the age-based RI was expressed as a percentage of the normal age-adjusted value (RI (%)). OSA patients showed a trend towards an increase in RI (69.1+/-8.8 vs. 66.5+/-8.3 %, p = 0.068) and RI (%) (10.2+/-12.9 vs. 6.4+/-11.4 %, p = 0.060), respectively. In patients with mild or moderate OSA (apnea-hypopnea-index [AHI] 5 - 30/h) this difference was significant (RI: 70.5+/-9.1 vs. 66.5+/-8.2, p = 0.012; RI (%): 12.1+/-13,4 vs. 6.5+/-11.4 %, p = 0.012). RI of patients with severe OSA did not significantly differ from those without OSA. In patients with mild and moderate OSA there was a significant linear association between AHI and RI or RI (%). This association was independent of hypertension or diabetes. An impairment of renal perfusion and renal parenchymal damage due to increased sympathetic activity may promote renal dysfunction in patients with obstructive sleep apnea.


Comprehensive dose evaluation of a Deep Learning based synthetic Computed Tomography algorithm for pelvic Magnetic Resonance-only radiotherapy.
Magnetic Resonance (MR)-only radiotherapy enables the use of MR without the uncertainty of MR-Computed Tomography (CT) registration. This requires a synthetic CT (sCT) for dose calculations, which can be facilitated by a novel Zero Echo Time (ZTE) sequence where bones are visible and images are acquired in 65 seconds. This study evaluated the dose calculation accuracy for pelvic sites of a ZTE-based Deep Learning sCT algorithm developed by GE Healthcare. ZTE and CT images were acquired in 56 pelvic radiotherapy patients in the radiotherapy position. A 2D U-net convolutional neural network was trained using pairs of deformably registered CT and ZTE images from 36 patients. In the remaining 20 patients the dosimetric accuracy of the sCT was assessed using cylindrical dummy Planning Target Volumes (PTVs) positioned at four different central axial locations, as well as the clinical treatment plans (for prostate (n = 10), rectum (n = 4) and anus (n = 6) cancers). The sCT was rigidly and deformably registered, the plan recalculated and the doses compared using mean differences and gamma analysis. Mean dose differences to the PTV D98% were ≤ 0.5% for all dummy PTVs and clinical plans (rigid registration). Mean gamma pass rates at 1%/1 mm were 98.0 ± 0.4% (rigid) and 100.0 ± 0.0% (deformable), 96.5 ± 0.8% and 99.8 ± 0.1%, and 95.4 ± 0.6% and 99.4 ± 0.4% for the clinical prostate, rectum and anus plans respectively. A ZTE-based sCT algorithm with high dose accuracy throughout the pelvis has been developed. This suggests the algorithm is sufficiently accurate for MR-only radiotherapy for all pelvic sites.


Colonization of hospital water systems by legionellae, mycobacteria and other heterotrophic bacteria potentially hazardous to risk group patients.
Occurrences of legionellae and nontuberculous mycobacteria were followed in water systems of a tertiary care hospital where nosocomial infections due to the two genera had been verified. The aim was to examine whether their occurrence in the circulating hot water can be controlled by addition of a heat-shock unit in the circulation system, and by intensified cleaning of the tap and shower heads. One hot water system examined had an inbuilt heat-shock system causing a temporary increase of temperature to 80 degrees C, the other was an ordinary system (60 degrees C). The heat-shock unit decreased legionella colony counts in the circulating hot water (mean 35 cfu/l) compared to the ordinary system (mean 3.6 x 10(3) cfu/l). Mycobacteria constantly present in the incoming cold water (mean 260 cfu/l) were never isolated from the circulating hot water. Water sampled at peripheral sites such as taps and showers contained higher concentrations of legionellae, mycobacteria, and mesophilic and Gram-negative heterotrophs than the circulating waters. The shower water samples contained the highest bacterial loads. The results indicate the need to develop more efficient prevention methods than the ones presently used. Prevention of mycobacteria should also be extended to incoming cold water.


Endoscopic treatment of vesicoureteral reflux with polydimethylsiloxane in adults: do location and appearance of the ureteric orifice have a role in the success rates?
Low success rate for high grade reflux and anatomical abnormality of ureteric orifices continues to be the most important dilemma of the endoscopic treatment of vesicoureteral reflux (VUR). The aim of this study was to evaluate the efficacy of endoscopic polydimethylsiloxane injection in adults with VUR concerning reflux severity and the status of the ureteric orifice. Fifty-three ureters (34 patients) were treated with endoscopic polydimethylsiloxane injection. The grade of VUR was I, II, III, IV and V in 2, 13, 25, 10 and 3 ureters, respectively. Any endoscopic characteristics of 'golf hole', broad appearance or lateral placement of ureteric orifices were classified as complex appearance ureters (CAU). Patients with persistent reflux were considered for second and third injections with the same material. Success was determined as no reflux. The total success rate was 100, 92.30, 92, 80 and 66.66% for grade I, II, III, IV and V reflux after the third injection, respectively. The cure rates of ureters with normal appearance were 100, 88.88, 90, 100 and 100% for grade I, II, III, IV and V reflux. The cure rates of CAU were 100% for both grade II and III, 60% for grade IV and 50% for grade V reflux. The injected volumes per renal unit ranged between 0.2 and 3.2 ml (mean 1.05 ml). Although there are disadvantages in the usage of higher volumes of injectable material for successful results and difficulty in subureteral injection both in high grade reflux and complex anatomical situations in adults when compared to children, our results indicate that endoscopic treatment of VUR is an effective therapy for adults.


The hammer and the nail: The triple lock of methods, realities and institutional contexts in Australian research on nightlife violence.
There is considerable public and policy debate in Australia about measures to reduce violence associated with alcohol and young people in the night-time economy. Though overrepresented in violence, the role of men and masculinities is rarely explicitly addressed in policy responses to such violence, which rest on a narrow range of mainly quantitative research and recommendations favouring blanket alcohol restrictions. Drawing on John Law and colleagues' account of the 'double social life of methods' (2011), we analyse interviews conducted with Australian quantitative researchers about the role of gender in such violence. According to Law et al., methods inhabit and reproduce particular ecologies and reflect the concerns of those who advocate them. From this 'triple lock' of methods, realities, and institutional advocacies and contexts emerges particular modes of knowing. Participants described a research ecology in which the authority of quantitative research methods emerged in relation to an imperative to respond in a 'timely' and 'pragmatic' fashion to public policy debates, and prevailing governmental and policy priorities and public framings of violence. Though participants frequently acknowledged the role of men in violence, these arrangements sustain taken-for-granted assumptions about the properties and effects of alcohol while displacing men and masculinities from policy attention. The political consequences of these arrangements demand the development of innovative policy responses and new modes of knowing that make visible the gendering of violence.


Control of respiration in proteoliposomes containing cytochrome aa3. II. Inhibition by carbon monoxide and azide.
1. Carbon monoxide (CO) acts competitively towards oxygen when the latter is taken up in respiration by cytochrome aa3-containing proteoliposomes, both in the presence of p-trifluoromethoxy carbonyl cyanide phenylhydrazone and valinomycin (deenergized state) and in their absence (energized state). At high levels of CO, the double reciprocal plots (1/v vs. 1/[O2]) in the energized and deenergized states are parallel, i.e. energization acts "anti-competitively" towards oxygen, and the "respiratory control ratio" decreases as the oxygen concentration decreases. 2. Azide acts non-competitively towards cytochrome c when the latter is oxidized by cytochrome aa3-containing proteoliposomes both in the energized and deenergized (plus p-trifluoromethoxy carbonyl cyanide phenylhydrazone and valinomycin) conditions. At low azide concentrations the apparent Ki for azide is unaffected by energization, but at high azide levels the Ki increases in energized liposomes, i.e. the "respiratory control ratio" decreases as the azide concentration increases. 3. It is concluded that the inhibitor experiments are consistent with but do not prove the concept that the oxidase molecules in a single vesicle are responding to a single "energization state" or set of electrochemical gradients. This and other models are discussed.


Medical hypnosis during therapeutic embolizations of the carotid and vertebral arteries.
Iatrogenic neurological deficit constitutes the greatest risk during therapeutic embolization in the vascular territories of the carotid and vertebral arteries. Constant monitoring of the patient's neurological status is therefore essential. The authors discuss the use of medical hypnosis to circumvent general anesthesia and to reduce chemical sedation to a minimum. Their experience with this technique is presented.


