Rheumatoid forefoot deformity: pathophysiology, evaluation and operative treatment options.
Despite recent advances in pharmacological management of rheumatoid arthritis, forefoot deformity, with its symptoms, remains a common problem, often requiring operative treatment. Typical deformities in these patients comprise hallux valgus and deformity of the lesser metatarsophalangeal (MTP) joints and toes. With regard to the lesser rays the standard operative procedure, advocated for the disabling forefoot pain in these patients, remains metatarsal head resection. It should be considered that with increasing success of pharmacological treatment the degree of forefoot deformity in these patients is becoming less and that resection of the lesser MTP joints is becoming more and more superfluous. This supports a trend towards metatarsal head-preserving surgery. The optimal treatment of the hallux deformity remains unclear. Fusion of the first MTP joint is, generally, recommended. This article will discuss the current surgical options in rheumatoid forefoot pathology.


Cotransplantation of human umbilical cord-derived mesenchymal stem cells and umbilical cord blood-derived CD34⁺ cells in a rabbit model of myocardial infarction.
The objective of the study is to investigate the effect of hypoxic preconditioning on the immunomodulatory properties of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and the effect of cotransplantation of hUC-MSCs and human umbilical cord blood (hUCB)-derived CD34(+) cells in a rabbit model of myocardial infarction. hUC-MSCs with or without hypoxic preconditioning by cobalt chloride were plated in a 24-well plate, and then cocultured with hUCB-CD34(+) cells and PBMCs for 96 h at 37 °C in a 5% CO₂ incubator. For the negative control, hUC-MSCs were omitted. The groups were divided as follows: A1 = HP-MSCs + hUCB-CD34(+) cells + PBMC, A2 = hUC-MSCs + hUCB-CD34(+) cells + PBMC, Negative Control = hUCB-CD34(+) cells + PBMC. Culture supernatants of each group were collected, and the IL-10 and IFN-γ levels were measured by ELISA. A rabbit model of MI was established using a modified Fujita method. The animals were then randomized into three groups and received intramyocardial injections of 0.4 ml of PBS alone (n = 8, PBS group), hUC-MSCs in PBS (n = 8, hUC-MSCs group), or hUC-MSCs + CD34(+) cells in PBS (n = 8, Cotrans group), at four points in the infarct border zone. Echocardiography was performed at baseline, 4 weeks after MI induction, and 4 weeks after cell transplantation, respectively. Stem cell differentiation and neovascularization in the infracted area were characterized for the presence of cardiac Troponin I (cTnI) and CD31 by immunohistochemical staining, and the extent of myocardial fibrosis was evaluated by hematoxylin and eosin (H&E) and Masson's trichrome. IFN-γ was 27.00 ± 1.11, 14.20 ± 0.81, and 7.22 ± 0.14 pg/ml, and IL-10 was 31.68 ± 3.08, 61.42 ± 1.08, and 85.85 ± 1.80 pg/ml for the Control, A1 and A2 groups, respectively, which indicated that hUCB-CD34(+) cells induced immune reaction of peripheral blood mononuclear cells, whereas both hUC-MSCs and HP-MSCs showed an immunosuppressive effect, which, however, was attenuated by hypoxic preconditioning. The Cotrans group had less collagen deposition in the infarcted myocardium and better heart function than the hUC-MSCs or PBS group. The presence of cTnI-positive cells and CD31-positive tubular structures indicated the differentiation of stem cells into cardiomyocytes and neovascularization. The microvessel density was 12.19 ± 3.05/HP for the hUC-MSCs group and 31.63 ± 2.45/HP for the Cotrans group, respectively (P < 0.01). As a conclusion, both hUC-MSCs and HP-MSCs have an immunosuppressive effect on lymphocytes, which, however, can be attenuated by hypoxic preconditioning. Cotransplantation of hUC-MSCs and hUCB-CD34(+) cells can improve heart function and decrease collagen deposition in post-MI rabbits. Thus, a combined regimen of hUC-MSCs and hUCB-CD34(+) cells would be more desirable than either cells administered alone. This is most likely due to the increase of cardiomyocytes and enhanced angiogenesis in the infarcted myocardium.


[Possibilities and limitations of statistical regression models for the calculation of threshold values for minimum provider volumes].
Inadequate statistical procedures are often applied for the derivation of threshold values in various medical research areas. The frequently applied method to establish threshold values on the basis of simple comparisons between arbitrarily defined low-volume and high-volume groups may be misleading because the result depends on the preceding classification. In this paper, the possibilities and limitations of statistical regression models for the calculation of threshold values are described. The features of these models for the selection of minimum volumes for hospitals or physicians are discussed. Simulated data examples are used to demonstrate that the definition of a useful minimum provider volume should not be based upon a calculated value of purely mathematical meaning without clinically assessing the risk curve. In the application of statistical regression models to retrospective observational data it should be noticed that calculated threshold values are only of a hypothesis-generating character. In order to verify that a minimum provider volume leads to the expected quality improvement, a prospective intervention study is required.


Optical interconnects using top-surface-emitting microlasers and planar optics.
Optical interconnections made using two-dimensional arrays of top-surface-emitting microlasers and integrated free-space optics are discussed for use in chip-to-chip communications. A demonstration setup with a 2 x 2 array of lasers is presented. System parameters, such as light efficiency, the number of data channels, thermal effects, power requirements, and the issue of hybrid integration of laser chips with passive optics, are considered.


Germ cell differentiation in the marmoset (Callithrix jacchus) during fetal and neonatal life closely parallels that in the human.
Testicular germ cell tumours (TGCT) are thought to originate from fetal germ cells that fail to differentiate normally, but no animal model for these events has been described. We evaluated the marmoset (Callithrix jacchus) as a model by comparing perinatal germ cell differentiation with that in humans. Immunohistochemical profiling was used to investigate germ cell differentiation (OCT4, NANOG, AP-2gamma, MAGE-A4, VASA, NANOS-1) and proliferation (Ki67) in fetal and neonatal marmoset testes in comparison with the human and, to a lesser extent, the rat. In marmosets and humans, differentiation of gonocytes into spermatogonia is associated with the gradual loss of pluripotency markers such as OCT4 and NANOG, and the expression of germ cell-specific proteins such as VASA. This differentiation occurs asynchronously within individual cords during fetal and early postnatal life. This contrasts with rapid and synchronous germ cell differentiation within and between cords in the rat. Similarly, germ cell proliferation in the marmoset and human occurs throughout perinatal life, in contrast to rats in which proliferation ceases during this period. The marmoset provides a good model for normal human germ cell differentiation and proliferation. The perinatal marmoset may be a useful model in which to establish factors that lead to failure of normal germ cell differentiation and the origins of TGCT.


GABA(B) receptor antagonism by 7-MBFG, a benzo[b]furan analogue of baclofen, in central and peripheral tissues.
(R,S)-4-Amino-3-(7-methylbenzo[b]furan-2-yl)-butanoic acid (7-MBFG), a new benzofuran analogue of the GABA(B) receptor agonist baclofen, has been evaluated for pharmacological activity on GABA(B) receptors in the guinea-pig isolated ileum and rat neocortical slices. 7-MBFG (300 and 500 microM) reversibly antagonized the (R,S)-baclofen induced depression of cholinergic twitch contractions in the guinea-pig ileum and shifted the concentration-response curve for baclofen to the right, in a parallel manner, giving an apparent pA2 value of 3.7+/-0.3. Likewise, 7-MBFG (300 and 500 microM) reversibly blocked the baclofen-induced suppression of spontaneous discharges, in rat neocortical slices maintained in Mg2+ -free Krebs medium, and caused a rightward, parallel shift of the baclofen concentration-response curve, giving an apparent pA2 value of 4.1+/-0.1. The compound 7-MBFG belongs to a novel, new class of antagonist at central and peripheral GABA(B) receptors, in which the antagonist properties reside in the pseudo-aromatic character of their 3-benzo[b]furan-2-yl substituents, and might provide useful leads for further development of GABA(B) receptor ligands.


KIN3 impacts arbuscular mycorrhizal symbiosis and promotes fungal colonisation in Medicago truncatula.
Arbuscular mycorrhizal fungi help their host plant in the acquisition of nutrients, and this association is itself impacted by soil nutrient levels. High phosphorus levels inhibit the symbiosis, whereas high nitrogen levels enhance it. The genetic mechanisms regulating the symbiosis in response to soil nutrients are poorly understood. Here, we characterised the symbiotic phenotypes in four Medicago truncatula Tnt1-insertion mutants affected in arbuscular mycorrhizal colonisation. We located their Tnt1 insertions and identified alleles for two genes known to be involved in mycorrhization, RAM1 and KIN3. We compared the effects of the kin3-2 and ram1-4 mutations on gene expression, revealing that the two genes alter the expression of overlapping but not identical gene sets, suggesting that RAM1 acts upstream of KIN3. Additionally, KIN3 appears to be involved in the suppression of plant defences in response to the fungal symbiont. KIN3 is located on the endoplasmic reticulum of arbuscule-containing cortical cells, and kin3-2 mutants plants hosted significantly fewer arbuscules than the wild type. KIN3 plays an essential role in the symbiotic response to soil nitrogen levels, as, contrary to wild-type plants, the kin3-2 mutant did not exhibit increased root colonisation under high nitrogen.


Overview of snakebite in Brazil: Possible drivers and a tool for risk mapping.
Snakebite envenoming affects close to 2.7 million people globally every year. In Brazil, snakebites are reported to the Ministry of Health surveillance system and cases receive antivenom free of charge. There is an urgent need to identify higher risk areas for antivenom distribution, and to develop prevention activities. The objective of this study is to provide an overview of the epidemiological situation of snakebite envenoming in Brazil and explore possible drivers; as well as to create a flowchart tool to support decision-makers identify higher risk areas. An ecological-type study was carried out using data by municipality (2013-2017). Study parts: 1) Create a geocoded database and perform a descriptive and cluster analysis; 2) Statistical analysis to measure the association of snakebite and possible environmental and socioeconomic drivers; 3) Develop a flowchart to support decision-makers and the application of this tool in one state (Rio Grande do Sul) as an example. An average of 27,120 snakebite cases per year were reported at the country level. Clusters of municipalities with high numbers of snakebites are mostly found in the Amazon Legal Region. The negative binomial regression model showed association with the snakebite case count: the type of major habitat, tropical or non-tropical; temperature; percentage of urbanization; precipitation; elevation; GDP per capita; a weaker relation with forest loss; and with venomous snake richness. The state where the instrument was applied reported 4,227 snakebites in the period. Most municipalities were considered as medium risk and 56/496 as high risk according to the tool created. Snakebite cases are distributed across the entire country with the highest concentration in the Legal Amazon Region. This creates a complex situation both for better understanding of the association of environmental and socioeconomic factors with snakebites and for the distribution and maintenance of antivenom to remote areas. Research into types of antivenom with a longer shelf life without the need for refrigeration is needed.


