Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis.
Arthrogryposis multiplex congenita (AMC) is characterized by the presence of multiple joint contractures resulting from reduced or absent fetal movement. Here, we report two unrelated families affected by lethal AMC. By genetic mapping and whole-exome sequencing in a multiplex family, a heterozygous truncating MAGEL2 mutation leading to frameshift and a premature stop codon (c.1996delC, p.Gln666Serfs∗36) and inherited from the father was identified in the probands. In another family, a distinct heterozygous truncating mutation leading to frameshift (c.2118delT, p.Leu708Trpfs∗7) and occurring de novo on the paternal allele of MAGEL2 was identified in the affected individual. In both families, RNA analysis identified the mutated paternal MAGEL2 transcripts only in affected individuals. MAGEL2 is one of the paternally expressed genes within the Prader-Willi syndrome (PWS) locus. PWS is associated with, to varying extents, reduced fetal mobility, severe infantile hypotonia, childhood-onset obesity, hypogonadism, and intellectual disability. MAGEL2 mutations have been recently reported in affected individuals with features resembling PWS and called Schaaf-Yang syndrome. Here, we show that paternal MAGEL2 mutations are also responsible for lethal AMC, recapitulating the clinical spectrum of PWS and suggesting that MAGEL2 is a PWS-determining gene.


Development and validation of the Work Stressor Inventory for Nurses in Oncology: preliminary findings.
This study is a report of the development and testing of the Work Stressor Inventory for Nurses in Oncology. Stressors in oncology nursing are generally assessed using generic stress scales like the Nursing Stress Scale or the Health Professions Stress Inventory. However, qualitative investigations have highlighted the specific nature of the stress to which nurses are exposed. The Work Stressor Inventory for Nurses in Oncology was developed using both qualitative and quantitative methodologies. For the item generation phase, a semi-structured interview was conducted with 59 nurses working in oncology units during 2007. A total of 51 work-related items were retained for the final survey. A convenience sample of 582 nurses working in oncology completed the survey between January 2008-June 2008. They also completed the General Health Questionnaire and the Maslach Burnout Inventory. The Work Stressor Inventory for Nurses in Oncology was further tested for theoretically supported constructs, internal consistency reliability and concurrent validity. The exploratory results revealed five factors: workload, dealing with death and dying, dealing with suffering, interpersonal conflicts, dealing with patients and relatives. The internal consistency of the five subscales was satisfactory. Correlation patterns between the Work Stressor Inventory for Nurses in Oncology dimensions and both mental health and burnout variables support the criterion-related validity of the scale. Future quantitative or qualitative studies using this scale could add knowledge about the experiences of emotional and organizational stressors related to this area of nursing.


Measurement of pulmonary CO2 elimination must exclude inspired CO2 measured at the capnometer sampling site.
The pulmonary elimination of the volume of CO2 per breath (VCO2/br, integration of product of airway flow (V) and PCO2 over a single breath) is a sensitive monitor of cardio-pulmonary function and tissue metabolism. Negligible inspired PCO2 results when the capnometry sampling site (SS) is positioned at the entry of the inspiratory limb to the airway circuit. In this study, we test the hypothesis that moving SS lungward will result in significant inspired CO2 (VCO2[I]), that needs to be excluded from VCO2/br. We ventilated a mechanical lung simulator with tidal volume (VT) of 800 mL at 10 breaths/min. CO2 production, generated by burning butane in a separate chamber, was delivered to the lung. Airway V and PCO2 were measured (Capnomac Ultima, Datex), digitized (100 Hz for 60 s), and stored by microcomputer. Then, computer algorithms corrected for phase differences between V and PCO2 and calculated expired and inspired VCO2 (VCO2[E] and VCO2[I]) for each breath, whose difference equalled overall VCO2/br. The lung and Y-adapter (where the inspiratory and expiratory limbs of the circuit joined) were connected by the SS and a connecting tube in varying order. During ventilation of the lung model (VT = 800 ml) with SS adjacent to the inspiratory limb, VCO2[E] was 16.8 +/- 0.4 ml and VCO2[I] was 1.1 +/- 0.1 ml, resulting in overall VCO2/br (VCO2[E] - VCO2[I]) of 15.7 +/- 0.4 ml. If VCO2[I] was ignored in the determination of VCO2/br, then the %error that VCO2[E] overestimated VCO2/br was 7.2 +/- 0.3%. This %error significantly increased (p < 0.05, Student's t-test) when VT was decreased to 500 mL (%error = 12.4 +/- 0.8%) or when SS was moved to the lungward side of a 60 mL connecting tube (VCO2[I] = 2.8 +/- 0.2, %error = 18.2 +/- 1.6) or a 140 mL tube (VCO2[I] = 5.9 +/- 0.3 mL, %error = 37.5 +/- 3.3). When the SS was moved lungward from the inspiratory limb, instrumental dead space (VDINSTR) increased and, at end-expiration, contained exhaled CO2 from the previous breath. During the next inspiration, this CO2 was rebreathed relative to SS (i.e. VCO2[I]), and contributed to VCO2[E]. Thus, VCO2[E] overestimated VCO2/br (%error) by the amount of rebreathing, which was exacerbated by larger VDINSTR (increased VCO2[I]) or smaller VT (increased VCO2[I]-to-VCO2/br ratio).


The influence of heel height on frontal plane ankle biomechanics: implications for lateral ankle sprains.
Wearing high heel shoes is thought to increase an individual's likelihood of experiencing a lateral ankle sprain. The purpose of this study was to evaluate the influence of heel height on frontal plane kinematics, kinetics, and electromyographic (EMG) activity of the ankle joint during walking. Eighteen healthy women participated. Three-dimensional kinematics, ground reaction forces, and EMG signals of the tibialis anterior (TA) and peroneus longus (PL) were recorded as subjects ambulated in high (9.5~cm) and low (1.3~cm) heel shoes at a self-selected walking velocity. Peak ankle plantarflexion, peak ankle inversion angle, and the peak ankle inversion moment during the stance phase of gait were evaluated. The EMG variables of interest consisted of the normalized average signal amplitude of the TA and PL during the first 50% of the stance phase. Paired t-tests were used to assess differences between the two shoe conditions. When compared to the low heel condition, wearing high heels resulted in significantly greater peak ankle plantarflexion and inversion angles (p < 0.001). In addition, the peak inversion moment and PL muscle activation was found to be significantly higher in the high heel condition (p < 0.001). No difference in TA muscle activity was found between shoe conditions (p = 0.30). The plantarflexed and inverted posture when wearing high heels may increase an individual's risk for experiencing a lateral ankle sprain. Data obtained from this investigation highlights the need for increased awareness and proper education related to the wearing of high heel shoes.


Ketogenesis contributes to intestinal cell differentiation.
The intestinal epithelium undergoes a continual process of proliferation, differentiation and apoptosis. Previously, we have shown that the PI3K/Akt/mTOR pathway has a critical role in intestinal homeostasis. However, the downstream targets mediating the effects of mTOR in intestinal cells are not known. Here, we show that the ketone body β-hydroxybutyrate (βHB), an endogenous inhibitor of histone deacetylases (HDACs) induces intestinal cell differentiation as noted by the increased expression of differentiation markers (Mucin2 (MUC2), lysozyme, IAP, sucrase-isomaltase, KRT20, villin, Caudal-related homeobox transcription factor 2 (CDX2) and p21Waf1). Conversely, knockdown of the ketogenic mitochondrial enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) attenuated spontaneous differentiation in the human colon cancer cell line Caco-2. Overexpression of HMGCS2, which we found is localized specifically in the more differentiated portions of the intestinal mucosa, increased the expression of CDX2, thus further suggesting the contributory role of HMGCS2 in intestinal differentiation. In addition, mice fed a ketogenic diet demonstrated increased differentiation of intestinal cells as noted by an increase in the enterocyte, goblet and Paneth cell lineages. Moreover, we showed that either knockdown of mTOR or inhibition of mTORC1 with rapamycin increases the expression of HMGCS2 in intestinal cells in vitro and in vivo, suggesting a possible cross-talk between mTOR and HMGCS2/βHB signaling in intestinal cells. In contrast, treatment of intestinal cells with βHB or feeding mice with a ketogenic diet inhibits mTOR signaling in intestinal cells. Together, we provide evidence showing that HMGCS2/βHB contributes to intestinal cell differentiation. Our results suggest that mTOR acts cooperatively with HMGCS2/βHB to maintain intestinal homeostasis.


Interleukin-3: molecular biology and biologic activities.
IL-3 is one of the primary factors capable of supporting the growth and development of hematopoietic cells in culture. In comparison with the other hematopoietic growth factors, IL-3 preferentially supports the proliferation of early multilineage progenitors or progenitors at early stages of development within the different lineages. Subsequently, the developing cells lose responsiveness to IL-3 while acquiring dependence on the later acting factors: GM-CSF, G-CSF, M-CSF, or Ep. In addition, IL-3 has been demonstrated to exert biologic effects with other target cell populations. These activities include the potentiation of the IL-2-dependent growth of normal T cells; the potentiation of the IL-2-dependent secretion of IgG by activated B cells; and the potentiation of the activities of eosinophils, basophils, and monocytes. The importance of any of these activities of IL-3 in vivo in either normal or stressed animals remains to be determined. Initial experiments in primates with IL-3 have yielded results consistent with its role as a regulator of early hematopoietic cell development. Although administration of IL-3 alone has relatively little effect on the levels of circulating blood cells, this treatment primes the animals to become hyper-responsive to subsequent administration of the later acting factors GM-CSF and Ep. Thus combinations of factors, at least in some situations, can provide a more potent stimulation of hematopoiesis than provided by the individual molecules, a finding that should greatly expand the utility of the different hematopoietins to more indications in the clinic.