Quantitative measures for assessing rheumatoid arthritis in clinical trials and clinical care.
There is no single 'gold standard' quantitative measure to assess and monitor the clinical status in patients with rheumatoid arthritis (RA). Therefore, a variety of measures have been used in clinical research and clinical care, including laboratory tests, radiographic scores, formal joint counts, physical measures of functional status, global measures and patient self-report questionnaires. These measures may address disease activity, joint damage, both activity and damage, or long-term outcomes. Measures of disease activity, such as joint swelling, are reversible and are emphasized in clinical trials. However, activity measures may be improved over 5 years while measures of damage, such as radiographic score, indicate disease progression. Two quantitative indices which are widely used in clinical trials are the (1) American College of Rheumatology (ACR) Core Data Set, which includes swollen joint count, tender joint count, physician assessment of global status, acute-phase reactant-erythrocyte sedimentation rate or C-reactive protein, functional status, pain, patient estimate of global status, a radiograph in studies over 1 year or longer, and (2) the disease activity score(DAs), which includes a swollen joint count, tender joint count, acute-phase reactant, and patient assessment of global status. Randomized controlled clinical trials provide the optimal method to evaluate new therapies, by comparing a therapy with a placebo or another therapy without selecting patients for specific therapies. However, randomized trials in chronic diseases have important limitations, including a relatively short observation period, patient selection for inclusion and exclusion criteria, inflexible dosage schedules, influence of the design on results despite a control group, emphasis on group data while ignoring individual variation in treatment responses, non-standardized interpretation of adverse effects, and others. Therefore, clinical trials in RA must be supplemented by long-term observational studies to assess results of therapy in regard to long-term outcomes such as work disability, joint replacement surgery and premature mortality. The most simple and effective method of collecting important long-term data from patients in routine clinical care is through patient self-report questionnaires.


Pharmacokinetics and pharmacodynamics of physostigmine after intravenous administration in beagle dogs.
The time course of physostigmine (Phy), its metabolites and activity of cholinesterase (ChE) in plasma were studied after intravenous bolus administration of [3H]Phy (100 micrograms/kg) to beagle dogs. The maximal inhibition of ChE (78%) in plasma at 2 min correlated with the largest concentration of physostigmine (124 ng/ml). The concentration of physostigmine decreased by 88% to 16 ng/ml at 45 min when the activity of ChE was still 59% inhibited. Acetylcholinesterase activity in four regions of the brain (medulla, striatum, cerebellum and cortex) was not significantly different from controls at 70 +/- 5 min after administration of physostigmine. Concentrations of physostigmine and its metabolites determined by HPLC were not significantly different in different regions. In plasma, physostigmine was found, together with eseroline and two other metabolites M1 and M2. At 45 min, only 18% of total radioactivity was due to physostigmine and 52% was due to the major metabolite M1. On the contrary, in regions of the brain, metabolite M1 represented only 1.9-3.37% of total radioactivity at 70 +/- 5 min. Pharmacokinetic parameters, obtained in the dog, were compared to previously published data in rat and man. The elimination half-life (beta) was 30.7 min in the dog as compared to 15 min in rat and and 21.7 min in man. The Vd (ml/kg) was higher than total body water volume in all three species: dog (1832), rat (1352) and man (664), indicating sequestration of the drug in body compartments. Clearance (ml/min/kg) was found to be 41.2 in dog, which compares to 62 in rat and 22 in man.(ABSTRACT TRUNCATED AT 250 WORDS)


Research progress on the biosynthesis and delivery of iron-sulfur clusters in the plastid.
Iron-sulfur (Fe-S) clusters are ancient protein cofactors ubiquitously exist in organisms. They are involved in many important life processes. Plastids are semi-autonomous organelles with a double membrane and it is believed to originate from a cyanobacterial endosymbiont. By learning form the research in cyanobacteria, a Fe-S cluster biosynthesis and delivery pathway has been proposed and partly demonstrated in plastids, including iron uptake, sulfur mobilization, Fe-S cluster assembly and delivery. Fe-S clusters are essential for the downstream Fe-S proteins to perform their normal biological functions. Because of the importance of Fe-S proteins in plastid, researchers have made a lot of research progress on this pathway in recent years. This review summarizes the detail research progress made in recent years. In addition, the scientific problems remained in this pathway are also discussed.


Prolonged survival after splenectomy in Wiskott-Aldrich syndrome: a case report.
Wiskott-Aldrich syndrome is a rare X-linked immunodeficiency disorder that is characterized by a variable clinical phenotype. Matched donor bone marrow transplantation is currently the only curative therapeutic option. We present the case of a 24-year-old male who was diagnosed at the age of seven with Wiskott-Aldrich syndrome. He did not respond to intravenous gammaglobulin and he experienced recurrent pulmonary infections despite prophylactic antibiotics. The patient had no matched donor. At the age of nine, he was submitted to splenectomy and his platelet count was normalized. Fifteen years later, the patient remains asymptomatic with a normal platelet count. He is still receiving prophylactic antibiotics and no bleeding episodes or septic complications have been reported. This case demonstrates that splenectomy can represent a safe therapeutic option in selected WAS patients, provided that there is a tight follow-up program, patient education and adherence to guidelines regarding post-splenectomy prophylaxis.


Stromal micropapillary pattern and CD44s expression predict worse outcome in lung adenocarcinomas with micropapillary pattern.
This study aims to investigate the clinicopathologic characteristics of lung adenocarcinoma with micropapillary pattern (MPP) and the expression of CD44s and CD44v6 in MPP. A total of 202 patients diagnosed with primary lung adenocarcinoma with MPP were included. We estimated the proportion of MPP in each tumor tissue and divided MPP into aerogenous micropapillary pattern (AMP) and stromal micropapillary pattern (SMP). The expression of CD44s and CD44v6 was estimated by immunohistochemical staining. Clinicopathologic data were collected from the patients' medical records. We also collected patients' follow-up data and used PFS (progression-free survival) as a survival indicator. Lung adenocarcinoma with MPP had a high risk of pleural invasion, lymph node metastasis, in advanced TNM stage, and a high rate of EGFR mutation. The presence of SMP indicated a higher rate of pleural invasion, lymphovascular invasion, lymph node metastasis, and a worse PFS compared with pure AMP. We found high expression of CD44s in micropapillary, especially in AMP, while the absence of CD44s expression indicated shorter survival, which was an independent unfavorable factor for PFS. Lung adenocarcinoma with micropapillary pattern indicated an unfavorable prognosis, which had two different pattens, AMP and SMP. SMP indicated a worse survival than AMP, and was an independent unfavorable factor for PFS. So, AMP/SMP subclassification is necessary to evaluate patient's prognosis. Furthermore, the absent expression of CD44s in micropapillary indicated shorter survival, especially in patients with EGFR mutation. Herein, CD44s may be a biological marker for micropapillary lung adenocarcinoma.


Cytogenetic study in cultured human lymphocytes treated with three commonly used preservatives.
Potassium sorbate, sodium benzoate and potassium nitrate have been tested for their genotoxic, cytostatic and cytotoxic potential in human peripheral blood cells in vitro. Potassium nitrate has shown no activity in the test system. When potassium sorbate and sodium benzoate were used at concentrations of 2.0, 0.2 and 0.02 mM no cytostatic activity was detected. However, concentrations of 4 and 8 mM have shown a weak cytostaticity. Additionally, a genotoxic activity using the SCE methodology has been observed at 8 mM of sodium benzoate and at 4 and 8 mM of potassium sorbate. No cytotoxic activity has been induced by the three preservatives. Data demonstrate that the preservatives at low concentrations can be considered as non genotoxic under conditions tested.


Antibiosis/antixenosis in tulip tree and quaking aspen leaves against the polyphagous southern armyworm, Spodoptera eridania.
Previous studies have shown leaves of tulip tree, Liriodendron tulipifera L. (of the Magnoliaceae) and of Populus tremuloides Michx. (of the Salicaceae) to be antixenotic/antibiotic to many Lepidoptera, including one of the most polyphagous of all phytophagous insects, the southern armyworm, Spodoptera eridania Cramer (Noctuidae). We investigated the physiological responses to this phytochemical activity on neonate and late instar armyworm larvae in controlled environments with particular emphasis upon the leaf extracts containing condensed tannins and hydrolysable tannins. These tannin-containing extracts of tulip tree leaves and quaking aspen leaves were generally toxic to neonate larvae. For later instars, growth suppression was not due to digestibility-reduction, but instead to suppressed consumption rates and greatly increased metabolic (respiratory) costs as reflected in reduced biomass conversion efficiencies.


EMG and EEG biofeedback training in the treatment of a 10-year-old hyperactive boy with a developmental reading disorder.
The serial application of electromyographic (EMG) and sensorimotor (SMR) biofeedback training was attempted with a 10-year-old boy presenting a triad of symptoms: an attention deficit disorder with hyperactivity, developmental reading disorder, and ocular instability. Symptom elimination was achieved, for all three aspects of the triad, following the procedure of first conditioning a decrease in EMG-monitored muscle tension and then conditioning increases in the amplitude of sensorimotor rhythm over the Rolandic cortex. The learned reduction of monitored EMG levels was accompanied by a reduction in the child's motoric activity level to below that which had been achieved by past administration of Ritalin. In addition, the attention deficit disorder with hyperactivity was no longer diagnosable following the EMG biofeedback training. The learned increase in the amplitude of monitored SMR was accompanied by remediation of the developmental reading disorder and the ocular instability. These results remained unchanged, as ascertained by follow-ups conducted over a 24-month period subsequent to the termination of biofeedback training.