[A trial of laparoscopic assisted radical nephrectomy].
We tried a new procedure of gas-less laparoscopy assisted radical nephrectomy. Prior to insertion of laparoscope, pararectal incision approximately 7 cm in length was made to enter into the intraabdominal cavity. A 12 mm trocar was placed just below the umbilicus and a flexible electroscope was inserted through it. A 10 cm size disposable fan for lifting up the abdominal wall was indwelled through the under space of trocar port. After appropriately lifting up the abdominal wall, a 10 mm trocar for working channel was placed at mid-axillar line. Under laparoscopic and trans-laparotomic views, radical nephrectomy was performed using the combined technique of laparoscopic and open surgery. Seven patients have been successfully treated with this procedure. The mean operating time of this procedure was significantly shorter than that of totally laparoscopic nephrectomy. The recovery time from the operation was as short as usual laparoscopic nephrectomy. We thought that this procedure could open a new scope of laparoscopic surgery.


Depression and anxiety in patients of chronic kidney disease undergoing haemodialysis: A study from western Rajasthan.
Chronic kidney disease (CKD) is a long standing debilitating medical condition. CKD patients who are undergoing hemodialysis commonly experience depressive and anxiety symptoms because of various physical and psychosocial factors. The present study aimed to assess psychiatric morbidities i.e., depression and/or anxiety in patients with CKD undergoing hemodialysis. The objective of study was to evaluate depressive and anxiety disorders and their relation to socio-demographic factors in patients with CKD. A cross-sectional study was conducted at Nephrology department of a tertiary care institution on 100 CKD patients undergoing hemodialysis; who fulfilled the inclusion criteria. Diagnosis of depression and anxiety disorder was made as per WHO (ICD-10) criteria. Hospital Anxiety and Depression scale (HADS) was applied to study severity of the disorders. Data collected was subjected to suitable statistical analysis (mean, standard deviation and Chi-square test). Majority (54 percent) of the CKD patients belonged to age group of 41 to 60 years, were Hindus, married and had low monthly income. The prevalence of depressive disorder and anxiety disorder among CKD patients was around 66% and 61%, respectively. Depression and anxiety were significantly associated with gender, occupation, income and duration of haemodialysis in these patients. Depression and anxiety are highly prevalent in CKD patients and have varying relations with different socio-demographic characteristics of patients. Clinicians should focus on these morbidities while managing such patients and provide holistic treatment using multidisciplinary approaches to improve the overall quality of life.


An annulation toward fused bicyclolactones.
The combination of Lewis and Bronsted acids catalyzed the addition of beta-ketoesters to cyclic diene. Lactonization occurs in situ to afford fused bicyclic lactones directly. The catalysis provides an expedient route to bicylic lactones via a zip-process.


Managing Disruption: A Case Study of Boundary Work around Alcohol Industry Sponsored Scientific Interventions.
Following recent work examining alcohol industry involvements in science, this is a case study that examines the ways in which the alcohol research community engages in 'boundary work' - in which scientists define and defend the demarcation between their community of knowledge makers and others, justifying their claim to legitimacy and authority - in response to alcohol industry-sponsored interventions. The case here involves an economist who disputes the research consensus positions and policy recommendations of the field, having been funded by the key global alcohol industry political organization. We examine the 'functional' statements of both sides of this issue to show the ways in which the scientific and policy consensus of the field is disputed. Three examples of the responses of the alcohol research community, presenting different types of response, are interrogated. In late-career and retirement, this economist published extensively in alcohol and health economics journals within the peer-reviewed literature on two key topics in alcohol policy; pricing/taxation measures and advertising restrictions. These commentaries, reviews and correspondence propose alternative policies favored by the alcohol industry which are at odds with the alcohol public health evidence-base. The three examples examined of 'boundary work' performed by alcohol public health researchers illustrate the variety of ways in which the legitimacy of these interventions has been questioned; on technical grounds, on explicitly normative grounds, and as a body of work as a whole. Interventions in the scientific literature create important resources for alcohol industry actors to oppose alcohol policy measures globally. The alcohol research field may benefit from discussion about how to respond to these kinds of interventions.


Arsenite pretreatment attenuates benzo[a]pyrene cytotoxicity in a human lung adenocarcinoma cell line by decreasing cyclooxygenase-2 levels.
Both simultaneous and sequential exposure to arsenite and benzo[a]pyrene (BaP) potentially occur in human populations drinking arsenic-contaminated water or burning arsenic-contaminated coal. Although arsenite and BaP are both well-documented hazardous substances and human carcinogens, interactions between these two agents have not been well defined. In this study, we demonstrated that posttreatment with arsenite synergistically enhanced the cytotoxicity of BaP for a human lung adenocarcinoma cell line, CL3. In contrast, pretreatment of CL3 cells with arsenite attenuated BaP cytotoxicity. Involvement of heat-shock protein 70 and heme oxygenase-1 in this arsenite-mediated attenuation of BaP cytotoxicity was ruled out. Our data also indicated that arsenite pretreatment did not affect the BaP-mediated induction of CYP1A1, the initial enzyme involved in its metabolic activation, but did result in a significant decrease in mRNA and protein levels of cyclooxygenase-2 (COX-2), which is required to convert the BaP metabolite BaP 7,8-dihydrodiol to the ultimate epoxide. In contrast to the high susceptibility of CL3 cells to BaP, the human lung carcinoma cells, H460, and CL3R15 cells (arsenic-resistant CL3 cells) showed normal CYP1A1 inducibility by BaP, had negligible amounts of COX-2, and were highly resistant to BaP. The involvement of COX-2 in BaP activation was confirmed by transfection of H460 cells with a recombinant adenovirus, Ad-pgk-Cox2, coding for COX-2, which resulted in a significant increase in the levels of the COX-2 product prostaglandin E2 in the medium and in the susceptibility of H460 cells to BaP. The present study confirms the importance of COX-2 in BaP activation and demonstrates that the arsenite-mediated attenuation of BaP cytotoxicity is mediated by a reduction in COX-2 levels.


[Palpebral ptosis, a rare ocular manifestation of Crohn's disease].
An 18 year-old-woman presented with abdominal pain, diarrhea, and ptosis in her left eye. Nuclear magnetic resonance imaging (NMRI) and the study of cerebrospinal fluid detected no abnormalities. Colonoscopy revealed a Crohn's disease (CD) confirmed by histological examination of biopsies. Ocular symptoms improved after appropriate treatment of the underlying CD. Inflammatory bowel disease (IBD) is associated with a wide variety of extra-intestinal manifestations, in fact it may be considered a systemic disorder with predominantly gastrointestinal tract manifestations. Extra-intestinal manifestations of inflammatory bowel disease (IBD) occur in one third of patients. Ocular complications are infrequent, occurring in less than 10% of cases, but can be associated with significant morbidity, including blindness. Ocular symptoms may precede a diagnosis of IBD. We report the first case of palpebral ptosis associated with Crohn's disease.


Targeted deletion of Hand2 in enteric neural precursor cells affects its functions in neurogenesis, neurotransmitter specification and gangliogenesis, causing functional aganglionosis.
Targeted deletion of the bHLH DNA-binding protein Hand2 in the neural crest, impacts development of the enteric nervous system (ENS), possibly by regulating the transition from neural precursor cell to neuron. We tested this hypothesis by targeting Hand2 deletion in nestin-expressing neural precursor (NEP) cells. The mutant mice showed abnormal ENS development, resulting in lethal neurogenic pseudo-obstruction. Neurogenesis of neurons derived from NEP cells identified a second nestin non-expressing neural precursor (NNEP) cell in the ENS. There was substantial compensation for the loss of neurons derived from the NEP pool by the NNEP pool but this was insufficient to abrogate the negative impact of Hand2 deletion. Hand2-mediated regulation of proliferation affected both neural precursor and neuron numbers. Differentiation of glial cells derived from the NEP cells was significantly decreased with no compensation from the NNEP pool of cells. Our data indicate differential developmental potential of NEPs and NNEPs; NNEPs preferentially differentiate as neurons, whereas NEPs give rise to both neurons and glial cells. Deletion of Hand2 also resulted in complete loss of NOS and VIP and a significant decrease in expression of choline acetyltransferase and calretinin, demonstrating a role for Hand2 in neurotransmitter specification and/or expression. Loss of Hand2 resulted in a marked disruption of the developing neural network, exemplified by lack of a myenteric plexus and extensive overgrowth of fibers. Thus, Hand2 is essential for neurogenesis, neurotransmitter specification and neural network patterning in the developing ENS.


Accuracy of methemoglobin detection by pulse CO-oximetry during hypoxia.
Methemoglobin in the blood cannot be detected by conventional pulse oximetry, although it can bias the oximeter's estimate (Spo2) of the true arterial functional oxygen saturation (Sao2). A recently introduced "Pulse CO-Oximeter" (Masimo Rainbow SET(R) Radical-7 Pulse CO-Oximeter, Masimo Corp., Irvine, CA) is intended to additionally monitor noninvasively the fractional carboxyhemoglobin and methemoglobin content in blood. The purpose of our study was to determine whether hypoxia affects the new device's estimated methemoglobin reading accuracy, and whether the presence of methemoglobin impairs the ability of the Radical-7 and a conventional pulse oximeter (Nonin 9700, Nonin Medical Inc., Plymouth, MN) to detect decreases in Sao2. Eight and 6 healthy adults were included in 2 study groups, respectively, each fitted with multiple sensors and a radial arterial catheter for blood sampling. In the first group, IV administration of approximately 300 mg sodium nitrite increased subjects' methemoglobin level to a 7% to 8% target and hypoxia was induced to different levels of Sao2 (70%-100%) by varying fractional inspired oxygen. In the second group, 15% methemoglobin at room air and 80% Sao2 were targeted. Pulse CO-oximeter readings were compared with arterial blood values measured using a Radiometer multiwavelength hemoximeter. Pulse CO-oximeter methemoglobin reading performance was analyzed by observing the incidence of meaningful reading errors at the various hypoxia levels. This was used to determine the impact on predictive values for detecting methemoglobinemia. Spo2 reading bias, precision, and root mean square error were evaluated during conditions of elevated methemoglobin. Observations spanned 66.2% to 99% Sao2 and 0.6% to 14.4% methemoglobin over the 2 groups (170 blood draws). Masimo methemoglobin reading bias and precision over the full Sao2 span was 7.7% +/- 13.0%. Best accuracy was found in the 95% to 100% Sao2 range (1.9% +/- 2.5%), progressing to its worst in the 70% to 80% range (24.8% +/- 15.6%). Occurrence of methemoglobin readings in error >5% increased over each 5-point decrease in Sao2 (P < 0.05). Masimo Spo2 readings were biased -6.3% +/- 3.0% in the 95% to 100% Sao2 range with 4% to 8.3% methemoglobin. Both the Radical-7 and Nonin 9700 pulse oximeters accurately detected decreases in Sao(2) <90% with 4% to 15% methemoglobin, despite displaying low Spo2 readings when Sao2 was >95%. The Radical-7's methemoglobin readings become progressively more inaccurate as Sao2 decreases <95%, at times overestimating true values by 10% to 40%. Elevated methemoglobin causes the Spo2 readings to underestimate Sao2 similar to conventional 2-wavelength pulse oximeters at high saturation. Spo2 readings from both types of instruments continue to trend downward during the development of hypoxemia (Sao2 <90%) with methemoglobin levels up to 15%.