Prospective Study of Optimal Obesity Index Cut-Off Values for Predicting Incidence of Hypertension in 18-65-Year-Old Chinese Adults.
Overweight and obesity increase the risk of elevated blood pressure; most of the studies that serve as a background for the debates on the optimal obesity index cut-off values used cross-sectional samples. The aim of this study was to determine the cut-off values of anthropometric markers for detecting hypertension in Chinese adults with data from prospective cohort. This study determines the best cut-off values for the obesity indices that represent elevated incidence of hypertension in 18-65-year-old Chinese adults using data from the China Health and Nutrition Survey (CHNS) 2006-2011 prospective cohort. Individual body mass index (BMI), waist circumference (WC), waist:hip ratio (WHR) and waist:stature ratio (WSR) were assessed. ROC curves for these obesity indices were plotted to estimate and compare the usefulness of these obesity indices and the corresponding values for the maximum of the Youden indices were considered the optimal cut-off values. Five-year cumulative incidences of hypertension were 21.5% (95% CI: 19.4-23.6) in men and 16.5% (95% CI: 14.7-18.2) in women, and there was a significant trend of increased incidence of hypertension with an increase in BMI, WC, WHR or WSR (P for trend < 0.001) in both men and women. The Youden index indicated that the optimal BMI, WC, WHR, WSR cut-off values were 23.53 kg/m2, 83.7 cm, 0.90, and 0.51 among men. The optimal BMI, WC, WHR, WSR cut-off values were 24.25 kg/m2, 79.9 cm, 0.85 and 0.52 among women. Our study supported the hypothesis that the cut-off values for BMI and WC that were recently developed by the Working Group on Obesity in China (WGOC), the cut-off values for WHR that were developed by the World Health Organization (WHO), and a global WSR cut-off value of 0.50 may be the appropriate upper limits for Chinese adults.


Case report of early aseptic loosening of total hip arthroplasty in monostotic paget disease, a diagnostic challenge.
Paget's disease of bone is a localised chronic osteopathy which produces bone deformities, bone hypervascularity, structural weakness and altered joint biomechanics. Although radiological diagnosis of Paget's disease of bone is usually straightforward, monostotic cases may potentially raise specific problems which require invasive and expensive procedures such as bone biopsies. The pelvis and upper femur are frequently affected, resulting in disabling hip disease that may require total hip arthroplasty. We report a case of Paget disease of bone in an 84-year-old woman, which was initially identified as avascular necrosis of the hip, reason for which she underwent total hip arthroplasty. During follow up, the patient complained about hip pain and in a few months she was not able to walk because of an early loosening with bone destruction. Radiological and laboratory exams were carried out with normal results except for alkaline phosphatase (AP). After treatment with biphosphonates hip pain relieved but hip reconstruction was not possible. In this paper we present an early aseptic loosening of hip arthroplasty due to monostotic Paget's disease of bone, a rare ethiology of loosening which poses particular diagnostic difficulties prompting an excessive use of excisional biopsies.


Heightened seizure severity in somatostatin knockout mice.
Patients and experimental models of temporal lobe epilepsy display loss of somatostatinergic neurons in the dentate gyrus. To determine if loss of the peptide somatostatin contributes to epileptic seizures we examined kainate-evoked seizures and kindling in somatostatin knockout mice. Somatostatin knockout mice were not observed to experience spontaneous seizures. Timm staining, acetylcholinesterase histochemistry, and immunocytochemistry for NPY, calbindin, calretinin, and parvalbumin revealed no compensatory changes or developmental abnormalities in the dentate gyrus of somatostatin knockout mice. Optical fractionator counting of Nissl-stained hilar neurons showed similar numbers of neurons in wild type and somatostatin knockout mice. Mice were treated systemically with kainic acid to evoke limbic seizures. Somatostatin knockout mice tended to have a shorter average latency to stage 5 seizures, their average maximal behavioral seizure score was higher, and they tended to be more likely to die than controls. In response to kindling by daily electrical stimulation of the perforant path, to more specifically challenge the dentate gyrus, mean afterdischarge duration in somatostatin knockout mice was slightly longer, but the number of treatments to five stage 4-5 seizures was similar to controls. Although we cannot exclude the possibility of undetected compensatory mechanisms in somatostatin knockout mice, these findings suggest that somatostatin may be mildly anticonvulsant, but its loss alone is unlikely to account for seizures in temporal lobe epilepsy.


Electrochemical epitaxial PbTe nanowires photodetector for NIR response.
Lead telluride nanowires deposited by electrochemical atomic layers have broad application prospects in the field of photodetectors. In this work, using the method of electrochemical atomic layer deposition, we obtained different morphologies of lead telluride materials by controlling the deposition parameters, such as deposition time, temperature, and potential, and characterized them using SEM, TEM, XPS, and other techniques. A lead telluride nanowire detector with good performance was prepared. The photoresponsivity of the detector is 102 mA W-1, the detectivity is 2.1 × 108Jones, and the response time and recovery time are 0.52 s and 0.54 s respectively at 2.7μm wavelength laser irradiation.


Variation in childhood asthma among former preterm infants.
The role of in utero and perinatal exposures in modifying asthma risk among children born prematurely was assessed. Study design Former preterm children (n=251) were identified from a birth cohort. Examinations, including lung function testing, were performed at ages 8 to 11 years. Perinatal exposures were ascertained from neonatal medical records. Univariate predictors of asthma included male gender, African American ethnicity, maternal asthma, and birth weight. Asthmatics were less likely to have been small for gestational age (SGA) than nonasthmatics (12.4% vs 22.7%, P=.04) and had more neonatal pulmonary disease. After adjusting for maternal asthma and demographic factors, asthma was associated with chronic lung disease of infancy, neonatal mechanical ventilation and corticosteroid use, and a higher childhood body mass index. Children who were septic postbirth and girls who were SGA were less likely to have asthma (OR for sepsis, 0.2; 95% CI, 0.1-0.6; OR for girls who were SGA compared with girls who were not SGA, 0.05; CI, 0.01-0.34). Among premature children, female SGA status and neonatal sepsis appear protective relative to the development of childhood asthma. Differential susceptibility to asthma among preterm children may relate to exposures that operate in the in utero and early postnatal environment to accelerate lung development, alter innate immunity, or both.


Identification of drugs in human serum by high-performance liquid chromatography with photodiode array detection and a search algorithm for ultraviolet spectra.
A system is described that identifies a number of unknown drugs (benzodiazepines, antidepressants and neuroleptics) in blood specimens for clinical-toxicological purposes. Reversed ion-pair high-performance liquid chromatography with a photodiode array detector saves the ultraviolet spectrum of every chromatographically significant peak. Post-run data-processing, provided by a microcomputer, retrieves candidate substances from a library of ultraviolet spectra. Selected standard ultraviolet spectra are compared with the unknown by five different similarity tests. The discriminatory efficiency of these algorithms has been determined. Multicomponent analysis, a built-in program of the spectrophotometer, provided the most reliable results.


Aggressive MOGAD with bilateral corticospinal tract lesions following infection with Jamestown Canyon virus.
We present a case of a rare viral encephalitis due to Jamestown Canyon virus precipitating a severe phenotype of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) with novel neuroimaging findings.


Osteocutaneous face transplantation.
Facial transplantation has the potential to become a viable option in the treatment of acquired and congenital facial deformities. Transplantation of the bony maxillofacial skeleton with the soft tissues (osteocutaneous face transplantation) has not been performed clinically nor has it been described experimentally in a human cadaver model. A mock osteocutaneous face transplant procedure was carried out on a cadaver model. The face was harvested in the subperiosteal plane and included the Le Fort III osseous segment. The allograft was inset by rigid internal fixation and soft tissue approximation. The face transplant procedure was technically feasible. On the basis of this experiment, review of prior investigations, and our experience in craniofacial surgery, the authors have identified 10 topics that present technical challenges specific to osteocutaneous transplantation of the face: customisation of the bony segment, sensory and motor innervation, extra-ocular movements, dentition, mastication, speech and swallowing, airway, vascular considerations, immunologic considerations, and identity issues. Once further advances in immunomodulatory therapy are made, face transplantation will likely still be reserved for only the most severe facial defects. Defects of such severity will likely include a substantial bony component in need of reconstruction. In addition to the challenges associated with facial allo-transplantation in general, there are many technical challenges associated specifically with osteocutaneous face transplantation. It is necessary to consider and discuss these challenges in anticipation of future advances that may allow composite face transplantation to become safe and clinically efficacious. This modality of transplantation has the potential to provide substantial benefit compared with autologous reconstruction.


Intractable epilepsy management: an EEG-oriented approach.
Intractable epilepsy has always posed a challenge to management; conventional, surgical and alternative techniques available so far (e.g., vagal nerve stimulation, i.e. VNS). The author has attempted to search for a novel alternative (drug-regime) approach to its management to minimise any invasive technique or surgery. The drug-regime is based primarily on EEG-background picture (namely synchronisation and de-synchronisation), which the author claims plays a crucial role in epileptogenesis and/or enhancement of epileptic recruitment. Thus an EEG (both in wake and sleep states) shall be a pre-requisite. The novel drug-regime promises to alter the cortical background-activity in a manner to render it un-favorable for epileptogenesis/enhancement of epileptic recruitment, thereby attempting to produce control over Intractable Epilepsy. The new drug-regime, by virtue of its properties to alter the EEG-background activity, thus could enhance the efficacy of conventional treatment and together, they could form a highly effective management for Intractable Epilepsy, thus minimising the intervention of invasive techniques like VNS and epilepsy brain surgery.


[Effects of functional septoplasty in obstructive sleep apnea syndrome].
To evaluate the efficacy of functional septoplasty in a group of patients with septal dysmorphy and obstructive sleep apnea syndrome (OSAS). 34 patients with nasal respiratory insufficiency and chronic snore were included from 1997 to 2003. All of them were diagnosed of OSAS by nocturnal polysomnography (PSG) and of septal dysmorphy by ORL physical examination. Patients were clinically followed-up at 1, 3 and 6 months after surgery. PSG was also evaluated at 6 months postsurgery. A significant objective reduction of the apnea-hypopnea index (AHI) (45.8 vs 31.9), severity of OSAS, and minimal mean oxygen saturation (76.4 to 83.1) was found. Moreover, we observed a significant improvement of subjective scales of sleepiness (13 vs 6) and the patients' satisfaction degree (72% of patients improved). Functional septoplasty is an effective treatment in patients with OSAS and septal dysmorphy.


Combined prime-boost vaccination against tick-borne encephalitis (TBE) using a recombinant vaccinia virus and a bacterial plasmid both expressing TBE virus non-structural NS1 protein.
Heterologous prime-boost immunization protocols using different gene expression systems have proven to be successful tools in protecting against various diseases in experimental animal models. The main reason for using this approach is to exploit the ability of expression cassettes to prime or boost the immune system in different ways during vaccination procedures. The purpose of the project was to study the ability of recombinant vaccinia virus (VV) and bacterial plasmid, both carrying the NS1 gene from tick-borne encephalitis (TBE) virus under the control of different promoters, to protect mice against lethal challenge using a heterologous prime-boost vaccination protocol. The heterologous prime-boost vaccination protocol, using a VV recombinant and bacterial plasmid, both containing the NS1 TBE virus protein gene under the control of different promoters, achieved a high level of protection in mice against lethal challenge with a highly pathogenic TBE virus strain. No signs of pronounced TBE infection were detected in the surviving animals. Heterologous prime-boost vaccination protocols using recombinant VV and bacterial plasmids could be used for the development of flavivirus vaccines.