High-Temperature Pulse Method for Nanoparticle Redispersion.
Nanoparticles suffer from aggregation and poisoning issues (e.g., oxidation) that severely hinder their long-term applications. However, current redispersion approaches, such as continuous heating in oxidizing and reducing environments, face challenges including grain growth effects induced by long heating times as well as complex procedures. Herein, we report a facile and efficient redispersion process that enables us to directly transform large aggregated particles into nanoscale materials. In this method, a piece of carbon nanofiber film was used as a heater and high treatment temperature (∼1500-2000 K) is rapidly elevated and maintained for a very short period of time (100 ms), followed by fast quenching back to room temperature at a cooling rate of 105 K/s to inhibit sintering. With these conditions we demonstrate the redispersion of large aggregated metal oxide particles into metallic nanoparticles just ∼10 nm in size, uniformly distributed on the substrate. Furthermore, the metallic states of the nanoparticles are renewed during the heat treatment through reduction. The redispersion process removes impurities and poisoning elements, yet is able to maintain the integrity of the substrate because of the ultrashort heating pulse time. This method is also significantly faster (ca. milliseconds) compared to conventional redispersion treatments (ca. hours), providing a pragmatic strategy to redisperse degraded particles for a variety of applications.


CB1 receptor expression and signaling are required for dexamethasone-induced aversive memory consolidation.
The molecular processes that underlie long-term memory formation involve signaling pathway activation by neurotransmitter release, which induces the expression of immediate early genes, such as Zif268, having a key role in memory formation. In this work, we show that the cannabinoid CB1 receptor signaling is necessary for the effects of dexamethasone on the behavioral response in an inhibitory avoidance task, on dexamethasone-induced ERK phosphorylation, and on dexamethasone-dependent Zif268 expression. Furthermore, we provide primary evidence for the mechanism responsible for this crosstalk between cannabinoid and glucocorticoid-mediated signaling pathways, showing that dexamethasone regulates endocannabinoid metabolism by inhibiting the activity of the Fatty acid amide hydrolase (FAAH), an integral membrane enzyme that hydrolyzes endocannabinoids and related amidated signaling lipids. Our results provide novel evidence regarding the role of the endocannabinoid system, and in particular of the CB1 receptor, as a mediator of the effects of glucocorticoids on the consolidation of aversive memories.


Examining the relationships between trust in providers and information, mistrust, and COVID-19 vaccine concerns, necessity, and intentions.
To facilitate maximum uptake of the COVID-19 vaccine, the roles of medical trust and mistrust of healthcare professionals must be examined. Previous work suggests that trust and mistrust may have differential impacts on vaccination intention via vaccine necessity and concerns. Multigroup structural equation modeling was utilized to test whether vaccine necessity and concerns mediated the associations between trust in providers and health information, mistrust of providers, and willingness to get the COVID-19 vaccine. The model was found to be invariant across Black and White respondents. Trust in providers and trust in healthcare information exerted indirect effects on intentions through vaccine necessity, while mistrust of providers exerted indirect effects through vaccine concerns. Unlike previous work, the forms of trust did not influence vaccine concerns. The findings have implications for future communication efforts from healthcare professionals and health messengers.


Structural effects of the Solanum steroids solasodine, diosgenin and solanine on human erythrocytes and molecular models of eukaryotic membranes.
This report presents evidence that the following Solanum steroids: solasodine, diosgenin and solanine interact with human erythrocytes and molecular models of their membranes as follows: a) X-ray diffraction studies showed that the compounds at low molar ratios (0.1-10.0mol%) induced increasing structural perturbation to dimyristoylphosphatidylcholine bilayers and to a considerable lower extent to those of dimyristoylphosphatidylethanolamine; b) differential scanning calorimetry data showed that the compounds were able to alter the cooperativity of dimyristoylphosphatidylcholine, dimyristoylphosphatidylethanolamine and dimyristoylphosphatidylserine phase transitions in a concentration-dependent manner; c) in the presence of steroids, the fluorescence of Merocyanine 540 incorporated to the membranes decreased suggesting a fluidization of the lipid system; d) scanning electron microscopy observations showed that all steroids altered the normal shape of human erythrocytes inducing mainly echinocytosis, characterized by the formation of blebs in their surfaces, an indication that their molecules are located into the outer monolayer of the erythrocyte membrane.


Effects of thermal denaturation on the longitudinal relaxation time (T1) of water protons in protein solutions: study of the factors determining the T1 of water protons.
The factors determining the longitudinal relaxation time (T1) of water protons in protein solutions were investigated by analyzing the effects of thermal denaturation on the T1 of the water protons. We treated the water protons and the protein protons "on a protein surface" as a dipole-dipole coupled two-spin system where relative translational diffusion is the dominant mechanism, and measured the change in the time development of the nuclear Overhauser effect (NOE) factors of the water protons. The T1 of the water protons was shortened markedly when the proteins were thermally denatured. Our analysis indicates that this relaxation enhancement is due to an increase in the value of the translational correlation time as well as the fraction of hydration water molecules, though the influence of "proton exchange" between the water protons and the labile protein protons cannot be completely neglected.


Comparison between flapless-guided and conventional surgery for implant placement: a 12-month randomized clinical trial.
The study was aimed at comparing implants installed with guided and conventional surgery. Twenty-nine total edentulous patients were selected, and maxillary contralateral quadrants were randomly assigned to static computer-aided implant surgery (S-CAIS): flapless computer-guided surgery, and conventional surgery (CS): flap surgery with conventional planning. Tomography scans were performed at baseline and 10 days after the surgery for deviation measurement, and radiography was done at baseline and after 6 and 12 months, for peri-implant bone level (PIBL) analysis. Peri-implant fluid and subgingival biofilm were collected to evaluate bone markers and periodontal pathogens. S-CAIS showed less linear deviation at the apical point and the midpoint and less angular deviation (p < 0.05), with greater depth discrepancy in the positioning of the platform (p < 0.05). Higher values of vertical PIBL were observed for the S-CAIS group at baseline (p < 0.05), while lower values of horizontal PIBL were observed for CS (p < 0.05). Bone markers and Tf presented higher levels in CS (p < 0.05). Flapless S-CAIS allowed smaller linear and angular deviations than the conventional technique. However, PIBL was higher in S-CAIS; the conventional technique led to a greater angiogenic and bone remodeling activity by elevating the angiogenic levels and bone markers. Evaluating the different implant insertion techniques can guide clinical and surgical regarding the accuracy, the release pattern of bone markers, and the peri-implant bone level. ReBEC-RBR-8556fzp.


Preferential S-sulfonate formation in lung and aorta.
S-sulfonate (S-SO-3) compounds have previously been identified as metabolites of sulfite in the plasma of several species of mammals [6--8]. We now report the formation of non-diffusible and relatively stable S-sulfonates in the aorta and lung lobes of rabbits exposed intravenously to constant arterial sulfite concentrations of approx. 550 microM. Under these conditions the kinetics of S-SO-3 formation were first order with coefficients in the range of 0.3--0.4 h-1 and asymptotic concentrations of approx. 900 and 9000 nmol S-SO-3/g dry wt. of lung and aorta respectively. The kinetics of this reaction in aorta tissue were closely approximated in vitro. Clearance of S-SO-3 from both lungs and aorta appeared to be first order with a half-life of 2--3 days.


The effect of polymer addition on granulation in an anaerobic baffled reactor (ABR). Part I: process performance.
The stability and performance of an anaerobic baffled reactor (ABR) treating an ice-cream wastewater at several organic loading rates have been investigated. Specifically, it was determined whether an ABR would promote phase separation and if a polymer additive was capable of enhancing granule formation in an ABR. In order to achieve these goals, two ABRs, having identical dimensions and configurations, were used to study the above objectives using a synthetic ice-cream wastewater. The ABR proved to be an efficient reactor configuration for the treatment of a high-strength synthetic ice-cream wastewater. An organic loading rate of around 15 kg CODm(-3) d(-1) was treated with a 99% COD removal efficiency. From the jar test and inhibition assay, it was concluded that Kymene SLX-2 was the most effective and least inhibitory polymer tested. The methane yield was higher in the polymer-amended reactor compared to the control reactor. In addition, polymer addition resulted in a considerably higher degree of biomass retention and lower solids washout from the ABR. Consequently, it demonstrated that there was a considerable potential for sludge conditioning in ABRs by facilitating better biomass retention within the reactor which in turn led to better process performance. Granulation was achieved in both ABRs within 3 months. However, the granules from the polymer-amended reactor appeared earlier and were generally larger and more compact, although this was not quantified in detail during the present study. The main advantage of using an ABR comes from its compartmentalised structure. The first compartment of an ABR may act as a buffer zone to all toxic and inhibitory material in the feed thus allowing the later compartments to be loaded with a relatively harmless, balanced and mostly acidified influent. In this respect, the latter compartments would be more likely to support active populations of the relatively sensitive methanogenic bacteria and partly explains why the best granules and the highest methane yield were obtained in Compartment 2. It is unlikely that a complete separation of phases (acidogenic and methanogenic) occurred within the ABRs since methane production was observed in all compartments, although this was low (approximately 40% of all gas composition) in Compartment 1, becoming higher (approximately 70%) in the following compartments.


