Epstein-Barr virus triggered rejection after kidney allograft transplantation.
Pediatric allograft recipients are at increased risk for Epstein-Barr virus (EBV)-associated disorders. We report on a 4-year-old boy who received a cadaver kidney transplant. The donor's viral status was not known. Twenty-one days after transplantation, serum creatinine and urea rose, giving evidence of transplant rejection. At this stage, EBV DNA in the recipient tested positive. The results of histological examination of the allograft kidney were interpreted as being EBV associated. For treatment of acute rejection immunosuppressive therapy was intensified. Finally, the renal transplant had to be explanted 46 days after implantation and peritoneal dialysis had to be restarted to compensate renal failure. In conclusion, EBV infection can lead to rapid rejection, and modification of immunosuppression does not necessarily improve allograft survival.


Interactions of human mast cell tryptase with biological protease inhibitors.
Tryptase from human mast cells has been shown (in vitro) to catalyze the destruction of fibrinogen and high-molecular-weight kininogen as well as the activation of C3a and collagenase. Although large amounts of tryptase are released in tissues by degranulating mast cells and levels as high as 1000 ng/ml have been measured in the circulation following systemic anaphylaxis, no specific physiologic inhibitor has yet been found for the protease. The current work tests several more inhibitors for their effects on tryptase and examines any effect of tryptase on these inhibitors. First, antileukoprotease and low-molecular-weight elastase inhibitor from human lung and hirudin and antithrombin III had no effect on tryptase activity in vitro. Second, the possibility that tryptase, being insensitive to the effects of inhibitors, might instead destroy them was also considered. Tryptase failed to cleave and inactivate antileukoprotease, low-molecular-weight elastase inhibitor, alpha 1 protease inhibitor, alpha 2 macroglobulin, and antithrombin III. Third, based on the knowledge that tryptase stability is regulated by its interaction with heparin, antithrombin III was used as a model heparin-binding protein to demonstrate that a protein competitor for heparin-binding sites, presumably by displacement of tryptase, destabilizes this enzyme. Conversely, tryptase, in excess, blocked the binding of antithrombin III to heparin, thereby attenuating the heparin-mediated inhibition of thrombin by antithrombin III.


Enhanced covertness class discriminative universal adversarial perturbations.
The main aim of class discriminative universal adversarial perturbations (CD-UAPs) is that the adversary can flexibly control the targeted class and influence remaining classes limitedly. CD-UAPs generated by the existing attack strategies suffer from a high fooling ratio of non-targeted source classes under non-targeted and targeted attacks, and face the increasing risk of discovery. In this paper, we propose a training framework for generating enhanced covertness CD-UAPs. It trains the targeted source class set and the non-targeted source classes set alternately to update the perturbation and introduces logit pairing to mitigate the influence of perturbation on the non-targeted source classes set. Further, we extend CD-UAPs on the targeted (one-targeted) attack to the multi-targeted attack, which perturbs a targeted source class to multiple targeted sink classes that seriously threaten the current scenario. It can not only provide the adversary with freedom of precise attack but reduce the risk of being detected. This attack poses a strong threat to security-sensitive applications. Extensive experiments on the CIFAR-10, CIFAR-100 and ImageNet datasets show our method can generate more deceptive perturbations and enhance the covertness of CD-UAPs. For example, our method improves the absolute fooling ratio gaps of ResNet-20 and VGG-16 by 9.46% and 6.94% compared with the baseline method, respectively. We achieve the multi-targeted attack with a high fooling ratio on the GTSRB dataset. The average absolute target fooling ratio gaps of ResNet-20 and VGG-16 are 81.89% and 76.33%, respectively.


A nuclear mutation conferring thiostrepton resistance in Chlamydomonas reinhardtii affects a chloroplast ribosomal protein related to Escherichia coli ribosomal protein L11.
We have isolated a nuclear mutant (tsp-1) of Chlamydomonas reinhardtii which is resistant to thiostrepton, an antibiotic that blocks bacterial protein synthesis. The tsp-1 mutant grows slowly in the presence or absence of thiostrepton, and its chloroplast ribosomes, although resistant to the drug, are less active than chloroplast ribosomes from the wild type. Chloroplast ribosomal protein L-23 was not detected on stained gels or immunoblots of total large subunit proteins from tsp-1 probed with antibody to the wild-type L-23 protein from C. reinhardtii. Immunoprecipitation of proteins from pulse-labeled cells showed that tsp-1 synthesizes small amounts of L-23 and that the mutant protein is stable during a 90 min chase. Therefore the tsp-1 phenotype is best explained by assuming that the mutant protein synthesized is unable to assemble into the large subunit of the chloroplast ribosome and hence is degraded over time. L-23 antibodies cross-react with Escherichia coli r-protein L11, which is known to be a component of the GTPase center of the 50S ribosomal subunit. Thiostrepton-resistant mutants of Bacillus megaterium and B. subtilis lack L11, show reduced ribosome activity, and have slow growth rates. Similarities between the thiostrepton-resistant mutants of bacteria and C. reinhardtii and the immunological relatedness of Chlamydomonas L-23 to E. coli L11 suggest that L-23 is functionally homologous to the bacterial r-protein L11.


Contribution of lymphatic transport to the systemic exposure of orally administered moxidectin in conscious lymph duct-cannulated dogs.
Moxidectin, a macrocyclic lactone (ML), is a potent parasiticide widely used in veterinary medicine and currently under development for use in humans. The contribution of the lymphatic route to the intestinal absorption and transport of moxidectin to the systemic circulation was evaluated in lymph duct-cannulated dogs. Beagle dogs were operated for lymph duct cannulation and were orally dosed with 38g of corn oil and moxidectin (0.2mg/kg, n=3). The lymph and plasma were collected over 24h and moxidectin and triglyceride concentrations were measured. Similarly, control dogs (n=5) were dosed orally with moxidectin and oil and subsequently with moxidectin intravenously. Pharmacokinetic parameters were calculated for moxidectin in the plasma of the dogs. Moxidectin readily accumulated in the lymph and reached a plateau 8h post-administration, paralleling triglyceride appearance. The percentage of moxidectin recovered in lymph was 22+/-3% of the total administered dose with 92% being associated with triglyceride-rich particles. The systemic bioavailability of oral moxidectin coadministered with lipid was only 40% in the lymph duct-cannulated dogs compared with 71% in the controls. Our data clearly indicate that the lymphatic transport process contributes significantly to the post-prandial intestinal absorption of moxidectin and subsequently to its systemic bioavailability. The lymphatic transport of moxidectin offers potential strategies based on lipid formulations to improve the bioavailability of MLs when administered orally.


Raine syndrome: Report of a novel mutation and review of the different antenatal imaging modalities used to diagnose this disease.
Raine syndrome is an autosomal recessive disorder characterized mainly by the presence of exophthalmos, choanal atresia or stenosis, osteosclerosis, and cerebral calcifications. There are around 50 cases described in the literature with a prevalence of less than 1/1,000,000. It is secondary to pathogenic variants in the FAM20 C gene, located on chromosome 7p22.3. We report a consanguineous family with three affected pregnancies. In the first two, exophthalmos and bone abnormalities were noted, ending in one intra-uterine demise and one neonatal death, without identifying any genetic disorder. During the couple's most recent pregnancy, fetal anomaly sonogram and fetal CT scan revealed microcephaly, intracranial calcifications, exophthalmos, hypertelorism, depressed nasal bridge, midface hypoplasia and thoracic hypoplasia. Fetal blood sampling for whole exome sequencing revealed a novel pathogenic homozygous variant c.1363+1G > A in the FAM20 C gene associated with Raine syndrome. Delivery occurred at 26 weeks of gestation after rupture of membranes followed by neonatal death due to respiratory failure. A review of the distinctive features of Raine syndrome, the contribution of different prenatal imaging modalities (Ultrasound, Computed Tomography and Magnetic Resonance Imaging) in making the diagnosis and the molecular characterization of this disorder is provided.


Identifying and circumventing the defect in Duchenne muscular dystrophy: clinical and biochemical restoration after practical intervention.
Both direct and indirect experimental evidence independently confirms that inadequate muscle purine biosynthesis is the basic lesion in Duchenne muscular dystrophy (DMD), and indicates the presence of a partial defect at adenylosuccinate synthetase. Purine conservation by oral allopurinol gives only limited improvement, but continuous infusion of adenylosuccinate causes an immediate and lasting increase in physical strength, with restoration to normal of the abnormal serum enzyme elevations, creatine/creatinine metabolism, heart rate and ECG. Mass screening of male infants by a blood-spot test is proposed for early detection and treatment of all DMD cases, including the mutant one third with no family history. Prospects of the eventual disappearance of clinical DMD now appear possible.


Pre-operative sensor-based gait parameters predict functional outcome after total knee arthroplasty.
Despite the general success of total knee arthroplasty (TKA) regarding patient-reported outcome measures, studies investigating gait function have shown diverse functional outcomes. Mobile sensor-based systems have recently been employed for accurate clinical gait assessments, as they allow a better integration of gait analysis into clinical routines as compared to laboratory based systems. In this study, we sought to examine whether an accurate assessment of gait function of knee osteoarthritis patients with respect to surgery outcome evaluation after TKA using a mobile sensor-based gait analysis system is possible. A foot-worn sensor-based system was used to assess spatio-temporal gait parameters of 24 knee osteoarthritis patients one day before and one year after TKA, and in comparison to matched control participants. Patients were clustered into positive and negative responder groups using a heuristic approach regarding improvements in gait function. Machine learning was used to predict surgery outcome based on pre-operative gait parameters. Gait function differed significantly between controls and patients. Patient-reported outcome measures improved significantly after surgery, but no significant global gait parameter difference was observed between pre- and post-operative status. However, the responder groups could be correctly predicted with an accuracy of up to 89% using pre-operative gait parameters. Patients exhibiting high pre-operative gait function were more likely to experience a functional decrease after surgery. Important gait parameters for the discrimination were stride time and stride length. The early identification of post-surgical functional outcomes of patients is of great importance to better inform patients pre-operatively regarding surgery success and to improve post-surgical management.


Hereditary persistence of fetal haemoglobin (HPFH) in conjunction with a chromosomal translocation involving the haemoglobin beta locus.
An HPFH syndrome was found in a woman and her daughter who also carry a 'balanced' cyclic translocation of chromosome segments involving four chromosomes, with one break point located in the region of the Hb beta locus. This HPFH is characterized by 5% and 8% Hb F in peripheral blood, uneven distribution of Hb F in the red cells, and a G gamma/G gamma + A gamma ratio of 0.4. The mapping of the non alpha gene cluster shows no detectable deletion in the entire gamma-delta-beta-globin gene region.


