[Significance of the morphogenetic proteins FGF-23 and Klotho as predictors of prognosis of chronic kidney disease].
To study the role of the morphogenetic proteins FGF-23 and Klotho in the progression of chronic kidney disease (CKD) and in the development of cardiovascular events, inflammation, protein-energy deficiency, and other complications. Examinations were made in 70 patients with Stages I-VD CKD: 41 with chronic glomerulonephritis (including 10 with nephritis in the presence of diffuse connective tissue diseases), 22 with tubulointerstitial nephritis, and 7 with hypertensive nephrosclerosis. There were a total of 30 men and 40 women whose age was 20 to 84 years; the mean age at the study inclusion was 41 +/- 6.7 years. The serum levels of FGF-23 (Human FGF-23 ELISA kit using monoclonal antibodies to complete molecule of FGF-23) and Klotho (Human alpha-K1 ELISA using anti-Klotho antibodies) were investigated in all the 70 patients with CKD. The sera of all the examinees with CKD showed elevated FGF-23 and decreased Klotho levels, the magnitude of a change in which increased from Stage I to VD. In patients with different stages of CKD, the increase in FGF-23 levels, as glomerular filtration rate reduced, outstripped that in the serum levels of phosphorus and intact parathyroid hormone. There was a strong correlation of the serum level of the morphogenetic proteins, Klotho in particular, with proteinuria, C-reactive protein level, protein-energy deficiency, indicating the pleiotropic effects of these proteins. There was also a strong correlation between serum Klotho and ferritin levels and transferrin saturation percentage, which suggests that Klotho may be involved in iron regulation. The results of the investigation lend credence to the experimental and clinical findings that the serum levels of the morphogenetic proteins FGF-23 (an increase) and Klotho (a decrease) are early markers for progressive CKD and that their changes begin just in Stage III CKD and progress as renal failure worsens.


Microvillar iron-binding glycoproteins isolated from the rabbit small intestine.
Rabbit intestinal microvillus membranes possess high-affinity receptors for iron whose activity reflects homeostatic changes in mucosal iron transport. To isolate and characterize these membrane components, purified microvilli were radiolabelled with 59Fe(II) and solubilized in Triton X-100. 59Fe in 105000g supernatants co-eluted with a major broad protein peak (Mr approx. 100000) on gel-permeation chromatography and was rendered diffusible by Pronase digestion but not mild periodate degradation. Fluorescence studies with castor-bean lectin conjugates showed specific binding of this affinity probe exclusively to brush-border membranes in the intestinal epithelium. Affinity chromatography of solubilized membrane proteins showed binding to columns of immobilized lectin. Elution with D(+)-galactose released glycoprotein-bound 59Fe purified up to sevenfold over initial membrane extracts. The lectin bound up to 82% of protein-bound 59Fe. In contrast polyspecific antisera raised against rabbit microvilli in guinea-pigs precipitated less than 10% of solubilized radioactivity. Significantly more protein-bound 59Fe in detergent extracts of microvilli purified from bled animals interacted specifically with the lectin, suggesting that membrane glycoprotein receptors are involved in the homeostatic control of intestinal iron transport.


Economic Impact of Subsequent Depression in Patients With a New Diagnosis of Stable Angina: A Population-Based Study.
Depression is strongly linked to increased morbidity and mortality in patients with chronic stable angina; however, its associated healthcare costs have been less well studied. Our objective was to identify the characteristics of chronic stable patients found to have depression and to determine the impact of an occurrence of depression on healthcare costs within 1 year of a diagnosis of stable angina. In this population-based study conducted in Ontario, Canada, we identified patients diagnosed with stable angina based on angiogram between October 1, 2008, and September 30, 2013. Depression was ascertained by physician billing codes and hospital admission diagnostic codes contained within administrative databases. The primary outcome was cumulative mean 1-year healthcare costs following index angiogram. Generalized linear models were developed with a logarithmic link and γ distribution to determine predictors of cost. Our cohort included 22 917 patients with chronic stable angina. Patients with depression had significantly higher mean 1-year healthcare costs ($32 072±$41 963) than patients without depression ($23 021±$25 741). After adjustment for baseline comorbidities, depression was found to be a significant independent predictor of cost, with a cost ratio of 1.33 (95% confidence interval, 1.29-1.37). Higher costs in depressed patients were seen in all healthcare sectors, including acute and ambulatory care. Depression is an important driver of healthcare costs in patients following a diagnosis of chronic stable angina. Further research is needed to understand whether improvements in the approach to diagnosis and treatment of depression will translate to reduced expenditures in this population.


Ultralow thermal conductivity of turbostratically disordered MoSe2 ultra-thin films and implications for heterostructures.
Films containing 8, 16, 24, 32 and 64 MoSe2 layers were synthesized using the modulated elemental reactants method. X-ray reflectivity patterns showed that the annealed films were the targeted number of MoSe2 layers thick with atomically smooth interfaces. In-plane x-ray diffraction (XRD) scans contained only hk0 reflections for crystalline MoSe2 monolayers. Specular XRD patterns contained only 00l reflections, also indicating that the hk0 plane of the MoSe2 layers are parallel to the substrate. Both XRD and electron microscopy techniques indicated that the hk0 planes are rotationally disordered with respect to one another, with all orientations equally probable for large areas. The rotational disorder between MoSe2 layers is present even when analyzed spots are within 10 nm of one another. Cross-plane thermal conductivities of 0.07-0.09 W m-1 K-1 were measured by time domain thermoreflectance, with the thinnest films exhibiting the lowest conductivity. The structural analysis suggests that the ultralow thermal conductivity is a consequence of rotational disorder, which increases the separation between MoSe2 layers. The bonding environment of the Se atoms also becomes significantly distorted from C 3v symmetry due to the rotational disorder between layers. This structural disorder efficiently reduces the group velocity of the transverse phonon modes but not that of longitudinal modes. Since rotational disorder between adjacent layers in heterostructures is expected if the constituents have incommensurate lattices, this study indicates that these heterostructures will have very low cross-plane thermal conductivity.