A toad (Bufo bufo) hemoglobin has been purified and two types of chain have been separated by counter-current distribution. The alpha-chain has a N-terminal sequence Ac-Ala-Leu and a C-terminal sequence Tyr-Arg. The beta-chain has a N-terminal sequence Val-His-Leu and a C-terminal sequence Tyr-His.


Neuroretinitis in secondary syphilis.
A 30-year-old man with bilateral neuroretinitis and uveitis associated with secondary syphilis is described. Characteristic lesions on the palms of the hands and the soles of the feet gave us the clue to the diagnosis. Treatment with penicillin resulted in a rapid cure. Syphilic neuroretinitis is often associated with secondary meningitis. Early diagnosis and adequate therapy are important in this serious but treatable condition.


Herpes simplex virus encephalitis: intrathecal synthesis of oligoclonal virus-specific IgG, IgA and IgM antibodies.
Paired specimens of serum and CSF from seven patients with acute herpes simplex virus encephalitis were examined during the acute illness or the convalescent stage or during both stages. Imprint immunofixation analyses of viral antibodies separated by agarose electrophoresis and by electrofocusing disclosed intrathecal production of herpes simplex virus IgG antibodies in all seven patients, and of IgA and IgM antibodies in six and three of six patients, respectively. Intrathecal production of herpes simplex virus-specific IgG and IgA was observed in two patients from whom samples were collected after 1 year, while intrathecal production of virus-specific IgM was not demonstrated later than 5 weeks after onset. The intrathecally synthesized IgG and IgM, and to a lesser extent IgA antibodies displayed oligoclonal characteristics. Oligoclonal bands of IgG were observed in the CSF of all patients. Evidence is presented to show that the bulk of the oligoclonal CSF IgG represents herpes simplex virus-specific antibodies. Intrathecally synthesized populations of herpes simplex virus antibodies cross-reacting with varicella-zoster virus were identified in three of the patients.


Efficacy and safety of combination therapy with vildagliptin and metformin versus metformin up-titration in Chinese patients with type 2 diabetes mellitus: study design and rationale of the vision study.
Limitations of the currently recommended stepwise treatment pathway for type 2 diabetes mellitus (T2DM), especially the failure of monotherapies to maintain good glycemic control, have prompted use of early, more aggressive combination therapies.The VISION study is designed to explore the efficacy and safety of vildagliptin as an add-on to metformin therapy compared with up-titration of metformin monotherapy in Chinese patients with T2DM. VISION, a 24-week, phase 4, prospective, randomized, multicenter, open-label, parallel-group study, will include 3312 Chinese T2DM patients aged ≥18 years who are inadequately controlled (6.5% >HbA1c ≤9%) by metformin (750-1000 mg/day). Eligible patients will be randomized to receive either vildagliptin plus metformin or up-titration of metformin monotherapy (5:1). Patients will also be subgrouped (1:1:1:1) based on their age and body mass index (BMI): <60 years and <24 kg/m²; <60 years and ≥24 kg/m²; ≥60 years and <24 kg/m²; and ≥60 years and ≥24 kg/m². The VISION study will test the hypothesis that early use of combination therapy with vildagliptin and metformin will provide good glycemic control and will be better tolerated than up-titration of metformin monotherapy. The study will also correlate these benefits with age and BMI.


Hepatosplanchnic vasoregulation and oxygen consumption during selective aortic blood flow reduction and reperfusion.
Several studies have shown that the distribution of cardiac output to the intra-abdominal organs may vary during low-flow states. In this study, we developed an experimental model to selectively reduce the abdominal aortic blood flow in order to assess the initial impact of selective hepatosplanchnic hypoperfusion on regional blood flow redistribution. Eight anesthetized and mechanically ventilated mongrel dogs were subjected to aortic blood flow reduction with an occluder in a stepwise manner by 50% and 100% for 45 min. After the ischemic period, the occluder was released, and animals were observed for an additional 45 min. Systemic hemodynamics were evaluated through a Swan-Ganz and arterial catheters, and gastrointestinal tract perfusion was evaluated by portal vein and hepatic arterial blood flows measurements (ultrasonic flowprobe). Intestinal O2-derived variables, intestinal mucosal (tonometric)-arterial and tonometric-(end-tidal-carbon-dioxide) gradients (Dt-apCO2 and Dt-EtpCO2) were also calculated. No significant changes in systemic and regional oxygen consumption were observed during the 50% reduction of aortic blood flow. On the other hand, both microregional pCO2 gradients (Dt-apCO2 e Dt-EtpCO2) showed a significant increase during this period. Aortic occlusion was associated with a marked reduction of systemic and regional oxygen delivery and consumption. During the reperfusion, no significant improvement in the tonometry-based pCO2 gradients was observed, in spite of the partial reestablishment of blood flow to the hepatosplanchnic territory. During selective intra-abdominal low-flow, a proportional reduction in the splanchnic and hepatic blood flows occurs. A selective reduction of approximately 50% in splanchnic oxygen delivery was not associated with significant changes in macroregional markers of hypoperfusion. In this situation, tonometry-based pCO2 gradients can be used for the assessment of hepatosplanchnic perfusion and histologic changes.


Effect of cytokines on growth and differentiation of leukaemic cells with translocation t(6;9)(p23;q34).
The translocation t(6;9)(p23;q34) is detected infrequently in subtypes of haematological malignancies including acute myelogenous leukaemia (AML) and myelodysplastic syndrome (MDS). Although the t(6;9) leukaemia is commonly associated with bone marrow basophilia, the cytological characteristics of leukaemic cells are unclear. In the current study, we examined the in vitro effects of several cytokines on growth and differentiation of t(6;9) leukaemic cells. Isolated bone marrow mononuclear cells from four patients with t(6;9) (two MDS and two AML) were cultured for 14 d in the presence or absence of each cytokine. At the end of culture, viable cells were counted, and their histology was examined. Bone marrow cells obtained from 22 patients (10 AML, six AML from MDS, six MDS) lacking t(6;9) were used as controls. Compared with control cultures, significantly higher numbers of blasts appeared in the culture of bone marrow cells from t(6;9)-positive patients in response to stimulation with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF) or interleukin 3 (IL-3). Stem cell factor (SCF) had little effect. Neutrophil counts were also significantly increased in the presence of G-CSF or IL-3. SCF and IL-3 were potent in increasing basophil counts from t(6;9)-positive cultures. These findings suggest that bone marrow cells obtained from t(6;9) patients are highly sensitive to growth- and/or differentiation-promoting cytokines. Special attention should be paid to the use of "therapeutic" cytokines in these patients.


Biocompatibility of Titanium Oxynitride Coatings Deposited by Reactive Magnetron Sputtering.
Titanium oxynitride coatings deposited by reactive magnetron sputtering improve biocompatibility of vascular stents by increasing NO production, viability, and adhesion of EA.hy926 cells. Thus, the application of titanium oxynitride coatings is a promising strategy for increasing the biocompatibility of nitinol stents.


Anticoagulants decrease the risk for catheter-related venous thrombosis in patients with chronic intestinal failure: A long-term cohort study.
Catheter-related venous thrombosis (CRVT) is a severe complication of home parental nutrition. Although primary prevention of CRVT is crucial, there is no consensus on anticoagulant use to prevent this adversity. The aim was to compare CRVT risk in patients with chronic intestinal failure (CIF) in the presence or absence of anticoagulants, and to identify CRVT risk factors. This retrospective cohort study comprised adult patients with CIF with a central venous access device (CVAD) between 2010 and 2020 that were treated at our national CIF referral center. Analyses were performed at a CVAD level. Overall, 1188 CVADs in 389 patients were included (540.800 CVAD days). Anticoagulants were used in 403 CVADs. In total, 137 CRVTs occurred in 98 patients, resulting in 0.25 CRVTs/1000 CVAD days (95% CI, 0.22-0.29). Anticoagulant use was associated with a decreased CRVT risk (odds ratio [OR] = 0.53; 95% CI, 0.31-0.89; P = 0.02). Left-sided CVAD insertion (OR = 2.00; 95% CI, 1.36-2.94), a history of venous thrombosis (OR = 1.73; 95% CI, 1.05-2.84), and a shorter period postinsertion (OR = 0.78; 95% CI, 0.65-0.92) were independently associated with an increased CRVT risk. Anticoagulants decreased the CRVT risk. In addition, we identified left-sided vein insertion, a history of venous thrombosis, and a shorter period post-CVAD insertion as CRVT risk factors. Further prospective studies should provide guidance whether prophylactic anticoagulant use, especially in higher-risk patients with a left-sided CVAD or a history of venous thrombosis, is justified.


[Surgical management of persistent diarrhea].
An 82-year-old patient presented with a cervical lesion and refractory diarrhea of many years' standing. Surgical therapy of a medullary thyroid carcinoma had been performed 16 years previously. Appropriate tumor follow-up had not been carried out hitherto. Significantly high levels of calcitonin as well as a suspicious octreotide scan indicated late recurrence of the disease. Diarrhea ceased following redo surgery.


Novel coumarins and 2-thioxo-coumarins as inhibitors of the tumor-associated carbonic anhydrases IX and XII.
A series of coumarins incorporating tert-butyl-dimethylsilyloxy- or allyoxy- moieties in positions 4-, 6 or 7 of the heterocyclic ring have been synthesized and then converted to the corresponding 2-thioxo-coumarins. Other derivatives incorporating hydroxyethyloxy-, tosylethoxy- and 2-fluroethyloxy- moieties in position 7 of the coumarin ring were synthesized together with derivatives of 4-methyl-7-amino coumarin incorporating acetamido, 3,5-dimethylphenylureido- and tert-butyloxycarbonylamido functionalities. All these compounds were assayed as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 184.108.40.206). The human (h) cytosolic isoforms hCA I and II were weakly inhibited (hCA I) or not inhibited at all (hCA II) by these (thioxo)coumarins whereas the tumor-associated transmembrane isoforms hCA IX and XII were inhibited with efficiencies from the submicromolar to the low micromolar range by many of these derivatives. The structure-activity relationship for these classes of less investigated CA inhibitors are delineated, with the potential of using them as leads to obtain isoform-selective inhibitors with excellent affinity for CA IX and XII (validated antitumor targets) which do not significantly inhibit the cytosolic offtarget isoforms hCA I and II.