Phospholipid flippases.
Protein mediated phospholipid translocation through membranes has been observed in rat liver endoplasmic reticulum and in the plasma membrane of erythrocytes as well as in a few other cell membranes. Lipid translocation in plasma membranes is ATP dependent and selectively accumulates aminophospholipids on the inner monolayers.


The prognostic role of tumor mutation burden on survival of breast cancer: a systematic review and meta-analysis.
As a potential genetic biomarker, tumor mutation burden (TMB) has made progress in numerous tumors. There are limited data regarding TMB and its prognostic role is controversial in breast cancer. This systematic review and meta-analysis were conducted to assess the prognostic value of TMB on survival of breast cancer. The databases PubMed, Embase, Web of Science, and Cochrane Library were searched for articles published through May 31, 2022. Moreover, effective data were extracted from included studies and calculated pooled effects of hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) by STATA 16.0. Heterogeneity was conducted by the I2 statistic and p-value. Using publication bias evaluation, sensitivity analysis, and subgroup analysis, the origin of heterogeneity was further investigated. They were up to 1,722 patients collected from sixteen cohorts for this analysis. The pooled effects of HR for both OS (HR: 1.14, 95% CI: 0.83,1.58, p > 0.01) and PFS (HR: 0.96, 95% CI: 0.53,1.71, p > 0.01) indicated no statistically significant difference in the high TMB and low TMB group. In immune checkpoint inhibitors (ICIs) subgroup, high TMB patients demonstrated benefit of OS (HR: 0.72, 95% CI: 0.59,0.87, p = 0.001) and PFS (HR: 0.52, 95% CI: 0.35,0.77, p < 0.001), whereas difference was not statistically significant in the non-ICIs subgroup (OS, HR:1.76, 95% CI: 0.97,3.20, p = 0.062; PFS, HR:2.31, 95% CI: 0.89,5.97, p = 0.086). In addition, sensitivity analysis revealed that the pooled effects were stable. The funnel plot and Begg's test suggested the absence of publication bias. Meta-analysis revealed that the prognostic relevance of TMB in breast cancer is limited in scope. High TMB may be associated with longer survival only in ICIs-based treatment, but the association is not evident in non-ICIs-based treatment. [ https://www.crd.york.ac.uk/PROSPERO ], Prospective Register of Systematic Reviews (PROSPERO), identifier: CRD42022342488.


Hormonal and metabolic characteristics of premenopausal women with a history of preeclamptic pregnancy.
To investigate whether women with a history of preeclampsia have more signs of hyperandrogenism and insulin resistance in the premenopausal period than women with history of normotensive pregnancies. Case-control study. University Hospital. Eighteen women with a history of preeclamptic first pregnancy and 19 women with prior normotensive first pregnancy studied 23-24 years after delivery. Diagnosis of metabolic syndrome was based on the International Diabetes Federation (IDF) criteria. Matsuda's whole-body insulin sensitivity index, serum concentrations of follicle-stimulating hormone (FSH), sex hormone-binding globulin, and total and free calculated testosterone were assessed. Polycystic ovary syndrome (PCOS) phenotype was defined using Rotterdam criteria. Insulin sensitivity, metabolic syndrome and signs of hyperandrogenism. Insulin sensitivity and total and free testosterone were similar in the two groups. However, in women with prior preeclampsia and FSH below the median, calculated free testosterone levels were higher than in women with prior preeclampsia and FSH above the median (median 13.4 range (8.0-22.5) vs. 7.1 (5.1-20.5), p = 0.03). Of the women with previous preeclampsia, 17% (3/18) had metabolic syndrome and 11% (2/18) PCOS, versus 11% (2/19) and 0% of the controls, respectively. In women with prior preeclampsia, premenopause was not associated with insulin resistance, but signs of hyperandrogenism were present if FSH was within a premenopausal level.


Low peripheral perfusion index values may indicate the need for antivenom in the early phase of scorpion envenomation.
Scorpion envenomation may cause local symptoms as well as life-threatening situations including shock, and death. Antivenom administration is the cornerstone of therapy, meticulous patient selection is needed because of the possible side effects of the antivenom including anaphylaxis. Peripheral perfusion index (PPI) is a simple, non-invasive test that is widely used for the detection of peripheral hypoperfusion. We aimed to investigate the value of using PPI to predict the need for antivenom administration for scorpion envenomation. This prospective observational study was conducted in the ED of a tertiary care center. We consecutively enrolled patients with scorpion envenomation on the extremities who are over 18 years old without pregnancy and a peripheral arterial disease between March 1, 2021, to October 31, 2021. Demographics included age, sex, sting zone, the time between sting and the ED admission, and vital parameters, we blindly measured PPI both on affected and contralateral extremities before any therapeutic intervention. We compared PPI levels, vital parameters, and the outcome including discharge from the ED, admission to ward or ICU, and death between patients who received antivenom and those who did not. Twenty-nine male (58.0%) and 21 (42.0%) female patients with scorpion envenomation were enrolled in the study. The median age was 46.5 [IQR 33.3]. Thirty-eight (76.0%) patients had Class I, 12 (24.0%) patients had Class II and III envenomation. The median duration of the ED admission after the sting was 90 [IQR 120] minutes. Antivenom was administered in 13 (26.0%) patients. PPI was significantly lower both on the affected and the contralateral extremities (p = 0.043 and p = 0.045, respectively) in patients who required antivenom. With a cut-off value of 2.4, PPI can predict the need for antivenom with a sensitivity of 61.54%, a specificity of 86.5%, a positive likelihood ratio of 4.55, a negative likelihood ratio of 0.44, a positive predictive value of 61.54%, a negative predictive value of 86.49%, and an accuracy of 80% (AUC 0.691, p < 0.05). PPI can better reflect the ongoing systemic inflammation and the need for antivenom compared to other vital parameters. Therefore, we suggest this noninvasive and objective test may have a significant role in detecting patients who need antivenom in the early phase of scorpion envenomation. However, more studies are needed to elucidate the role of PPI in scorpion envenomation.


Plasmablastic lymphoma involving breast: a case diagnosed by fine-needle aspiration and core needle biopsy.
Plasmablastic lymphoma (PBL) is a rare lymphoma originating from B-cells with terminal differentiation. Most common anatomic site involved by PBL is the oral cavity. Involvement of other body sites has only rarely been reported. Herein, we report a rare case of EBV-negative PBL involving the breast of an HIV positive 47-year-old woman. The patient presented with decreased vision and photophobia. During physical examination, she was found to have bilateral breast masses and multiple lymphadenopathy. Fine-needle aspiration of one of the breast masses showed large malignant cells with plasmacytoid features. Immunohistochemical studies performed on the core biopsy showed that the tumor cells were positive for common leukocyte antigen CD45 and plasma cell marker CD138, but negative for the pan-B cell markers CD20 and CD79a. Molecular genetic studies showed clonal rearrangement of the immunoglobulin kappa light chain gene. This is the first case of PBL involving the breast reported in English cytological literature.


Effectiveness of different supplementary protocols for remaining filling material removal in endodontic reintervention: an integrative review.
The aim of this study was to perform an integrative review to identify the most effective supplementary protocols used after filling material (FM) removal and root canal reinstrumentation, during endodontic reintervention. The literature search was performed on the electronic databases PubMed and Latin American and Caribbean Health Sciences Literature (LILACS), using a combination of specific scientific descriptors. Selection criteria accepted articles published in English, Spanish and Portuguese languages, up to August 2021, involving in vitro and ex vivo studies. After applying the eligibility criteria, 46 articles were included for qualitative analysis. The tool for qualitative analysis of quasi-experimental studies of the Joanna Briggs Institute was used to determine the risk of bias of the included articles. The selected articles provided important data regarding the following supplementary protocols: sonic and ultrasonic activation of the irrigating solution; the use of ultrasonic inserts, XP-endo system instruments, and photon-induced photoacoustic streaming for mechanical debridement; and new devices as GentleWave system, and the self-adjusting file. Overall, all supplementary protocols demonstrated efficacy in removing the remaining FM. The implementation of various supplementary protocols can effectively remove the remaining FM from the root canal walls, although complete removal is not always achieved. However, it was not possible to determine the most effective protocol. Conversely, their association can enhance remaining FM removal. Remaining FM attached to root canal walls hinders proper chemical-mechanical preparation during endodontic reintervention. Supplementary protocols optimize the remaining FM removal, enhancing cleaning and disinfection of root canal.