Coupling of histone and DNA synthesis in the somatic cell cycle.
The coupling of histone and DNA synthesis was examined in the temperature-sensitive hamster fibroblast cell line K12. By monitoring total cellular histone synthesis at various times after quiescent cells were stimulated to proliferate at permissive and nonpermissive temperatures, a direct correlation was found between the rates of DNA and histone synthesis. Furthermore, when DNA synthesis was blocked by the K12 mutation, histone synthesis was reduced to the basal rate.


Methods for estimation of model accuracy in CASP12.
Methods to reliably estimate the quality of 3D models of proteins are essential drivers for the wide adoption and serious acceptance of protein structure predictions by life scientists. In this article, the most successful groups in CASP12 describe their latest methods for estimates of model accuracy (EMA). We show that pure single model accuracy estimation methods have shown clear progress since CASP11; the 3 top methods (MESHI, ProQ3, SVMQA) all perform better than the top method of CASP11 (ProQ2). Although the pure single model accuracy estimation methods outperform quasi-single (ModFOLD6 variations) and consensus methods (Pcons, ModFOLDclust2, Pcomb-domain, and Wallner) in model selection, they are still not as good as those methods in absolute model quality estimation and predictions of local quality. Finally, we show that when using contact-based model quality measures (CAD, lDDT) the single model quality methods perform relatively better.


Benzodiazepine Delorazepam Induces Locomotory Hyperactivity and Alterations in Pedal Mucus Texture in the Freshwater Gastropod Planorbarius corneus.
Benzodiazepines, psychotropic drugs, are ubiquitous in the aquatic environment due to over-consumption and inefficient removal by sewage treatment plants. Bioaccumulation with consequent behavioral and physiological effects has been reported in many aquatic species. However, the responses are species-specific and still poorly understood. To improve the knowledge, we exposed the freshwater snail Planorbarius corneus to 1, 5, or 10 µg/L of delorazepam, the most widely consumed benzodiazepine in Italy. Conventional behavioral tests were used to assess the effects on locomotor and feeding behavior. Histological and biochemical analyses were also performed to detect possible changes in the structure and composition of the foot mucus and glands. The results show a paradoxical response with reduced feeding activity and locomotor hyperactivity. Pedal mucus was altered in texture but not in composition, becoming particularly rich in fibrous collagen-like material, and a significant change in the protein composition was highlighted in the foot. In conclusion, exposure to delorazepam induces disinhibited behavior in Planorbarius corneus, potentially increasing the risk of predation, and an increase in mucus protein production, which, together with reduced feeding activity, would severely compromise energy resources.


Dentists' knowledge of chronic orofacial pain.
Orofacial pain (OFP) is a unique group of dental conditions with focus on chronic nonodontogenic pain affecting mouth, jaws, and face. The aim of this study is to investigate the knowledge of dentists in Saudi Arabia toward OFP assessment. An English language questionnaire containing 20 close-ended questions was used to capture data. The questionnaire included diagnostic criteria and clinical symptoms and signs of various OFP conditions. It was distributed to general dental practitioners (GDP) and dental specialists in four major provinces in Saudi Arabia. A total of 318 questionnaires were completed by 163 males and 155 females. Most participants were GDPs (193/318) and the remaining were specialists from different dental specialties. A majority of participants were not able to diagnose neuropathic OFP or neurovascular/vascular OFP conditions (33% and 28.6%, respectively). On the other hand, only 40.3% were confident enough to diagnose different types of temporomandibular disorders. The results also showed that graduates from non-Saudi programs had significantly higher self and knowledge assessment score (59.8% and 43.4%, respectively) compared with graduates from Saudi programs (39.9% and 22.6%, respectively). The dental specialists had higher self-assessment scores compared with GDPs (48% vs. 43.7%). Overall, there was a weak positive correlation between self-assessment and knowledge assessment (20.2%). This study demonstrates a higher OFP knowledge and confidence for dental specialists compared with GDPs. However, this difference does not necessarily translate into more competencies in clinical practice. Therefore, the implementation of OFP courses in dental schools' curricula may benefit future dentists and improve patients' care.


Pharmacology of Bradykinin-Evoked Coughing in Guinea Pigs.
Bradykinin has been implicated as a mediator of the acute pathophysiological and inflammatory consequences of respiratory tract infections and in exacerbations of chronic diseases such as asthma. Bradykinin may also be a trigger for the coughing associated with these and other conditions. We have thus set out to evaluate the pharmacology of bradykinin-evoked coughing in guinea pigs. When inhaled, bradykinin induced paroxysmal coughing that was abolished by the bradykinin B2 receptor antagonist HOE 140. These cough responses rapidly desensitized, consistent with reports of B2 receptor desensitization. Bradykinin-evoked cough was potentiated by inhibition of both neutral endopeptidase and angiotensin-converting enzyme (with thiorphan and captopril, respectively), but was largely unaffected by muscarinic or thromboxane receptor blockade (atropine and ICI 192605), cyclooxygenase, or nitric oxide synthase inhibition (meclofenamic acid and N(G)-nitro-L-arginine). Calcium influx studies in bronchopulmonary vagal afferent neurons dissociated from vagal sensory ganglia indicated that the tachykinin-containing C-fibers arising from the jugular ganglia mediate bradykinin-evoked coughing. Also implicating the jugular C-fibers was the observation that simultaneous blockade of neurokinin2 (NK2; SR48968) and NK3 (SR142801 or SB223412) receptors nearly abolished the bradykinin-evoked cough responses. The data suggest that bradykinin induces coughing in guinea pigs by activating B2 receptors on bronchopulmonary C-fibers. We speculate that therapeutics targeting the actions of bradykinin may prove useful in the treatment of cough.