Performance and comparison of the Cockcroft-Gault and simplified Modification of Diet in Renal Disease formulae in estimating glomerular filtration rate in a Chinese Type 2 diabetic population.
Our aim was to assess performances of the Cockcroft-Gault and simplified Modification of Diet in Renal Disease (MDRD) formulae in estimating glomerular filtration rate (GFR) in Chinese diabetic populations and their association with vascular risks. A total of 1009 patients with Type 2 diabetes were categorized into low estimated GFR groups (GFR < 60 ml/min/1.73 m(2)) and control groups by the two equations. The performances of these formulae were assessed at different stages of kidney function. Carotid artery intima-media thickness (IMT) and the prevalence of diabetic retinopathy or albuminuria were compared among the groups. The ability of these formulae to identify established vascular risk markers using sensitivity, specificity, positive and negative predictive values were also compared. The prevalence of low estimated GFR was 32.7% with the Cockcroft-Gault formula and 5.2% with the MDRD formula, respectively. In low estimated GFR subjects by the MDRD formula, IMT was significantly thicker than those by the Cockcroft-Gault formula (1.2 mm vs. 1.0 mm; P < 0.05), with a higher prevalence of albuminuria (78.4 vs. 52.8%, P < 0.05) and diabetic retinopathy (46.5 vs. 30.5%; P < 0.05). The Cockcroft-Gault formula gave a specificity of 71.7% and a sensitivity of 37.0%, and the MDRD formula gave a specificity of 96.6% and a sensitivity of 7.9% in estimating low GFR relevant for established vascular risks. These formulae performed differently in Chinese diabetic populations. The simplified MDRD formula is minimally superior to the Cockcroft-Gault formula for its high specificity and positive predictive values in estimating low GFR relevant for vascular risks.


Inhibiting prepotent responses in the elderly: Distraction and disinhibition.
In this study, we aimed to examine whether older adults, relative to younger adults, suffer from generic inhibition, selective inhibition, and/or distraction deficits, as assessed by behavioral and electrophysiological measures in a go/no-go task paradigm that included manipulations of no-go stimulus type (irrelevant vs. conflict) and no-go probability. A total of 96 individuals were recruited; each of three experiments included 32 participants (16 adults above and 16 adults below 60 years of age). The older adults performed more poorly than the younger adults in our behavioral test; however, the event-related potential results showed that irrelevant and conflict no-go stimuli incurred different processes that were differentially impacted by aging, as was reflected in the N2 and P3. That is, the older adults' inhibition deficits might be due to different underlying mechanisms: disproportionate processing of irrelevant no-go stimuli, and disproportionate suppression of conflicting information when executing or withholding a response to conflict no-go stimuli. The present results therefore support the theories of age-related selective inhibition and distraction deficits.


Two Older Hematological Malignancy Patients for Whom Nutrition Rehabilitation Was Effective Against Global Leadership Initiative on Malnutrition-Defined Malnutrition and Sarcopenia.
The long-term survival rate of hematological malignancy patients with Global Leadership Initiative on Malnutrition (GLIM)-defined malnutrition and sarcopenia is poor, but nutritional rehabilitation effects in such patients are unknown. Here, two cases of older hematological malignancy patients in whom nutritional rehabilitation was effective against GLIM-defined malnutrition and sarcopenia are reported. By undergoing nutritional rehabilitation, the myeloma patient increased her six-meter walking speed and her maintained body mass index (BMI), appendicular skeletal muscle mass (ASM), and hand grip strength, whereas the Hodgkin lymphoma patient regained his hand grip strength and maintained his BMI, ASM, and six-meter walking speed.


Surface Microhardness of Bulk-Fill Resin Composites Handled With Gloves.
It has been reported that resin composites may experience alterations in their mechanical properties when they come into contact with glove powder. Therefore, the present study aimed to compare the surface microhardness of 3 bulk-fill resin composites handled with latex and nitrile gloves prior to light curing. This in vitro experimental study consisted of 90 resin composite specimens with a 6-mm diameter and a 4-mm height divided equally and randomly into 9 groups. Prior to light curing, the resin composites were handled with latex gloves, nitrile gloves, or only a spatula (control). Subsequently, the surface microhardness was measured with an Electronic Vickers Hardness Tester. The Kruskal-Wallis nonparametric H test with Bonferroni correction was used for comparisons. A significance level of 5% (P < .05) was considered. When comparing surface microhardness of each resin composite according to type of handling received, significant differences were observed in Filtek One Bulk Fill (P < .001) and Opus Bulk Fill (P < .001). In addition, these resin composites presented significantly higher surface microhardness than Tetric N-Ceram Bulk Fill resin (P < .05) when handled with latex gloves, nitrile gloves, and only a spatula. Finally, Filtek Bulk Fill resin presented significantly higher surface microhardness compared to Opus Bulk Fill resin when handled with nitrile gloves (P = .038) and a spatula only (P = .033). The surface microhardness of Filtek One Bulk Fill and Opus Bulk Fill resin composites decreased significantly when handled with latex or nitrile gloves, showing no variation in Tetric N-Ceram Bulk Fill resin composite. In addition, Filtek One Bulk Fill resin composite showed significantly higher surface microhardness than Opus Bulk Fill and Tetric N-Ceram Bulk Fill resin composites when handled with nitrile gloves. It is recommended that bulk-fill resin composites be handled with a spatula, because the use of latex or nitrile gloves could adversely affect their clinical performance.


Performance and Advancement of the Kidney Solid Organ Response Test.
The kidney solid organ response test (kSORT) has been investigated for the prediction of acute rejection in kidney transplant recipients with conflicting results. We aimed to investigate if the kSORT assay score is associated with rejection or immune quiescence. The blinded association between rejection and kSORT > 9 were investigated. Optimization of kSORT prediction was evaluated after unblinding to determine the optimal prediction cutoff value of kSORT score. Additionally, the predictive capability of the kSORT gene set was assessed using blinded normalized gene expression data from microarray (Affymetrix) and qPCR assays. Of the 95 blood samples analyzed, 18 patients had blood samples before transplant, 77 patients after transplant and 71 had clinically indicated biopsies of which 15 biopsies showed acute rejection and 16 showed chronic active antibody-mediated rejection. When 31 patients with rejection were compared to the remaining 64 patients, positive predictive value (PPV) was 54.29% and negative predictive value (NPV) was 75% when stratified using a kSORT score > 9, and PPV was 57.89% and NPV was 78.95% when stratified using a kSORT score > 5. Using the kSORT assay for detection of rejection showed an area under the curve value of 0.71. Microarray data improved prediction accuracy with PPV of 53% and NPV of 84% compared to qPCR results (PPV and NPV were 36% and 66%), respectively. The kSORT assay has the potential to be used as a predictive tool for active rejection and/or immune quiescence, but additional studies will be useful in improving and refining the kSORT assay, in particular the prediction algorithm.


Modulation by somatostatin of glutamate sensitivity during development of mouse hypothalamic neurons in vitro.
Glutamate sensitivity development and interactions of somatostatin (SRIF) with AMPA/Kainate receptor-mediated glutamate responses were studied in dissociated hypothalamic neurons from 16-day-old mouse embryos grown in vitro. Only 18% of functionally innervated cells could be found at 6-9 DIV whereas the percentage of innervated neurons progressively increased thereafter to reach 100% at 19-22 DIV. The glutamate sensitivity, estimated from glutamate-induced peak inward current, was very low at 6-9 DIV, sharply increased at 11-14 DIV and developed at a low increase rate thereafter. SRIF either unaffected glutamate peak current (27% of the cells), or significantly decreased (50%) or increased it (23%). Pertussis Toxin pretreatment abolished the SRIF-induced decrease of the glutamate response without affecting the excitatory effect. The number of glutamate responsive neurons inhibited by SRIF increased with time in culture whereas that of neurons responding to SRIF by an increased glutamate response was not statistically modified by functional innervation. The present data suggest that increased glutamate sensitivity coincides with the onset of functional synaptogenesis in mouse hypothalamic neurons in culture. SRIF can modulate glutamate sensitivity of hypothalamic neurons with either synergistic or antagonistic effects. Since glutamate has been shown to stimulate SRIF synthesis and secretion from hypothalamic neurons, the reverse capacity of SRIF to modulate the glutamate response suggests that both transmitters exhibit complex reciprocal interactions.


Aberrant expression of interleukin-17A in mast cells contributes to the pathogenesis of hidradenitis suppurativa.
Hidradenitis suppurativa (HS) significantly diminishes the quality of life for patients. Delayed diagnosis represents a significant challenge in effectively managing HS. To identify and characterize the key mediator in HS. Bioinformatic transcriptomic analysis was applied to identify potential candidates contributing to the disease process of HS. Skin samples from 40 patients with HS, four with psoriasis and 29 with normal skin were included. The expression of interleukin (IL)-17A was evaluated and compared among samples of normal skin, psoriatic skin and skin from different stages of HS by immunohistochemistry or dual-colour immunofluorescence. In vitro experiments and RNA sequencing analysis were also conducted to validate the expression of IL-17A and its pathogenic effect in HS. Transcriptomic database analyses identified IL-17 signalling as a potential contributor to HS. In HS, the predominant IL-17A+ cell population was identified as mast cells. IL-17A+ mast-cell density was significantly elevated in HS, especially in samples with advanced Hurley stages, compared with normal skin and psoriasis samples. The close contact between IL-17A+ mast cells and IL-17 receptor A (IL-17RA)-expressing keratinocytes was demonstrated, along with the significant effects of IL-17A on keratinocyte cell proliferation and HS pathogenic gene expression. Treatment with biologics (brodalumab or adalimumab) reduced the severity of the disease and the number of IL-17A+ mast cells in affected tissues. The presence of high-density IL-17A+ mast cells may serve as a valuable pathological marker for diagnosing HS. Moreover, developing therapeutic drugs targeting IL-17A+ mast cells may provide a new approach to treating HS.


Dopamine agonist 3-PPP fails to protect against MPTP-induced toxicity.
We investigated the neuroprotective effect of the dopamine agonist, 3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine] against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP (30 mg/kg, i.p., twice, 16 h apart) causes significant dopamine depletion in nucleus caudatus putamen (NCP) by 1 week. 3-PPP had no effect on the monoamine oxidase-B activity (MAO-B) activity in NCP. 3-PPP did not affect dopamine uptake, whereas mazindol significantly blocked the uptake of dopamine dose dependently. MPTP-induced behavioral changes in mice were not reduced by pretreatment with 3-PPP. This dopamine agonist did not prevent dopamine depletion caused by MPTP. MPP+ (20 microM) significantly inhibited the cell proliferation of SH-SY5Y dopaminergic neuronal cells. 3-PPP had no effect on the SH-SY5Y neuronal cell growth in culture and did not block the MPP(+)-induced cytotoxicity. This study shows that the dopamine agonist 3-PPP failed to protect against MPTP-induced dopaminergic neurotoxicity.