Epithelial ovarian tumor in a phenotypic male.
Laparotomy in a 41-year-old married man with non-treated left cryptorchidism revealed female internal genitals on the left side, and an epithelial ovarian tumor of intermediate malignancy. Germinal malignancies are frequent in intersexes, but non-germinal gonadal neoplasms are rare. This is the second reported case of epithelial ovarian tumor in intersexes, and the first case of epithelial ovarian tumor in an intersex registered as male.


High cut-off renal replacement therapy for removal of myoglobin in severe rhabdomyolysis and acute kidney injury: a case series.
Rhabdomyolysis is associated with the release of myoglobin into the circulation, promoting acute kidney injury (AKI). In severe rhabdomyolysis, dialysis-dependent AKI doubles mortality. Standard blood purification techniques have limited efficacy in removing myoglobin. We describe high cut-off (HCO) renal replacement therapy (RRT) as a novel approach for extracorporeal elimination of myoglobin in rhabdomyolysis-associated AKI. With an in vivo molecular cut-off at 45 kDa, HCO filters are effective in removing myoglobin (17.8 kDa). Clearances across standard and HCO filters using continuous or intermittent RRT are reviewed in a case series of 11 patients with severe rhabdomyolysis and dialysis-dependent AKI. Median myoglobin clearance across standard high-flux filters was 3.3 (interquartile range 2.3-3.9) ml/min for sustained low-efficiency daily dialysis (SLEDD) batch hemodialysis (HD) and 3.7 (2.9-6.7) ml/min for conventional HD. Respective clearances using HCO filters (membrane surface area: 1.1 m(2)) were 21.7 (20.3-26.1) ml/min (SLEDD) and 44.2 (41.3-47.0) ml/min (HD). Corrected for filter size, up to 20-fold higher clearances were obtained using HCO filters, resulting in profound and sustained reduction of plasma myoglobin concentration. As a novel approach, HCO RRT allows for rapid and effective removal of myoglobin from the circulation. In light of the pathogenic role in AKI, reducing exposure of the kidney to myoglobin may improve renal recovery and patient outcome. Our data pave the way for prospective trials, addressing this issue.


Chrysomya pinguis (Walker) (Diptera: Calliphoridae), blow fly of forensic importance: A review of bionomics and forensic entomology appraisal.
Role of blow flies as the entomological evidence used in forensic investigations has risen dramatically worldwide. As the diverse habitats of Thailand suitably endowed with biodiversity of insects, blow flies of forensic importance need investigation in their bionomics, which are further applied in forensic investigations. Chrysomya pinguis (Walker, 1858) (Diptera: Calliphoridae) make up one of the most common blow fly species found associated with the human corpses and/or death scenes in several countries of the Asia continent. Given the major species as forensically important, this review is performed by the need for gathering information of C. pinguis from literature search in the future application in the regions where this species exists. This review deals with morphology, current knowledge on bionomics and forensic entomology involvement. Important morphological characteristics of egg, larva, puparium and adult were highlighted with illustration and/or micrographs. Search pertaining to molecular analysis used for fly identification and developmental rate of larvae were included. Furthermore, we outline potential issues and challenges of C. pinguis research that necessitate forensic applications in the future.


Comparison of 30-min and 3-h infusion regimens for imipenem/cilastatin and for meropenem evaluated by Monte Carlo simulation.
Imipenem/cilastatin and meropenem are carbapenem antibiotics that are infused intravenously (IV) over 30 to 45 min. We evaluated probability of target attainment and cumulative probability of target attainment of 30-min and 3-h infusions for imipenem/cilastatin and meropenem. Eighteen healthy adults in a randomized, 4-phase, crossover study received 1000 mg of imipenem/cilastatin or meropenem as a single-dose IV over 30 min or 3 h. A population pharmacokinetics analysis using a 2-compartment IV infusion model was performed. Monte Carlo simulations using various dosage regimens at steady-state and 30-min and 3-h infusion rates were performed to evaluate the probabilities of attaining 20% (bacteriostatic), 30%, and 40% (maximum kill) time above the MIC. Three-hour infusions of imipenem/cilastatin and meropenem improved the cumulative probability of target attainment for a variety of populations of microorganisms compared to 30-min infusions. Prolonged infusions have the potential to optimize efficacy of imipenem/cilastatin and meropenem.


Sentinel lymph node detection by means of indocyanine green using the Karl Storz VITOM® fluorescence camera: a comparison between primary sentinel lymph node biopsy versus sentinel lymph node biopsy after neoadjuvant chemotherapy.
The usage of radioactive Technetium99m (Tc99m) colloid for the purpose of sentinel lymph node biopsy (SLNB) in early breast cancer is considered the gold standard in Germany. However, new tracers, such as near-infrared (NIR) imaging agents like indocyanine green (ICG) could offer an alternative in future, as they overcome drawbacks associated with radioactive Technetium99m (Tc99m) like limited availability, high costs and radioactivity exposure for both patients and surgeons. In this double-arm retrospective study, we sought to establish the usefulness of indocyanine green as an alternative or an addition to the conventional Technetium99m (Tc99m) in the identification of the SLN in early breast cancer. Among the 161 patients who underwent primary SLNB, 34 patients had at least 1 SLN with metastasis. Among these patients with SLN metastasis, 33 had the SLN detected by ICG; while 31 had the SLN detected by Tc99m. The conventional Technetium99m radiotracer failed to detect 2 patients with metastasis in this Arm of the study. Among the 87 patients who underwent SLNB after NACT, 13 patients had at least 1 SLN with metastasis. Among these 13 patients with SLN metastasis, ICG and Tc99m had detected the SLN among 12 patients, while 1 patient had been detected by ICG alone. Our results show that ICG is as effective as the radioisotope for SLNB even among patients who have undergone NACT. This trial is registered with the German Clinical Trial Register, ID: DRKS00013606.


Psychological Characteristics of Problem Gamblers With and Without Mood Disorder.
Problem and pathological gamblers are significantly more likely to experience mood disorders, compared with the general population. Our study examined the relation of psychological characteristics (personality, trait impulsiveness, and gambling motives) to current co-occurring mood disorder (major depression and dysthymia) status among problem and pathological gamblers. Problem and pathological gamblers (N = 150) underwent a clinical interview to assess current co-occurring mood disorders; participants completed measures of problem gambling severity, personality, impulsiveness, and gambling motives. Problem and pathological gamblers with a current co-occurring mood disorder were more likely to be female, older, and to report higher lifetime and past-year gambling severity. A co-occurring mood disorder was associated with higher personality scores for alienation and stress reaction, lower scores for well-being, social closeness, and control, as well as higher impulsiveness scores for urgency and lack of premeditation, and lower sensation seeking scores. Participants with a co-occurring mood disorder also reported higher coping motives for gambling. Multivariate logistic regression analyses demonstrated that personality factors (lower social closeness and higher alienation) contributed to the greatest likelihood of being diagnosed with a co-occurring mood disorder. Mood disorders frequently co-occur with problem and pathological gambling, and they are associated with greater gambling severity. These findings highlight that interpersonal facets of personality contribute substantially to co-occurring mood disorder status. Implications for treatment will be discussed.


Automatic Three-Dimensional Magnetic Resonance-based measurements of tumour prominence and basal diameter for treatment planning of uveal melanoma.
Three-dimensional (3D) Magnetic Resonance Imaging (MRI) is increasingly used to complement conventional two-dimensional ultrasound in the assessment of tumour dimension measurement of uveal melanoma. However, the lack of definitions of the 3D measurements of these tumour dimensions hinders further adaptation of MRI in ocular radiotherapy planning. In this study, we composed 3D MR-based definitions of tumour prominence and basal diameter and compared them to conventional ultrasound. Tumours were delineated on 3DT2 and contrast-enhanced 3DT1 (T1gd) MRI for 25 patients. 3D definitions of tumour prominence and diameter were composed and evaluated automatically on the T1gd and T2 contours. Automatic T1gd measurements were compared to manual MRI measurements, to automatic T2 measurements and to manual ultrasound measurements. Prominence measurements were similar for all modalities (median absolute difference 0.3 mm). Automatic T1gd diameter measurements were generally larger than manual MRI, automatic T2 and manual ultrasound measurements (median absolute differences of 0.5, 1.6 and 1.1 mm respectively), mainly due to difficulty defining the axis of the largest diameter. Largest differences between ultrasound and MRI for both prominence and diameter were found in anteriorly located tumours (up to 1.6 and 4.5 mm respectively), for which the tumour extent could not entirely be visualized with ultrasound. The proposed 3D definitions for tumour prominence and diameter agreed well with ultrasound measurements for tumours for which the extent was visible on ultrasound. 3D MRI measurements generally provided larger diameter measurements than ultrasound. In anteriorly located tumours, the MRI measurements were considered more accurate than conventional ultrasound.


Outcomes and survival following thoracic endovascular repair in patients with aortic aneurysms limited to the descending thoracic aorta.
Thoracic endovascular aortic repair (TEVAR) is a well-established therapy for descending aortic aneurysms (DTA). There is a paucity of large series reporting the mid- and long-term outcomes from this era. The main aim of this study was to evaluate the outcomes of TEVAR with regards to the effect of aortic morphology and procedure-related variables on survival, reintervention and freedom from endoleaks. In this retrospective single center study, we evaluated the clinical outcomes among 158 consecutive patients with DTA than underwent TEVAR between 2006 and 2019 at our center. The cohort included 51% patients with device landing zones proximal to the subclavian artery and 25.9% patients undergoing an emergent or urgent TEVAR. The primary outcome was survival, and secondary outcomes were reintervention and occurrence of endoleaks. Median follow-up was 33 months [IQR 12 to 70] while 50 patients (30.6%) had longer than 5-year follow-up. With a median patient age of 74 years, post-operative Kaplan Meyer survival estimates were 94.3% (95%CI 90.8-98.0, SE 0.018%) at 30 days, 76.4% (95%CI 70.0-83.3, SE 0.034%) at one year and, 52.9% (95%CI 45.0-62.2, SE 0.043%) at five years. Freedom from reintervention at 30 days, one year, and five years was 92.9% (95%CI 89.0-97.1, SE 0.021%), 80.0% (95%CI 72.6-88.1, SE 0.039%), and 52.8% (95%CI 41.4-67.4, SE 0.065%), respectively. On cox regression analysis greater aneurysm diameter, and the use of device landing zones in aortic regions 0-1 were associated with an increased probability of all-cause mortality, and with reintervention during follow-up. Independent of aneurysm size undergoing urgent or emergent TEVAR was associated with higher mortality risk for the first three years post-operative but not on long-term follow-up. Larger aneurysms and those requiring stent-graft landing in aortic zones 0 or 1, are associated with higher risk for mortality and reintervention. There remains a need to optimize clinical management and device design for larger proximal aneurysms.