Determination of antifungal activity and action mechanism of the modified Aurein 1.2 peptide derivatives.
With the emergence of drug-resistant fungi and the increased population prone to fungal infections, more effective antifungal drugs are needed. Aurein 1.2 is a potent antimicrobial peptide. Here, we designed a novel derivative of Aurein 1.2, called Aurein N3, which is a modified form of Aurein N2 (another Aurein 1.2 derivative), in which Lys 8 residue was replaced with Leu 13, and was also modified by creating two other mutations. Aurein N3 was designed using several algorithms and docking studies. All peptides were synthesized and some of their bio-activity indices such as antifungal properties on 11 fungi, cytotoxicity, hemolysis, and time of the killing were investigated. Electron microscopy, lived/dead staining, and ergosterol binding assay were performed to study their mechanism of action. In comparison to Aurein 1.2 and N2, the docking studies showed that Aurein N3 has reduced binding energy toward ergosterol. The antifungal assessments showed that both Aurein N2 and N3 had strong activity against many fungi. Aurein N3 had lower cytotoxicity and higher binding capability to ergosterol. The hemolytic activity of Aurein N2 and N3 was less than parental Aurein 1.2. All peptides were able to attack the cell wall/membrane and enter the fungi cells. Here we introduced a novel derivative of Aurein 1.2 which has lower cytotoxicity, higher ergosterol-binding capability, and comparable antifungal activity compared to the original peptides. It can bind to ergosterol and can also attack the cell wall/membrane of fungi, although more studies are required to find its accurate mechanism of action.


Smoking during pregnancy: comparison of self-reports and cotinine levels in 496 women.
To validate self-reported smoking habits in smoking pregnant women and estimate the prevalence of substantial exposure to passive smoking in non-smoking pregnant women. Retrospective, quantitative study, consecutively collected samples. One antenatal clinic in Blekinge County, Sweden. 509 pregnant women. Information about smoking habits were taken from the antenatal records of 496 women (97%). Serum samples from these women were tested for cotinine, a nicotine metabolite. Self-reported smoking habits and cotinine levels in ng/mL. Of 407 women, reporting to be non-smokers, 6% were most likely smokers, and 3% had cotinine levels suggesting exposure to substantial passive smoking. Of 60 women, reporting smoking 1-10 cigarettes per day, 32% were likely to smoke more. If the true facts about exposure to tobacco smoke are not revealed, a number of women who might benefit from information and support at the antenatal clinic will miss the opportunity of such assistance, resulting in increased risks for both the woman and her fetus.


Combined mitoxantrone and anti-TGFβ treatment with PD-1 blockade enhances antitumor immunity by remodelling the tumor immune landscape in neuroblastoma.
Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we identified a combinatorial in situ immunomodulation strategy based on the administration of selected immunogenic drugs and immunotherapy to sensitize poorly T-cell-infiltrated neuroblastoma (NB) to the host antitumor immune response. 975A2 and 9464D NB cell lines derived from spontaneous tumors of TH-MYCN transgenic mice were employed to study drug combinations able of enhancing the antitumor immune response using in vivo and ex vivo approaches. Migration of immune cells towards drug-treated murine-derived organotypic tumor spheroids (MDOTS) were assessed by microfluidic devices. Activation status of immune cells co-cultured with drug-treated MDOTS was evaluated by flow cytometry analysis. The effect of drug treatment on the immune content of subcutaneous or orthotopic tumors was comprehensively analyzed by flow-cytometry, immunohistochemistry and multiplex immunofluorescence. The chemokine array assay was used to detect soluble factors released into the tumor microenvironment. Patient-derived organotypic tumor spheroids (PDOTS) were generated from human NB specimens. Migration and activation status of autologous immune cells to drug-treated PDOTS were performed. We found that treatment with low-doses of mitoxantrone (MTX) recalled immune cells and promoted CD8+ T and NK cell activation in MDOTS when combined with TGFβ and PD-1 blockade. This combined immunotherapy strategy curbed NB growth resulting in the enrichment of a variety of both lymphoid and myeloid immune cells, especially intratumoral dendritic cells (DC) and IFNγ- and granzyme B-expressing CD8+ T cells and NK cells. A concomitant production of inflammatory chemokines involved in remodelling the tumor immune landscape was also detected. Interestingly, this treatment induced immune cell recruitment against PDOTS and activation of CD8+ T cells and NK cells. Combined treatment with low-dose of MTX and anti-TGFβ treatment with PD-1 blockade improves antitumor immunity by remodelling the tumor immune landscape and overcoming the immunosuppressive microenvironment of aggressive NB.


Giant solitary hydatid cyst of spleen-A case report.
Primary hydatid disease of the spleen is very rare and even rarer to cause (any complication … pancreatitis.). Usually, splenic hydatid cysts are secondary, either resulting from spontaneous spread of cysts or occurring after operations involving hydatidosis in other regions. Here, we report a case of a primary isolated splenic hydatid cyst treated with a classical surgical approach. This case report and literature review describes the management of hydatid splenic invasion. We report the case of a 28-year-old female who presented with left hypochondriac non tender swelling/(mass). Abdominal ultrasonography and computed tomography (CT) revealed a cyst located in the spleen. The diagnosis was confirmed by a serological test. Surgical treatment involved a radical en bloc splenic resection (together with resection of the diaphragm and subcutaneous tissue.) The postoperative course was uneventful with three weeks of albendazole treatment. CT follow-up at six months demonstrated the absence of recurrence. Histopathologic examination revealed a hydatid cyst. Complete aggressive surgical en bloc resection resection is the gold standard treatment of patients with hydatid cysts with the aim to remove all parasitic and pericystic tissues. The infrequency with which it is encountered makes splenic hydatid disease a formidable early diagnostic challenge especially in nonendemic areas. Hydatid disease should be considered in the differential diagnosis of all cystic masses in the spleen/(abdomen), especially in the geographical regions where the disease is endemic.


Defined clinical classifications are associated with outcome of patients with anatomically resectable pancreatic adenocarcinoma treated with neoadjuvant therapy.
We previously introduced a classification system for patients with localized pancreatic adenocarcinoma that integrates assessments of tumor anatomy, cancer biology, and patient physiology. By means of this system, we sought to analyze outcomes of patients with resectable anatomy but heterogeneous biology and physiology who were treated with neoadjuvant therapy. We evaluated consecutive patients (2002-2007) with anatomically potentially resectable cancers treated with chemotherapy or chemoradiation before potential pancreatectomy. We compared clinical factors and outcomes of patients classified as having disease that was clinically resectable (CR; no extrapancreatic disease, preserved performance status); suspicion for extrapancreatic disease (BR-B); or marginal performance status or significant comorbidity (BR-C). Patients with borderline resectable anatomy (BR-A) were excluded. Resection rates for 138 CR, 41 BR-B, and 38 BR-C patients were 75, 46, and 37%, respectively (P < 0.001). Metastases, detected during treatment in 23% of patients, were the most common contraindication to resection among CR (15%) and BR-B (46%) patients. Performance status rarely precluded surgery except among BR-C (32%) patients. Factors associated with selection against surgery were older age, poor performance status, pain, and therapeutic complications (P < 0.05). The median overall survival of all patients was 21 months. Resected and unresected BR-B and BR-C patients had median overall survival durations similar to those of resected and unresected CR patients, respectively (P > 0.22). This system describes discrete clinical subgroups of patients with pancreatic cancer who have similar, potentially resectable tumor anatomy but heterogeneous physiology and cancer biology. It may be used with neoadjuvant therapy to predict outcomes, individualize treatment algorithms, and optimize survival.


The multiplicity problem in linkage analysis of gene expression data - the power of differentiating cis- and trans-acting regulators.
In this report, we focused on the multiplicity issue in Problem 1 of Genetic Analysis Workshop 15. We investigated and compared the performance of the stratified false-discovery rate control method with the traditional aggregated approach, in an application to genome-wide linkage analyses of single-nucleotide polymorphism-to-gene expression data. We showed the importance of utilizing the available map information and demonstrated the power gained by conducting false-discovery rate control separately for cis and trans regulators under three different frameworks: fixed rejection region, fixed false-discovery rate, and fixed number of rejections.


Microsatellite DNA marker inheritance indicates preferential pairing between two highly homologous genomes in polyploid and hemisexual dog-roses, Rosa L. Sect. Caninae DC.
According to previous cytological evidence, the hemisexual dog-rose species, Rosa sect. Caninae, transmit only seven chromosomes (derived from seven bivalents) through their pollen grains, whereas egg cells contain 21, 28 or 35 chromosomes (derived from seven bivalents and 14, 21 or 28 univalents) depending on ploidy level. Two sets of reciprocal pairwise interspecific crosses involving the pentaploid species pair R. dumalis and R. rubiginosa, and the pentaploid/tetraploid species pair R. sherardii and R. villosa, were analysed for 13 and 12 microsatellite DNA loci, respectively. Single loci were represented by a maximum of three simultaneously occurring alleles in R. villosa, and four alleles in the other three parental plants. In the experimentally derived offspring, the theoretical maximum of five alleles was found for only one locus in the pentaploid progenies. Microsatellite DNA allele composition was identical with that of the maternal parent in 10 offspring plants, which were probably derived through apomixis. Almost all microsatellite DNA alleles were shared with the maternal parent also in the remaining offspring, but 1-4 alleles shared only with the paternal parent, indicating sexual seed formation. Analysis of quantitative peak differences allowed a tentative estimation of allelic configuration in the individual plants, and suggested that bivalent formation preferentially takes place between chromosomes that consistently share the same microsatellite alleles and therefore appear to be highly homologous. Moreover, alleles that were shared between the species in each cross combination comparatively often appear to reside on the bivalent-forming chromosomes, whereas species-specific alleles instead occur comparatively often on the univalent-forming chromosomes and are therefore inherited through the maternal parent only. Recombination then takes place between very similar genomes also in interspecific crosses, resulting in a reproduction system that is essentially a mixture between apomixis and selfing.