Dolutegravir-containing HIV therapy reversibly alters mitochondrial health and morphology in cultured human fibroblasts and peripheral blood mononuclear cells.
Given the success of combination antiretroviral therapy (cART) in treating HIV viremia, drug toxicity remains an area of interest in HIV research. Despite newer integrase strand transfer inhibitors (InSTIs), such as dolutegravir (DTG) and raltegravir (RAL), having excellent clinical tolerance, there is emerging evidence of off-target effects and toxicities. Although limited in number, recent reports have highlighted the vulnerability of mitochondria to these toxicities. The aim of the present study is to quantify changes in cellular and mitochondrial health following exposure to current cART regimens at pharmacological concentrations. A secondary objective is to determine whether any cART-associated toxicities would be modulated by human telomerase reverse transcriptase (hTERT). We longitudinally evaluated markers of cellular (cell count, apoptosis), and mitochondrial health [mitochondrial reactive oxygen species (mtROS), membrane potential (MMP) and mass (mtMass)] by flow cytometry in WI-38 human fibroblast with differing hTERT expression/localization and peripheral blood mononuclear cells. This was done after 9 days of exposure to, and 6 days following the removal of, seven current cART regimens, including three that contained DTG. Mitochondrial morphology was assessed by florescence microscopy and quantified using a recently developed deep learning-based pipeline. Exposure to DTG-containing regimens increased apoptosis, mtROS, mtMass, induced fragmented mitochondrial networks compared with non-DTG-containing regimens, including a RAL-based combination. These effects were unmodulated by telomerase expression. All effects were fully reversible following removal of drug pressure. Taken together, our observations indicate that DTG-containing regimens negatively impact cellular and mitochondrial health and may be more toxic to mitochondria, even among the generally well tolerated InSTI-based cART.


Herpes Zoster Reactivation After mRNA and Adenovirus-Vectored Coronavirus Disease 2019 Vaccination: Analysis of National Health Insurance Database.
Our study aimed to determine the risk of herpes zoster reactivation and coronavirus disease 2019 (COVID-19) vaccination (mRNA vaccine [BNT162b2] and adenovirus-vectored vaccine [ChAdOx1 nCoV-19]). This retrospective study analyzed herpes zoster cases diagnosed between 26 February 2021 and 30 June 2021 and registered in the National Health Insurance Service database. A matched case-control study with a 1:3 matching ratio and a propensity score matching (PSM) study with a 1:1 ratio of vaccinated and unvaccinated individuals were performed. In the matched case control analysis, BNT162b2 was associated with an increased risk of herpes zoster reactivation (first dose adjusted odds ratio [aOR], 1.11; 95% confidence interval [CI], 1.06-1.15; second dose aOR, 1.17; 95% CI, 1.12-1.23). PSM analysis revealed a statistically significant increase in risk within 18 days following any vaccination (adjusted hazard ratio [aHR], 1.09; 95% CI, 1.02-1.16). BNT162b2 was associated with an increased risk at 18 days postvaccination (aHR, 1.65; 95% CI, 1.35-2.02) and second dose (aHR, 1.10; 95% CI, 1.02-1.19). However, the risk did not increase in both analyses of ChAdOx1 vaccination. mRNA COVID-19 vaccination possibly increases the risk of herpes zoster reactivation, and thus close follow-up for herpes zoster reactivation is required.


Adverse effects of (15S)-15-methyl-prostaglandin E1 in normal and paraquat-exposed rats.
Single, daily injections of approximately 1 mg/kg of (15S)-15-methyl-PGE1 (mPGE1), a PGE1 analog, have been reported to inhibit inflammation and to prolong survival in several animal models of local and systemic inflammation. We examined the effect of this dose of mPGE1 on paraquat toxicity in rats. A significant increase in early mortality was identified in mPGE1-treated rats as early as 3 hr following injection of paraquat and appeared associated with increased respiratory effort. Rats given mPGE1 without paraquat also appeared to increase respiratory effort but did not die. Rats killed at 3 hr following injections demonstrated increased lung weights in both paraquat-injected and control animals receiving mPGE1. Although a neutrophilia was identified in these animals, no significant increase in lung lavage neutrophils or albumin was identified. These data suggest that large intermittent doses of a PGE1 analog may adversely affect the respiratory system of normal and injured animals, and will accelerate mortality following exposure to potentially lethal doses of paraquat.


Cloning and characterization of the mvrC gene of Escherichia coli K-12 which confers resistance against methyl viologen toxicity.
A new gene mvrC conferring resistance to methyl viologen, a powerful superoxide radical propagator, was cloned on 13.5 kilo base (kb) EcoRI DNA fragment. It gave resistance against methyl viologen to even a wild-type strain with gene dosage dependence. From the physical maps obtained by restriction enzyme digestions, it was predicted to locate at 580 kbp (12.3 min) on the physical map of E.coli. This was confirmed by the Southern hybridization of lambda phages covering this region with mvrC probe. The DNA sequence of mvrC gene was determined and its deduced protein encoding a 12 kd hydrophobic protein was confirmed by maxicell labeling of MvrC protein.


Enhanced glycolysis-mediated energy production in alveolar stem cells is required for alveolar regeneration.
Impaired differentiation of alveolar stem cells has been identified in a variety of acute and chronic lung diseases. In this study, we investigate the mechanisms that modulate alveolar regeneration and understand how aging impacts this process. We have discovered that the process of alveolar type II (AT2) cells differentiating into AT1 cells is an energetically costly process. During alveolar regeneration, activated AMPK-PFKFB2 signaling upregulates glycolysis, which is essential to support the intracellular energy expenditure that is required for cytoskeletal remodeling during AT2 cell differentiation. AT2 cells in aged lungs exhibit reduced AMPK-PFKFB2 signaling and ATP production, resulting in impaired alveolar regeneration. Activating AMPK-PFKFB2 signaling in aged AT2 cells can rescue defective alveolar regeneration in aged mice. Thus, beyond demonstrating that cellular energy metabolism orchestrates with stem cell differentiation during alveolar regeneration, our study suggests that modulating AMPK-PFKFB2 signaling promotes alveolar repair in aged lungs.


Effect of hydroxypropyl-β-cyclodextrin in fluid and semi-solid submicron emulsions on physiological skin parameters during regular in vivo application.
The aim of the present study was to evaluate the effect of hydroxypropyl-β-cyclodextrin (HP-β-CD) in cosmetic submicron emulsions and submicron emulsion gels on physiological skin parameters during regular application in a clinical set-up. Formulation morphology was investigated using cryo-transmission electron microscopy. Stability of the employed formulations was determined by photon correlation spectroscopy, measurement of pH and rheological properties. Effect on physiological skin parameters was evaluated during regular application over four weeks in a parallel group study (n = 15, healthy forearm skin) with a Corneometer, Sebumeter, skin-pH-Meter, Aquaflux and an Epsilon sensor. Confocal Raman spectroscopy was employed to monitor urea and NMF levels. Both submicron emulsions and gels showed satisfying storage stability irrespective of cyclodextrin incorporation. No statistically significant effects on skin barrier function and any of the observed parameters were obtained, indicating good skin tolerability of all tested formulations. Results suggest good skin tolerability of the developed cosmetic submicron emulsions and gels with HP-β-CD.


DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability.
Molecular chaperone HSP70s are attractive targets for cancer therapy, but their substrate broadness and functional non-specificity have limited their role in therapeutical success. Functioning as HSP70's cochaperones, HSP40s determine the client specificity of HSP70s, and could be better targets for cancer therapy. Here we show that tumors defective in HSP40 member DNAJA2 are benefitted from immune-checkpoint blockade (ICB) therapy. Mechanistically, DNAJA2 maintains centrosome homeostasis by timely degrading key centriolar satellite proteins PCM1 and CEP290 via HSC70 chaperone-mediated autophagy (CMA). Tumor cells depleted of DNAJA2 or CMA factor LAMP2A exhibit elevated levels of centriolar satellite proteins, which causes aberrant mitosis characterized by abnormal spindles, chromosome missegregation and micronuclei formation. This activates the cGAS-STING pathway to enhance ICB therapy response in tumors derived from DNAJA2-deficient cells. Our study reveals a role for DNAJA2 to regulate mitotic division and chromosome stability and suggests DNAJA2 as a potential target to enhance cancer immunotherapy, thereby providing strategies to advance HSPs-based cancer therapy.


Four Pairs of Neuroprotective Aryldihydronaphthalene-Type Lignanamide Enantiomers from the Herbs of Solanum lyratum.
Four pairs of aryldihydronaphthalene-type lignanamide enantiomers were isolated from Solanum lyratum (Solanaceae). The enantiomeric separation was accomplished by chiral-phase HPLC, and five undescribed compounds were elucidated. Analysis by various spectroscopy and ECD calculations, the structures of undescribed compounds were illuminated. The neuroprotective effects of all compounds were evaluated using H2 O2 -induced human neuroblastoma SH-SY5Y cells and AchE inhibition activity. Among them, compound 4 a exhibited remarkable neuroprotective effects at high concentrations of 25 and 50 μmol/L comparable to Trolox. Compound 1 a showed the highest AchE inhibition with the IC50 value of 3.06±2.40 μmol/L. Molecular docking of the three active compounds was performed and the linkage between the compounds and the active site of AchE was elucidated.


L-arginine preferentially dilates stenotic segments of coronary arteries thereby increasing coronary flow.
Oxidized LDL cholesterol and cytokines increase arginase and decrease nitric oxide (NO) synthase expression in human endothelial cells, leading to a decrease in NO production. In arteriosclerotic plaques, characterized by increased oxidized LDL and cytokine levels, a sustained local NO reduction might enhance sensitivity of the downstream guanylyl cyclase system towards an acute NO increase. We tested whether application of the NO synthase substrate l-arginine (l-arg, 150 micromol min(-1)) or the NO donor isosorbide dinitrate (ISDN; 0.3 mg) preferentially dilates stenotic coronary artery segments (CS) subsequently increasing poststenotic coronary blood flow (CBF) in patients with coronary artery disease (CAD). Changes in coronary diameter and circumferential surface area were assessed by quantitative coronary angiography (QCA) in a nonstenotic upstream segment, the CS, downstream the CS and in a reference vessel (n = 24). CBF was estimated in a subset of 13 patients by QCA and intracoronary Doppler. CS ranged from 62% to 89% (77 +/- 5%). l-arg increased minimal luminal diameter of the stenotic segment from 0.98 +/- 0.06 to 1.14 +/- 0.07 mm (P < 0.05) without affecting other coronary segments. Poststenotic CBF increased by 24 +/- 3%. ISDN dilated all segments again with a predominance of CS (25 +/- 4%) and increased poststenotic CBF by 38 +/- 9%. In a multifactorial anova, a medication with an angiotensin-converting enzyme inhibitor (decreasing inflammation and radical formation) and a ratio of LDL/HDL <3.5 were predictive for an l-arg-induced dilation. The increase in poststenotic CBF without affecting nondiseased arteries highlights the therapeutic potential of l-arg in patients with CAD.