Estimation of measles vaccination coverage and longer-term vaccine efficacy in a Queensland State High School during the 1993-94 measles epidemic.
The parents of 470 students randomly selected from 1321 students attending a state high school were surveyed during the 1993-94 measles epidemic, by means of a take-home questionnaire. The response rate was 87%. Thirty stated that their child had measles during this epidemic; nine of these 30 gave a history of previous vaccination. Overall, 312 of the 470 (76%) stated that their child had been vaccinated, but only 34% indicated that they had vaccination records. There were no measles cases during this epidemic in the group with records. Those not vaccinated were at 10 times increased risk of contracting measles compared to those who had been vaccinated with or without records. Vaccine efficacy estimated in general a decade after vaccination based on parental recall of vaccination status regardless of whether they had vaccination records or not was 91% (95% CI 80%-96%). This calculation excluded 123 who claimed to have had measles prior to 1993 and 30 uncertain of their vaccination status.


Investigation on the mechanism of exacerbation of myasthenia gravis by aminoglycoside antibiotics in mouse model.
To investigate the underlying mechanism of the exacerbation of myasthenia gravis by aminoglycoside antibiotics. C57/BL6 mice were immunized with acetylcholine receptor (AChR), extracted from electric organ of Narcine timilei according to Xu Haopeng's methods, in complete Fruends adjuvant (CFA) to establish experimental autoimmune myasthenia gravis (EAMG). EAMG mice were divided randomly into 5 groups: MG group, NS group and three antibiotics groups. The clinical symptom scores of mice were evaluated on d7 after the last immunization and d14 of antibiotics treatment. Repetitive nerve stimulation (RNS) was performed and the levels of anti-AChR antibody (AChR-Ab) were tested at the same time. The mean clinical symptom grades of gentamycin group (1.312, 2.067), amikacin group (1.111, 1.889) and etimicin group (1.263, 1.632) were significantly higher than those of MG group (1.000, 1.200) (P<0.05). The positive rates of RNS of three antibiotics groups were 69.23%, 58.82% and 63.16% respectively, which were significantly higher than those of MG group and NS group (40.00%, 40.00%, P<0.05). The AChR-Ab level in serum and the expression of AChR on neuromuscular junction (NMJ) of mice in three antibiotics groups were also higher than those of MG group. Our results indicated that aminoglycoside antibiotics could aggravate the symptom of myasthenia gravis. The exacerbation of myasthenia gravis by these antibiotics probably involves competitively restraining the release of acetylcholine from presynaptic membrane, impairing the depolarization of postsynaptic membrane, depressing the irritability of myocyte membrane around the end-plate membrane and consequently leading to the blockade of neuromuscular junction.


Angiotensin AT1 receptors in Clone 9 rat liver cells: Ca2+ signaling and c-fos expression.
In C9 (Clone 9) liver cells, angiotensin 11 increased the intracellular Ca2+ content, inositol phosphate production and c-fos mRNA expression. Other angiotensins were also active with the order of potency being angiotensin II = angiotensin III >> angiotensin I > angiotensin IV. Losartan, but not PD 123177 (1-(4-amino-3-methyl)-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imida zo [4,5c]pyridine-6-carboxylic acid), blocked the effects of angiotensin II. Pertussis toxin did not alter these actions of angiotensin II. These data indicate that the effects were mediated through angiotensin AT1 receptors involving pertussis toxin-insensitive G-proteins. Phorbol myristate acetate was also able to increase c-fos mRNA expression. The action of angiotensin II was consistently greater than that of the active phorbol ester. Staurosporine but not genistein inhibited this effect of angiotensin II. Angiotensin II- and phorbol myristate acetate-induced proto-oncogene mRNA expression was attenuated in cells incubated overnight with the active phorbol ester, which suggests a major role of protein kinase C.


Clinical and histopathological findings in Bannayan-Riley-Ruvalcaba syndrome.
Bannayan-Riley-Ruvalcaba syndrome is a rare autosomal dominant genodermatosis with the classical triad of macrocephaly, genital lentiginosis, and intestinal polyposis. Characteristic mucocutaneous manifestations include vascular malformations, lipomatosis, speckled lentiginosis of the penis or vulva, facial verrucae-like or acanthosis nigricans-like lesions, and multiple acrochordons of the neck, axilla, and groin. We present a case of Bannayan-Riley-Ruvalcaba syndrome with macrocephaly, abnormal facies, lipoma, tender and painful arteriovenous hemangiomas, lymphangiokeratomas, musculoskeletal abnormalities, and localized myopathy. We also describe previously unreported findings, including peripheral neuropathy, punctate cystic changes in acral tubular bones, and enostosis of talus. Bannayan-Riley-Ruvalcaba syndrome needs recognition by dermatologists because affected patients may present with mucocutaneous and subcutaneous lesions that may simulate other dermatological disorders.


Surveying nonvisual arrestins reveals allosteric interactions between functional sites.
Arrestins are important scaffolding proteins that are expressed in all vertebrate animals. They regulate cell-signaling events upon binding to active G-protein coupled receptors (GPCR) and trigger endocytosis of active GPCRs. While many of the functional sites on arrestins have been characterized, the question of how these sites interact is unanswered. We used anisotropic network modeling (ANM) together with our covariance compliment techniques to survey all the available structures of the nonvisual arrestins to map how structural changes and protein-binding affect their structural dynamics. We found that activation and clathrin binding have a marked effect on arrestin dynamics, and that these dynamics changes are localized to a small number of distant functional sites. These sites include α-helix 1, the lariat loop, nuclear localization domain, and the C-domain β-sheets on the C-loop side. Our techniques suggest that clathrin binding and/or GPCR activation of arrestin perturb the dynamics of these sites independent of structural changes.


A schistosome miRNA promotes host hepatic fibrosis by targeting transforming growth factor beta receptor III.
MicroRNAs (MiRNAs) derived from parasites, and even from plants, have been detected in body fluids and are known to modulate host genes. In this study, we aimed to investigate if the schistosome miRNAs are involved in the occurrence and progression of hepatic fibrosis during Schistosoma japonicum (S. japonicum) infection. The presence of miRNAs from S. japonicum (sja-miRNAs) in hepatic stellate cells (HSCs) was detected by RNA sequencing. sja-miRNAs were screened by transfecting HSCs with sja-miRNA mimics. The role of sja-miR-2162 in hepatic fibrosis was evaluated by either elevating its expression in naïve mice or by inhibiting its activity in infected mice, through administration of recombinant adeno-associated virus serotype 8 vectors expressing sja-miR-2162 or miRNA sponges, respectively. We identified a miRNA of S. japonicum, sja-miR-2162, that was consistently present in the HSCs of infected mice. Transfection of sja-miR-2162 mimics led to activation of HSC cells in vitro, characterized by elevation of collagens and α-SMA. The rAAV8-mediated delivery of sja-miR-2162 to naïve mice induced hepatic fibrosis, while sustained inhibition of sja-miR-2162 in infected mice attenuated hepatic fibrosis. The transforming growth factor beta receptor III (TGFBR3), a negative regulator of TGF-β signaling, was a direct target of sja-miR-2162 in HSCs. This study demonstrated that pathogen-derived miRNAs directly promote hepatic fibrogenesis in a cross-species manner, and their efficient and sustained inhibition might present a promising therapeutic intervention for infectious diseases. A schistosome-specific microRNA, sja-miR-2162, is consistently present in the hepatic stellate cells of mice infected with S. japonicum, where it promotes hepatic fibrosis in the host through cross-species regulation of host fibrosis-related genes. The efficient and sustained inhibition of pathogen-derived micRNAs may represent a novel therapeutic intervention for infectious diseases.


Platinum-induced mutations to 8-azaguanine resistance in Chinese hamster ovary cells.
6 platinum (Pt) compounds were compared in suspension cultured Chinese hamster ovary (CHO-S) cells with respect to their inhibition of growth, their reduction of cloning efficiency, and their induction of mutants resistant to 200 microM (30 micrograms/ml) 8-azaguanine (8-AG) and 3 mM ouabain (OUA), respectively. The toxicity of these compounds can be ranked by the medium concentrations which decrease suspension growth/or cloning efficiency by 50%: cis-Pt(NH3)2-Cl2 (0.9/1.5 microM) greater than Pt(SO4)2 + methylcobalamin (MeB-12) methylation product (20/10 microM) greater than K2PtCl4 (32/50 microM) = K2PtCl6 (34/50 microM) = MePtCl2-3 (60/50 microM) greater than Pt(SO4)2 (66/105 microM). Following 20 h exposures to concentrations which resulted in relative survivals of 80-2%, none of the foregoing compounds increased consistently the frequency of OUA(R) mutants above the spontaneous frequency (6.0 x 10(-6)). Parallel treatments with 800 microM (100 micrograms/ml) ethyl methanesulfonate (EMS) increased the OUA(R) mutant frequency 10--12-fold. Using 8-AG for mutant selection, dose-dependent increases of 5--7-fold above the spontaneous frequency (3--8 x 10(-5) were obtained with cis-Pt(NH3)2Cl2, Pt(S04)2, and the product from Pt(SO4)2 + MeB-12. Identical 20 h exposures to varying amounts of K2PtCl4, K2PtCl6, and MePtCl2-3 did not induce 8-AG(R) mutants. Optimal detection of Pt-induced 8-AG(R) mutants required 7 post-treatments, expression doublings in suspension culture. Under our selection conditions 8/8 spontaneous and 24/24 Pt-induced 8-AG(R) variants contained reduced hypoxanthine-guanine phosphoribosyl transferase (HGPRT) specific activities (means ranging from 3 to 11% of the parental CHO-S cells). When compared from linear plots of the 8-Ag(r) frequency against the initial medium concentration, cis-Pt(NH3)2Cl2 is 134 times and Pt(SO4)2 si 3.5 times more mutagenic than EMS. However, on a cell-survival basis EMS is 8--10-fold more mutagenic than these two Pt-compounds. 6-Thioguanine (10 microM) can be substituted for 8-AG to assay mutant induction by cis-Pt(NH3)2Cl2 and Pt(SO4)2 in CHO-S cells. The sensitivity of the CHO-S HGPRT locus for detecting mutagenesis by Pt complexes can be increased several fold by continuous subculture in the presence of these agents for 10--25 population doublings. By this procedure K2PtCl6 is seen to be weakly mutagenic and 20 microM Pt(SO4)2 produces 8-AG(R) mutants at frequencies requiring 7--8-fold higher concentrations when a fixed 20 h exposure is used.


How Should Surgeons Balance Transplantation Innovation With Acceptance of a Trauma Survivor's Appearance?
Clinical and ethical issues involved in counseling a patient about reconstructive surgery for a traumatic and disfiguring injury require special consideration. This article proposes prioritizing 2 considerations: (1) the influence of traumatic experiences on a survivor's cognitive processes and (2) insights into a survivor's acceptance of his or her posttrauma appearance or consent to high-risk or experimental surgery, which can be gained from dialectical behavior therapy. This article argues that these priorities should be explicitly discussed by plastic surgeons counseling patients whose appearances are altered by trauma.