Comparing survival and recurrence in curative stage I to III colorectal cancer in transfused and nontransfused patients.
Evidence of the association between blood transfusions and its impact on prognostic outcomes in patients who undergo curative resection of colorectal cancer remains controversial. The aim of this study was to determine whether receiving peri-operative blood transfusions during curative colorectal cancer resection affected overall survival, cancer-related survival, and cancer recurrence. This retrospective study was undertaken at The Royal Brisbane and Women's Hospital, Australia, between 1984 and 2004. The outcomes of 1370 patients undergoing curative colorectal cancer resection for TNM stage I to III were analyzed. Four hundred twenty three patients (30.9%) required transfusion and 947 patients (69.1%) did not. Peri-operative transfusion was associated with higher rates of cancer recurrence on multivariate analysis (P = 0.024, RR, 1.257, 95% CI, 1.03-1.53); however, it was not independently associated with poorer overall or cancer-related survival. Where the aim is curative resection, this study contributes to a body of evidence that blood transfusions may be associated with poorer outcomes.


Hypochlorous acid hygiene solution in patients affected by blepharitis: a prospective randomised study.
To investigate the clinical outcomes and antimicrobial activity of an hypochlorous acid hygiene solution compared with hyaluronic acid wipes for blepharitis treatment in patients with dry eye disease (DED). This study involved 48 eyes of 48 patients affected by blepharitis with mild to moderate DED. 24 patients were treated with a hypochlorous acid hygiene solution (HOCL group) and 24 patients were treated with hyaluronic acid wipes (HYAL group) for a period of 4 weeks. The following clinical outcomes were assessed before (V0) and after the treatment period (V1): non-invasive keratograph break up time (NIK-BUT), tear film BUT (TF-BUT) tear meniscus height (TMH), Keratograph meibography, Meibomian Gland Yield Secretion Score (MGYSS), Corneal Staining Score (CSS), Schirmer test I, Keratograph conjunctival redness score and Ocular Surface Disease Index (OSDI). Moreover, microbiological analysis of upper and lower eyelid margins was performed at V0 both before and 5 min after treatment. After 1-month NIK-BUT and TF-BUT significantly increased in HOCL group, while they did not show a statistically significant difference in HYAL group compared with baseline. OSDI, TMH and MGYSS showed a significant difference in both groups, while Schirmer test, meibography, CSS and conjunctival redness score did not significantly change in both groups. Bacterial load showed a significant reduction in both groups, more pronounced in HOCL group compared with HYAL group. Hypochlorous acid hygiene solution can be securely employed in blepharitis treatment considering the satisfying clinical outcomes and antimicrobial activity compared with hyaluronic acid wipes.


Comparison of double-hole and single-hole pencil-point needles for spinal anesthesia with hyperbaric bupivacaine.
The use of thin single-hole pencil-point (SHPP) spinal needles may be a reason for subarachnoid maldistribution of local anesthetic. A new double-hole pencil-point (DHPP) needle may be preferable because of a theoretic more uniform initial distribution of local anesthetic. This was a prospective, double-blinded study of 50 patients randomly selected to have spinal anesthesia using either single-hole 27-gauge (B. Braun, Melsungen, Germany) or double-hole 26-gauge (A.L.B. Medical Inc., U.S.A.) pencil-point needles. The former were inserted with the side port directed caudally and the latter with openings in both caudal and cranial direction. Two milliliters of hyperbaric 0.5% bupivacaine were injected in 1 minute, and sensory and motor block were studied at regular intervals during spinal anesthesia. All patients were interviewed on the first (personal) and the seventh (mailed questionnaire) postoperative day. Furthermore, microscopic inspection of the spinal needles was performed. There were no statistically significant differences in sensory or motor block levels between the two needle types at any time during spinal anesthesia. Likewise, there was no difference in the duration of spinal block. The postanesthetic side effects (headache, backache, pricking, numbness, weakness) were similar in both groups. Light and electron microscopic examination showed resistance of the SHPP needles to tip damage. On the other hand, the DHPP needle tips seemed to be distorted quite frequently, and, even in unused needles, the tip was blunt and asymmetric. There was no difference between the spread of analgesia using either SHPP or DHPP spinal needles. The DHPP needles appear to be vulnerable to tip damage from mechanical contact.


Efficient reduction of antibiotic residues and associated resistance genes in tylosin antibiotic fermentation waste using hyperthermophilic composting.
Insufficient removal of antibiotics and antibiotic resistance genes (ARGs) from waste products can increase the risk of selection for antibiotic resistance in non-clinical environments. While composting is an efficient way to reduce ARGs, most conventional methods are ineffective at processing highly contaminated antibiotic fermentation waste. Here we explored the efficacy and underlying mechanisms of hyperthermophilic composting at removing tylosin antibiotic fermentation residues (TFR) and associated ARGs and mobile genetic elements (MGEs; plasmids, integrons and transposon). Hyperthermophilic composting removed 95.0% of TFR, 75.8% of ARGs and 98.5% of MGEs and this reduction mainly occurred after extended exposure to temperatures above 60 °C for at least 6 days. Based on sequencing and culture-dependent experiments, reduction in ARGs and MGEs was strongly associated with a decrease in the number of bacterial taxa that were initially associated with ARGs and MGEs. Moreover, we found 94.1% reduction in plasmid genes abundances (ISCR1 and IncQ-oriV) that significantly correlated with reduced ARGs during the composting, which suggests that plasmids were the main carriers for ARGs. We verified this using direct culturing to show that ARGs were more often found in plasmids during the early phase of composting. Together these results suggest that hyperthermophilic composting is efficient at removing ARGs and associated resistance genes from antibiotic fermentation waste by decreasing the abundance of antibiotic resistance plasmids and associated host bacteria.