The vertebral level of origin of spinal nerves in the rat.
Several dissections were performed to determine the level of spinal cord termination and the vertebral level at which the dorsal and ventral roots of spinal nerves C1-S4 emerged from the spinal cord in the rat. These levels of emergence were then compared to the level of exit from the vertebral canal. The dissections demonstrated that the effect of differential growth between spinal cord and vertebral column begins in the lower cervical region and becomes progressively more pronounced throughout thoracic and lumbar levels. The disparity between the vertebral level of emergence of spinal roots from the spinal cord and their level of exit via intervertebral foramina was found to be considerably larger than was previously reported by Greene ('68). It was further noted that the spinal cord terminated at the level of the intervertebral disc between the third and fourth lumbar vertebrae, not between the fourth and fifth lumbar vertebrae as reported by Greene ('68).


Hematologic malignancies in the Japanese patients with inflammatory bowel disease.
Although attention has been focused for over 20 years on the possible increased risk for hematologic malignancies (HM) in patients with inflammatory bowel diseases (IBD) receiving immune-modulators or anti-TNF-alpha antibodies, the association is still controversial. To understand the actual conditions of HM in the Japanese patients with IBD, the research committee for IBD supported by the Ministry of Health, Welfare and Labor of Japan (IBD-MHWL) conducted a multi-center retrospective study. Questionnaires for the development of HM in IBD patients were sent to the 70 facilities participating with IBD-MHWL in the first survey, followed by the second survey using a more detailed questionnaire, sent to the 27 members with HM patients. Out of a total of 36,939 IBD patients in 70 facilities, 28 cases of HM related with IBD [12 of 10,500 UC patients (0.11 %), 16 of 6,310 CD patients (0.25 %)] were analyzed. The numbers of UC patients who developed HM were 2 (0.15 %) from the group receiving and 10 (0.13 %) from the group non-receiving thiopurine, without significant differences. The numbers of CD patients who developed HM were 4 (0.39 %) from the group receiving and 12 (0.21 %) from the group non-receiving thiopurine, without significant differences. The odds ratios of developing HM by thiopurine were 1.37 (95 % CI 0.30-6.24) in UC patients and 1.86 (95 % CI 0.60-5.78) in CD patients. Our results suggested that thiopurine therapy may not be a risk factor for HM in Japanese patients with IBD. Further accumulation of cases and prospective studies are necessary to conclude this important issue.


Intracranial pressure during epileptic seizures.
A comatose 31-year-old male with presumed viral encephalitis and frequent partial motor seizures was paralyzed with pancuronium in an attempt to reduce recurrent elevation of intracranial pressure (ICP) associated with each seizure. ICP was continuously monitored with a Richmond Bolt and 5 electrographic seizures originating in the left frontal area were recorded. Each ictal episode was associated with stable blood pressure and an increase of ICP. The average seizure duration was 78 +/- 17 sec (mean +/- S.D.) and the average maximum increase of ICP above baseline during the seizures was 6.5 +/- 0.6 mm Hg with average peak ICP of 16.0 +/- 0.86 mm Hg. A simple mathematical model predicts the rate of increase of ICP, the peak ICP, the phase difference between maximum spike frequency and maximum ICP, and the rate at which ICP returns to pre-ictal values after termination of the seizure. The predicted values of ICP closely approximate the experimentally derived data. Therefore, the time course of the ICP appears to be determined by the frequency of the fundamental units of abnormal synchronized activity (the epileptogenic spike) and the CSF pressure-volume dynamics existing at the time of the seizure. An average increment of ICP per spike can be calculated for each seizure. The model also predicts that patients may develop high ICPs due to prolonged seizures. Prolonged unrecognized seizures may occur in patients who are therapeutically paralyzed as demonstrated by the case described here.


Molecular analysis of an NAD-dependent alcohol dehydrogenase from the zygomycete Mucor circinelloides.
NAD-dependent alcohol dehydrogenase (ADH) activity was detected mainly in the cytosol of aerobically cultured mycelium and in anaerobically grown yeast cells of Mucor circinelloides. ADH levels were about 2.5-fold higher in yeast cells than in mycelium; zymogram analysis suggested that the same ADH enzyme is produced in both developmental stages. The enzyme, named ADH1, was purified to homogeneity from yeast cells, using ion-exchange and affinity chromatography. The active ADH1 appears to be a homomeric tetramer of 37,500-kDa subunits. Km values obtained for acetaldehyde, ethanol, NADH and NAD+ indicated that in vivo the enzyme mainly serves to reduce acetaldehyde to ethanol. Amino acid sequences of internal peptides obtained from the purified ADH1 were used to design oligonucleotides that allowed the cloning of the corresponding cDNA by RT-PCR, and the characterization of the genomic DNA sequence. The adh1 ORF is interrupted by two small introns located towards the 5'-end. M. circinelloides adh1 encodes a protein of 348 amino acids, which display moderate to high overall identity to several hypothetical ADH enzymes from the related zygomycete Rhizopus oryzae. adh1 mRNA is expressed at similar levels in aerobic mycelium and anaerobic yeast cells. During exponential growth under aerobic conditions, the level of adh1 transcript was correlated with the glucose concentration in the growth medium.


The quantitative analysis of polymorphism on human chromosomes 1, 9, 16, and Y. II. Comparison of the C segments in male and female individuals (group characteristics).
Comparative analysis of the polymorphism of C segments on chromosomes 1, 9, 16, and Y was conducted in 50 normal boys and 50 normal girls. Quantitative methods revealed that the mean lengths of C segments, their variability, and their distribution on the chromosomes mentioned are quite identical in the two groups. Methodological problems related to the study of chromosome polymorphism are discussed.


Some thoughts on the origin of RNA, and the roles of ribosomes, the nucleolus and the nucleus.
The deciphering of DNA's structure led to the formulation of Crick's central dogma, implicit in which is that all RNA is chromosomal in origin. The detection of RNA synthesis at nucleolar sites, plus the similarity between r RNA and nucleolar RNA has firmly established the idea that the nucleolus is responsible for r RNA production. But neither of these considerations actually prove that this is so. An analysis of RNA synthesis in E coli suggests that its r RNA is not chromosomal in origin, but arises by semi conservative replication. The likelihood therefore exists that eukaryotic r RNA also arises by self replication and is not a product of the nucleolus. This concept is favoured by the behaviour of the nucleolus in the differentiating cell in which it seems to have an important role.


The SUMAMOS EXCELENCIA Project.
The gap between research and clinical practice leads to inconsistent decision-making and clinical audits are an effective way of improving the implementation of best practice. Our aim is to assess the effectiveness of a model that implements evidence-based recommendations for patient outcomes and healthcare quality. National quasi-experimental, multicentre, before and after study. This study focuses on patients attending primary care and hospital care units and associated socio-healthcare services. It uses the Joanna Brigg's Institute Getting Research into Practice model, which improves processes by referring to prior baseline clinical audits. The variables are process and outcome criteria for pain, urinary incontinence, and fall prevention, with data collection at baseline and key points over 12 months drawn from clinical histories and records. Project funding was received from the Spanish Strategic Health Action in November 2014. The project results will provide knowledge on the effectiveness of the Getting Research into Practice model, to apply evidence-based recommendations for the detection and management of pain, urinary incontinence, and fall prevention. It will also establish whether using research results, based on clinical audits and situation analysis, is effective for implementing evidence-based recommendations and improving patients' health. This nationwide Spanish project aims to detect and prevent high-prevalence healthcare problems, namely pain in patients at any age and falls and urinary incontinence in people aged 65 and over. Tailoring clinical practice to evidence-based recommendations will reduce unjustified clinical variations in providing healthcare services. Clinical Trial ID: NCT03725774.


Growth of the penaeid shrimp virus infectious hypodermal and hematopoietic necrosis virus in a fish cell line.
An established fish cell line, epithelioma papillosum cyprini (EPC), originating from the carp (Cyprinus carpio) was found to be susceptible to the penaeid shrimp virus, infectious hypodermal and hematopoietic necrosis virus (IHHNV). This economically important pathogen of penaeid shrimp raised in mariculture has been previously limited to growth only in young post-larval shrimps. This is, to our knowledge, the first reported successful growth of the penaeid virus in a fish cell line; it promises to provide a sensitive and convenient cell culture system for the primary isolation and detection of IHHNV which will aid immensely the production of IHHNV-free penaeid shrimp stocks for mariculture. Of added significance is the replication of a crustacean virus in a fish cell line which has never before been reported. The use of this sensitive cell line will also greatly facilitate the characterization of the IHHN virus and other crustacean viruses.


EGS plus: Predicting futility in LVAD patients with emergency surgical disease.
While emergent, non-cardiac surgery can be safely performed in LVAD patients, the inherent perioperative challenges of these rare procedures and the perception that these patients may be poor surgical candidates can contribute to reluctance to perform necessary emergency general surgery (EGS) procedures. We, therefore, sought to identify predictors of inpatient mortality to assist perioperative decision-making. The Nationwide Inpatient Sample (2010-2015Q3) was used to identify patients with previously placed LVADs with a subsequent EGS admission diagnosis. Multivariable logistic regression analysis was performed to identify independent predictors of 30-day mortality, and a risk-adjusted probability of death was calculated for significant patient subgroups across age. Additional demographic variables were included in the regression due to clinical relevance. There were 1805 (weighted) LVAD-EGS patients with an overall mortality rate of 11%. Independent predictors of mortality were intestinal ischemia and sepsis present on admission. Patients older than 70 with sepsis had an 80% probability of in-hospital mortality (10.6 OR, 1.70-65.5 95% CI) while those over 70 presenting with intestinal ischemia had a 38% probability of death (3.6 OR, 1.50-8.78 95% CI). Mortality risk for younger patients with sepsis was still approximately 50%. Older LVAD patients presenting with either sepsis or intestinal ischemia have a substantial mortality risk while younger patients have a modest risk. These results can be used to guide treatment discussions when emergency surgery is being considered in LVAD patients.