Development of global visual processing: From the retina to the perceptive field.
Young children exhibit poorer visual performance than adults due to immaturity of the fovea and of the fundamental processing of visual functions such as masking and crowding. Recent studies suggest that masking and crowding are closely related to the size of the fundamental processing unit-the perceptive field (PF). However, while it is known that the retina and basic visual functions develop throughout childhood, it is not clear whether and how changes in the size of the PF affect masking and crowding. Furthermore, no retinal and perceptual development data have been collected from the same cohort and time. Here we explored the developmental process of the PF and the basic visual functions. Psychophysical and imaging methods were used to test visual functions and foveal changes in participants ranging from 3-17 years old. Lateral masking, crowding and contrast sensitivity were tested using computerized tasks. Foveal measurements were obtained from spectral-domain optical coherence tomography (OCT). The children patterns below 6 years exhibited high crowding, while the expected facilitation was found only at a larger target-flanker distance than required for children above 6 years, who exhibited the typical adult. Foveal thickness and macular volume for the children below 6 years were significantly lower than for the older group. Significant correlation was found for contrast sensitivity, foveal thickness and macular volume with age and between contrast sensitivity and foveal thickness. Our data suggest that the developmental processes at the retina and visual cortex occur in the same age range. Thus, in parallel to maturation of the PF, which enables reduction in crowding, foveal development contributes to increasing contrast sensitivity.


A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex® (nabiximols).
Open-label studies are not ideal for providing robust evidence for long-term maintenance of efficacy of medicines, especially where medicines provide symptom relief and where long-term use of a placebo may be problematic and not ethical. To evaluate the maintenance of efficacy of Sativex in subjects who have gained long-term symptomatic relief of spasticity in multiple sclerosis (MS), and to assess the impact of sudden medicine withdrawal. An enriched enrolment randomized withdrawal study design was used. Eligible subjects with ongoing benefit from Sativex for at least 12 weeks entered this 5-week placebo-controlled, parallel-group, randomized withdrawal study. Each subjects' previous effective and tolerated dose was continued. A total of 18 subjects per group were enrolled. Demographics showed a mean duration of MS of 16.4 years, spasticity 12.7 years, mean duration of Sativex use of 3.6 years (median 3.4 years) and a mean daily dose of 8.25 sprays. Primary outcome of time to treatment failure was significantly in favour of Sativex (p = 0.013). Secondary endpoints showed significant changes in the Carer and Subject's Global Impression of Change scales in favour of Sativex. Maintenance of Sativex efficacy in long-term symptomatic improvement of spasticity to a group of subjects with MS has been confirmed using this study design.


Prevention of contrast induced nephropathy with sodium bicarbonate (the PROMEC study).
Contrast-induced nephropathy is a common complication of radiographic procedures. Different measures have been used to avoid this damage, but the evidence is controversial. New investigations are required to clarify it. We investigated the efficacy and safety of sodium bicarbonate solution compared with sodium chloride solution to prevent contrast induced nephropathy in patients with or at risk of renal dysfunction. A prospective, single-center, randomized clinical trial conducted from May 1, 2007 to February 8, 2008. Inpatients in a tertiary center, scheduled to undergo a procedure with the nonionic radiographic contrast agent iohexol. There were 220 patients with serum creatinine levels of at least 1.2 mg/dL (106.1 µmol/L) and/or type 2 diabetics, who were randomized to receive an infusion of sodium chloride (n = 113) or sodium bicarbonate (n = 107) before and after contrast dye administration. The intervention were "A" group received 1 ml/kg/hour of normal saline solution, starting 12 hours before and continuing 12 hours after iohexol contrast. "B" group received 3 ml/kg of sodium bicarbonate solution (150 mEq/L) one hour prior to procedure and then drip rate was decreased to 1 ml/kg/hour until 6 hours post procedure. Our main outcome measure was change in serum creatinine. The mean creatinine value after the procedure was 1.26 mg/dL in the saline group and 1.22 mg/dL in the bicarbonate group (mean difference: 0.036; CI 95%: -0.16 to 0.23, p = 0.865). The diagnosis of contrast-induced nephropathy, defined by increase in serum creatinine on 25% or more within 2 days after administration of radiographic contrast, was done in twelve patients (12%) in the bicarbonate group and eighth patients (7.1%) in the saline group (RR: 1.68, CI 95%: 0.72 to 3.94). Our investigation showed that there were no differences between normal saline solution (extended infusion) vs. bicarbonate solution for nephroprotection.


A TNF-p100 pathway subverts noncanonical NF-κB signaling in inflamed secondary lymphoid organs.
Lymphotoxin-beta receptor (LTβR) present on stromal cells engages the noncanonical NF-κB pathway to mediate RelB-dependent expressions of homeostatic chemokines, which direct steady-state ingress of naïve lymphocytes to secondary lymphoid organs (SLOs). In this pathway, NIK promotes partial proteolysis of p100 into p52 that induces nuclear translocation of the RelB NF-κB heterodimers. Microbial infections often deplete homeostatic chemokines; it is thought that infection-inflicted destruction of stromal cells results in the downregulation of these chemokines. Whether inflammation per se also regulates these processes remains unclear. We show that TNF accumulated upon non-infectious immunization of mice similarly downregulates the expressions of these chemokines and consequently diminishes the ingress of naïve lymphocytes in inflamed SLOs. Mechanistically, TNF inactivated NIK in LTβR-stimulated cells and induced the synthesis of Nfkb2 mRNA encoding p100; these together potently accumulated unprocessed p100, which attenuated the RelB activity as inhibitory IκBδ. Finally, a lack of p100 alleviated these TNF-mediated inhibitions in inflamed SLOs of immunized Nfkb2-/- mice. In sum, we reveal that an inhibitory TNF-p100 pathway modulates the adaptive compartment during immune responses.


Neural antagonists modulate pulmonary vascular pressure-flow plots in conscious dogs.
Multipoint pulmonary vascular pressure-cardiac index (P/Q) plots were constructed in conscious dogs during normoxia by graded constriction of the thoracic inferior vena cava to reduce Q. P/Q plots were generated with the autonomic nervous system (ANS) intact and following total autonomic ganglionic block, cholinergic block, and sympathetic alpha- and beta-adrenergic block alone and in combination. With the ANS intact, the relationship between the pulmonary vascular pressure gradient [pulmonary arterial pressure (PAP)--pulmonary capillary wedge pressure (PCWP)] and Q was linear with an extrapolated pressure intercept of 0 mmHg. Total autonomic ganglionic block increased PAP-PCWP over the entire range of Q studied (60-140 ml . min-1 . kg-1). Cholinergic block resulted in a small increase in PAP-PCWP at a Q of 60 ml . min-1 . kg-1, a small decrease in PAP-PCWP at a Q of 140 ml . min-1 . kg-1, but no change in PAP-PCWP over the midrange of Q. Sympathetic beta-adrenergic block increased, and sympathetic alpha-adrenergic block decreased PAP-PCWP over the entire range of Q studied. Combined sympathetic alpha- and beta-adrenergic block also increased PAP-PCWP at each level of Q. Thus the ANS, either directly or via circulating catecholamines, exerts an active regulatory influence on the pulmonary vascular P/Q relationship of intact conscious dogs during normoxia over a wide range of Q. Activation of sympathetic beta-adrenergic receptors results in pulmonary vasodilatation, whereas, alpha-receptor activation results in vasoconstriction. Surprisingly, based on the effects of total autonomic ganglionic block and combined sympathetic alpha- and beta-adrenergic block, the net effect of the ANS on PAP-PCWP/Q during normoxia appears to be pulmonary vasodilatation.


Use of transcriptional profiling to delineate the initial response of mice to intravaginal herpes simplex virus type 2 infection.
Intravaginal (ivag) infection of mice with herpes simplex virus type 2 (HSV-2) causes genital tissue damage, quickly followed by development of fatal encephalopathy. To delineate initial host responses generated by HSV-2 infection, here oligonucleotide microarrays compared gene expression in vaginal tissue from uninfected mice and mice 1, 2, 3, 4, 5, 6, or 7 days after ivag infection with 10(4) pfu HSV-2. While comparison of mRNA expression in uninfected and HSV-infected vaginal tissue detected few changes during the first 2 days post infection (dpi), there were 156 genes whose expression was first significantly altered 3 dpi that remained significantly modified at all later time points examined. These 156 genes were significantly enriched in canonical pathways associated with interferon (IFN) signaling, activation of IFN elements by intracellular pattern recognition receptors, and antiviral immunity induced by cytosolic RIG-like receptors. Evaluation of this gene set with the National Center for Biotechnology Information Gene and INTERFEROME databases corroborated pathway analysis, as function of most (53%) were linked to IFN-mediated host immunity. In the final set of experiments, ivag administration of the Toll-like receptor 3 agonist polyinosinic: polycytidylic acid (poly I:C) 24 h before ivag HSV-2 infection reduced the incidence of genital pathology and encephalopathy, while these poly I:C-treated mice were subsequently protected from ocular HSV-2 challenge lethal to uninfected controls. The latter results imply that the exuberant antiviral immunity produced in our experimental model is simply formed too late to prevent viral replication and dissemination, and that poly I:C-induced formation of an antiviral state protecting against primary ivag infection also permits development of HSV-specific protective immunity.