Loss of CHFR in human mammary epithelial cells causes genomic instability by disrupting the mitotic spindle assembly checkpoint.
CHFR is an E3 ubiquitin ligase and an early mitotic checkpoint protein implicated in many cancers and in the maintenance of genomic stability. To analyze the role of CHFR in genomic stability, by siRNA, we decreased its expression in genomically stable MCF10A cells. Lowered CHFR expression quickly led to increased aneuploidy due to many mitotic defects. First, we confirmed that CHFR interacts with the mitotic kinase Aurora A to regulate its expression. Furthermore, we found that decreased CHFR led to disorganized multipolar mitotic spindles. This was supported by the finding that CHFR interacts with alpha-tubulin and can regulate its ubiquitination in response to nocodazole and the amount of acetylated alpha-tubulin, a component of the mitotic spindle. Finally, we found a novel CHFR interacting protein, the spindle checkpoint protein MAD2. Decreased CHFR expression resulted in the mislocalization of both MAD2 and BUBR1 during mitosis and impaired MAD2/CDC20 complex formation. Further evidence of a compromised spindle checkpoint was the presence of misaligned metaphase chromosomes, lagging anaphase chromosomes, and defective cytokinesis in CHFR knockdown cells. Importantly, our results suggest a novel role for CHFR regulating chromosome segregation where decreased expression, as seen in cancer cells, contributes to genomic instability by impairing the spindle assembly checkpoint.


Efficiency of Airborne Sample Analysis Platform (ASAP) bioaerosol sampler for pathogen detection.
The threat of bioterrorism and pandemics has highlighted the urgency for rapid and reliable bioaerosol detection in different environments. Safeguarding against such threats requires continuous sampling of the ambient air for pathogen detection. In this study we investigated the efficacy of the Airborne Sample Analysis Platform (ASAP) 2800 bioaerosol sampler to collect representative samples of air and identify specific viruses suspended as bioaerosols. To test this concept, we aerosolized an innocuous replication-defective bovine adenovirus serotype 3 (BAdV3) in a controlled laboratory environment. The ASAP efficiently trapped the surrogate virus at 5 × 10(3) plaque-forming units (p.f.u.) [2 × 10(5) genome copy equivalent] concentrations or more resulting in the successful detection of the virus using quantitative PCR. These results support the further development of ASAP for bioaerosol pathogen detection.


Abdominal radical trachelectomy: a fertility-preserving option for women with early cervical cancer.
Abdominal radical trachelectomy is a fertility-preserving alternative to radical hysterectomy or chemoradiation for young women with stage IA2 to IB cervical cancers. Thirty-three patients were offered this procedure. The mean age was 30.5 years (range 23-37). Three procedures were abandoned because of positive pelvic nodes (two patients) and involvement of the margin between the amputated cervix and uterine fundus (one patient). Of the remaining 30 patients, 10 had stage IA2 tumours, 15 had stage IB1 and 5 had stage IB2. During follow up of a median of 47 months (mean 32 months, range 14-75 months), no recurrences have been detected. A normal menstrual pattern resumed within eight weeks of surgery in all but two patients. Five patients attempted to conceive. Three women have fallen pregnant, resulting in one first trimester miscarriage and two caesarean section deliveries at term. Our experience suggests that abdominal radical trachelectomy provides a method of treating women with stage IA2 to IB cervical cancers with conservation of fertility without apparently compromising recurrence or survival rates. It appears to provide equivalent oncological safety to a standard Wertheim hysterectomy using a technique familiar to all practising gynaecologic oncologists.


Studies on the conversion of 60s yeast ribosomes into a 50S component.
The process of conversion of the larger (60s) subunit of yeast ribosomes into a 50s component was studied. The release of any RNA or protein material during conversion was assayed by using (32)P- or (35)S-labelled ribosomes; ribosomal RNA distributions of the particles were examined and protein/RNA ratios of subunits were determined. The change in sedimentation coefficients was found to be due, not to loss of material, but to a structural change. The change in structure was shown by electron microscopy.


Serine 937 phosphorylation enhances KCC2 activity and strengthens synaptic inhibition.
The potassium chloride cotransporter KCC2 is crucial for Cl- extrusion from mature neurons and thus key to hyperpolarizing inhibition. Auditory brainstem circuits contain well-understood inhibitory projections and provide a potent model to study the regulation of synaptic inhibition. Two peculiarities of the auditory brainstem are (i) posttranslational activation of KCC2 during development and (ii) extremely negative reversal potentials in specific circuits. To investigate the role of the potent phospho-site serine 937 therein, we generated a KCC2 Thr934Ala/Ser937Asp double mutation, in which Ser937 is replaced by aspartate mimicking the phosphorylated state, and the neighbouring Thr934 arrested in the dephosphorylated state. This double mutant showed a twofold increased transport activity in HEK293 cells, raising the hypothesis that auditory brainstem neurons show lower [Cl-]i. and increased glycinergic inhibition. This was tested in a mouse model carrying the same KCC2 Thr934Ala/Ser937Asp mutation by the use of the CRISPR/Cas9 technology. Homozygous KCC2 Thr934Ala/Ser937Asp mice showed an earlier developmental onset of hyperpolarisation in the auditory brainstem. Mature neurons displayed stronger glycinergic inhibition due to hyperpolarized ECl-. These data demonstrate that phospho-regulation of KCC2 Ser937 is a potent way to interfere with the excitation-inhibition balance in neural circuits.


[Structural and aggregational stability of lecithin liposomes based on light-scattering data].
The light scattering method for investigation of structural and aggregate stability is proposed, based on the comparison between angle and time dependence of total intensity of scattering light and its depolarized component. The structural evolution of liposome is observed by the anisotropic light scattering method. It is shown that the sols aggregate stability violation follows the appearance and increase of small-scale defects of vesicules. The interpretation of light scattering data is confirmed by electron micrographs.


Sodium in feline nutrition.
High sodium levels in cat food have been controversial for a long time. Nonetheless, high sodium levels are used to enhance water intake and urine volume, with the main objective of reducing the risk of urolithiasis. This article is a review of current evidence of the putative risks and benefits of high dietary sodium levels. Its secondary aim is to report a possible safe upper limit (SUL) for sodium intake. The first part of the manuscript is dedicated to sodium physiology, with a focus on the mechanisms of sodium homeostasis. In this respect, there is only few information regarding possible interactions with other minerals. Next, the authors address how sodium intake affects sodium balance; knowledge of these effects is critical to establish recommendations for sodium feed content. The authors then review the consequences of changes in sodium intake on feline health, including urolithiasis, blood pressure changes, cardiovascular alterations and kidney disease. According to recent, long-term studies, there is no evidence of any deleterious effect of dietary sodium levels as high as 740 mg/MJ metabolizable energy, which can therefore be considered the SUL based on current knowledge.