Keeping it Simple: Balloon Devices for Atrial Fibrillation Ablation Therapy.
Atrial fibrillation is a common disease of increasing prevalence. Catheter ablation has evolved into an established therapeutic option that mainly aims to electrically isolate the pulmonary veins from atrial myocardium. The traditional method comprises point-by-point radiofrequency current ablation guided by electroanatomical mapping and has proven to be effective and safe in experienced hands. However, this approach is technically highly demanding and associated with a long learning curve, limiting its widespread utilization. To address these shortcomings, simplified ablation tools for pulmonary vein isolation are needed. In this context, balloon devices promise to ease the procedure by approaching the entire orifice of a targeted pulmonary vein in a single maneuver. This requires less catheter manipulation in the left atrium and often allows ablation of a large volume of tissue with a single application of ablative energy. Two balloon devices-one using cryoenergy, the other laser energy-have already been established in clinical routine and have demonstrated noninferiority when compared with radiofrequency ablation in large randomized trials. More balloon devices are on the verge of being introduced into clinical practice and bear the potential to expand the interventional electrophysiologist's armamentarium when treating atrial fibrillation. The authors review the use of the established balloon devices available for atrial fibrillation ablation and provide a detailed outlook on upcoming balloon technologies, including 3 different balloons utilizing radiofrequency energy as well as a novel cryoballoon.


Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), design, synthesis and biological evaluation of novel PI3Kα selective inhibitors.
Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), three series of novel 1,3,5-triazine or pyrimidine derivatives containing semicarbazones have been designed and synthesized to obtain new potent and selective PI3Kα inhibitors. Their inhibitory activities in vitro were evaluated against PI3Kα and three tumor-derived cell lines (U87-MG, MCF-7, and PC-3). We also tested promising compounds (A4, A6, A10, and B1) for other PI3K class I subtype (PI3Kβ, PI3Kδ, and PI3Kγ) activity. The representative compound A10 exhibited an IC50 value of 0.32 nM against PI3Kα, and demonstrated extraordinary subtype selectivity. Furthermore, compound A10 obviously inhibited proliferation of MCF-7 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, and arrested G2 phase in a dose-dependent manner. Additionally, compound A10 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line without an obvious sign of toxicity upon 20 mg/kg oral administration. Compound A10 may serve as a PI3Kα-selective inhibitor and provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.


Function of adenovirus E3 proteins and their interactions with immunoregulatory cell proteins.
This manuscript will contain a brief review of adenovirus (Ad) biology including its structure and the spectrum of clinical diseases that it causes. Newer findings about the interactions of Ad early region 3 (E3) proteins with host proteins and signal transduction processes, which control the inflammatory response, will be described. Some of these processes affect the strategies for using Ads as vectors for gene therapy. There are many excellent reviews of some of these aspects 1. The history of the discoveries that led to the use of Ads as vectors as well as key experiments that resulted in improvements to various aspects of these systems have also been reviewed recently 2. The use of Ad E3 immunoregulatory genes to facilitate allogeneic transplantation and prevent autoimmune diabetes will be described.


Slow wave changes in amygdala to visual, auditory, and social stimuli following lesions of the inferior temporal cortex in squirrel monkey (Saimiri sciureus).
Radiotelemetry of slow wave activity of the amygdala was recorded under a variety of conditions. Power, and the percentage of power in the delta band, increased in response to stimulation. Recordings of monkey vocalizations and slides of ethologically relevant, natural objects produced a greater increase in power than did control stimuli. The responses to auditory stimuli increased when these stimuli were presented in an unrestrained, group setting, yet the responses to the vocalizations remained greater than those following control stimuli. Both the natural auditory and visual stimuli produced a reliable hierarchy with regard to the magnitude of response. Following lesions of inferior temporal cortex, these two hierarchies are disrupted, especially in the auditory domain. Further, these same stimuli, when presented after the lesion, produced a decrease, rather than an increase, in power. Nevertheless, the power recorded from the natural stimuli was still greater than that recorded from control stimuli in that the former produced less of a decrease in power, following the lesion, than did the latter. These data, in conjunction with a parallel report on evoked potentials in the amygdala, before and after cortical lesions, lead us to conclude that sensory information, particularly auditory, available to the amygdala, following the lesion, is substantially the same, and that it is the interpretation of this information, by the amygdala, which is altered by the cortical lesion.


Polymeric-Ig receptor gene expression in rabbit mammary gland during pregnancy and lactation: evolution and hormonal regulation.
The polymeric immunoglobulin receptor (poly Ig-R) mediates transcytosis of IgA and IgM antibodies produced by local plasma cells across epithelial cells of mucosal and glandular tissues. Gene expression of the poly-Ig R was analyzed in rabbit mammary gland during pregnancy and lactation. The poly Ig-R was expressed as early as day 8 (G8) of gestation and mRNA accumulation remained low until about G18. From G21, the mRNA abundance increased and reached steady state levels approximately 5-fold higher at day 15 of lactation (L15) when compared to basal levels at G8. The hormonal regulation of poly-Ig receptor gene expression was assessed in mammary organ cultures. Poly-Ig R mRNA accumulation in mammary explants cultured for 24 or 48 h in the presence of ovine prolactin (oPRL) was significantly increased to a maximal 4-fold level at 1 microgram ml-1 of oPRL. Estradiol (100 pg ml-1) or progesterone (1 microgram ml-1) did not further stimulate poly-Ig R expression. In contrast, their combination resulted in a significant 30-50% decrease of poly-Ig-R mRNA levels. The addition of 1 microgram ml-1 of cortisol to medium in the absence or presence of estradiol or progesterone decreased the amount of poly-Ig-R mRNA. The results suggest that until mid-pregnancy, poly-Ig-R expression is inhibited by elevated progesterone-estradiol concentrations and that the subsequent increase is due to the concomitant decrease of the two circulating steroids and the increase of serum prolactin levels.


Residual effectiveness of insect growth regulators applied to carpet for control of cat flea (Siphonaptera: Pulicidae) larvae.
Three insect growth regulators, fenoxycarb, methoprene, and pyriproxyfen, formulated as total release aerosols, were tested for their residual effectiveness on carpet in bioassays with cat flea, Ctenocephalides felis (Bouché), larvae. All treatments except methoprene produced significant mortality for the 7-mo duration of the test. In general, fenoxycarb and the higher rates of pyriproxyfen reduced adult flea emergence by > 80%.


Laparoendoscopic single-site (LESS) retroperitoneal adrenalectomy using a homemade single-access platform and standard laparoscopic instruments.
This study aimed to evaluate laparoendoscopic single-site (LESS) adrenalectomy via the retroperitoneal approach using the Alexis wound retractor with standard laparoscopic instrumentation. Since October 2009, seven LESS retroperitoneal adrenalectomies have been completed successfully with a homemade single port created using an Alexis wound retractor as an access platform through a 3-cm incision beneath the tip of the 12th rib. All the LESS procedures for these seven patients with adrenal tumors (size, 1.3-6.0 cm; 4 right, 1 left) were completed successfully without traditional laparoscopic conversion or complication. The average operative time was 159 min, and the estimated blood loss was 100 ml. The average hospital stay was 2 days (range, 1-3 days). The preliminary results show that LESS retroperitoneal adrenalectomy is a safe and feasible procedure for functional adrenal tumors using standard laparoscopic instruments.


Developing a consensus-based definition of out-of-hospital clinical deterioration: A Delphi study.
Clinical deterioration is a time-critical medical emergency requiring rapid recognition and intervention. Deteriorating patients are seen across various healthcare settings, including the out-of-hospital (OOH) environment. OOH care is an evolving area of medicine where decisions are made regarding priority and timing of clinical interventions, ongoing management, and transport to appropriate care. To date, the literature lacks a standardised definition of OOH clinical deterioration. The objective of this study was to create a consensus-based definition of OOH clinical deterioration informed by emergency medicine health professionals. A Delphi study consisting three rounds was conducted electronically between June 2020 and January 2021. The expert panel consisted of 30 clinicians, including emergency physicians and paramedics. A consensus-based definition of OOH clinical deterioration was identified as changes from a patient's baseline physiological status resulting in their condition worsening. These changes primarily take the form of measurable vital signs and assessable symptoms but should be evaluated in conjunction with the history of events and pertinent risk factors. Clinicians should be suspicious that a patient could deteriorate when changes occur in one or more of the following vital signs: respiratory rate, heart rate, blood pressure, Glasgow Coma Scale, oxygen saturation, electrocardiogram, and skin colour. Almost all participants (92%) indicated an early warning system would be helpful to assist timely recognition of deteriorating patients. The creation of a consensus-based definition of OOH clinical deterioration can serve as a starting point for the development and validation of OOH-specific early warning systems. Moreover, a standardised definition allows meaningful comparisons to be made across health services and ensures consistency in future research. This study has shown recognition of OOH clinical deterioration to be a complex issue requiring further research. Improving our understanding of key factors contributing to deterioration can assist timely recognition and intervention, potentially reducing unnecessary morbidity and mortality.


Template protocol for clinical trials investigating vaccines--focus on safety elements.
This document is intended as a guide to the protocol development for trials of prophylactic vaccines. The template may serve phases I-IV clinical trials protocol development to include safety relevant information as required by the regulatory authorities and as deemed useful by the investigators. This document may also be helpful for future site strengthening efforts.


Reduced antigen-induced proliferation and surface Ia expression of peripheral blood T cells following tetanus booster immunization.
Immune regulatory changes after tetanus booster immunization were studied by measuring T-cell proliferation and surface Ia expression after cocultivation of T cells with autologous tetanus toxoid pulsed macrophages. Both soluble and aluminium-absorbed tetanus toxoid was used as antigen. T cells proliferated readily prior to immunization, if TTAl was used as an antigen (when proliferation was measured by the uptake of [3H]thymidine: mean +/- SEM 64.5 +/- 11.5 X 10(3) dpm). The proliferative response of the peripheral blood T cells studied decreased significantly to 29.3 +/- 9.3 X 10(3) dpm (P less than 0.01) 1 week postimmunization, returned to preimmunization values after 2 to 4 weeks, and increased further thereafter. Surface Ia expression paralleled the proliferative response at every point pre- and postimmunization. Serum antibody levels increased steadily during the first weeks. These results demonstrate a functional parallel to the previously described changes in T-cell phenotypes (M. M. Eibl, J. W. Mannhalter, and G. Zlabinger, N. Engl. J. Med 310, 198, 1984) after tetanus booster immunization.