Immunopathological effects of malaria pigment or hemozoin and other crystals.
Blood-stage malaria parasites produce insoluble hemozoin (Hz) crystals that are released in the blood circulation upon schizont rupture. In general, endogenous crystal formation or inhalation of crystalline materials is often associated with pathology. As the immune system responds differently to crystalline particles than to soluble molecules, in this review, the properties, immunological recognition, and pathogenic responses of Hz are discussed, and compared with two other major pathogenic crystals, monosodium urate (MSU) and asbestos. Because of the size and shape of MSU crystals and asbestos fibers, phagolysosomal formation is inefficient and often results in leakage of lysosomal content in the cell cytoplasm and/or in the extracellular environment with subsequent cell damage and cell death. Phagolysosomal formation after Hz ingestion is normal, but Hz remains stored inside these cells for months or even longer without any detectable degradation. Nonetheless, the different types of crystals are recognized by similar immune receptors, involving Toll-like receptors, the inflammasome, antibodies, and/or complement factors, and through similar signaling cascades, they activate both proinflammatory and anti-inflammatory immune responses that contribute to inflammation-associated pathology.


Saposin B Binds the Lipofuscin Bisretinoid A2E and Prevents its Enzymatic and Photooxidation.
Vitamin A based bisretinoid accumulation is a major focus in the study of macular degeneration. Whether specific endogenous lysosomal proteins can bind A2E, a pronounced bisretinoid in lipofuscin granules in retinal pigment epithelial cells, and interfere with enzymatic or photoinduced oxidation of such, has not been explored. Herein, using fluorescence and electronic absorption spectroscopy and mass spectrometry, we demonstrate that Saposin B, a critical protein in the degradation of sulfatides and "flushing" of lipids, can bind A2E, preventing its H2O2-dependent enzymatic oxidation by horseradish peroxidase and photooxidation by blue light (λ=450-460 nm).


Valdecoxib.
In ten large, well-controlled, randomised trials (n = 203 to 1089), valdecoxib, a selective inhibitor of cyclo-oxygenase-2, was significantly more effective than placebo in the treatment of osteoarthritis, rheumatoid arthritis and pain associated with primary dysmenorrhoea, and for postsurgical analgesia. Valdecoxib 1.25 to 10mg twice daily and valdecoxib 10mg once daily were more effective than placebo for the relief of pain in patients with osteoarthritis of the knee, and dosages above 5mg twice daily were similar in efficacy to naproxen 500mg twice daily. Similarly, valdecoxib 5 and 10 mg/day were as effective for osteoarthritis of the hip as naproxen 500mg twice daily. In patients with rheumatoid arthritis, valdecoxib 10, 20 or 40 mg/day was significantly more effective than placebo, and similar in efficacy to naproxen 500mg twice daily; there were no significant differences in efficacy between the three dosages of valdecoxib. Valdecoxib 20 or 40mg administered 1 to 3 hours before and 12, 24 and 36 hours after hip arthroplasty provided significantly better analgesia than placebo, and significantly reduced the amount of morphine taken by patients. Single doses of valdecoxib 10 to 80mg administered before foot or oral surgery provided significantly better analgesia than placebo; when administered after oral surgery, valdecoxib 20 or 40mg provided greater sustained analgesia than oxycodone 10mg/paracetamol 1000mg or rofecoxib 50mg. In contrast to three nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), valdecoxib 40mg twice daily did not cause significant changes in platelet function and bleeding times. Chronic users of NSAIDs who were switched to valdecoxib 10 or 20 mg/day for 12 weeks experienced significantly fewer gastroduodenal erosions or ulcers than patients receiving ibuprofen 2400 mg/day or diclofenac 150 mg/day for 12 weeks. Valdecoxib was generally well tolerated in clinical trials, with a similar incidence of adverse events to placebo.


[Progress on polyhydroxyalkanoates (PHA)].
Microbial polyhydroxyalkanoates (PHA) has developed with more diversity and more advanced manufacturing technology. Diversity has now been reflected by diverse monomers, diverse structures and diverse polymerization modes, giving the concept of "PHAome". In addition, the application of synthetic biology and the development of seawater-based biotechnology reduce the production cost of PHA, making PHA more economically competitive. Some examples of commercialized PHA products are described here. Besides, PHA with high value added applications has been exploited.


Phylogenetic evidence for mid-Cenozoic turnover of a diverse continental biota.
Rapid climatic change at the beginning of the Oligocene epoch is concordant with global biotic turnover in the fossil record. However, while Southern Hemisphere geological movement played a key role in shaping these global climatic shifts, given generally poor terrestrial fossil records, evidence for matching turnover in entire Austral biotas is lacking. Emerging comprehensive phylogenetic frameworks provide alternative avenues to explore for signals of mass turnover or restructuring. Here, we combine phylogenetic data with empirical and simulation-based approaches to understand the temporal dynamics of the origins of a diverse and highly endemic continental biota (Australian lizards and snakes). These analyses indicate that the temporal clustering of major radiation ages in Gondwanan endemic lineages and immigration into Australia is narrower than expected under time-continuous models assuming no overarching external perturbation. Independent phylogenetic dating analyses further indicate that the timing of both processes is concentrated in the period post-dating the Eocene-Oligocene transition (~34 million years ago). Epoch-defining processes around the start of the Oligocene appear to have also played a decisive role in reshaping a diverse Southern Hemisphere biota-by both re-setting Gondwanan endemic diversity and opening the way to successful immigration from the north.


A mutation in the lipoprotein lipase gene is the molecular basis of chylomicronemia in a colony of domestic cats.
Members of a domestic cat colony with chylomicronemia share many phenotypic features with human lipoprotein lipase (LPL) deficiency. Biochemical analysis reveals that these cats do have defective LPL catalytic activity and have a clinical phenotype very similar to human LPL deficiency. To determine the molecular basis underlying this biochemical phenotype, we have cloned the normal and affected cat LPL cDNAs and shown that the affected cat has a nucleotide change resulting in a substitution of arginine for glycine at residue 412 in exon 8. In vitro mutagenesis and expression studies, in addition to segregation analysis, have shown that this DNA change is the cause of LPL deficiency in this cat colony. Reduced body mass, growth rates, and increased stillbirth rates are observed in cats homozygous for this mutation. These findings show that this LPL deficient cat can serve as an animal model of human LPL deficiency and will be useful for in vivo investigation of the relationship between triglyceride rich lipoproteins and atherogenic risk and for the assessment of new approaches for treatment of LPL deficiency, including gene therapy.


An immuno polymerase chain reaction screen for the detection of CJC-1295 and other growth-hormone-releasing hormone analogs in equine plasma.
CJC-1295 is a 30 amino acid peptide-based drug that stimulates the release of growth hormone (GH) from the pituitary gland. It is unique among performance-enhancing peptides due to the presence of a reactive maleimidopropionic acid group that covalently links the peptide to free thiols on the surface of plasma proteins. Once conjugated, CJC-1295 remains active in the bloodstream for significantly longer than non-conjugated peptide-based drugs that are rapidly excreted. Conjugation of CJC-1295 to plasma proteins prevents its detection by top-down mass-spectrometry-based peptide screening protocols as it effectively becomes a macromolecular protein with an undefined molecular weight. Using a pair of monoclonal antibodies raised against the CJC-1295 peptide, we present an immuno-polymerase chain reaction (I-PCR) assay that is capable of detecting the CJC-1295-protein conjugate at concentrations down to 0.8 pg/mL. Detection of endogenous equine GHRH necessitated a screening threshold for CJC-1295 in equine plasma of 50 pg/mL. The effectiveness of the assay for controlling the illicit use of CJC-1295 was confirmed in equine blood samples after administration in thoroughbred race horses.


Impairment of phagosome-lysosome fusion in HIV-1-infected macrophages.
Phagosome-lysosome fusion is critical for intracellular killing of most organisms and is inhibited by some viruses, notably influenza. We explored the effects of infection in vitro with HIV-1 (IIIB or Ada-M) on phagosome-lysosome fusion in blood monocyte-derived macrophages. After 8 days of infection, fusion was assessed from the fluorescence change occurring up to 2 h after labeling the lysosome compartment with acridine orange and loading of phagosomes with opsonized yeast. Compared with mock-infected control macrophages, the proportion of cells showing fusion after infection was reduced from a mean of 70% to a mean of 47% (p = 0.0001). Inhibition was seen with heat-killed HIV-1 IIIB but not virus-free filtrate. It was mimicked by recombinant gp 120 and blocked by soluble CD4 or antibody to CD4 but not by a neutralizing antibody to the V3 loop of gp 120. The inhibitory effect was seen 8 days after the original, transient exposure to gp 120. These results suggest that a lasting abnormality of phagosome-lysosome fusion results from interaction between gp 120 and CD4, contributing, perhaps, to the increased susceptibility to opportunistic infections of people infected with HIV.


Modulation of the H2O2-induced SOS response in Escherichia coli PQ300 by amino acids, metal chelators, antioxidants, and scavengers of reactive oxygen species.
The SOS chromotest is a simple colorimetric genotoxicity assay that monitors DNA repair by measuring the induction of the gene sfiA in Escherichia coli K-12. E. coli PQ300, a diagnostic SOS tester strain for the detection of oxidative genotoxins, carries a mutation in a key gene for antioxidative defense, oxyR. This mutation renders PQ300 more sensitive to oxidative genotoxins, particularly to H2O2. We found that induction of the SOS response by H2O2 in E. coli PQ300 is dependent on the composition of the incubation medium; a substantially reduced response was obtained in minimal phosphate buffered saline (PBS) as opposed to complex Luria broth (LB) medium. Supplementation of PBS with histidine or cysteine stimulated H2O2-induced SOS induction to levels exceeding those found in LB medium. Low concentrations of glutathione (20-70 microM) also enhanced the H2O2-induced SOS response in E. coli PQ300, whereas higher concentrations (> 150 microM) were protective. Preincubation of tester cells with the chelators o-phenanthroline, 2,2-dipyridyl, and ethylenediaminetetraacetic acid (EDTA) protected cells from the effects of H2O2, although EDTA was only partially effective. Pretreatment of PQ300 with the antioxidant ascorbic acid or the hydroxyl radical scavenger dimethyl sulfoxide also diminished the SOS response, whereas mannitol and glucose were ineffective. The results show that the net effect of H2O2-induced DNA damage is influenced by the balance of oxidative and antioxidative factors and, furthermore, can be modulated by constituents of the extracellular milieu.