Disulfide-dependent self-assembly of adiponectin octadecamers from trimers and presence of stable octadecameric adiponectin lacking disulfide bonds in vitro.
Adiponectin is a circulating insulin-sensitizing hormone that homooligomerizes into trimers, hexamers, and higher molecular weight (HMW) species. Low levels of circulating HMW adiponectin appear to increase the risk for insulin resistance. Currently, assembly of adiponectin oligomers and, consequently, mechanisms responsible for decreased HMW adiponectin in insulin resistance are not well understood. In the work reported here, we analyzed the reassembly of the most abundant HMW adiponectin species, the octadecamer, following its collapse to smaller oligomers in vitro. Purified bovine serum adiponectin octadecamer was treated with reducing agents at pH 5 to obtain trimers. These reduced trimers partially and spontaneously reassembled into octadecamers upon oxidative formation of disulfide bonds. Disulfide bonds appear to occupy a greater role in the process of oligomerization than in the structural stabilization of mature octadecamer. Stable octadecamers lacking virtually all disulfide bonds could be observed in abundance using native gel electrophoresis, dynamic light scattering, and collision-induced dissociation nanoelectrospray ionization mass spectrometry. These findings indicate that while disulfide bonds help to maintain the mature octadecameric adiponectin structure, their more important function is to stabilize intermediates during the assembly of octadecamer. Adiponectin oligomerization must proceed through intermediates that are at least partially reduced. Accordingly, fully oxidized adiponectin hexamers failed to reassemble into octadecamers at a rate comparable to that of reduced trimers. As the findings from the present study are based on in vitro experiments, their in vivo relevance remains unclear. Nevertheless, they describe a redox environment-dependent model of adiponectin oligomerization that can be tested using cell-based approaches.


Injectional anthrax in human: A new face of the old disease.
Unusual human behavior leads to the emergence of new forms of infectious diseases and new routes of infection. In recent years, a new form of anthrax, called injectional anthrax, emerged and was related to 2 human anthrax outbreaks in Europe. The infection was caused by heroin contaminated with anthrax spores. The new form of anthrax differs from the earlier known "natural" forms of the disease in symptoms, length of the incubation period and recommended treatment. Despite medical treatment, the mortality rate in injectional anthrax is about 35%. This article presents an overview of the forms of anthrax infection in humans, with focus on injectional anthrax syndrome, as well as actual recommendations for treatment, including antibiotic therapy, surgery and possibilities of administering anthrax antitoxin. As a source of contamination of heroin have not been identified and new cases of injectional anthrax might occur again in any country in the future.


Expression of c-myc and other cell cycle-dependent genes in human colon neoplasia.
We have investigated the expression of certain cell cycle-dependent genes in total RNA isolated from normal and neoplastic cells of human epithelial colon tissue. The genes studied had been previously identified as cell cycle dependent in rodent and human fibroblasts. Levels of expression of G1 genes were compared to the level of expression of the S-phase-specific gene H3 in normal and adjacent neoplastic epithelial cells of six different individuals. We have found that the increase in the expression of c-myc gene detected in colon tumor cells is accompanied by a parallel increase in the expression of two G1-specific genes (p2A9 and ornithine decarboxylase) and the S-phase-specific gene histone H3. An important conclusion that can be drawn from these findings is that the increased level of a cell cycle-specific RNA in a tumor may not indicate overexpression of that gene but simply reflect the increased fraction of cycling cells, unless the ratio of expression between G1 genes and G1-S-phase genes is altered.


Laparoscopic versus Open Repair of Para-Umbilical Hernia- A Prospective Comparative Study of Short Term Outcomes.
Para-Umbilical Hernia (PUH) is one of the most common surgical problems. Since the prosthetic repair has become the standard of practice for inguinal hernia management, the same has been adapted for para-umbilical hernia management with better outcome. There is still debate going on regarding the optimal surgical approach. There are very few prospective studies comparing the laparoscopic and open method of para-umbilical hernia mesh repair. This study compared the short term outcomes following laparoscopic versus open mesh repair of PUH. To compare the early complications of open repair with laparoscopic repair of PUH. To compare the post-operative hospital stay of open repair with laparoscopic repair of PUH. This was a prospective comparative clinical study done from August 2014 to August 2016. All the patients above the age of 13 who attended our surgical outpatient department with PUH were taken into our study. Exclusion criteria included 1) Patients with obstructed or strangulated PUH 2) Patients with abdominal malignancies 3) Patients with coagulopathy, severe cardiopulmonary disease, ascites and renal failure 4) Patients who had PUH repair in combination with another major surgical operation such as laparoscopic cholecystectomy and inguinal hernia repair 5) Patients with recurrent PUH. Institute Ethical Committee clearance was obtained for this study. Out of 40 patients with PUH, 20 received open meshplasty and 20 patients received laparoscopic meshplasty. Postoperative pain and length of hospital stay is significantly less in laparoscopic PUH repair. Postoperative complications like wound infection, seroma, and haematoma are relatively less in laparoscopic group though statistically not significant. Laparoscopic PUH repair has significantly better outcome in terms of postoperative pain and postoperative hospital stay.