[Liver and heart T2* measurement in secondary haemochromatosis].
To determine whether there is iron overload by calculating the T2* value in the liver and myocardium in patients with secondary haemochromatosis. To analyse the correlation of the values obtained with the iron levels in blood, with the liver iron concentration (LIC) calculated using magnetic resonance (MR) imaging, and the correlation between them. A total of 16 patients (13 males, 3 females), with a mean age of 61 years, were included and evaluated in the years 2008 and 2009. Fifteen of them had received multiple transfusions, and one was diagnosed with hereditary sideroblastic anaemia. The measurements included, blood ferritin, LIC by MRI, cardiac function using MRI and the T2* value by means of multi-echo sequences in the liver (TR/TE1/ΔTE/No of echos/α: 21/1,18/1.0/20/35°) and myocardium (26/1.04/0.8/30/60°). A correlation-regression analysis was performed by comparing the cardiac and liver T2* values with the ferritin, LIC and between each of them. A total of 13 patients had ferritin values greater than 1000ng/ml (median/minimum/maximum: 1762/294/3785ng/ml). An increased LIC greater than 80μmol/g (median/minimum/maximum: 125.4/41.2/241.5μmol/g) was observed in 13 patients. In all cases cardiac function was conserved, and in 15 cases the liver T2* value was less than 6.3ms. The myocardium T2* value was less than 20ms. in only one case. A high correlation was observed between the liver T2* values and the LIC (r:-0.912). The correlation was statistically significant between the liver T2* value and ferritin (r:-0.541). The correlations between myocardium T2* and ferritin, myocardium T2* and LIC, and myocardium T2* and liver T2* were not statistically significant. The liver T2* showed a high correlation with LIC and a statistically significant correlation with ferritin. No association was observed between the myocardium T2* values and ferritin in blood, the LIC or the liver T2* value.


A case of jejunal GIST revealed by hematemesis: Unusual situation.
Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal (GI) tract, which can occur in majorly stomach, and rarely in the small intestine, rectum, and large intestine. We report a jejunal GIST presented with massive hematemesis in the current study. A 39-years-old male, without any underlying history, was presented to our center with the complaint of massive hematemesis. Given the unstable hemodynamics of the patient, an upper GI endoscopy was requested, associated with a large amount of blood in the duodenal bulb without any sign of bleeding. The patient was sent to the operation room, and after laparotomy, a mass was seen in the jejunum, revealed as GIST after pathological study. Small-intestine-related etiologies are rare conditions related to upper GI bleeding (UGIB). Jejunal GIST usually manifests as asymptomatic subepithelial mass and is associated with abdominal discomfort or GI bleeding. Sudden unset bleeding is a rare manifestation of jejunal GIST, but it can be associated with the emergency outcome and may need emergency intervention. UGIB can occur in jejunal GIST, which should be considered in the management of UGIB.


Predictors of functional capacity changes in a US population of Medicare home health care (HHC) patients with heart failure (HF).
Functional capacity is widely recognized as a key factor in maintaining the ability of older people to live independently and safely at home. Promoting functional capacity is an important priority particularly in HHC. The purpose of the study was to examine predictors of functional capacity change among HHC patients with HF. Clinical and administrative data from 2005 from the Medicare Chronic Conditions Warehouse were linked at the population level for HHC patients with a primary diagnosis of HF. The primary outcome was change in functional capacity score from HHC admission to HHC discharge. Over the course of the episode (M=44 days), most (70%) patients improved, 15.6% stayed the same, and 14.4% declined in activities of daily living (ADL) scores. The mean change score was modest (mean=-0.74, SD=1.11) with a median change of -0.58. Multivariate analyses (R(2)=0.23) showed that the largest influence was the admission ADL score followed by receiving any physical therapy (PT), admission ability to manage oral medications, cognitive functioning, rehabilitation prognosis, and urinary incontinence. There is a modest rate of improvement from admission to discharge that likely represents the progressive nature of HF and/or the short time frames over which HHC is provided. Providers may want to use the predictive factors to identify patients most at risk for functional decline.


Molecular dynamics and free energy studies on the carboxypeptidases complexed with peptide/small molecular inhibitor: mechanism for drug resistance.
As one potent plant protease inhibitor, potato carboxypeptidase inhibitor (PCI) can competitively inhibit insect digestive metallocarboxypeptidases (MCPs) through interfering with its digestive system that causes amino acid deficiencies and leading to serious developmental delay and mortality. However, this effective biological pest control is significantly impaired by the PCI-resistant insect MCPs. Therefore, deep understanding of the resistant mechanism of insect MCPs is particularly necessary for designing new durable pest control regimen and developing effective pesticides. In this study, the binding of PCI and small molecular inhibitor THI to insect PCI-sensitive/-resistant MCPs and human MCP was investigated by docking, molecular dynamics (MD) simulations and thermodynamic analysis. The structural analysis from MD simulations indicates that the PCI-resistant mechanism of CPBHz is mainly dominated by the Trp277A, which changes the conformation of β8-α9 loop and therefore narrow the access to the active site of CPBHz, prohibiting the entrance of the C termini tail of PCI. Additionally, the insertion of Gly247A weakens the stabilization of CPBHz and PCI through disrupting the hydrogen bond formation with its surrounding residues. Furthermore, the predicted binding free energies gives explanation of structure affinity relationship of PCI and THI with MCPs and suggest that the electrostatic energy is the main contribution term affecting the difference in binding affinities. Finally, the decomposition analysis of binding free energies infers that the key residues Glu72, Arg127, Ile247/Leu247 and Glu270 are critical for the binding of PCI/THI to MCPs.


Gastrin and colorectal cancer: where now?
Gastrin exerts a trophic influence on various regions of the gastrointestinal (GI) tract and this has led to an interest in its potential role in the growth of GI tumours. There is little evidence that elevated circulating levels of gastrin predispose to colonic tumours. However, the hormone can be detected within some colonic tumour tissues and a possible paracrine or autocrine role has been proposed. At present, evidence for such a role is conflicting, as is the evidence that colonic tumour cells possess receptors for the mature hormone. Colonic tumours have been found to contain much higher concentrations of incompletely processed gastrin precursors such as glycine extended gastrin and recent studies indicate that they may exert trophic effects mediated by specific receptors. Further studies of this are required. Whether specific hormone receptor antagonists will have a role in the clinical management of colonic tumours remains unclear.


Role of Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection in the Management of Barrett's Related Neoplasia.
Endoscopic resection has been proven to be safe and highly effective for removing early neoplastic lesions in Barrett esophagus. It enables accurate histopathological assessment and is therefore considered as the cornerstone in the endoscopic work-up for patients with Barrett neoplasia. Various techniques are available to perform endoscopic resection. Multiband mucosectomy is the most commonly used resection technique. However, endoscopic submucosal dissection is gaining ground in the Western world. Endoscopic resection for low-risk submucosal lesions already is fully justified. Future studies have to point out whether endoscopic resection and subsequent follow-up are also justified in selected patients with high-risk submucosal tumors.


The surgical aspects of insulinomas.
The clinical diagnosis of insulinoma rests on the demonstration of Whipple's triad (symptoms of hypoglycimia, low circulating glucose and prompt relief of symptoms after glucose administration). Biochemically, the association of an increased value of immunoreactive insulin with a low glucose value is diagnostic of insulin-mediated hypoglycemia. Angiographic localization of these tumors is accomplished in more than 90% of cases. The pathologic changes are usually due to a single adenoma, for which surgical enucleation is the procedure of choice. Malignancy and persistent hypoglycemia occur in slightly less than 10% of cases and can be fairly successfully managed by diazoxide and streptozotocin.


Neurological complications of 5-fluorouracil chemotherapy: case report and review of the literature.
Neurological complications of 5-fluorouracil (5-FU) chemotherapy are uncommon events. The two patients presented demonstrate two manifestations of 5-FU neurotoxicity, namely a cerebellar syndrome in association with global motor weakness and bulbar palsy, and a bilateral third cranial (oculomotor) nerve palsy. Both highlight the rapid onset and severity of these unusual side effects but also emphasize that, unlike paraneoplastic syndromes or central nervous system involvement by tumour, complete spontaneous recovery is a potential outcome.