Serum ribonucleases in pancreatic cancer: relation to tumor histology.
Serum Ribonuclease (RNase, EC. 3. 1. 4. 22) of normal persons and of patients with chronic pancreatitis, or pancreatic cancer was determined with poly (C) as substrate. Strikingly abnormal elevations occured in the serum RNase of patients with pancreatic cancer (p less than 0.001). Average serum RNase values of 18 normal persons, 10 patients with chronic pancreatitis and 26 patients with pancreatic cancer were 92, 118, and 249 units, respectively. In patients with pancreatic cancer, we compared the RNase level with four histologic types (ductar cell adenocarcinoma, anaplastic cell carcinoma, acinar cell carcinoma, and islet cell carcinoma). Adenocarcinoma showed higher activity than the other histologic types (p less than 0.005). When we compared the serum of pancreatic cancer and pancreatic cancer tumor extract with normal serum and normal pancreas extract, strikingly different phosphocellulose chromatographic pattern were evident. The correlation of increased serum RNase levels with tumor histology and different chromatographic pattern may explain the new enzyme production in cancer patients, and have biological significance in the development of pancreatic cancer.


Thermo-behavioural responses to orally applied l-menthol exhibit sex-specific differences during exercise in a hot environment.
This study investigated the efficacy of l-menthol mouth-rinsing on thermal sensation and perceived effort in females and males, using a fixed-rating of perceived exertion (RPE) exercise protocol in a hot environment. Twenty-two participants (eleven females, eleven males) completed two trials using a fixed-RPE protocol at an exercise intensity between 'hard' and 'very hard', equating to 16 on the RPE scale at ~35 °C. Participants adjusted power output to maintain RPE-16. In a randomised, double-blind, crossover design, l-menthol or a control mouthwash was administered at an orally neutral temperature (~32 °C) prior to exercise and at 10 min intervals thereafter. Measures of mechanical power output, core temperature, heart rate, perception of thermal sensation and thermal comfort, and whole-body sweat loss are reported. Thermal sensation was lowered by l-menthol in both sexes (P < 0.05), however during exercise this was only maintained for 40% of the trial duration in females. Thermal comfort did not differ between conditions (P > 0.05). No differences in exercise duration were observed compared to control, despite a ~4% and ~6% increase in male and females respectively. Power output increased by ~6.5% males (P = 0.039) with no difference in females ~2.2% (P = 0.475), compared to control. Core temperature, heart rate and whole-body sweat loss was not different between condition or sex. l-menthol lowered perceptual measures of thermal sensation in females, but did not attenuate a greater rate of rise in thermal sensitivity when exercising in a hot environment, compared to males. Males appeared to adopt a higher risk strategy by increasing power output following l-menthol administration in contrast to a more conservative pacing strategy in females. Therefore, there appear to be sex-specific differences in l-menthol's non-thermal cooling properties and subsequent effects on thermo-behavioural adjustments in work-load when exercising in a hot environment.


The effect of varenicline and nicotine patch on smoking rate and satisfaction with smoking: an examination of the mechanism of action of two pre-quit pharmacotherapies.
In recent years, there has been growing research interest in using nicotine replacement medications to aid smoking reduction prior to a quit attempt. Gaining a better understanding of how treatments influence smoking reduction may allow for better tailoring of treatments and, ultimately, better cessation outcomes. The objective of the current study was to test the effects of the pre-quit use of varenicline and nicotine patch on smoking rate and satisfaction with smoking. All participants were required to attend up to five study visit sections. Participants (n = 213) who were interested in quitting were randomised (open-label) to receive either pre-quit patch or varenicline (both treatments started 2 weeks prior to an assigned quit day, followed by 10 weeks post-quit) or standard patch (10 weeks starting from an assigned quit day). Participants used modified smartphones to monitor their smoking in real time for 4 weeks. Participants in the two pre-quit treatment groups reported significant reductions in both their satisfaction with smoking (p < 0.001) and smoking rate (p < 0.001) from baseline to the end of pre-quit period; participants in the standard patch group did not. The observed reduction of smoking rate was associated with the satisfaction with smoking (p < 0.01), although the mediation effect of satisfaction was small. Pre-quit treatment caused reductions in satisfaction with smoking and smoking rate. Satisfaction was associated with changes in smoking rate, but the relationship was weak. As such, monitoring reductions in satisfaction do not appear to be a viable method of evaluating responsiveness to treatment.


New dammarane-type triterpenoid saponins from Panax notoginseng saponins.
Panax notoginseng saponin (PNS) is the extraction from the roots and rhizomes of Panax notoginseng (Burk.) F. H. Chen. PNS is the main bioactive component of Xuesaitong, Xueshuantong, and other Chinese patent medicines, which are all bestselling prescriptions in China to treat cardiocerebrovascular diseases. Notoginsenoside R1 and ginsenoside Rg1, Rd, Re, and Rb1 are the principal effective constituents of PNS, but a systematic research on the rare saponin compositions has not been conducted. The objective of this study was to conduct a systematic chemical study on PNS and establish the HPLC fingerprint of PNS to provide scientific evidence in quality control. In addition, the cytotoxicity of the new compounds was tested. Pure saponins from PNS were isolated by means of many chromatographic methods, and their structures were determined by extensive analyses of NMR and HR-ESI-MS studies. The fingerprint was established by HPLC-UV method. The cytotoxicity of the compounds was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5 -diphenyltetrazolium bromide assay. Three new triterpenoid saponins (1-3) together with 25 known rare saponins (4-28) were isolated from PNS, except for the five main compounds (notoginsenoside R1 and ginsenoside Rg1, Rd, Re, and Rb1). In addition, the HPLC fingerprint of PNS was established, and the peaks of the isolated compounds were marked. The study of chemical constituents and fingerprint was useful for the quality control of PNS. The study on antitumor activities showed that new Compound 2 exhibited significant inhibitory activity against the tested cell lines.


Determination of ivermectin in bovine liver by optical immunobiosensor.
A rapid and sensitive biosensor immunoassay was developed for residues of the antiparasitic agent ivermectin in bovine liver. A detection limit of 19.1 ng g(-1) was achieved. The sensor employed was a Biacore optical instrument based on surface plasmon resonance. 5-O-succinoylivermectin-apo-transferrin conjugate was used to produce monoclonal antibody while a second derivative, ivermectin-oxime, was immobilised onto the surface of a sensor chip. A range of assay parameters (flow rate, injection time, temperature) and extraction techniques were investigated. In the final assay procedure, ivermectin was extracted with acetonitrile followed by C(8) SPE clean-up. Matrix effect was minimised by increasing the flow rate to 25 microl min(-1) and reducing the sample injection time to 2 min. The average value for liver samples spiked at 100 ng g(-1) (the MRL for the drug) and 50 ng g(-1) concentrations were 93.7 and 43.2 ng g(-1), respectively.


Videodermoscopy and doppler-ultrasound in spider naevi: towards a new classification?
Spider naevi (SN) are considered a subtype of telangiectasias, currently classified as low-flow vascular malformations. To describe the videodermoscopy and Doppler-ultrasound (US) features of a large group of SN. A retrospective study of cases of SN collected at our Dermatology department during the period between June 2015 and June 2017 was performed. Clinical images, dermoscopic, videodermoscopic and Doppler-US files were reviewed. For each case, the age of the patient, time since onset, size and dermoscopic pattern of the lesions were recorded. The presence of pulsatility was also evaluated visually on the videodermoscopy. Two hundred and thirty-three SN in 189 patients were included. The mean age was 39.5 years (range: 10-76 years). Mean size of the lesions was 4.1 ± 2.0 mm. We described three dermoscopic patterns: network, star and looping. Older age, longer time since onset and larger size were found associated with higher frequency of the looping and star patterns compared to that of network pattern (P < 0.01). Pulsatility during videodermoscopy was found in 88 patients (37%). This pulsatility phenomenon was more commonly associated with the looping pattern (64.7%) than star- (40.3%) or network-like patterns (29.9%) (P < 0.001). In Doppler-US studies, a high-flow with arterial biphasic waveform was found. In the light of the results, we support that SN could be reconsidered in upcoming classifications as lesions closer to the group of high-flow arteriovenous malformations.


Serum concentration of zinc is elevated in clinically stable bipolar disorder patients.
Bipolar disorder (BD) is a chronic psychiatric disorder characterized by recurrent mood episodes interspersed with euthymic periods. A growing number of studies have indicated that zinc plays an important role in coordinating immune responses, as well as being involved in synaptic transmission. In the current study, we set out to measure serum levels of zinc in a meticulously phenotyped cohort of 121 euthymic BD subjects and 30 matched controls. Serum levels of zinc were measured by photometry. To assess the interplay between zinc levels and immune activation in BD, we measured serum levels of high-sensitive C-reactive protein (hsCRP) levels by immunoturbidimetric assay, and serum levels of monocyte chemoattractant protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble cluster of differentiation 14 (sCD14) by electrochemiluminescence enzyme-linked immunosorbent assays. The baseline clinical diagnostic instrument for BD was the Affective Disorder Evaluation, and executive functioning was assessed by using the Delis-Kaplan Executive Function System. Controlling for potential confounding factors, BD patients displayed increased serum levels of zinc unrelated to hsCRP, MCP-1, YKL-40, and sCD14 levels. Serum levels of zinc did not associate with executive functioning or measurements of disease severity. This study suggests that the zinc homeostasis is disturbed in BD and that this dyshomeostasis is not related to ongoing mood symptoms or immune activation. Of note, serum levels were increased and hence do not support continuous zinc supplementation in BD.


Case reports of new-onset eating disorders in older adult cancer survivors.
It is unusual for a de novo eating disorder to emerge in late adulthood. Across a number of years, a number of patients were identified who experienced severe and unexpected weight loss post curative management of an upper abdominal cancer (i.e., cancer survivors). Each of the patients was readmitted to the tertiary surgical hospital due to complications of severe malnutrition. Each presentation was initially considered to have a major physical health problem (such as cancer recurrence). Each required extensive investigations and multidisciplinary team involvement and were later conceptualised as a new-onset (in later adulthood) eating disorder that emerged post curative cancer treatment. The team wished to better understand this group and/or characterise and/or inform the scientific community of this phenomena if not already well described. The review identified that the re-emergence of pre-existing eating disorders at the time of cancer treatment was described; however, there was no identification of similar new-onset in later adulthood cases of eating disorders in cancer survivors in the medical literature. Once ethics and consent was obtained, then the clinical course of four complex individuals were reviewed, including the use of a multidisciplinary Delphi review process, to understand commonalities and then plot a common care pathway with potential intervention points. Common factors identified among the four patients included the lack of a physical health (organic) cause to the weight loss and ongoing weight loss despite intense multidisciplinary care. All had abnormal attitudes and behaviours relating to food, nutritional rehabilitation and/or recovery. None returned to a healthy weight and/or healthy eating despite extensive team input. The presentations were ultimately conceptualised as having severe disordered eating behaviours and in at least three cases met criteria for a formal eating disorder. The cohort had similar psychosocial characteristics including low socioeconomic status and complex family dynamics. None had prior formal psychiatric care. The outcomes were poor; one patient died, another required admission to a specialist eating disorder admission with a subsequent relapsing remitting course, and the remaining two had complicated chronic courses. Similar cases may be underreported. If identified earlier, there may be a role for intervention to prevent high morbidity and mortality and to support clinical teams managing similar complex patients.