Mutator phenotypes conferred by MLH1 overexpression and by heterozygosity for mlh1 mutations.
Loss of DNA mismatch repair due to mutation or diminished expression of the MLH1 gene is associated with genome instability and cancer. In this study, we used a yeast model system to examine three circumstances relevant to modulation of MLH1 function. First, overexpression of wild-type MLH1 was found to cause a strong elevation of mutation rates at three different loci, similar to the mutator effect of MLH1 gene inactivation. Second, haploid yeast strains with any of six mlh1 missense mutations that mimic germ line mutations found in human cancer patients displayed a strong mutator phenotype consistent with loss of mismatch repair function. Five of these mutations affect amino acids that are homologous to residues suggested by recent crystal structure and biochemical analysis of Escherichia coli MutL to participate in ATP binding and hydrolysis. Finally, using a highly sensitive reporter gene, we detected a mutator phenotype of diploid yeast strains that are heterozygous for mlh1 mutations. Evidence suggesting that this mutator effect results not from reduced mismatch repair in the MLH1/mlh1 cells but rather from loss of the wild-type MLH1 allele in a fraction of cells is presented. Exposure to bleomycin or to UV irradiation strongly enhanced mutagenesis in the heterozygous strain but had little effect on the mutation rate in the wild-type strain. This damage-induced hypermutability may be relevant to cancer in humans with germ line mutations in only one MLH1 allele.


The effect of Pretoria Pasteurization on bacterial contamination of hand-expressed human breastmilk.
One of the challenges facing the development of programs to reduce mother to child transmission of HIV in developing countries remains the problem of infant feeding. One of the alternative feeding methods under investigation for infants of HIV-infected mothers is heat treatment of expressed breastmilk by Pretoria Pasteurization. The objective of this study was to determine the effect of Pretoria Pasteurization on commensal and pathogenic bacteria in hand-expressed human breastmilk, and to determine the duration of time for which milk can be kept safely without refrigeration after Pretoria Pasteurization. Samples of milk were hand expressed by lactating women in the postnatal ward. The samples were split into control and pasteurized specimens. The pasteurized specimens underwent Pretoria Pasteurization. All samples were stored at room temperature and were sampled for bacterial culture every 4 h, up to 12 h. Clinically significant levels of bacterial contamination occurred in 59 per cent of control and 7.8 per cent of pasteurized samples. Four pasteurized samples showed significant contamination. There is strong evidence that the contaminating organisms in these samples were introduced by handling after pasteurization. The 53 (91 per cent) pasteurized samples that had no contamination at 4 h remained sterile for the remainder of the standing period of 12 h. Forty-one per cent of control samples already had significant growth after standing at room temperature for 4 h. In conclusion, Pretoria Pasteurization kills pathogenic and commensal bacteria in hand-expressed breastmilk. Expressed breastmilk that has undergone Pretoria Pasteurization can be kept without refrigeration for up to 12 h with minimal probability of bacterial contamination provided that it is kept in the pasteurization container and is not handled.


The Pregnancy Exposome: Multiple Environmental Exposures in the INMA-Sabadell Birth Cohort.
The "exposome" is defined as "the totality of human environmental exposures from conception onward, complementing the genome" and its holistic approach may advance understanding of disease etiology. We aimed to describe the correlation structure of the exposome during pregnancy to better understand the relationships between and within families of exposure and to develop analytical tools appropriate to exposome data. Estimates on 81 environmental exposures of current health concern were obtained for 728 women enrolled in The INMA (INfancia y Medio Ambiente) birth cohort, in Sabadell, Spain, using biomonitoring, geospatial modeling, remote sensors, and questionnaires. Pair-wise Pearson's and polychoric correlations were calculated and principal components were derived. The median absolute correlation across all exposures was 0.06 (5th-95th centiles, 0.01-0.54). There were strong levels of correlation within families of exposure (median = 0.45, 5th-95th centiles, 0.07-0.85). Nine exposures (11%) had a correlation higher than 0.5 with at least one exposure outside their exposure family. Effectively all the variance in the data set (99.5%) was explained by 40 principal components. Future exposome studies should interpret exposure effects in light of their correlations to other exposures. The weak to moderate correlation observed between exposure families will permit adjustment for confounding in future exposome studies.


CRISPR/Cas9 -mediated gene knockout of Anopheles gambiae FREP1 suppresses malaria parasite infection.
Plasmodium relies on numerous agonists during its journey through the mosquito vector, and these agonists represent potent targets for transmission-blocking by either inhibiting or interfering with them pre- or post-transcriptionally. The recently developed CRISPR/Cas9-based genome editing tools for Anopheles mosquitoes provide new and promising opportunities for the study of agonist function and for developing malaria control strategies through gene deletion to achieve complete agonist inactivation. Here we have established a modified CRISPR/Cas9 gene editing procedure for the malaria vector Anopheles gambiae, and studied the effect of inactivating the fibrinogen-related protein 1 (FREP1) gene on the mosquito's susceptibility to Plasmodium and on mosquito fitness. FREP1 knockout mutants developed into adult mosquitoes that showed profound suppression of infection with both human and rodent malaria parasites at the oocyst and sporozoite stages. FREP1 inactivation, however, resulted in fitness costs including a significantly lower blood-feeding propensity, fecundity and egg hatching rate, a retarded pupation time, and reduced longevity after a blood meal.


Salmonella contamination during production of cantaloupe: a binational study.
Six cantaloupe farms and packing plants in South Texas (950 cantaloupe, 140 water, and 45 environmental samples), including the Rio Grande Valley area, and three farms in Colima State, Mexico (300 cantaloupe, 45 water, and 15 environmental samples), were sampled to evaluate cantaloupe contamination with Salmonella and Escherichia coli during production and processing. Samples collected from external surfaces of cantaloupes, water, and the environments of packing sheds on cantaloupe farms were examined for the presence of Salmonella and E. coli. Of a total of 1,735 samples collected, 31 (1.8%) tested positive for Salmonella. Fifteen Salmonella serotypes were isolated from samples collected in Texas, and nine from samples collected in Colima. Two serotypes (Poona and Oranienburg) that have been associated with three large Salmonella outbreaks in the United States and Canada linked to the consumption of contaminated cantaloupe were found in water samples collected at four farms (three from the United States). Susceptibility of Salmonella isolates to 10 antimicrobials was evaluated by disk diffusion. Eighty-eight percent of the isolates from the United States and Mexico were pansusceptible to the antimicrobials tested; eight isolates from the United States demonstrated an intermediate susceptibility to streptomycin and only two isolates were resistant to the same antimicrobial. From Mexico, four isolates showed an intermediate susceptibility to streptomycin and one isolate was resistant to nalidixic acid and streptomycin. Repetitive sequence-based PCR analysis of Salmonella isolates helped to trace potential sources of Salmonella contamination in source water and in subsequent water samples obtained after the filtration systems of U.S. and Mexican cantaloupe farms. No differences could be seen between the levels of Salmonella contamination in melons from both countries.