Diversity of group A rotavirus strains circulating in Paraguay from 2002 to 2005: detection of an atypical G1 in South America.
Group A rotaviruses are the main cause of severe gastroenteritis in children worldwide. To survey human rotavirus strains circulating in Paraguay. One hundred ninety-six rotavirus-positive fecal samples collected from children up to 5 years old, from 2002 to 2005, were characterized. The most common G genotype detected was G9 (36.2%), followed by G1 (34.2%), G2 (11.7%) and G4 (8.7%). Changes in the G genotype frequency were observed from year to year. The G4 genotype was predominant in 2002; G1 in 2003; and G9 from 2004 to 2005. Sequence and phylogenetic analysis of the VP7 gene from Paraguayan G1 strains suggested that the high frequency of G1 in 2003 could be due to the introduction of an atypical sub-lineage. In addition, there were amino acid changes in the variable/antigenic regions of the VP7 gene from G4 and G9 strains detected in different years. This study further indicates that antigenic pressure can drive the evolution of rotaviruses, and also suggests that a vaccine that protects against the most prevalent strains and its variants, will be necessary to elicit a protective immune response against the range of rotavirus types currently circulating in Paraguay.


Synergistic effect between iron and gadolinium in MRI.
Different combinations of iron glycerophosphate (Fe) and gadolinium-diethylene triamine pentaacetic acid (DTPA) (Gd) were imaged with a three-dimensional (3D) gradient-recalled echo (GRE), a 2D GRE, and a HASTE sequence on a 1.5-T MR scanner. A combination of Fe and Gd results in a synergistic effect, which improves the signal gain for selective 3D imaging of the colon and simultaneously decreases the endoluminal signal on the HASTE and 2D GRE images for better visualization of water and Gd-enhanced structures in the gut wall.


Induction of differentiation of human embryonic stem cells into functional hair-cell-like cells in the absence of stromal cells.
Sensorineural hearing loss and vestibular dysfunction have become the most common forms of sensory defects. Stem cell-based therapeutic strategies for curing hearing loss are being developed. Several attempts to develop hair cells by using chicken utricle stromal cells as feeder cells have resulted in phenotypic conversion of stem cells into inner ear hair-cell-like cells. Here, we induced the differentiation of human embryonic stem cells (hESCs) into otic epithelial progenitors (OEPs), and further induced the differentiation of OEPs into hair-cell-like cells using different substrates. Our results showed that OEPs cultured on the chicken utricle stromal cells with the induction medium could differentiate into hair-cell-like cells with stereociliary bundles. Co-culture with stromal cells, however, may be problematic for subsequent examination of the induced hair-cell-like cells. In order to avoid the interference from stromal cells, we cultured OEPs on laminin with different induction media and examined the effects of the induction medium on the differentiation potentials of OEPs into hair-cell-like cells. The results revealed that the culture of OEPs on laminin with the conditioned medium from chicken utricle stromal cells supplemented with EGF and all-trans retinoic acid (RA) could promote the organization of cells into epithelial clusters displaying hair-cell-like cells with stereociliary bundles. These cells also displayed the expected electrophysiological properties.


Altered thiol group status in the heart ornithine decarboxylase inactivated following perfusion with t-butylhydroperoxide.
1. The perfusion for 15 min of isolated rat hearts with 100 microM t-butylhydroperoxide leads to a 75% diminuition of the tissue GSH/GSSG ratio. 2. After t-butylhydroperoxide infusion, the isoproterenol-stimulated heart ODC was strongly inhibited. The addition of 2 mM DTT in the assaying buffer removed the ODC inactivation. 3. The inhibited ODC had an eluition profile similar to active ODC when chromatographed on a Sephacryl S-200 column; moreover, the ODC activity recovered after a thiol affinity chromatography as unbound fraction, was two times increased in the t-butylhydroperoxide perfused hearts in comparison to control. 4. The hearts perfused with 1 mM acetylcysteine after 15 min of perfusion with t-butylhydroperoxide recovered almost completely the initial ODC activity.


Transmural trophic effect of short chain fatty acid infusions on atrophic, defunctioned rat colon.
This study was designed to investigate and quantify trophic alterations in the defunctioned, atrophic rat colon after short chain fatty acid (SCFA) treatment was administered in a clinically relevant way. Diverting colostomy with exclusion of distal colon was performed on adult female rats (58), and treatment was started four weeks later. Enemas of either a SCFA solution of sodium-acetate, sodium-propionate and sodium-butyrate (concentration, 780 mM), or isotonic saline (placebo) were instilled through the anus into the defunctioned colon. This was done twice daily for 7 or 14 days before death. After SCFA instillation for 14 days, the colonic wet weight was 18 percent higher compared with placebo (P < 0.01), and there was a similarly significant difference in dry weight (P < 0.05). Using stereologic assessment to determine the histologic composition of defunctioned colon, we found significant increases among SCFA-treated rats in the weight of the mucose (P < 0.05), the submucosa (P < 0.05), and the muscularis propria (P < 0.05) and a 30 percent increase in the mucosal surface area compared with placebo-treated in the mucosal surface area compared with placebo-treated rats (P < 0.05). Measurements of breaking strength and hydroxyproline content showed no differences between treatment groups. SCFA enemas have a transmural trophic effect and preserve mucosal surface area of defunctioned and atrophic colon in rats.


Specific and nonspecific regeneration of motor axons after sciatic nerve injury and repair in the rat.
The pattern of motor axon regeneration following unilateral sciatic nerve lesions (freezing or transection) was studied in adult rats. Transected nerves were repaired with epineurial or fascicular sutures. Four months after the lesion, the motor neuron cell body localization in the spinal cord of plantar or common peroneal nerve axons were examined bilaterally with retrograde transport of horseradish peroxidase. Motor neuron cell body localization was similar bilaterally after freezing, indicating that regenerating axons had reached their original peripheral innervation territory. However, after nerve transection, irrespective of whether epineurial or fascicular sutures were used, motor neuron cell body distribution on the operated side was abnormal with numerous labeled cell bodies located outside the area of the normal motor neuron pool. This finding indicates that after nerve transection the normal pattern of motor axon innervation is not restored even after fascicular nerve repair.


Risk factors for postoperative recurrence of Crohn's disease.
To identify potential risk factors that influence postoperative recurrence rates of Crohn's disease, the postoperative recurrence-free survival of 93 patients who underwent their first resections at The Mount Sinai Hospital between 1964 and 1973 has been examined. Features analyzed individually and jointly were age, sex, anatomic location, operative procedure, and preoperative disease duration. In patients with Crohn's colitis, recurrence rates appeared somewhat lower among 11 patients with ileostomy than among 5 patients with anastomosis. In the entire series, recurrence rates were lowest in patients with longest preoperative durations (p = 0.02). This same tendency was especially marked among the 68 patients without ileostomies (p = 0.005). Likewise, among the 38 patients with ileitis, the relative risk of recurrence was significantly lower for those with disease duration exceeding 10 yr (p = 0.01). Relative risk of recurrence in the entire series for patients with 2-yr duration was 1.5 compared with those who had 10-yr duration. This inverse association between preoperative disease duration and postoperative recurrence rate may reflect persisting differences between inherently more aggressive versus more indolent forms of Crohn's disease.


Electrochemical immunosensor based on AuNPs/Zn/Ni-ZIF-8-800@graphene for rapid detection of aflatoxin B1 in peanut oil.
Peanut oil is a basic food raw material in life. However, aflatoxin contamination in peanut oil is considered to be one of the most serious food safety problems in the world. Based on AuNPs/Zn/Ni-ZIF-8-800@graphene composite, a simple, efficient and sensitive electrochemical immunosensor was developed to detect aflatoxin B1 (AFB1) in peanut oil. The bare glassy carbon electrode was modified by graphene, bimetallic organic framework material (Zn/Ni-ZIF-8-800), chitosan and gold nanoparticles. The electrochemical immunosensor was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FT-IR) and cyclic voltammetry (CV), and the electrochemical signal changes after antibody and AFB1 binding were investigated in detail. Under the optimal conditions, the linear range of the electrochemical immunosensor was 0.18-100 ng/mL, and the detection limit was 0.18 ng/mL. In addition, the prepared sensor has high selectivity and long-term stability, which lays a foundation for the simple, rapid and sensitive detection of AFB1 in peanut oil.


"I never went to see that doctor again": A qualitative study examining Australian women's experiences requesting removal of LARC within 12 months of insertion.
Removal or discontinuation of long-acting reversible contraception (LARC) requires cooperation of healthcare providers. The objective of this study was to explore young women's experiences when they request removal of LARC within 12 months of insertion. We conducted a qualitative study using individual semi-structured telephone interviews with women living in Victoria, Australia. We recruited participants using physical and online advertising flyers. We audio-recorded and transcribed interviews and thematically analyzed the data. Fifteen women participated in an interview. The experience of unacceptable side effects prompted "early" LARC removal in all cases. The non-autonomous nature of LARC removal was not considered by women pre-insertion and participants reported confidence in their ability to access LARC removal when requested. Although satisfaction was reported when LARC was removed on request, participants reported negative feelings towards their healthcare provider when there was perceived pressure to continue with LARC for longer than desired. This had implications for the patient-clinician relationship. Women experienced resistance to removal as a challenge to their bodily autonomy and this resulted in a loss of trust in health services. Resistance to removal of LARC can damage the patient-clinician relationship and be experienced as a challenge to women's autonomy and reproductive rights. Patients have confidence in their ability to get their LARC removed on request and autonomy is not largely considered prior to LARC initiation. Supportive removal services should be emphasized for women who request removal of LARC at any point after insertion in order to maintain trust in healthcare providers and health services.