Hypoxia-responsive nanocarriers for chemotherapy sensitization via dual-mode inhibition of hypoxia-inducible factor-1 alpha.
The overexpression of hypoxia-inducible factor-1 alpha (HIF-1α) in solid tumor compromises the potency of chemotherapy under hypoxia. The high level of HIF-1α arises from the stabilization effect of reduced nicotinamideadeninedinucleotide(phosphate) NAD(P)H: quinone oxidoreductase 1 (NQO1). It was postulated that the inhibition of NQO1 could degrade HIF-1α and sensitize hypoxic cancer cells to antineoplastic agents. In the current work, we report hypoxia-responsive polymer micelles, i.e. methoxyl poly(ethylene glycol)-co-poly(aspartate-nitroimidazole) orchestrate with a NQO1 inhibitor (dicoumarol) to sensitize the ovarian cancer cell line (SKOV3) to a model anticancer agent (sorafenib) at low oxygen conditions. Both cargos were physically encapsulated in the nanoscale micelles. The placebo micelles transiently induced the depletion of reduced nicotinamideadeninedinucleotidephosphate (NADPH) as well as glutathione and thioredoxin under hypoxia, which further inactivated NQO1 because NADPH was the cofactor of NQO1. As a consequence, the expression of HIF-1α was repressed due to the dual action of dicoumarol and polymer. The degradation of HIF-1α significantly increased the vulnerability of SKOV3 cells to sorafenib-induced apoptosis, as indicated by the enhancement of cytotoxicity, and increase of caspase 3 and cytochrome C. The current work opens new avenues of addressing hypoxia-induced drug resistance in chemotherapy.


Pathogenesis and prophylaxis of cardiac lesions in stress.
Emotional or painful stress excites the brain centers which trigger stress reactions, this excitement being followed by an increase in catecholamine concentration. The following chain of events is thought to occur under the influence of the catecholamine excess: activation of lipid peroxidation in the membranes; labilization of lysosomes; damage to sarcolemmal membranes which are responsible for calcium transport; increased calcium concentration in the heart sarcoplasm. The contraction of myofibrils, the decrease in efficiency of ATP resynthesis in the mitochondria, and the activation of phosphorylase and proteases all arise from the calcium excess. This results in necrotic foci and alterations of heart function. The damages can be effectively prevented by suppression of stress-responding centers with gamma-aminobutyric acid, blockade of beta receptors with propranolol, inhibition of lipid peroxidation by antioxidants, inhibition of proteolytic lysosomal enzymes with trasilol, or blocking of calcium entry into the myocytes with verapamil. The possible application to clinical practice of chemical prophylaxis of stress damage in the heart is discussed.


PlGF repairs myocardial ischemia through mechanisms of angiogenesis, cardioprotection and recruitment of myo-angiogenic competent marrow progenitors.
Despite preclinical success in regenerating and revascularizing the infarcted heart using angiogenic growth factors or bone marrow (BM) cells, recent clinical trials have revealed less benefit from these therapies than expected. We explored the therapeutic potential of myocardial gene therapy of placental growth factor (PlGF), a VEGF-related angiogenic growth factor, with progenitor-mobilizing activity. Myocardial PlGF gene therapy improves cardiac performance after myocardial infarction, by inducing cardiac repair and reparative myoangiogenesis, via upregulation of paracrine anti-apoptotic and angiogenic factors. In addition, PlGF therapy stimulated Sca-1(+)/Lin(-) (SL) BM progenitor proliferation, enhanced their mobilization into peripheral blood, and promoted their recruitment into the peri-infarct borders. Moreover, PlGF enhanced endothelial progenitor colony formation of BM-derived SL cells, and induced a phenotypic switch of BM-SL cells, recruited in the infarct, to the endothelial, smooth muscle and cardiomyocyte lineage. Such pleiotropic effects of PlGF on cardiac repair and regeneration offer novel opportunities in the treatment of ischemic heart disease.


Development and experience of quality control methods for digital breast tomosynthesis systems.
To develop tomosynthesis quality control (QC) test methods and use them alongside established two-dimensional (2D) QC tests to measure the performance of digital breast tomosynthesis (DBT) systems used in a comparative trial with 2D mammography. DBT QC protocols and associated analysis were developed, incorporating adaptions of some 2D tests as well as some novel tests. The tomosynthesis tests were: mean glandular dose to the standard breast model; contrast-to-noise ratio in reconstructed focal planes; geometric distortion; artefact spread; threshold contrast detail detection in reconstructed focal planes, alignment of the X-ray beam to the reconstructed image and missed tissue; reproducibility of the tomosynthesis exposure; and homogeneity of the reconstructed focal planes. Summaries of results from the tomosynthesis QC tests are presented together with some 2D results for comparison. The tomosynthesis QC tests and analysis methods developed were successfully applied. The lessons learnt, which are detailed in the Discussion section, may be helpful to others embarking on DBT QC programmes. DBT performance test equipment and analysis methods have been developed. The experience gained has contributed to the subsequent drafting of DBT QC protocols in the UK and Europe.


Identification of deletions and duplications in the Duchenne muscular dystrophy gene and female carrier status in western India using combined methods of multiplex polymerase chain reaction and multiplex ligation-dependent probe amplification.
The technique of multiplex ligation-dependent probe amplification (MLPA) assay is an advanced technique to identify deletions and duplications of all the 79 exons of DMD gene in patients with Duchenne/Becker muscular dystrophy (DMD/BMD) and female carriers. To use MLPA assay to detect deletions which remained unidentified on multiplex polymerase chain reaction (mPCR) analysis, scanning 32 exons of the "hot spot" region. Besides knowing the deletions and/or duplications, MLPA was also used to determine the carrier status of the females at risk. Twenty male patients showing no deletions on mPCR and 10 suspected carrier females were studied by MLPA assay using P-034 and P-035, probe sets (MRC Holland) covering all the 79 exons followed by capillary electrophoresis on sequencing system. On MLPA analysis, nine patients showed deletions of exons other than 32 exons screened by mPCR represented by absence of peak. Value of peak areas were double or more in four patients indicating duplications of exons. Carrier status was confirmed in 50% of females at risk. Combining the two techniques, mPCR followed by MLPA assay, has enabled more accurate detection and extent of deletions and duplications which otherwise would have remained unidentified, thereby increasing the mutation pick up rate. These findings have also allowed prediction of expected phenotype. Determining carrier status has a considerable significance in estimating the risk in future pregnancies and prenatal testing options to limit the birth of affected individuals.


Endometriosis may contribute to oocyte retrieval-induced pelvic inflammatory disease: report of eight cases.
Pelvic inflammatory disease is a rare complication of transvaginal oocyte retrieval. It results in failure of assisted reproductive procedure. During a 6-year period, 5958 transvaginal ultrasound-guided oocyte retrievals resulted in 10 cases of acute pelvic inflammatory disease (0.12%). Eight of the 10 patients were diagnosed infertile because of endometriosis. Two patients had mild ovarian, three had stage III, and two had stage IV endometriosis. One patient had a 3-4 cm ovarian endometrioma. After treatment, no mortality was encountered among the 10 patients, although none of them conceived. This observation supports the previous reports that endometriosis can raise the risk of pelvic inflammatory disease after oocyte retrieval. More vigorous antibiotic prophylaxis and better vaginal preparation are recommended when oocyte pickup is performed in patients with endometriosis.


OX40L enhances the immunogenicity of dendritic cells and inhibits tumor metastasis in mice.
A well preserved immune system is a powerful tool to prevent foreign invasion or to suppress internal mutation, which must be tightly controlled by co-stimulatory molecules in different pathophysiological conditions. One such critical molecule is OX40L expressed on activated antigen-presenting cells (APCs). Consistently, its abnormality is associated with various immunological disorders such as autoinflammatory diseases and allergy. However, a comprehensive analysis of the immune-moderating role of OX40L in dendritic cells (DCs), the most powerful APCs to initiate immune responses in vivo, and investigation of its anti-tumor efficacy in the disease setting have not been performed properly. In this study, genetic approaches for both gain-of-function and reduction-of-function were employed to reveal that OX40L was required for the efficient presentation, but not uptake, of antigens by DCs to stimulate CD4+ , as well as CD8+ T cells in vivo. As a result, CD4+ T cells were promoted towards Th1, but inhibited on Treg differentiation, by the LPS-induced OX40L on DCs, which was supported by their altered expression of co-inhibitory receptor, PD-L1. CD8+ T cells, on the other hand, also enhanced their cytotoxicity towards target cells in response to OX40L expression on the DCs transferred in vivo. Finally, in a DC-mediated tumor immunity model, the strong immunogenic roles of OX40L on DCs led to better metastasis inhibition in vivo. Collectively, our results demonstrate that OX40L could serve as a potential target in the DC-based vaccine for enhanced anti-tumor efficacy in vivo.


Theory of the NO+CO surface-reaction model.
We derive a pair approximation (PA) for the NO+CO model with instantaneous reactions. For both the triangular and square lattices, the PA, derived here using a simpler approach, yields a phase diagram with an active state for CO-fractions y in the interval y(1)<y<y(2), with a continuous (discontinuous) phase transition to a poisoned state at y(1) (y(2)). This is in qualitative agreement with simulation for the triangular lattice, where our theory gives a rather accurate prediction for y(2). To obtain the correct phase diagram for the square lattice, i.e., no active stationary state, we reformulate the PA using sublattices. The (formerly) active regime is then replaced by a poisoned state with broken symmetry (unequal sublattice coverages), as observed recently by Kortlüke et al. [Chem. Phys. Lett. 275, 85 (1997)]. In contrast with their approach, in which the active state persists, although reduced in extent, we report here the qualitatively correct theory of the NO+CO model on the square lattice. Surface diffusion of nitrogen can lead to an active state in this case. In one dimension, the PA predicts that diffusion is required for the existence of an active state.