Fluorinated Iron Metal-Organic Frameworks for Activatable 19F Magnetic Resonance Imaging and Synergistic Therapy of Tumors.
Due to their appealing physiochemical properties, metal-organic frameworks (MOFs) have been widely employed in biomedical fields. In this study, we utilize ferric ions and fluorine-containing organic ligands as both structural and functional units to develop a stimulus-responsive nanoagent, 19FIMOF-TA nanoparticles, for activatable 19F magnetic resonance imaging (MRI) and synergistic therapy of tumors. This nanoagent could respond to excess GSH in a tumor microenvironment, discharging fluorinated organic ligands and reduced ferrous ions. The release of these fluorine-containing small molecules results in boosting of the 19F MRI signals, which could be further enhanced by the photothermal effect of this nanoagent to achieve a responsive cascaded amplification of 19F MRI signals for tumor visualization. Meanwhile, ferroptosis promoted by the ferrous ions leads to significant tumor cell death, which is synergistically aggravated by the photothermal effect. The encouraging results illustrate the promising potential of our nanoagent for effective tumor imaging and combinative cancer therapy.


Production of aerobactin by some species of the genus Yersinia.
Seventy-seven isolates of Yersinia species were examined for evidence of hydroxamate biosynthesis. A total of 7 of 12 Y. frederiksenii, 1 of 5 Y. kristensenii, and 5 of 5 Y. intermedia isolates synthesized an hydroxamate species which was chromatographically and electrophoretically identical to aerobactin. Proof that this material was indeed aerobactin was obtained for one strain of Y. frederiksenii by using mass spectrometry. None of 50 Y. enterocolitica nor any of 5 Y. pseudotuberculosis isolates produced hydroxamates.


Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons.
Maturation of neuronal synapses is thought to involve mitochondria. Bcl-xL protein inhibits mitochondria-mediated apoptosis but may have other functions in healthy adult neurons in which Bcl-xL is abundant. Here, we report that overexpression of Bcl-xL postsynaptically increases frequency and amplitude of spontaneous miniature synaptic currents in rat hippocampal neurons in culture. Bcl-xL, overexpressed either pre or postsynaptically, increases synapse number, the number and size of synaptic vesicle clusters, and mitochondrial localization to vesicle clusters and synapses, likely accounting for the changes in miniature synaptic currents. Conversely, knockdown of Bcl-xL or inhibiting it with ABT-737 decreases these morphological parameters. The mitochondrial fission protein, dynamin-related protein 1 (Drp1), is a GTPase known to localize to synapses and affect synaptic function and structure. The effects of Bcl-xL appear mediated through Drp1 because overexpression of Drp1 increases synaptic markers, and overexpression of the dominant-negative dnDrp1-K38A decreases them. Furthermore, Bcl-xL coimmunoprecipitates with Drp1 in tissue lysates, and in a recombinant system, Bcl-xL protein stimulates GTPase activity of Drp1. These findings suggest that Bcl-xL positively regulates Drp1 to alter mitochondrial function in a manner that stimulates synapse formation.


Effect of proteolytic enzymes on transepithelial solute transport.
The effects of proteases on air-space clearance (AC) of small ([14C]sucrose, 342 daltons) and large (125I-neutral dextran, 70,000 daltons) solutes were studied in isolated, fluid-filled hamster lungs that were perfused in a nonrecirculating system. When instilled into the air spaces, porcine pancreatic elastase (0.1-0.4 mg/ml) and bovine pancreatic trypsin (BPT) (0.5-2.0 mg/ml), but neither Clostridium histolyticum collagenase (5.0 mg/ml) nor phenylmethylsulfonyl fluoride-inactivated BPT caused large increases in the AC of both tracer molecules. BPT-induced solute clearance was further characterized functionally and morphologically. The functional characteristics of solute AC under steady-state conditions did not indicate that transepithelial transport was diffusion-limited. Inhibition by millimolar concentrations of Zn2+ and by lung cooling, along with electron microscopic studies employing horseradish peroxidase as a macromolecule tracer, were consistent with epithelial solute transport by a vesicular mechanism (transcytosis). Solute transport from the interstitial compartment to the lung exterior was shown to occur via two pathways. By unknown mechanisms BPT caused small amounts of water to flow through an incompletely identified, extravascular pathway. In BPT-exposed lungs efflux of 125I-dextran 70 occurred almost exclusively through this pathway, whereas [14C]sucrose was transported to the lung exterior partly through this same pathway and partly through the vasculature. The large differences in the diffusion coefficients of the two tracers may have accounted for these observed patterns of solute efflux from the lung. The possible significance of our findings to the pathogenesis of experimental emphysema are discussed.