Gaps in public preparedness to be a substitute decision-maker and the acceptability of high school education on resuscitation and end-of-life care: a mixed-methods study.
When a patient is incapable of making medical decisions for him- or herself, a substitute decision-maker makes choices according to the patient's previously expressed wishes, values and beliefs; however, little is known about public readiness to act as a substitute decision-maker in Canada. Our primary objective was to measure public self-reported preparedness to act as a substitute decision-maker, and explore the attitudes, barriers and enablers associated with preparedness. From November 2017 to June 2018, we conducted a mixed-methods street intercept survey at 12 pedestrian areas in Ottawa, Ontario. We used descriptive statistics and logistic regression analysis to assess predictors of perceived preparedness to be a substitute decision-maker and determine support for high school education. We analyzed qualitative interview questions using inductive thematic analysis. Of the 626 eligible respondents, 196 refused to participate, leaving 430 participants (response rate 68.7%). A total of 404 surveys (94.0%) were fully complete with no missing data. The respondents were mostly female (243 [56.5%]) and residents of Ontario (364 [84.6%]). The average age was 33.9 years. Although 314 respondents (73.0%) felt prepared to be a substitute decision-maker, 194 (45.1%) reported never having had meaningful conversations with loved ones to understand their wishes in the event of critical illness. A total of 293 participants (68.1%) identified important barriers to feeling prepared. Most respondents (309 [71.9%]) agreed that high school students should learn about being a substitute decision-maker, citing age appropriateness, potential societal benefit and improved decision-making, while cautioning the need to respect different maturity levels, cultures and experiences. he lack of conversation between loved ones reveals a gap between perceived and actual preparedness to be a substitute decision-maker for a loved one with a critical illness. The overall acceptability of high school education warrants further exploration.


Interareal coupling reduces encoding variability in multi-area models of spatial working memory.
Persistent activity observed during delayed-response tasks for spatial working memory (Funahashi et al., 1989) has commonly been modeled by recurrent networks whose dynamics is described as a bump attractor (Compte et al., 2000). We examine the effects of interareal architecture on the dynamics of bump attractors in stochastic neural fields. Lateral inhibitory synaptic structure in each area sustains stationary bumps in the absence of noise. Introducing noise causes bumps in individual areas to wander as a Brownian walk. However, coupling multiple areas together can help reduce the variability of the bump's position in each area. To examine this quantitatively, we approximate the position of the bump in each area using a small noise expansion that also assumes weak amplitude interareal projections. Our asymptotic results show the motion of the bumps in each area can be approximated as a multivariate Ornstein-Uhlenbeck process. This shows reciprocal coupling between areas can always reduce variability, if sufficiently strong, even if one area contains much more noise than the other. However, when noise is correlated between areas, the variability-reducing effect of interareal coupling is diminished. Our results suggest that distributing spatial working memory representations across multiple, reciprocally-coupled brain areas can lead to noise cancelation that ultimately improves encoding.


Pneumocystis pneumonia in patients with rheumatic diseases receiving prolonged, non-high-dose steroids-clinical implication of primary prophylaxis using trimethoprim-sulfamethoxazole.
To investigate the incidence of pneumocystis pneumonia (PCP) and its risk factors in patients with rheumatic disease receiving non-high-dose steroid treatment, along with the risks and benefits of PCP prophylaxis. This study included 28,292 treatment episodes with prolonged (≥ 4 weeks), non-high-dose steroids (low dose [< 15 mg/day, n = 27,227] and medium dose [≥ 15 to < 30 mg/day, n = 1065], based on prednisone) over a 14-year period. Risk factors for PCP and prophylactic effect of trimethoprim-sulfamethoxazole (TMP-SMX) were investigated if the 1-year incidence rate (IR) of PCP in each dose group was > 0.1/100 person-years. Cox regression with LASSO was used for analysis. One-year PCP IR in the low-dose group was 0.01 (95% CI 0.001-0.03)/100 person-years, and only the medium-dose group showed eligible PCP IR for further analysis. In the medium-dose group, prophylactic TMP-SMX was administered in 45 treatment episodes while other episodes involved no prophylaxis (prophylaxis group vs. control group). In 1018.0 person-years, 5 PCP cases occurred exclusively in the control group, yielding an IR of 0.5 (0.2-1.2)/100 person-years. Concomitant steroid-pulse treatment and baseline lymphopenia were the most significant risk factors for PCP. Treatment episodes with at least one of these factors (n = 173, high-risk subgroup) showed higher 1-year PCP IR (3.4 (1.1-8.0)/100 person-years), while no PCP occurred in other treatment episodes. TMP-SMX numerically reduced the risk (adjusted HR = 0.2 (0.001-2.3)) in the high-risk subgroup. The IR of adverse drug reactions (ADRs) related to TMP-SMX was 41.5 (22.3-71.6)/100 person-years, including one serious ADR. The number needed to treat with TMP-SMX to prevent one PCP in the high-risk subgroup (31 (17-226)) was lower than the number needed to harm by serious ADR (45 (15-∞)). Incidence of PCP in patients with rheumatic diseases receiving prolonged, medium-dose steroids depends on the presence of risk factors. Prophylactic TMP-SMX may have greater benefit than potential risk in the high-risk subgroup.


[Streptokinase-induced jaundice].
Streptokinase is a thrombolytic agent used very frequently for the early treatment of acute myocardial infarction. A 35-year-old male with inferior acute myocardial infarction was admitted to the Coronary Care Unit and treated with systemic streptokinase. At the time of admission, he was a healthy male and he was not receiving any hepatotoxic agent. Six hours after thrombolysis, he developed high fever, painful hepatomegaly, jaundice and coluric urine. Leucocytosis with left deviation was observed in the hemogram and the liver function tests showed slight enzymatic elevation and hyperbilirubinemia. This condition was progressively improving and the patient was free of symptoms on the eighth day of evolution. Jaundice as secondary effect of streptokinase has been previously communicated in very few medical reports.


COVID-19: Risk perception, risk communication, and behavioral intentions.
Critical to limiting the spread of Coronavirus disease 2019 (COVID-19) and future pandemics is compliance with behavioral recommendations such as mask wearing and social distancing. Compliance may depend upon understanding the seriousness of the health consequences and the likelihood they will occur. However, the statistics that speak to these issues in an ongoing pandemic are complex and may be misunderstood. An online experiment with a U.S. sample tested the impact on perceived likelihood, trust, concern, behavioral intentions, and agreement with government response of numeric (mortality/infection percentage by age group) and gist expressions (which age group was smaller [mortality] or roughly equivalent [infected]). While the differences in risk perception and willingness to engage in activities between younger and older participants were small, "gist infection and mortality" increased willingness to wear a mask among younger participants. Government restrictions (e.g., social distancing) impacted willingness to engage is risk-reduction and risk-seeking activities. The biggest differences were due to political ideology. Although conservatives perceived similar levels of risk as did liberals, they were much less willing to engage in protective behaviors and support government policies. However, conservatives were affected by some risk communication formats and restrictions suggesting that future work should be aimed at this issue. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Early intertwin differences in myocardial performance during the twin-to-twin transfusion syndrome.
In the twin-to-twin transfusion syndrome (TTTS), pressure rather than volume overload is increasingly considered as a key factor in the pathogenesis of the cardiomyopathy of the recipient twin. If this is the case, cardiac dysfunction should be among the first signs observed with TTTS. The objective of this study was to determine whether intertwin differences in myocardial function are modified early in the course of TTTS and whether they can help to differentiate this condition from intrauterine growth restriction (IUGR). Eight variables were analyzed on the first fetal echocardiography on 21 pairs of twins with TTTS and 11 with IUGR. No difference was found between the 2 groups for the cardiothoracic ratio, pulsatility indices in the umbilical and middle cerebral arteries, and peak velocity of the middle cerebral artery. Significant difference was found for ventricular septal thickness, but with no association with the conditions under study. With TTTS, left ventricular shortening fraction was consistently greater in the donor twins, and myocardial performance indices (MPIs) were elevated in the recipient twins. This increase in MPI was caused by a lengthening of the isovolumic periods compared with those of the donor twin: left ventricular and right ventricular isovolumic periods 0.105+/-0.047 and 0.097+/-0.026 seconds, respectively, for the recipient twins versus 0.0561+/-0.46 and 0.065+/-0.03 seconds, respectively, for the donor twins (P<0.001). These changes in the isovolumic periods were mainly due to significant prolongation of isovolumic relaxation times. A change in left ventricular MPI > or =0.09 combined with a change in right ventricular MPI > or =0.05 would identify a TTTS with a sensitivity of 75% and a false-positive rate of 9%. The observed diastolic function impairment goes along with the pressure-overload pathogenic concept proposed in TTTS. Assessment of intertwin difference in MPI is a valuable tool for early differential diagnosis between TTTS and isolated IUGR.


Phase I-II study of irinotecan in combination with mitomycin C in patients with advanced gastrointestinal cancer.
This phase I-II study was conducted to determine the maximum tolerated dose and optimal schedule of a combination of irinotecan (CPT 11) and mitomycin C (MMC) in a population of previously treated patients with gastrointestinal malignancies. Four cohorts of patients were recruited with MMC given at 8 mg/m2 for the first 3 levels together with irinotecan at 300 mg/m2, 325 mg/m2, and 350 mg/m2; the fourth dose level was given with MMC at 10 mg/m2 and irinotecan at 325 mg/m2. All treatment was repeated at 21-day intervals. The dose-limiting toxicity was hematologic (thrombocytopenia at level 4), and the recommended doses for subsequent phase II studies are MMC 8 mg/m2 with irinotecan 325 mg/m2. Evidence of efficacy was seen at all dose levels examined and justifies further exploration of this combination in a less heavily pretreated patient population.


Chemosystematic significance of flavonoids isolated from Diplotaxis acris (Brassicaceae) and related taxa.
The chemosystematic relationship of four Diplotaxis species; Diplotaxis acris, Diplotaxis erucoides, Diplotaxis harra and Diplotaxis muralis were surveyed from the flavonoids point of view. These species were found to produce 33 flavonoids (7 flavones and 26 flavonols), including 11 compounds were isolated in the present study from D. acris. Among them, seven flavonoids were identified for the first time; luteolin (4), kaempferol (8), kaempferol 3-O-β-glucopyranoside-7-O-α-rhamnopyranoside (13), quercetin 3-O-β-glucopyranoside (16), quercetin 7-O-β-glucopyranoside (20), isorhamnetin (22) and isorhamnetin 3-O-β-glucopyranoside-7-O-α-rhamnopyranoside (32). Their structures were recognized on the basis of chemical and spectroscopic techniques (1D & 2D NMR, UV, EI & ESI/MS). The isolated flavonoids may provide useful taxonomic characters at the infraspecific levels of classification where the flavonoid profile of D. acris and D. harra is similar and different from the other species.