Role of the conidium in dimorphism of Blastomyces dermatitidis.
Fine details of yeastlike cell development of Blastomyces dermatitidis from its conidium are described and illustrated by electron micrographs. When cultured in an enriched medium at 37C, conidia of two strains of B. dermatitidis readily underwent ultrastructural changes consistent with mycelial to yeast dimorphism. Although hyphal cells contained in the conversion cultures were observed consistently to undergo profound degenerative changes, the conidia rapidly germinated to give rise to short germ tubes which subsequently enlarged to form intermediate yeast mother cells (YMC). The wall of the germ tube arose from the innermost layer of the wall of the germinant. During the transition globoid osmiophilic inclusions of unknown origin and function were observed in vacuolated areas of the germ tube and YMC cytoplasm. Yeastlike daughter cells then budded from the intermediate YMC. Since transformation was readily accomplished under in vitro conditions favoring mycelial to yeast dimorphism, it is suggested that the conidium of B. dermatitidis represents the primary infective unit of this pathogenic fungus.


Differential Diagnosis of Acute Liver Failure in Children: A Systematic Review.
To develop a probability-based differential diagnosis for pediatric acute liver failure (PALF) based on age and socioeconomic status of the country of origin. Comprehensive literature search using PubMed, EMBASE, and SCOPUS databases was performed. Children 0-22 years of age who met PALF registry criteria were included. Articles included >10 children, and could not be a case report, review article, or editorial. No language filter was utilized, but an English abstract was required. Etiology of PALF, age of child, and country of origin was extracted from included articles. 32 full text articles were reviewed in detail; 2,982 children were included. The top diagnosis of PALF in developed countries was acetaminophen toxicity (9.24%; 95% CredI 7.99-10.6), whereas in developing countries it was Hepatitis A (28.9%; 95% CredI 26.3-31.7). In developed countries, the leading diagnosis of PALF in children aged <1 year was metabolic disorder (17.2%; 95% CredI 10.3-25.5), whereas in developing countries it was unspecified infection (39.3%; CredI 27.6-51.8). In developed countries, the leading diagnosis in children aged >1 year was Non-A-B-C Hepatitis (8.18%; CredI 5.28-11.7), whereas in developing countries it was Hepatitis A (32.4%; CredI 28.6-36.3). The leading causes of PALF in children aged 0-22 years differ depending on the age and developmental status of their country of origin, suggesting that these factors must be considered in the evaluation of children with PALF.


Quantum cryptography protocols robust against photon number splitting attacks for weak laser pulse implementations.
We introduce a new class of quantum key distribution protocols, tailored to be robust against photon number splitting (PNS) attacks. We study one of these protocols, which differs from the original protocol by Bennett and Brassard (BB84) only in the classical sifting procedure. This protocol is provably better than BB84 against PNS attacks at zero error.


On the presence of serotonin in mammalian cardiomyocytes.
Pleiotropic effects of serotonin (5-HT) in the cardiovascular system are well documented. However, it remains to be elucidated, whether 5-HT is present in adult mammalian cardiomyocytes. To address this issue, we investigated the levels of 5-HT in blood, plasma, platelets, cardiac tissue, and cardiomyocytes from adult mice and for comparison in human right atrial tissue. Immunohistochemically, 5-HT was hardly found in mouse cardiac tissue, but small amounts could be detected in renal preparations, whereas adrenal preparations revealed a strong positive immunoreaction for 5-HT. Using a sensitive HPLC detection system, 5-HT was also detectable in the mouse heart and human atrium. Furthermore, we could identify 5-HT in isolated cardiomyocytes from adult mice. These findings were supported by detection of the activity of 5-HT-forming enzymes-tryptophan hydroxylase and aromatic L-amino acid decarboxylase-in isolated cardiomyocytes from adult mice and by inhibition of these enzymes with p-chlorophenylalanine and 3-hydroxybenzyl hydrazine. Addition of the first intermediate of 5-HT generation, that is 5-hydroxytryptophan, enhanced the 5-HT level and inhibition of monoamine oxidase by tranylcypromine further increased the level of 5-HT. Our findings reveal the presence and synthesis of 5-HT in cardiomyocytes of the mammalian heart implying that 5-HT may play an autocrine and/or paracrine role in the heart.


Sonoelastography techniques in the evaluation and diagnosis of parotid neoplasms.
Ultrasound is the first-line imaging investigation in the evaluation of parotid gland lesions; however, ultrasound alone cannot differentiate between benign and malignant lesions. An imaging technique with this capability would be of great value, as fine needle aspiration cytology (FNAC) is not always accurate and partial/total parotidectomy is associated with facial nerve palsy and Frey's syndrome. Sonoelastography is a novel imaging technique that has been employed in the research setting in the evaluation of tissues including breast, thyroid, prostate and the salivary glands. More recently it has been used as a diagnostic adjunct in the sonographic evaluation of major salivary gland lesions. This review article outlines the current role of sonoelastography in the diagnostic imaging of parotid lesions, with particular reference to the findings of two research papers published in European Radiology. These papers employ slightly different techniques: the first utilises shear wave elastography whilst the second uses real-time sonoelastography. Sonoelastography may have potential as a diagnostic imaging adjunct to conventional ultrasound. However, it seems likely that FNAC/core biopsy will continue to be necessary. Further studies to evaluate the reproducibility of sonoelastographic results across a range of operators and systems are also needed. Key Points • Ultrasound is the initial and often definitive investigation for parotid lesions • Ultrasound-based strain elastography has been attempted but offered little additional information • New shear wave elastographic techniques did not confer much advantage either • However, analysis of elastographic patterns seems to provide advantages over ultrasound alone.


Antimicrobial activity of sodium citrate against Streptococcus pneumoniae and several oral bacteria.
The aim of this study is to assess the antibacterial activity of sodium citrate against Streptococcus pneumoniae and several oral bacteria. The antibacterial activity was determined by broth microdilution method. The results showed that although Enterocuccus faecium OB7084 and Klebsiella pneumoniae OB7088 had high tolerance to sodium citrate, several oral bacteria including Fusobacterium nucleatum JCM8532(T) , Streptococcus mutans JCM5705(T) and Strep. pneumoniae NBRC102642(T) were susceptible. Furthermore, the bactericidal activity of sodium citrate against Strep. pneumoniae NBRC102642(T) was not influenced by pH in the range of 5·0-8·0, whereas that of sodium lactate was weakened at neutral or weak alkaline pH. When Strep. pneumoniae NBRC102642(T) was treated with sodium citrate for 2 h, many burst cells were observed. However, addition of MgCl(2) or CaCl(2) to an assay medium weakened the antimicrobial activity although ZnCl(2) or MnCl(2) did not influence. Independent of pH, sodium citrate inhibited the growth of oral bacteria, which suggests that the mechanism is different from that of sodium lactate. The results presented in this study would be available for understanding the antimicrobial property of sodium citrate.


Subfascial expansive plasty for intrathecal baclofen pump replacement. A technical note.
Although intratechal pump replacement is a common technique, it can be sometimes complicated when aiming to replace a 20 ml pump with a bigger one (40 ml). We developed a simple and straightforward technique to relax the wall of the pocket of the pump, preserving its fascial layer. A 20-year-old boy with spastic tetraparesia was admitted for pump replacement. After scar opening and pump removal, various lineal incisions were performed in the posterior layer of the subfascial pocket in a cranio-caudal direction. A 40 ml pump was placed without skin incision ampliation and preserving subfascial plane. This easy, expansive technique for infusion pump replacement preserves subfascial plane and prevents the need for more extensive surgeries.


Imaging regional changes in the spontaneous activity of the brain: an extension of the minimum-norm least-squares estimate.
This paper describes methods for inferring mathematically unique local distributions of primary cortical current that underly changes in the average pattern of power of the ongoing ("spontaneous") extracranial magnetic field of the brain. In previous work we demonstrated that mathematically unique solutions to the inverse problem are possible for current sources of the brain's field, without assuming a small set of current dipoles as a source model. In principle, it is possible to locate and delineate patterns of current of any configuration. In practice this approach applies to synchronized neuronal activity, e.g., activity which is known to underly average evoked or event-related brain responses. This paper extends that approach to local changes in incoherent activity, e.g., activity yielding fields or potentials that tend to be self-cancelling when averaged over time. This includes the spontaneous brain activity normally treated as background noise when it accompanies event-related responses. We demonstrate that local changes in this ongoing incoherent activity may also be uniquely delineated in space and time. The solution is a covariance matrix characterizing activity across an image surface. Its diagonal elements represent the spatial pattern of mean current power. Evidence is reviewed indicating that the distribution of the brain's magnetic field, due to both its synchronized and incoherent neural activity, is affected by early sensory-perceptual processes and by higher cognitive processes. Hence, in principle, the ability to delineate both kinds of sources in space and time makes it possible to form more comprehensive dynamic functional images of the human brain.


An attenuated strain of Bacillus anthracis (CDC 684) has a large chromosomal inversion and altered growth kinetics.
An isolate originally labeled Bacillus megaterium CDC 684 was found to contain both pXO1 and pXO2, was non-hemolytic, sensitive to gamma-phage, and produced both the protective antigen and the poly-D-glutamic acid capsule. These phenotypes prompted Ezzell et al., (J. Clin. Microbiol. 28:223) to reclassify this isolate to Bacillus anthracis in 1990. We demonstrate that despite these B. anthracis features, the isolate is severely attenuated in a guinea pig model. This prompted whole genome sequencing and closure. The comparative analysis of CDC 684 to other sequenced B. anthracis isolates and further analysis reveals: a) CDC 684 is a close relative of a virulent strain, Vollum A0488; b) CDC 684 defines a new B. anthracis lineage (at least 51 SNPs) that includes 15 other isolates; c) the genome of CDC 684 contains a large chromosomal inversion that spans 3.3 Mbp; d) this inversion has caused a displacement of the usual spatial orientation of the origin of replication (ori) to the termination of replication (ter) from 180° in wild-type B. anthracis to 120° in CDC 684 and e) this isolate also has altered growth kinetics in liquid media. We propose two alternative hypotheses explaining the attenuated phenotype of this isolate. Hypothesis 1 suggests that the skewed ori/ter relationship in CDC 684 has altered its DNA replication and/or transcriptome processes resulting in altered growth kinetics and virulence capacity. Hypothesis 2 suggests that one or more of the single nucleotide polymorphisms in CDC 684 has altered the expression of a regulatory element or other genes necessary for virulence.