Unconscious processing of direct gaze: evidence from an ERP study.
Humans detect faces with direct gaze more rapidly than they do faces with averted gaze. Evidence suggests that the visual information of faces with direct gaze reaches conscious awareness faster than that of faces with averted gaze. This suggests that faces with direct gaze are effectively processed in the brain before they reach conscious awareness; however, it is unclear how the unconscious perception of faces with direct gaze is processed in the brain. To address this unanswered question, we recorded event-related potentials while observers viewed faces with direct or averted gaze that were either visible or rendered invisible during continuous flash suppression. We observed that invisible faces with direct gaze elicited significantly larger negative deflections than did invisible faces with averted gaze at 200, 250, and 350 ms over the parietofrontal electrodes, whereas we did not observe such effects when facial images were visible. Our results suggest that the visual information of faces with direct gaze is preferentially processed in the brain when they are presented unconsciously.


BDE-47 exposure modulates cellular responses, oxidative stress and biotransformation related-genes in Mytilus galloprovincialis.
Polybrominated diphenyl ethers (PBDEs) are flame retardants, characterized by elevated stability in the marine environment, where are accumulated by organisms, inducing a wide panel of negative effects. In this study, some biochemical patterns related to toxicity, biotransformation and oxidative stress, were studied in the marine model system, Mytilus galloprovincialis, exposed to BDE-47. Mussels were fed with microalgae, previously treated with increasing concentrations of PBDEs (maximum dose 100 ng L-1 of BDE-47 per day). After 15 days of treatment, mussels were fed with the same diet without BDE-47, for additional 15 days. Gills and digestive glands were analyzed at T 0, at 15 and 30 days. Histopathological lesions were assessed in digestive glands of contaminated mussels, while expression of genes, related to cell cycle, multidrug resistance, oxidative stress and detoxification was evaluated on both gills and digestive glands. After 15 days, BDE-47 exposure significantly affected the cell activity in digestive gland and, at 30 days, only mussels exposed to the lower doses showed a certain recovery. Regarding the gene expression, both gills and digestive glands showed a significant down-regulation of the target genes at 15 days, although most of them were up-regulated at 30 days in digestive gland. The results on BDE-47 accumulation in mussels revealed a dose-dependent concentration in tissues, which remained elevated after further 15 days of depuration. This trend supports the responses of the biomarkers, indicating that exposure, at environmentally realistic concentrations of BDE-47, strongly modulates oxidative stress and related patterns of gene expression, suggesting concerns for long-term effect in the biota.


Management of ovarian cyst detected antenatally.
Ovarian cyst was diagnosed in nine fetuses by antenatal ultrasonographic examination. All deliveries were uncomplicated; two were delivered by cesarean section. The clinical condition in all cases was good. Five of the neonates with a large cyst (more than 5 cm in diameter) were managed surgically, while four were merely followed with repeated ultrasonic examinations. In three of the latter four infants, the cysts disappeared without clinical complications during the subsequent 12 months, and one has been followed for only 2 weeks. The treatment of neonatal ovarian cyst is controversial. Since small ovarian cysts are not clinically significant and may involute, conservative treatment after birth is possible. Repeated ultrasonographic examination may be used to follow small cysts in asymptomatic patients. However, surgical excision in the newborn period has been suggested for larger lesions and/or those with solid components inside the cyst before life-threatening complications occur.


Quinoline-Conjugated Ruthenacarboranes: Toward Hybrid Drugs with a Dual Mode of Action.
The role of autophagy in cancer is often complex, ranging from tumor-promoting to -suppressing effects. In this study, two novel hybrid molecules were designed, containing a ruthenacarborane fragment conjugated with a known modulator of autophagy, namely a quinoline derivative. The complex closo-[3-(η6 -p-cymene)-1-(quinolin-8-yl-acetate)-3,1,2-RuC2 B9 H10 ] (4) showed a dual mode of action against the LN229 (human glioblastoma) cell line, where it inhibited tumor-promoting autophagy, and strongly inhibited cell proliferation, de facto blocking cellular division. These results, together with the tendency to spontaneously form nanoparticles in aqueous solution, make complex 4 a very promising drug candidate for further studies in vivo, for the treatment of autophagy-prone glioblastomas.


Transvenous cryoablation reduces platelet activation during pulmonary vein ablation compared with radiofrequency energy in patients with atrial fibrillation.
Radiofrequency (RF) ablation procedures for atrial fibrillation (AF) are associated with potential risks of thromboembolism, which may be minimized by the use of cryoablation that preserves the integrity of endocardium. The objective of this study was to compare the thrombogenic potential of transvenous cryoablation versus RF ablation during pulmonary vein (PV) isolation. Thirty consecutive patients with paroxysmal AF were randomized to undergo segmental PV isolation procedure using 4-mm tip RF ablation (n = 15) or cryoablation (CryoCor, San Diego, CA, USA) (n = 15). Blood samples were drawn after sheath insertion (baseline), after transseptal puncture, before ablation (after heparin administration), and after isolation of a superior PV. Activation of coagulation was measured with plasma levels of prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin III complex (TAT), and platelets by plasma level of beta-thromboglobulin (beta-TG) and flow cytometric enumerating of P-selectin (CD62)-positive platelets. In both groups, the plasma level of beta-TG, F1 + 2, and TAT were elevated after sheath insertion. The percentage changes in plasma level of beta-TG, F1 + 2, and TAT and CD41/62-positive platelets from baseline after transseptal puncture and before ablation were similar (P > 0.05). However, the percentage changes in CD62-positive platelets from baseline were significantly higher in patients treated with RF ablation (82 +/- 20%) than with cryoablation (22 +/- 14%, P = 0.02), although their plasma levels of beta-TG, F1 + 2, and TAT were not different (P > 0.05). Significant platelet and coagulation activations were observed during PV ablation procedures, and heparin administration only prevented activation of coagulation but not platelets. Persistent platelets activation was observed during RF energy application, but not during cryoablation.


The development of some elements of the arthropod fauna of a new polder.
The carabid and spider faunas of a young polder, reclaimed from a tidal flat, was studied in two areas with pitfall traps. Data are presented on the soil and the vegetation.A total of 100000 specimens of 58 carabid and 55 spider species was caught. Those catches could be compared with data from a nearby area in an older polder representing a later successional stage. The data are described with d (an index of dominance), α (the index of diversity), AV (a measure of the annual variability of population growth rates), and with dominance-diversity curves. After six years the carabid and spider faunas of the polder areas were less diverse than those outside the polder. The carabid fauna was very unstable, the spider fauna less so. This indicates that carabids reflect the changes in the habitat more clearly.Principal component analysis shows the development of the vegetation to have a major influence on the saline habitat; in carabids desalination of the soil also is important. The way in which the carabid and spider faunas developed is related to the low resource levels and high adversity and to the durational instability of the polder habitat.


The role of GATA switch in benzene metabolite hydroquinone inhibiting erythroid differentiation in K562 cells.
The phenolic metabolite of benzene, hydroquinone (HQ), has potential risks for hematological disorders and hematotoxicity in humans. Previous studies have revealed that reactive oxygen species, DNA methylation, and histone acetylation participate in benzene metabolites inhibiting erythroid differentiation in hemin-induced K562 cells. GATA1 and GATA2 are crucial erythroid-specific transcription factors that exhibit dynamic expression patterns during erythroid differentiation. We investigated the role of GATA factors in HQ-inhibited erythroid differentiation in K562 cells. When K562 cells were induced with 40 μM hemin for 0-120 h, the mRNA and protein levels of GATA1 and GATA2 changed dynamically. After exposure to 40 μM HQ for 72 h, K562 cells were induced with 40 μM hemin for 48 h. HQ considerably reduced the percentage of hemin-induced Hb-positive cells, decreased the GATA1 mRNA, protein, and occupancy levels at α-globin and β-globin gene clusters, and increased the GATA2 mRNA and protein levels significantly. ChIP-seq analysis revealed that HQ reduced GATA1 occupancy, and increased GATA2 occupancy at most gene loci in hemin-induced K562 cells. And GATA1 and GATA2 might play essential roles in the erythroid differentiation protein interaction network. These results elucidate that HQ decreases GATA1 occupancy and increases GATA2 occupancy at the erythroid gene loci, thereby downregulating GATA1 and upregulating GATA2 expression, which in turn modulates the expression of erythroid genes and inhibits erythroid differentiation. This partially explains the mechanism of benzene hematotoxicity.


Quercetin induces apoptosis of Trypanosoma brucei gambiense and decreases the proinflammatory response of human macrophages.
In addition to parasite spread, the severity of disease observed in cases of human African trypanosomiasis (HAT), or sleeping sickness, is associated with increased levels of inflammatory mediators, including tumor necrosis factor (TNF)-alpha and nitric oxide derivatives. In the present study, quercetin (3,3',4',5,7-pentahydroxyflavone), a potent immunomodulating flavonoid, was shown to directly induce the death of Trypanosoma brucei gambiense, the causative agent of HAT, without affecting normal human cell viability. Quercetin directly promoted T. b. gambiense death by apoptosis as shown by Annexin V binding. In addition to microbicidal activity, quercetin induced dose-dependent decreases in the levels of TNF-alpha and nitric oxide produced by activated human macrophages. These results highlight the potential use of quercetin as an antimicrobial and anti-inflammatory agent for the treatment of African trypanomiasis.


Effect of membrane additives on vesicle fusion.
A large variety of alkyl derivatives were found to either slow or block the low-temperature induced fusion of dipalmitoylphosphatidylcholine small unilamellar vesicles (DPPC SUV) when incorporated into the SUV bilayer at five mol%. Only corn oil was fusogenic.


Acute scrotum secondary to filarial infection: a case report.
A 23-year-old man immigrated from Sri Lanka came to our observation for an acute painful volume increase of the right scrotum without fever. Clinical examination suggested a diagnosis of testis torsion. An exploratory surgical procedure was performed. An inflammatory spermatic cord and epididymis with a purple nodule of the middle portion were found. The nodule was excised and sent to pathologist that diagnosed a filarial infection. The patient was successfully treated with diethylcarbamazine.


Intestinal calcium absorption during hyperinsulinemic euglycemic glucose clamp in healthy humans.
The influence of postprandial-like plasma insulin levels on intestinal calcium absorption (CaA) was studied in 9 healthy men. On separate occasions, they received either an i.v. infusion of 40 mU/m2 minute synthetic human insulin as well as a variable glucose infusion in order to clamp the plasma glucose at the baseline level (= glucose clamp), or insulin- and glucose-free vehicle infusions (= vehicle). During these infusions, an oral load containing 326 mg Ca in the form of Ca chloride was administered and CaA was determined thereafter with a 47Ca/85Sr double tracer method. During glucose clamp, mean plasma insulin was 172 +/- (1 SEM) 10 as compared to 6 +/- 1 microU/ml during vehicle infusions. During the clamp, 3-hour cumulative CaA rose significantly by 14% as compared to vehicle (39.2 +/- 2.5 vs. 34.4 +/- 2%, P less than 0.02). AT the same time, serum potassium and phosphorus dropped significantly, whereas serum parathyroid hormone (PTH) and 1,25(OH)2D levels were unchanged as compared to vehicle. The urinary excretions of potassium, sodium, and inorganic phosphorus, as well as the urinary specific activity of 47Ca, dropped significantly during glucose clamp, whereas the urinary excretion of cAMP was unchanged as compared to vehicle. The results suggest that, under the conditions of euglycemic hyperinsulinemic clamp, insulin stimulates CaA of healthy humans in a PTH- and 1,25(OH)2D-independent manner. Insulin may thus possibly be regarded as a factor participating in the regulation of CaA in humans.