The Association between Inflammatory Bowel Disease and Periodontal Conditions: Is There a Common Bacterial Etiology?
The gastrointestinal system is strongly associated with the oral mucosa including periodontal tissues. Infl ammatory bowel disease (IBD) has two common forms: Crohn's disease (CD) and ulcerative colitis (UC). Local inflammation in periodontal diseases (PD) has an impact on infl ammatory diseases in various parts of the body. The existence of periodontitis in IBD patients suggests the possibility that the two inflammatory conditions may have common pathogenic pathways. Both diseases are multifactorial conditions in which genetic and environmental factors initiate and maintain the chronic inflammatory response. The aim of this review was to determine the current state of understanding of the characteristics and mechanisms underlying the association between IBD and periodontal diseases, with emphasis on the role of microorganisms. A computer-assisted MEDLINE search was performed to find the relevant articles concerning IBD and periodontal diseases published until September 2016. A number of studies have showed an association between PD and IBD. Both diseases share genetic and environmental etiological factors. The precise role of intestinal bacteria remains vague. The periodontal microbiota that might be involved in the association of these diseases are Fusobacterium nucleatum, Campylobacter rectus and Campylobacter concisus. Fungal and viral microbiota dysbiosis should also be evaluated as common pathogenic pathways in IBD and periodontal disease.


Fast, optically controlled Kerr phase shifter for digital signal processing.
We demonstrate an optically controlled Kerr phase shifter using a room-temperature 85Rb vapor operating in a Raman gain scheme. Phase shifts from zero to π relative to an unshifted reference wave are observed, and gated operations are demonstrated. We further demonstrate the versatile digital manipulation of encoded signal light with an encoded phase-control light field using an unbalanced Mach-Zehnder interferometer. Generalizations of this scheme should be capable of full manipulation of a digitized signal field at high speed, opening the door to future applications.


Active Bleeding after Cardiac Surgery: A Prospective Observational Multicenter Study.
To estimate the incidence of active bleeding after cardiac surgery (AB) based on a definition directly related on blood flow from chest drainage; to describe the AB characteristics and its management; to identify factors of postoperative complications. AB was defined as a blood loss > 1.5 ml/kg/h for 6 consecutive hours within the first 24 hours or in case of reoperation for hemostasis during the first 12 postoperative hours. The definition was applied in a prospective longitudinal observational study involving 29 French centers; all adult patients undergoing cardiac surgery with cardiopulmonary bypass were included over a 3-month period. Perioperative data (including blood product administration) were collected. To study possible variation in clinical practice among centers, patients were classified into two groups according to the AB incidence of the center compared to the overall incidence: "Low incidence" if incidence is lower and "High incidence" if incidence is equal or greater than overall incidence. Logistic regression analysis was used to identify risk factors of postoperative complications. Among 4,904 patients, 129 experienced AB (2.6%), among them 52 reoperation. Postoperative bleeding loss was 1,000 [820;1,375] ml and 1,680 [1,280;2,300] ml at 6 and 24 hours respectively. Incidence of AB varied between centers (0 to 16%) but was independent of in-centre cardiac surgical experience. Comparisons between groups according to AB incidence showed differences in postoperative management. Body surface area, preoperative creatinine, emergency surgery, postoperative acidosis and red blood cell transfusion were risk factors of postoperative complication. A blood loss > 1.5 ml/kg/h for 6 consecutive hours within the first 24 hours or early reoperation for hemostasis seems a relevant definition of AB. This definition, independent of transfusion, adjusted to body weight, may assess real time bleeding occurring early after surgery.


Collision energy optimization of b- and y-ions for multiple reaction monitoring mass spectrometry.
Multiple reaction monitoring (MRM) is a highly sensitive and increasingly popular method of targeted mass spectrometry (MS) that can be used to selectively detect and quantify peptides and their corresponding proteins of interest within biological samples. The sensitivity of MRM-MS is highly dependent upon the tuning of transition-specific parameters, especially the collision energy (CE) applied during peptide fragmentation. Currently, empirical equations for CE work best for y-type ions and are much less effective for other types of transitions, such as b-type ions and small y-type transitions across particular amide bonds, which could also be useful for MRM-MS if optimized for maximum signal transmission. In this work, we have performed a CE optimization of all transitions for 80 doubly charged peptides, the results of which were used to define separate CE equations for b-ions and y-ions, as well as for small y-type ions derived from the fragmentation of amide bonds bounded on the amino-terminal side by aspartic or glutamic acid residues (D/E-X transitions). This analysis yielded four major observations: (1) b-ions tend to require lower collision energies than y-ions for optimal fragmentation, while D/E-X transitions tend to require more; (2) CE equations predict the optimal CEs more closely when product ion m/z dependence is included, in addition to the current standard of precursor ion m/z dependence; (3) separate CE equations for y-ions, b-ions, and D/E-X transitions are more effective than the previous one-size-fits-all equations, but best results are achieved by optimizing transitions individually; and (4) while b-ions gain substantial signal from CE optimization-often increases of several-fold-they still tend to rank lower than y-ions from the same peptide. These results confirm the notion that y-ions are usually the first-choice transitions for MRM experiments but also demonstrate, for the first time, that b-ions can be viable targets as well, if the proper collision energies are used.


Evaluation of blood levels of nitric oxide as a means of differentiation between neonatal hepatitis and extrahepatic biliary atresia: A pilot study.
The differentiation between neonatal hepatitis (NH) and extrahepatic biliary atresia (EHBA) is not always possible despite all the currently available diagnostic modalities. In this study, an attempt has been made to evaluate the role of nitric oxide (NO) levels in the peripheral blood to differentiate between the two conditions, one requiring early surgical intervention (EHBA) and the other amenable to conservative medical management (NH). Twenty patients who presented to the pediatric surgical service, over a 2 years period, with features of neonatal cholestasis were enrolled in the study. The diagnostic workup included documentation of history and clinical examination, biochemical liver function tests, ultrasonography, hepatobiliary scintigraphy (HS), and magnetic resonance cholangio-pancreaticography (MRCP). These patients did not show excretion on HS and intrahepatic ducts on MRCP. Hence, they were subjected to mini-laparotomy and operative cholangiography (OC). The EHBA patients were treated with the Kasai's portoenterostomy procedure, and the extrahepatic ducts were flushed with normal saline in NH patients. All patients were evaluated preoperatively for levels of NO in the peripheral blood by the Greiss reaction spectrophotometrically at 540 nm. Normal values were determined from a cohort of controls. The median (range) levels of NO in patients with EHBA and NH were compared, and the statistical significance of the difference was calculated by applying the Wilcox Rank Sum test. A P = 0.05 was considered as significant. Of the 20 patients enrolled in the study, 17 patients were treated for EHBA (Group I) and the remaining 3 patients had patent ducts on OC and were thus diagnosed as NH (Group II). The mean age of the patients in Groups I and II was comparable: 2.79 ± 0.75 and 2.67 ± 0.58 months, respectively (P = 0.866). The median NO levels were significantly elevated in each of the two groups as compared to the controls (5.6 μmol/l, range 1.26-11.34 μmol/l); when compared among themselves, the NO levels were significantly higher in Group I, 64.05 μmol/l (range 24.11-89.43 μmol/l), when compared with Group II, 41.72 μmol/l (range 23.53-45.63 μmol/l) (P = 0.022). The serum levels of NO were found to be significantly higher in patients with EHBA as compared to those with NH. Hence, this may be a useful biochemical marker for the preoperative differentiation of EHBA from NH. However, a larger study is required for establishing the validity of the statistical significance.


Comparison of the ultrastructural and immunophenotypic characteristics of human umbilical cord-derived mesenchymal stromal cells and in situ cells in Wharton's jelly.
The umbilical cord contains mucinous connective tissue, called Wharton's jelly. It consists of stromal cells, collagen fibers, and amorphous ground substances composed of proteoglycan. Recently, these stromal cells have been redefined as a new cell therapy source, named human umbilical cord-derived mesenchymal stromal cells (hUCMSCs). However, there are few studies on the ultrastructural features and immune-phenotypic characteristics of isolated hUCMSCs and comparisons with the cells found in original cord tissues. In this study, the authors describe and compare the phenotypic characteristics of hUCMSCs with cells in the umbilical cord in order to know the kinds of cells and ultrastructural changes. Isolated hUCMSCs showed similar ultrastructure with few structural differences from in situ stromal cells, and they are relatively homogenous and well-developed mesenchymal cells that demonstrate a myofibroblastic phenotype.


Polymorphism and chromosomal localization of the porcine signal transducer and activator of transcription 5B gene (STAT5B).
Signal transducers and activators of transcription (STATs) are a family of transcription factors. STAT5A and 5B are two highly related proteins encoded by two distinct genes. Transgenic knockout mice studies have indicated the importance of STAT5 proteins for the regulation of both lactation and growth performance. Moreover, different studies determine the role of STAT5 proteins in the modulation of adipocyte function. In this study, we sequenced one fragment of STAT5B gene from animals of six breeds (Duroc, Iberian, Landrace, Large White, Piétrain and Meishan) to identify genetic variants. A G/A single nucleotide polymorphism in intron 14 creates a polymorphic PstI restriction site and was genotyped by polymerase chain reaction restriction fragment length polymorphism in the six breeds. Allele G was only present in Large White, Piétrain and Meishan populations, detecting only G allele in this last pig breed. The STAT5B gene was located by radiation hybrid mapping to porcine chromosome 12, within the confidence interval for the fatty acid composition quantitative trait loci, previously identified in an Iberian x Landrace cross.


[Virulence factors in Pseudomonas aeruginosa: mechanisms and modes of regulation].
Pseudomonas aeruginosa is a bacterium responsible for severe nosocomial infections, life-threatening infections in immunocompromised persons, and chronic infections in cystic fibrosis patients. The bacterium's virulence depends on a large number of cell-associated and extracellular factors. The virulence factors play an important pathological role in the colonization, the survival of the bacteria and the invasion of tissues. There are two types of virulence factors: (1) factors involved in the acute infection: these factors are either on the surface of P. aeruginosa, either secreted. The pili allow adherence to the epithelium. The exoenzyme S and other adhesins reinforce the adherence to epithelial cells. The exotoxin A is responsible of tissue necrosis. Phospholipase C is a thermolabile haemolysin. The pathogenic role of exoenzyme S is attributable to the disruption of normal cytoskeletal organization, the destruction of immunoglobulin G and A, leads to depolymerization of actin filaments and contributes to the resistance to macrophages. P. aeruginosa produces at least four proteases causing bleeding and tissue necrosis; (2) factors involved in the chronic infection: siderophores (pyoverdin and pyochelin), allow the bacteria to multiply in the absence of ferrous ions. The strains isolated from patients with cystic fibrosis have a pseudocapsule of alginate that protects the bacterium from phagocytosis, dehydration and antibiotics. Moreover, it improves adherence to epithelial cells forming a biofilm. Two different types of regulation systems control the expression of the majority of these virulence factors: the two-component transcriptional regulatory system and the quorum sensing system. These two mechanisms are necessary to the survival and the proliferation of this microorganism in the host.