COVID-19's impact on family medicine resident training and wellness.
The COVID-19 global pandemic has raised many challenges in training family medicine residents. Family medicine is at the frontline for treating and managing patients with COVID-19. Attention is needed on the critical issue of the effect of the pandemic on resident training, the safety of those performing needed medical services, and the psychological well-being of trainees. We performed a cross-sectional, 25-question survey-based study to evaluate the perceived effect of the COVID-19 pandemic on family medicine residents' training and residents' well-being in the state of Texas. A total of 250 Texas-based family medicine residents were surveyed with a response rate of 12.8% (n = 32). After the pandemic began, all residents worried about exposing their loved ones to COVID-19, and 65% felt like the COVID-19 pandemic negatively impacted their training overall. Respondents indicated that changes occurred in their respective residency curricula that altered training such as canceling of scheduled lectures (84.3%) and more telemedicine visits (56.25%). There was a significant difference for postgraduate year level and the effect on rotation assignments, with more disruption to the first- and third-year residents (P = 0.03). The COVID-19 pandemic has had a notable impact on the perception of quality of training and mental health within family medicine. Our findings may guide programs in how to proactively target pandemic-related training challenges.


Functional polymorphisms of matrix metalloproteinase-9 and survival in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy.
To investigate the prognostic role of major matrix metalloproteinase (MMP) gene polymorphisms in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with chemoradiotherapy. Four hundred twenty-one consecutive NPC patients were prospectively recruited. Two hundred patients were randomly selected as the training cohort, and the remaining 221 patients were the validation cohort. Twelve polymorphisms in the MMP-1, 2, 3, 7, 8, and 9 genes were genotyped by ligase detection reaction-PCR. MMP-9 rs2250889 PR/RR (HR = 2.287, 95% CI 1.400-3.735) and rs17576 RQ/QQ (HR = 2.347, 95% CI 1.431-3.849) genotypes were significantly related with increased death risk in the training cohort. Analysis of the validation cohort confirmed these results (rs2250889: HR = 2.231, 95% CI 1.281-3.886; rs17576: HR = 2.987, 95% CI 1.674-5.330). Multivariate analysis showed that rs17576 (HR = 2.284, 95% CI 1.123-4.643, P = 0.023) was still an independent prognostic factor. The MMP-9 rs17576 is a novel independent prognostic marker in patients with locoregionally advanced NPC treated with chemoradiotherapy.


Restoration of euthyroidism does not improve cardiovascular risk factors in patients with subclinical hypothyroidism in the short term.
Subclinical hypothyroidism (SH) is being accepted as a condition that is associated with increased risk of cardiovascular disease. Restoration of euthyroidism might be involved in prevention of cardiovascular disease. Thus, we evaluated biochemical risk factors of 75 patients with SH without evidence of any other diseases before and after restoration of euthyroidism and compared to 27 healthy controls. Before and a mean of 18.2+/-4.4 weeks after restoration of euthyroidism, serum total and LDL cholesterol, lipoprotein (Lp) (a), total homocysteine (t-Hyc) and highly sensitive C-reactive protein (hsCRP) levels were analyzed. Pre-treatment levels of TSH (10.04+/-5.36 vs 1.74+/-1.1 mIU/l, p<0.05), total cholesterol (204+/-68 vs 179+/-26 mg/dl, p<0.05) and LDL cholesterol (129+/-50 vs 106+/-16 mg/dl, p<0.05) were significantly higher than controls while Lp (a), t-Hyc, and hsCRP levels were not different. None of these biochemical risk factors have improved after euthyroidism in patients with SH with average dose of 85+/-30 microg/day, when compared to pre-treatment levels. Only in a subgroup of patients (no. 30) with higher TSH levels (>10 mIU/l), did serum LDL cholesterol levels decrease significantly (139+/-38 vs 112+/-35 mg/dl, p<0.05). Lp (a), t-Hyc and hsCRP levels were not significantly different after treatment with levothyroxine therapy even in this subgroup of patients. We conclude that clinical management of SH does not contribute to prevention of cardiovascular disease in the short term, and monitoring risk factors of cardiovascular disease does not offer additional benefits for treating patients with SH.


Damage-specific DNA binding protein 1 (DDB1): a protein with a wide range of functions.
Damage-specific DNA binding protein 1 (DDB1) is a multifunctional protein that was first isolated as a subunit of a heterodimeric complex that recognises the UV-induced DNA lesions in the nucleotide excision repair pathway. DDB1 and DDB2 form a complex that promotes the global genome repair (GG-NER), whereas DDB1 and Cockayne syndrome group A protein (CSA) form a complex that contributes to the transcription-coupled repair (TC-NER) pathway. DDB1 is also a component of an ubiquitin-E3 ligase complex and functions as substrate or adapter protein between Cullin 4A (Cul4A) and CUL4-associated factors (DCAFs) to target substrates for ubiquitination. CUL4-DDB1 E3-ligase complex regulates the selective proteolysis of key proteins in DNA repair, replication and transcription. In addition, DDB1 plays a role in transcriptional regulation of UV-induced genes. It is conceivable that DDB1 acts as a sensor of damage to maintain the balance between genome integrity and cell cycle progression. However, the temporal order between these two events remains to be established.


Rediscovering latent trauma: An adopted adult's perspective.
Though studies showing a causal relationship between adoption and trauma are scarce, there is enough cross-disciplinary research to suggest such a connection. Likewise, there are many adult adopted persons, like myself, who see their adoption narratives as traumatic in one way or another. Mental health outcomes for adopted people also indicate adoption might be a source of and not just a preventative measure against trauma. In this paper, I utilize an autoethnographic approach to highlight the relationship between infant adoption and what I refer to as "latent traumatic memories." Recounting several major life events that led to traumatic upheavals in my understanding of my own identity as an adopted person, I then relate my story to current research on trauma experienced very early in life and how it is remembered implicitly in the body. My account, I argue, highlights the need to further research adopted people's evolving views about their adoption and how and to what extent certain events in adulthood precipitate the rediscovery of latent trauma.


A randomized, double-blind, noninferiority study to compare two regimens of levonorgestrel for emergency contraception in Nigeria.
Unplanned pregnancies are common in Nigeria. Much of the unplanned pregnancies is due to low contraceptive prevalence and high contraceptive user failure rates. High user failure rates suggest the important role of emergency contraception to prevent unplanned pregnancy. Randomized, controlled, double-blind, multicenter, noninferiority trial comparing efficacy and side effects of two emergency contraceptive regimens up to 5 days after unprotected intercourse among 3022 Nigerian women: levonorgestrel administered in two doses of 0.75 mg given 12 h apart and levonorgestrel administered in a single dose of 1.5 mg. Efficacy was similar between the treatment groups; post-treatment pregnancy proportions were 0.57% in the two-dose regimen vs. 0.64% in the single-dose regimen (risk difference 0.07% (95% CI -0.50 to 0.64). The majority of women menstruated the first day of expected menses and the groups did not differ regarding reported side effects. This study shows the simplified emergency contraceptive regimen of single-dose levonorgestrel is not inferior in efficacy to the two-dose regimen among Nigerian women.


Permanent pacemaker lead implantation via the transhepatic route.
A 4-year-old male with transposition of the great arteries, status post-Senning repair, required placement of an atrial pacemaker for sinus node dysfunction and atrial flutter. Multiple systemic venous occlusions precluded conventional transvenous lead implantation. A transhepatic approach resulted in successful placement of an endocardial atrial pacing lead.


Stimulus-dependent effects of CI-986 on arachidonic acid metabolism by human neutrophils.
CI-986 (5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3, 4-thiadizole-2(3H)-thione, choline salt) was evaluated for its effect on arachidonic acid metabolism by human neutrophils in response to different stimuli. Leukotriene B4 (LTB4) release in response to calcium ionophore A23187 was 15 to 35 fold greater than the responses to N-formyl-methionyl-leucyl-phenylalanine (FMLP) or serum-opsonized zymosan (SOZ), respectively, while the thromboxane B2 (TXB2) release response was similar for the three stimuli tested. CI-986 inhibited the release of LTB4 and TXB2 in response to A23187 with IC50s of 63.4 and 1.6 microM, respectively. In comparison, the compound inhibited SOZ-stimulated LTB4 release with an IC50 of 11.2 microM, while having no effect on TXB2 at concentrations up to 100 microM. Conversely, CI-986 inhibited FMLP-stimulated LTB4 release by 42% at 100 microM, while inhibiting TXB2 release with an IC50 of 0.13 microM. These results demonstrate a stimulus-dependent inhibitory effect of CI-986 on human neutrophil eicosanoid metabolism.


Circuit for the electromanipulation of plant protoplasts.
An electric circuit for plant protoplast manipulation is described. The circuit used readily available materials and was designed for use in teaching. This integrated circuit can be placed in a single small box with controls for the aligning voltage, the aligning frequency, the pulse voltage, and the pulse timing. The circuit can be supplied by any suitable source of dc power and can be easily altered for individual requirements. The circuit, as presented here, can be assembled for less than $250.