[Serum IgE levels in scabies. Study about 100 cases].
IgE levels were determinated in 100 cases of human scabies. In 85 cases, the values are normal (mean value =160 UI/ml, 2 S.D.=528). In 15 cases with raised values, an associated disease (cirrhosis, atopic dermatitis) was always found. The results were compared with those of other authors.


Learning curve of endoscopic submucosal dissection (ESD) with prevalence-based indication in unsupervised Western settings: a retrospective multicenter analysis.
As there is still no consensus about the adequate training strategy for ESD in Western countries, we evaluated unsupervised prevalence-based learning curves including detailed organ-specific subgroup analysis. The first 120 ESDs of four operators (n = 480) were divided into three groups (1: ESD 1-40, 2: ESD 41-80, 3: ESD 81-120). Outcome parameters were rates of technical success, en bloc and R0 resection, the resection speed, rates of conversion to EMR, curative resection, adverse events, surgery due to adverse events, and recurrence. In addition, we analyzed the achievement of quality benchmarks indicating levels of expertise. After exclusion of pretreated lesions, 438 procedures were enrolled in the final analysis. Technical success rates were > 96% with significant improvements regarding rate of en bloc resection (from 82.6 to 91.2%), resection speed (from 4.54 to 7.63 cm2/h), and rate of conversion to EMR (from 22.0 to 8.1%). No significant differences could be observed for rates of R0 resection (65.9 vs. 69.6%), curative resection (55.8 vs. 55.7%), adverse events (16.3 vs. 11.7%), surgery due to adverse events (1.5 vs. 1.3%), and recurrence (12.5 vs. 4.5%). Subgroup and benchmark analysis revealed an improvement in esophageal, gastric, and rectal ESD with achievement of competence levels for the esophagus and stomach within 80 and most of the benchmarks for proficiency level within 120 procedures. Some of the benchmarks could also be achieved in rectal ESD. This trial confirms safety and feasibility of unsupervised ESD along the initial learning curve with prevalence-based indication and exclusion of colonic cases.


Triterpenoid saponins from Becium grandiflorum var. obovatum.
Two new triterpenoid saponins, beciumecine 1 and 2, were isolated from the root bark of Becium grandiflorum var. obovatum and their structures established as 3-O-(beta-D-glucopyranosyl) terminolic acid 28-O-beta-D-apiofuranosyl(1-3)-[alpha-L-rhamnopyranosyl (1-3)-beta-D-xylopyranosyl(1-4)]-alpha-L-rhamnopyranosyl (1-2)-alpha-L-arabinopyranoside and 3-O-(beta-D-glucopyranosyl) 24-hydroxyterminolic acid 28-O-alpha-L-rhamnopyranosyl(1-3)-beta-D-xylopyranosyl(1-4)-alpha-L- rhamnopyranosyl(1-2)-alpha-L-arabinopyranoside, respectively.


[Quality management systems are compulsory: clinics have the choice. Comparison of the systems DIN EN ISO 9000 ff, KTQ and EFQM].
According to §§135-137 SGB V (German Civil Code), German hospitals are required to introduce and develop an institutional quality management (QM) system. They are, however, currently not obliged to undergo a certification. The prime responsibility to introduce a QM system lies with the top management. The aim is to continuously monitor and improve the quality of the processes and practices in the hospital. QM systems are one of the major constituents which influence the prosperity of an enterprise. Hospitals are able to improve the quality of their processes without significantly increasing the costs. The Excellence Barometer® Health Care (ExBa) of the Fraunhofer Institute has shown that deficits are usually not identified in the professional competence of the medical personnel but rather in respect to leadership abilities, communication and motivation. The introduction of QM in a hospital requires an in-depth familiarity with the various QM systems to select an appropriate model for the own institution. The systems most commonly in use in German hospitals are DIN EN ISO ff, EFQM and KTQ®. The article illustrates and compares the layout, requirements and assessment criteria of the various systems.


Time trend analysis of social inequalities in psychological distress among young adults before and during the pandemic: evidence from the UK Household Longitudinal Study COVID-19 waves.
Despite concerns about mental health problems among those aged 16-24 in England, which social groups have been most at risk, both over the past decade and during the COVID-19 pandemic, remains unclear. We examined trends in psychological distress among young adults 16-24 years old in England using data from the UK Household Longitudinal Study. Using longitudinal data as repeated cross-sectional waves, we examined differences over time in mean General Health Questionnaire (GHQ) scores from wave 1 (2009-2010) to wave 10 (2018-2019) and six COVID-19 waves collected between April and November 2020, by economic activity, cohabitation with parents, parental education, area deprivation, ethnicity, age and sex. Compared with 2009-2010, increases in GHQ scores in 2018-2019 were higher in women than men (2.1 vs 1.3), those aged 16-18 than aged 22-24 (2.6 vs 0.9), those from white UK group versus other ethnic minorities, and those out of the labour force (3.6) or employed part time (2.2) than those employed full time (0.8). Compared with 2018-2019, psychological distress in 2020 also further increased among young adults residing in the most deprived areas (4.1 vs 1.2 in the least deprived areas). In 2020, losing one's job or most of one's work hours was associated with higher psychological distress and attenuated the differences between deprivation quartiles by 17%. In England, inequalities in psychological distress among young adults may have changed and increased during the COVID-19 pandemic. Investing in opportunities for young adults, particularly in more deprived areas, may be key to improve population levels of mental health.


Robot-assisted versus laparoscopic single-incision cholecystectomy: results of a randomized controlled trial.
Although single-port laparoscopic cholecystectomy (SILC) is safe and effective, inherent surgeons' discomfort has prevented a large-scale adaptation of this technique. Recent advances in robotic technology suggest that da Vinci Single-Site™ cholecystectomy (dVSSC) may overcome this issue by reducing the stress load of the surgeon compared to SILC. However, evidence to objectively assess differences between the two approaches is lacking. 60 patients [36 women, 24 men (mean age 52 years)] with benign gallbladder disease were randomly assigned to dVSSC (n = 30) or SILC (n = 30) in this single-centre, single-blinded controlled trial. The primary endpoint was surgeon's stress load. Secondary endpoints included operating time, conversion rates, additional trocar placement, blood loss, length of hospital stay, procedure costs, health-related quality of life, cosmesis and complications. Data were collected preoperatively, during the hospital stay, and at 1 and 12 months' follow-up. The dVSSC group showed a significant reduction of mental stress load of the surgeon compared to SILC [Subjective Mental Effort Questionnaire (SMEQ) score: median 25.0 (range 8-89) vs. 42.5 (range 13-110) points; p = 0.002] and a trend towards reduced physical stress load [Local Experienced Discomfort (LED) score: median 8 (range 2-27) vs. 12 (range 0-64) points; p = 0.088]. The length of hospital stay was longer in the SILC group [mean 3.06 (median 2; range 1-26) vs. 1.9 (median 2; range 1-4) days, p = 0.034] but overall hospital costs were higher for dVSSC [median 9734 (range 5775-16729) vs. 6900 (range 4156-99977) CHF; p = 0.001]. There were no differences in the rate of postoperative complications that required re-intervention (Dindo-Clavien grade ≥ IIIa; SILC n = 2 vs. dVSSC n = 0, p = 0.492) or other secondary endpoints. Da Vinci Single-Site™ cholecystectomy provides significant benefits over Single-Port Laparoscopic Cholecystectomy in terms of surgeon's stress load, matches the standards of the laparoscopic single-incision approach with regard to patients' outcomes but increases expenses. Clinicaltrials.gov registration-No.: NCT02485392.


The effectiveness of skilled breathing and relaxation techniques during antenatal education on maternal and neonatal outcomes: a systematic review.
Several studies have investigated the relationship between antenatal education classes and pregnancy outcomes. These studies have shown positive effects on mothers, such as a lower epidural rate in the intervention groups. However, until now, the impact on outcomes for mothers and newborns of antenatal education classes that focus on breathing and relaxation techniques has not been examined. Investigate the effects of skilled breathing and relaxation techniques provided in antenatal education classes on maternal and neonatal birth outcomes. The protocol for this study was registered with PROSPERO (ID: CRD42020192289). A systematic literature search was undertaken and completed in January 2022, using the databases MEDLINE, CINAHL, clinicalTrials.gov, Cochrane Library, Embase and MIDIRS according to a priori formulated PICO criteria: population (pregnant women), intervention (antenatal education classes with integrated breathing and relaxation techniques), comparison (antenatal education classes that do not include skilled breathing and relaxation techniques), and outcome (maternal and neonatal outcomes). The quality of the studies was assessed by two reviewers using the standardised instruments RoB 2 and ROBINS-I. Ten studies were included in this review, nine randomised controlled trials and one quasi-experimental study. The results indicate that skilled breathing and relaxation techniques may positively influence self-efficacy, the need for pharmacological support, specifically the use of epidural anaesthesia, and the memory of labour pain. No effects were found in relation to predefined neonatal outcomes. The quality of evidence on maternal and neonatal outcomes is inconsistent across studies, as different antenatal education classes with varying interventions, including breathing and relaxation techniques, were offered in the studies. Women who attended an antenatal education class with breathing and relaxation techniques appear to benefit from the intervention. This applies to the practical implementation and use of breathing and relaxation techniques during labour, increased self-confidence and self-efficacy, and a increased feeling of being in control during labour. This demonstrates the importance of information provision and a focus on breathing and relaxation techniques in antenatal education.


The Role of the p16 and p53 Tumor Suppressor Proteins and Viral HPV16 E6 and E7 Oncoproteins in the Assessment of Survival in Patients with Head and Neck Cancers Associated with Human Papillomavirus Infections.
The role of HPV in the survival prognosis of patients with head and neck squamous cell carcinoma, especially patients with laryngeal squamous cell carcinoma (LSCC) and hypopharyngeal squamous cell carcinoma (HPSCC), is still somewhat ambiguous. The present study aimed to explore the significance of tumor suppressor proteins and HPV16 E6 and E7 oncoproteins in the assessment of survival in patients with oropharyngeal squamous cell carcinoma (OPSCC), LSCC, and HPSCC associated with high-risk (HR-) and low-risk (LR-) HPV infections. By utilizing molecular and immunohistochemical investigations of HNSCC samples and patient data, univariate and multivariate survival analyses were conducted. The presence of HPV DNA (LR- and HR-HPV) was associated with a better 5-year OS and DSS for OPSCC and LSCC. The IHC overexpression of HPV16 E6 protein and p16 protein was associated with better survival in the univariate (for OPSCC) and multivariate (OPSCC and HPSCC) survival analyses. The overexpression of p53 was associated with better survival in OPSCC. HPV infection plays a significant role in the tumorigenesis of HNSCC, and the immunohistochemical assessment of HPV16 E6 protein expression should be interpreted as a useful prognostic marker for OPSCC and HPSCC.