Systems Approaches to Unravel T Cell Function and Therapeutic Potential in Autoimmune Disease.
Producing Ag-specific immune responses constrained to target tissues or cells that can be engaged or disengaged at will is predicated on understanding the network of genes governing immune cell function, defining the rules underlying Ag specificity, and synthesizing the tools to engineer them. The successes and limitations of chimeric Ag receptor (CAR) T cells emphasize this goal, and advances in high-throughput sequencing, large-scale genomic screens, single-cell profiling, and genetic modification are providing the necessary data to bring it to fruition-including a broader application into the treatment of autoimmune diseases. In this review, we delve into the implementation of these developments, survey the relevant works, and propose a framework for generating the next generation of synthetic T cells informed by the principles learned from these systems approaches.


Judgment, 25 November 1987.
The Court held unconstitutional Article 20 of the Preliminary Dispositions of the Civil Code, which provide that relations between a parent and child who are nationals of different countries are governed by the national law of the father if he is known and acknowledges paternity. It ruled that this Article violated Article 3, paragraph 1, and Article 29, paragraph 2, of the Constitution, which mandate equality of the sexes and equality of spouses, respectively.


Neuropsychological aspects of vascular dementia.
Vascular dementia (VaD) is the second most common cause of dementia in the elderly. Neuropsychologically, VaD has been characterized traditionally as having a "patchy" pattern of cognitive deficits. Newly developed diagnostic criteria for VaD suggest that this "patchy" pattern is associated with one type of VaD-multiple cortical infarctions, and that several additional subtypes of VaD exist, each featuring a characteristic pattern of neuropsychological deficits. Strategic infarct dementias have unique features that reflect the specific brain region affected. Lacunar state and Binswanger's disease produce subcortical dementia with disproportionate executive dysfunction. The profile of neuropsychological disturbances observed in VaD patients provides important insight into the localization and pathophysiology of the underlying cerebrovascular disease.


Bioanalysis of the peptide des-enkephalin-gamma-endorphin. On-line sample pretreatment using membrane dialysis and solid-phase isolation.
Des-enkephalin-gamma-endorphin is a neuroleptic endogenous peptide that is active in the central nervous system in extremely low concentrations. The pharmacokinetics of this peptide could not be studied in detail as a bioanalytical method for determining endogenous levels of this peptide in biological matrices was not available. Liquid chromatography with fluorescence reaction detection in principle offers sufficient sensitivity for this application, provided that a selective sample pretreatment can be performed. The development of a pretreatment method for plasma samples is described. After protein precipitation with trichloroacetic acid, high-molecular-weight compounds are removed using on-line continuous-flow dialysis. After dialysis, polar low-molecular-weight compounds, including those containing amino functions, are removed by solid-phase isolation, while simultaneously the analyte is concentrated. By means of valve switching the pretreatment system is coupled on-line to the liquid chromatographic system. With the developed system it is possible to determine desenkephalin-gamma-endorphin in plasma in the range 10-100 ng/ml.


A dominant negative mutant of Helicobacter pylori vacuolating toxin (VacA) inhibits VacA-induced cell vacuolation.
Most Helicobacter pylori strains secrete a toxin (VacA) that causes structural and functional alterations in epithelial cells and is thought to play an important role in the pathogenesis of H. pylori-associated gastroduodenal diseases. The amino acid sequence, ultrastructural morphology, and cellular effects of VacA are unrelated to those of any other known bacterial protein toxin, and the VacA mechanism of action remains poorly understood. To analyze the functional role of a unique strongly hydrophobic region near the VacA amino terminus, we constructed an H. pylori strain that produced a mutant VacA protein (VacA-(Delta6-27)) in which this hydrophobic segment was deleted. VacA-(Delta6-27) was secreted by H. pylori, oligomerized properly, and formed two-dimensional lipid-bound crystals with structural features that were indistinguishable from those of wild-type VacA. However, VacA-(Delta6-27) formed ion-conductive channels in planar lipid bilayers significantly more slowly than did wild-type VacA, and the mutant channels were less anion-selective. Mixtures of wild-type VacA and VacA-(Delta6-27) formed membrane channels with properties intermediate between those formed by either isolated species. VacA-(Delta6-27) did not exhibit any detectable defects in binding or uptake by HeLa cells, but this mutant toxin failed to induce cell vacuolation. Moreover, when an equimolar mixture of purified VacA-(Delta6-27) and purified wild-type VacA were added simultaneously to HeLa cells, the mutant toxin exhibited a dominant negative effect, completely inhibiting the vacuolating activity of wild-type VacA. A dominant negative effect also was observed when HeLa cells were co-transfected with plasmids encoding wild-type and mutant toxins. We propose a model in which the dominant negative effects of VacA-(Delta6-27) result from protein-protein interactions between the mutant and wild-type VacA proteins, thereby resulting in the formation of mixed oligomers with defective functional activity.


Obstructive Sleep Apnea With Objective Daytime Sleepiness Is Associated With Hypertension.
Subjective daytime sleepiness is considered a significant risk factor of hypertension in patients with obstructive sleep apnea (OSA). In this study, our goal was to examine the joint effect on hypertension of OSA and objective daytime sleepiness measured by the multiple sleep latency test (MSLT). A total of 1338 Chinese patients with OSA and 484 primary snorers were included in the study. All subjects underwent 1 night polysomnography followed by MSLT. The MSLT values were classified into 3 categories: >8 minutes, 5 to 8 minutes, and <5 minutes. Hypertension was defined based either on direct blood pressure measures or on diagnosis by a physician. After controlling for confounders, OSA combined with MSLT of 5 to 8 minutes increased the odds of hypertension by 95% (odds ratio, 1.95; 95% confidence interval, 1.10-3.46), whereas OSA combined with MSLT <5 minutes further increased the odds of hypertension by 111% (odds ratio, 2.11; 95% confidence interval, 1.22-3.31) compared with primary snorers with MSLT >8 minutes. In stratified analyses, the association of hypertension with MSLT in OSA patients was seen among both sexes, younger ages, both obese and nonobese patients, and patients with and without subjective excessive daytime sleepiness. We conclude that objective daytime sleepiness is associated with hypertension in patients with OSA.


Redox reactions of tocopherol monoglucoside in aqueous solutions: a pulse radiolysis study.
The reactions between tocopherol monoglucoside (TMG), a water-soluble vitamin-E derivative, with Br2.-, N3., (SCN)2.-, NO2., OH. and various halogenated peroxyl radicals were examined using a pulse radiolysis technique. The results demonstrate that TMG forms a stable phenoxyl radical at pH > 6.8. The thus-formed phenoxyl radical shows pH-dependent decay kinetics and is disproportionated by 2nd order kinetics at pH 2.3. It was observed that the TMG reactivity towards a halogenated peroxyl radical increases with the number of halogen atoms at the carbon atom having a peroxyl group. The reaction between the TMG phenoxyl radical and ascorbic acid was also examined using a pulse radiolysis technique. The results indicate that the TMG phenoxyl radical is repaired by ascorbate. Kinetic studies indicate that TMG may act as an antioxidant to repair free-radical damage to some biologically important compounds. The one-electron reduction potential for TMG was found to be 0.522 V +/- 0.06 vs. NHE.


Carcinoid tumor of the larynx. A critical review of the literature.
Typical carcinoid neoplasms of the larynx are extremely rare tumors. The total number of known and documented cases is likely no more than 13. The neoplasm mainly affects males at an average age of 58 years and appears grossly as a polypoid or sessile submucosal nodule with an average 1.8 cm in size. Their predominant location is the supraglottis with the arytenoid and the aryepiglottic fold being the most frequent sites. Histologically, they are characterized by organoid architecture, uniform cellular features and lack of pleomorphism, necrosis and mitosis. Typical laryngeal carcinoids are less aggressive than their atypical counterparts but late distant metastasis and death may occur. The management of these neoplasms is conservative surgery.


[Effect of indomethacin on fibronectin and plasminogen activator inhibitor-1 in cultured human peritoneal mesothelial cells].
To determine the effect of indomethacin on high concentration glucose and lipopolysaccharide (LPS) induced fibronectin (FN) and plasminogen activator inhibitor-1 (PAI-1) secretion in cultured human peritoneal mesothelial cells. Mesothelial cells were isolated from human omental specimens by trypsin disaggregation and incubated by 2.5% glucose or LPS together with different concentrations of indomethacin. Enzyme-linked immunosorbent assay determined the quantity of FN and PAI-1 in the cultured supernatants. Compared with the control group, the levels of FN and PAI-1 in the cultured supernatants were increased significantly exposuring to high concentration glucose and LPS (P <0.01). The different concentrations of indomethacin decreased FN and PAI-1 secretion in the 2.5% glucose or the LPS group within 24 h (P < 0.05). Indomethacin can inhibit the synthesis and secretion of extracellular matrix in human peritoneal mesothelial cells, which may be effective in the gene therapy for peritoneal fibrosis.


Transformations Among Colloidal Semiconductor Magic-Size Clusters.
A knowledge of colloidal semiconductor magic-size clusters (MSCs) is essential for understanding how fundamental properties evolve during transformations from individual molecules to semiconductor quantum dots (QDs). Compared to QDs, MSCs display much narrower optical absorption bands; the higher cluster stability gives rise to a narrower size distribution. During the production of binary QDs such as II-VI metal (M) chalcogenide (E) ones, binary ME MSCs observed were interpreted as side products and/or the nuclei of QDs. Prior to the current development of our two-step approach followed by our two-pathway model, it had been extremely challenging to synthesize MSCs as a unique product without the nucleation and growth of QDs. With the two-step approach, we have demonstrated that MSCs can be readily engineered as a sole product at room temperature from a prenucleation stage sample, also called an induction period (IP) sample. It is important that we were able to discover that the evolution of the MSCs follows first-order reaction kinetics behavior. Accordingly, we proposed that a new type of compound, termed as "precursor compounds" (PCs) of MSCs, was produced in an IP sample. Such PCs are optically transparent at the absorption peak positions of their MSC counterparts as well as to longer wavelengths. It is thought that quasi isomerization of a single PC results in the development of one MSC.In this Account, we provide an overview of our latest advances regarding the transformations among binary CdE MSCs as well as from binary CdTe to ternary CdTeSe MSCs. Optical absorption spectroscopy has been employed to study these transformations, all of which display well-defined isosbestic points. We have proposed that these MSC to MSC transformations occur via their corresponding PCs, also called immediate PCs. It is reasonable that the as-synthesized PC (in an IP sample) and the immediate PC (in an incubated and/or diluted sample) probably have different configurations. A transformation between two PCs may involve an intermolecular reaction, with either first-order reaction kinetics or a more complicated time profile. A transformation between one immediate PC and its counterpart MSC may contain an intramolecular reaction. The present Account, which addresses the PC-enabled MSC transformations with isosbestic points probed by optical absorption spectroscopy, calls for more experimental and theoretical attention to understand these magic species and their transformation processes more precisely.