Binding of viral nuclear localization signal peptides to importin-α nuclear transport protein.
Using all-atom replica-exchange molecular dynamics simulations, we mapped the mechanisms of binding of the nuclear localization signal (NLS) sequence from Venezuelan equine encephalitis virus (VEEV) capsid protein to importin-α (impα) transport protein. Our objective was to identify the VEEV NLS sequence fragment that confers native, experimentally resolved binding to impα as well as to study associated binding energetics and conformational ensembles. The two selected VEEV NLS peptide fragments, KKPK and KKPKKE, show strikingly different binding mechanisms. The minNLS peptide KKPK binds non-natively and nonspecifically by adopting five diverse conformational clusters with low similarity to the x-ray structure 3VE6 of NLS-impα complex. Despite the prevalence of non-native interactions, the minNLS peptide still largely binds to the impα major NLS binding site. In contrast, the coreNLS peptide KKPKKE binds specifically and natively, adopting a largely homogeneous binding ensemble with a dominant, highly native-like conformational cluster. The coreNLS peptide retains most of native binding interactions, including π-cation contacts and a tryptophan cage. While KKPK binding is governed by a complex multistate free energy landscape featuring transitions between multiple binding poses, the coreNLS peptide free energy map is simple, exhibiting a single dominant native-like bound basin. We argue that the origin of the coreNLS peptide binding specificity is several electrostatic interactions formed by the two C-terminal amino acids, Lys10 and Glu11, with impα. The coreNLS sequence is then sufficient for native binding, but none of the amino acids flanking minNLS, including Lys10 and Glu11, are strictly necessary for the native pose. Our analyses indicate that the VEEV coreNLS sequence is virtually unique among human and viral proteins interacting with impα making it a potential target for VEEV-specific inhibitors.


Escherichia coli R-factors unstable in Salmonella typhi are deleted before being segregated in this host.
Although resistant Salmonella typhi strains are found in the environment, many epidemiological data indicate that most isolates are multisensitive. Plasmids are not common in S. typhi, contrasting with other enterobacteria. Since S. typhi is able to receive R plasmids from other enterobacteria, such plasmidless condition may be due to destabilization of the plasmids acquired. The segregation process of three plasmids known to behave unstably in S. typhi strains was analyzed, and evidence was obtained that the three of them lost an antibiotic-resistance determinant due to small deletions before plasmid loss occurred. Once deleted, the plasmids entered a segregation phase with particular kinetic features in each case. Selective pressure prevented plasmid deletion and segregation. Like their parental plasmids, the deleted plasmids were unstable in S. typhi but stable in Escherichia coli, suggesting that deletions imply loss of genetic information relevant for a plasmid stability mechanism operative in S. typhi, but not in E. coli.


Therapeutic approaches in the improvement of cognitive performance in Down syndrome: past, present, and future.
Clinical trials with drugs aimed at treatment of Alzheimer disease to decelerate cognitive decline and translated mimetically to demented and young nondemented Down syndrome patients have been unable to demonstrate improvements in cognitive performance and functioning. Unfortunately, results from clinical trials do not support the use of NMDA antagonists like memantine and we should await at the development of safer GABA(A) antagonists to conclude about the efficacy of approaching Down syndrome therapeutics by modulating neurotransmission systems altered in this pathology. The use of folinic acid or antioxidants in DS patients is not supported by scientific evidence and do not provide improvement in cognitive performance to patients. Alternatively to the modulation of neurotransmission systems, future therapeutic approaches should focus at normalizing the expression levels or function of candidate molecules. Epigallocatechin gallate, a green tea polyphenol, that modulates DYRK1A functioning has already shown preliminarily that this approach may prove useful in therapeutics.


Recurrent bicycle falls by an elderly man who developed multiple intramuscular abscesses associated with urine leakage secondary to posterior urethral injury caused by pelvic ring disruption.
With the aging of the population, physicians need to pay more attention to assessing the presence or absence of pelvic fractures and urinary retention associated with urethral injury due to such fractures in the elderly when falling from bicycles. Walking ability does not rule out the presence of pelvic fractures. Many geriatric patients are likely to fall off bicycles. Physicians should pay more attention when assessing complications related to urethral trauma caused by pelvic fractures in the elderly after falling from bicycles.


Human herpesvirus-8 infection in Tunisian adult acute leukemia patients.
Human herpesvirus 8 (HHV-8) has been linked to the development of Kaposi's sarcoma (KS)and multiple other hematologic malignant disorders. However, the role of HHV-8 in acute leukemia patients is unknown. The objective of this study was to determine the prevalence of HHV-8 in Tunisian acute leukemia patients and in healthy blood donors. An indirect immunofluorescence test was used to detect the presence of anti-HHV8 antibodies. Nested PCR was used for the detection of HHV-8 DNAemia in samples of plasma. The seroprevalence of HHV-8 was significantly higher in acute leukemia patients (21,4% ,15/70) than in healthy blood donors (7,1%, 5/70), (p= 0.02). Gender, type of disease, status of disease, prior blood transfusion, and outcome were not associated with HHV-8 seroprevalence. However, among acute leukemia patients, HHV-8 seroprevalence was statistically associated with older age > 40 years of age, (p=0.002). HHV-8 DNAemia was detected (1,4%) in only one patient of acute myeloid leukemia (AML) and none of the healthy blood donors. The seroprevalence of HHV-8 infection in Tunisian adult acute leukemia patients was three times as high compared to healthy blood donors, suggesting that patients with acute leukemia might be at increased risk of HHV-8 infection.


Comparative effects of intraduodenal infusions of lauric and oleic acids on antropyloroduodenal motility, plasma cholecystokinin and peptide YY, appetite, and energy intake in healthy men.
The regulation of gastrointestinal function and energy intake by fatty acids depends on their chain length. Animal studies suggest that lauric acid (C12) may have more potent suppressive effects on energy intake than does oleic acid (C18). We compared the effects of equicaloric loads of C12 and C18 on antropyloroduodenal (APD) motility, plasma concentrations of cholecystokinin (CCK) and peptide YY (PYY), appetite, and energy intake. Thirteen healthy men (aged 20-46 y) were studied on 3 occasions in double-blind, randomized fashion. APD pressure waves, plasma hormones, and appetite perceptions were measured during 60-min intraduodenal infusions of 1) C12, 2) C18, or 3) 0.9% saline as control (rate: 4 mL/min; energy load for C12 and C18: 0.4 kcal/min); between 60 and 90 min, the subjects consumed a meal. Energy intake at a buffet meal was quantified. C12 and C18 both reduced antral (P < 0.001) and duodenal (P < 0.01) pressure waves and stimulated isolated pyloric pressure waves (P < 0.01) and plasma CCK (P < 0.001), with no differences between them. Although C12 and C18 both increased basal pyloric pressure (P < 0.05), C12 had a greater effect than did C18 (P < 0.01). In contrast, although both C12 and C18 increased plasma PYY (P < 0.001), C18 had a greater effect than C12. C12, but not C18, suppressed energy intake (P < 0.05). At the load administered, C12, but not C18, suppressed energy intake, and C12 was a more potent stimulant of basal pyloric pressure. These discrepant effects are not apparently accounted for by changes in CCK or PYY secretion.


Frontline-matched sibling donor transplant of aplastic anemia patients using primed versus steady-state bone marrow grafts.
Priming donors with G-CSF before BM harvest is reported to improve engraftment and GvHD in recipients. These effects are highly desirable when transplanting patients with non-neoplastic hematologic diseases, particularly AA patients. Here we retrospectively report the outcomes of 39 AA patients receiving a primed BM graft from MSD to 43 patients receiving a steady-state BM graft from MSD, otherwise transplanted using a uniform transplant platform. The graft had higher TNC and CD34 cell concentrations in the primed group (p < 0.001), and that was reflected in higher TNC and CD34 doses per kilogram of recipient in the primed group (p = 0.004 and 0.03, respectively). The OS for primed BM graft recipients was 97.4% and 78.9% for the steady-state BM graft recipients, p-value = 0.01. The cumulative incidence of death without GF was 2.6% in the primed group and 16.3% in the steady-state group, p-value = 0.03. There was no difference in GvHD incidence between the two groups. We confirm that priming improved the TNC and CD34 graft concentration and cell dose; this evidence along with other reported studies constitute reasonable evidence to prove that BM priming improve engraftment. We observed no increase in GvHD using primed BM graft.


Microwave-assisted intramolecular [2 + 2] Allenic cycloaddition reaction for the rapid assembly of bicyclo[4.2.0]octa-1,6-dienes and bicyclo[5.2.0]nona-1,7-dienes.
Microwave irradiation of alkynyl allenes affords an intramolecular [2 + 2] cycloaddition reaction. This cycloaddition provides an efficient route to bicyclomethylenecyclobutenes. The reaction occurs with complete regioselectivity for the distal double bond of the allene for the selective formation of a variety of hetero- and carbocyclic substrates. Bicyclo[4.2.0]octadienes and bicyclo[5.2.0]nonadienes have been prepared in high yield. [reaction: see text]


Response of intramuscular Walker 256 rat tumor to sustained-release cyclophosphamide and ARA-C capsules.
Randomly bred Sprague-Dawley rats with the intramuscular form of Walker 256 tumor growing in the right thigh region were treated with sustained-release cyclophosphamide capsules as well as with cytosine arabinoside capsules. A disk-shaped caps-le was implanted subcutaneously adjacent to the tumor mass. Tumor regression, weight gain, and prolongation of lifespan were observed in animals treated with cyclophosphamide capsules of 10 mg or 20 mg total drug content each. However, the walker 256 intramuscular tumor did not respond to ARA-C capsules implanted, and the animals died at the same rate as the controls, with large ulcerated tumor masses and some metastasis. The in vitro diffusion data of ARA-C capsules is shown. Gross and histological changes associated with cyclophosphamide administered in this manner are reported.


Tuberculous Bronchoesophageal Fistula in Nephrotic Syndrome: A Silent Assassin.
Tuberculosis, a global public health concern, is emerging as an important complication in children with nephrotic syndrome. We report a case of an adolescent with nephrotic syndrome who developed fatal miliary tuberculosis after initiation of steroid therapy, presenting as a bronchoesophageal fistula. The case highlights the importance of maintaining a high index of suspicion prior to starting immunosuppressive therapy in pediatric patients of nephrotic syndrome.