Malignant infantile osteopetrosis.
Osteopetrosis, a rare congenital genetic disease characterized by increased bone density due to impaired bone resorption by osteoclasts. It is classified into three forms: Infantile malignant autosomal recessive (AR) osteopetrosis, intermediate (AR) osteopetrosis and autosomal dominant (AD) osteopetrosis. Incidence of infantile malignant AR is 1/2,00,000 and if untreated has a fatal outcome. The condition is commonly diagnosed in infancy with symptoms of significant hematologic abnormalities with bone marrow failure, hepatosplenomegaly, macrocephaly with frontal bossing and bone fractures. Because of rarity of this type of malignant infantile form of osteopretrosis, we like to report this case of malignant infantile osteopetrosis who presented with bronchopneumonia, anemia with melaena at 2 months 15 days of age.


Purification, crystallization and preliminary X-ray analysis of a Nup107-Nup133 heterodimeric nucleoporin complex.
The nuclear pore complex (NPC), the sole gateway of traffic between the nucleus and the cytoplasm, is built up from multiple copies of about 30 proteins collectively termed nucleoporins (nups). Nups are organized into distinct subcomplexes. Nup107 and Nup133 are members of the essential Nup107-160 subcomplex, a component of the central NPC architecture. A dimeric complex of the C-terminal domains of human Nup107 and Nup133 was expressed from a bicistronic vector in Escherichia coli, purified and crystallized in two different crystal forms. Crystals grown in the presence of 18-22% PEG 3350 belong to space group P2(1)2(1)2(1) and diffracted to 2.9 A. Native and seleno-L-methionine-derivative crystals grown in the presence of 1.1 M sodium malonate belong to space group C2 and diffracted to 2.55 and 2.9 A, respectively. Structure determination of this complex will give the first insights into the protein-protein interactions within a core module of the NPC.


[Effect of bestatin on immuno-suppressive acidic protein in patients with stomach cancer].
Serum immuno-suppressive acidic protein (IAP) levels increased with the invasion of cancer in to the gastric wall, the progress of lymph nodes metastasis, and also with the increase of tumor diameter of the gastric mucosa. The immunopotentiator, Bestatin was administered for 7 days to 28 patients with gastric cancer before any other therapeutic treatment. high IAP levels (over 500 micrograms/ml) in patients with stage IV cancer were remarkably improved with this treatment.


[The effect of bradykinin, vasopressin and ACTH (4-10) on the morphine withdrawal syndrome in morphine-dependent rats of 2 inbred strains].
The effect of intranasal administration of bradykinin, ACTH(4-10) fragment, and vasopressin on the withdrawal syndrome was studied in morphine-dependent rats of two inbred strains, WAG/G and Fischer-344. Morphine dependence was stronger and the withdrawal syndrome had a more severe course in WAG/G rats. Intranasal administration of bradykinin and the ACTH(4-10) fragment in the dose used had no effect on the expression of the withdrawal syndrome in rats of both strains. Intranasal administration of vasopressin intensified the withdrawal syndrome in Fischer-344 rats but not in WAG-G rats. It may thus be supposed that the genetic differences in the level of endogenous vasopressin or the sensitivity of its receptors are related to the resistance to morphine dependence formation. These data, however, are of a preliminary character and study of their mechanisms will be the purpose of further research.


[Space closure after anterior tooth loss due to trauma].
The orthodontic treatment of space closure after loss of anterior teeth due to trauma asks not only for a dental movement but for careful consideration. These depend on various factors such as age, tooth shape, tooth size, extent of the traumatic damage and the present malocclusion. The possibilities and limits of an orthodontic treatment have to be estimated to allow a correct decision for each patient, whereby some compromise has to be accepted. This is demonstrated with two examples.


Production and secretion of naphthoquinones is mediated by the MFS transporter MFS1 in the entomopathogenic fungus Ophiocordyceps sp. BCC1869.
Naphthoquinones are deep red polyketide pigments produced by the ant-pathogenic fungus Ophiocordyceps sp. BCC1869. In culture, biosynthesis of these naphthoquinones remains at a low level during the first 20 days and reaches its maximum production level at approximately 50 days. The MFS transporter gene MFS1 was previously identified in Ophiocordyceps sp. BCC1869 from a subtractive EST library between the fungus grown under naphthoquinone-inductive and naphthoquinone-repressive conditions. We cloned and sequenced this transporter gene, which has an open reading frame of 1505 bp and three introns (48, 52, and 58 bp). Phylogenetic analysis showed this MFS transporter was tightly clustered with fungal riboflavin transporters. Functional analysis of this gene was performed by overexpression of MFS1 under the control of a strong, constitutive promoter. We successfully transformed the fungus with this overexpression plasmid using PEG-protoplast transformation, which generated nine transformants per µg of plasmid. RT-PCR indicated that the MFS1 expression level in the overexpressing strains increased 3- to 10-fold compared to the wild type. HPLC analysis of crude extracts of mutants and wild type demonstrated that four naphthoquinone derivatives, erythrostominone, epierythrostominol, deoxyerythrostominone, and deoxyerythrostominol, were the major naphthoquinones produced and excreted in staggering quantities (20- to 2300-fold) in 7-day old liquid cultures by the mutant C7, compared to the wild type. High resolution electrospray ionization mass spectrometry verified mass spectra of these purified metabolites. Three other naphthoquinone derivatives, whose structures have not been identified, were also detected in high amount in the mutant liquid cultures.


The combination of PRRS virus and bacterial endotoxin as a model for multifactorial respiratory disease in pigs.
This paper reviews in vivo studies on the interaction between porcine reproductive and respiratory syndrome virus (PRRSV) and LPS performed in the authors' laboratory. The main aim was to develop a reproducible model to study the pathogenesis of PRRSV-induced multifactorial respiratory disease. The central hypothesis was that respiratory disease results from an overproduction of proinflammatory cytokines in the lungs. In a first series of studies, PRRSV was shown to be a poor inducer of TNF-alpha and IFN-alpha in the lungs, whereas IL-1 and the anti-inflammatory cytokine IL-10 were produced consistently during infection. We then set up a dual inoculation model in which pigs were inoculated intratracheally with PRRSV and 3-14 days later with LPS. PRRSV-infected pigs developed acute respiratory signs for 12-24h upon intratracheal LPS inoculation, in contrast to pigs inoculated with PRRSV or LPS only. Moreover, peak TNF-alpha, IL-1 and IL-6 titers were 10-100 times higher in PRRSV-LPS inoculated pigs than in the singly inoculated pigs and the cytokine overproduction was associated with disease. To further prove the role of proinflammatory cytokines, we studied the effect of pentoxifylline, a known inhibitor of TNF-alpha and IL-1, on PRRSV-LPS induced cytokine production and disease. The clinical effects of two non-steroidal anti-inflammatory drugs (NSAIDs), meloxicam and flunixin meglumine, were also examined. Pentoxifylline, but not the NSAIDs, significantly reduced fever and respiratory signs from 2 to 6h after LPS. The levels of TNF-alpha and IL-1 in the lungs of pentoxifylline-treated pigs were moderately reduced, but were still 26 and 3.5-fold higher than in pigs inoculated with PRRSV or LPS only. This indicates that pathways other than inhibition of cytokine production contributed to the clinical improvement. Finally, we studied a mechanism by which PRRSV may sensitize the lungs for LPS. We hypothesized that PRRSV would increase the amount of LPS receptor complex in the lungs leading to LPS sensitisation. Both CD14 and LPS-binding protein, two components of this complex, increased significantly during infection and the amount of CD14 in particular was correlated with LPS sensitisation. The increase of CD14 was mainly due to infiltration of strongly CD14-positive monocytes in the lungs. The PRRSV-LPS combination proved to be a simple and reproducible experimental model for multifactorial respiratory disease in pigs. To what extent the interaction between PRRSV and LPS contributes to the development of complex respiratory disease is still a matter of debate.


The evolutionary history of the sarafotoxin/endothelin/endothelin-like superfamily.
The evolutionary relationships among 17 protein and nucleic acid sequences from the sarafotoxin/endothelin/endothelin-like superfamily of peptides were studied. The endothelin/endothelin-like gene family has diverged from an ancestral gene that has experienced an exon duplication event followed by two complete gene duplications. The sarafotoxin lineage diverged from the ancestral gene prior to the first gene duplication event. In several lineages, the peptides have independently accumulated identical amino acid replacements in position 2. This finding supports the hypothesis that residue 2 is crucial to biological activity.


Rapid determination of vial heat transfer parameters using tunable diode laser absorption spectroscopy (TDLAS) in response to step-changes in pressure set-point during freeze-drying.
The purpose of this study was to perform a rapid determination of vial heat transfer parameters, that is, the contact parameter K(cs) and the separation distance l(v), using the sublimation rate profiles measured by tunable diode laser absorption spectroscopy (TDLAS). In this study, each size of vial was filled with pure water followed by a freeze-drying cycle using a LyoStar II dryer (FTS Systems) with step-changes of the chamber pressure set-point at to 25, 50, 100, 200, 300, and 400 mTorr. K(cs) was independently determined by nonlinear parameter estimation using the sublimation rates measured at the pressure set-point of 25 mTorr. After obtaining K(cs), the l(v) value for each vial size was determined by nonlinear parameter estimation using the pooled sublimation rate profiles obtained at 25 to 400 mTorr. The vial heat transfer coefficient K(v), as a function of the chamber pressure, was readily calculated, using the obtained K(cs) and l(v) values. It is interesting to note the significant difference in K(v) of two similar types of 10 mL Schott tubing vials, primary due to the geometry of the vial-bottom, as demonstrated by the images of the contact areas of the vial-bottom.