Oxidative stress mediated arterial dysfunction in patients with obstructive sleep apnoea and the effect of continuous positive airway pressure treatment.
Several studies suggest an increase of oxidative stress and a reduction of endothelial function in obstructive sleep apnoea syndrome (OSAS). We assessed the association between OSAS, endothelial dysfunction and oxidative stress. Further aim was to evaluate the effect of nasal continuous positive airway pressure (nCPAP) on oxidative stress and arterial dysfunction. We studied 138 consecutive patients with heavy snoring and possible OSAS. Patients underwent unattended overnight home polysomnography. Ten patients with severe OSAS were revaluated after 6 months of nCPAP therapy. To assess oxidative stress in vivo, we measured urinary 8-iso-PGF2α and serum levels of soluble NOX2-derived peptide (sNOX2-dp). Serum levels of nitrite/nitrate (NOx) were also determined. Flow-mediated brachial artery dilation (FMD) was measured to asses endothelial function. Patients with severe OSAS had higher urinary 8-iso-PGF2α (p<0.001) and serum NOX2 and lower NOx. A negative association was observed between FMD and OSA severity. Apnea/hypopnea index was significantly correlated with the indices of central obesity and with urinary 8-isoprostanes (r=0.298, p<0.001). The metabolic syndrome (t=-4.63, p<0.001) and urinary 8-isoprostanes (t=-2.02, p<0.05) were the only independent predictors of FMD. After 6-months nCPAP treatment, a significant decrease of serum NOX2, (p<0.005) and urinary 8-iso-PGF2α (p<0.01) was observed, while serum NOx showed only a minor increase. A statistically significant increase of FMD was observed (from 3.6% to 7.0%). The results of our study indicate that patients with OSAS and cardiometabolic comorbidities have increased oxidative stress and arterial dysfunction that are partially reversed by nCPAP treatment.


Partial purification and characterization of a polymannuronic acid depolymerase produced by a mucoid strain of Pseudomonas aeruginosa isolated from a patient with cystic fibrosis.
An exopolysaccharide depolymerase was isolated from a mucoid strain of Pseudomonas aeruginosa of cystic fibrosis origin. Purified preparations of the depolymerase showed maximum activity against the unacetylated polymannuronic acid exopolysaccharide from the same strain and little activity against commercially prepared alginic acid. The evidence suggests that the enzyme is either periplasmic in location or associated with the outer cell membrane and is released extracellularly, in the absence of cell lysis, after a reduction of the culture magnesium (Mg2+) concentration below 3.0 mM. The depolymerase is also released after the addition of sublethal concentrations of EDTA to cultures containing 3.0 mM Mg2+. A survey of additional mucoid P. aeruginosa isolates recovered from patients with cystic fibrosis showed that nearly 60% demonstrated similar depolymerase activity while none of the nonmucoid revertants of the parent strains produced detectable depolymerase activity.


[Postoperative ileus: part II (Clinical therapy)].
To avoid or reduce postoperative ileus, the operative trauma should be minimized and epidural anesthesia for spinal inhibition of the sympathetic nervous system or i. v. lidocaine should be used, all of which probably act by reducing visceral afferent nerve fiber activity. Recent data suggest that perioperative fluid restriction might reduce postoperative ileus. Epidural anesthesia with local anesthetics and replacing opioids by non-steroidal anti-inflammatory drugs (NSAIDs) for postoperative pain treatment improve the recovery of gastrointestinal motility disturbances. Prior to the operation, the patient should be informed regarding postoperative motility disorders, its length and the presumed resumption of oral food intake, which has been shown to shorten hospital stay. Early postoperative food intake stimulates small and large bowel motility via interenteric reflex arches, avoids i. v. lines and renders discharge acceptable for the patient. Treatment of postoperative ileus includes osmotic laxatives and prokinetic drugs like erythromycine and acetylcholinesterase inhibitors. By combining epidural anesthesia and the sparse use of i. v. opioids with early food intake and, if necessary, laxatives or prokinetics, postoperative ileus should be coped adequately. Nevertheless, the development of new specific prokinetic drugs with minimal or no side effects should remain a target for drug companies to further improve treatment of postoperative ileus.


Using public health detailing and a family-centered ecological approach to promote patient-provider-parent action for reducing childhood obesity.
This paper describes the research and development of the Obesity in Children Action Kit, a paper-based chronic disease management tool of the Public Health Detailing Program (PHD) at the New York City (NYC) Department of Health and Mental Hygiene (DOHMH). It also describes PHD's process for developing the Obesity in Children detailing campaign (targeting healthcare providers working with children aged 2-18) and its results, during which the Action Kit materials were a focal point. The campaign goals were to impact healthcare provider clinical behaviors, improve the health literacy of parents and children, instigate patient-provider-parent dialogue, and change family practices to prevent obesity. Qualitative research methods consisted of healthcare provider in-depth interviews and parent focus groups to aid campaign development. Evaluation of the Obesity in Children campaign included self-reported data on uptake and usage of clinical tools and action steps of matched assessments from 237 healthcare provider initial and follow-up visits, material stock counts, and DOHMH representative qualitative visit excerpts. Key themes identified in parent focus groups were concerns about childhood diabetes and high blood pressure, awareness of cultural pressure and our "supersize" culture, frustration with family communication around overweight and obesity, lack of knowledge about food quality and portion size, economic pressures, and the availability of healthy and nutritious foods. During the Obesity in Children campaign, six representatives reached 161 practices with 1,588 one-on-one interactions, and an additional 461 contacts were made through group presentations. After these interactions, there was a significant increase in the percentage of physicians self-reported use of key recommended practices: Use of BMI percentile-for-age to assess for overweight or obesity at every visit increased from 77% to 88% (p < 0.01); counseling all patients and their parents/caregivers about healthy eating and physical activity increased from 67% to 85% (p < 0.01); counseling all patients on reducing sugar-sweetened beverages increased from 63% to 78% (p < 0.01); and working with families to set realistic goals increased from 64% to 86% (p < 0.01). Clinical tools such as a soda bottle showing sugar content, pediatric plate planners, and goal setting posters were widely adopted (62%, 78%, and 41% respectively). The Obesity in Children campaign, as well as its predecessor, the Adult Obesity campaign and Action Kit, were amongst the best-received and most successful campaigns PHD has conducted since the inception of the program. They have elicited the most attention from healthcare providers and staff, with Obesity in Children Action Kit materials being requested throughout NYC, as well as nationally.


Generation of human iPSCs from human peripheral blood mononuclear cells using non-integrative Sendai virus in chemically defined conditions.
Human-induced pluripotent stem cells (hiPSCs) have received enormous attention because of their ability to differentiate into multiple cell types that demonstrate the patient's original phenotype. The use of hiPSCs is particularly valuable to the study of cardiac biology, as human cardiomyocytes are difficult to isolate and culture and have a limited proliferative potential. By deriving iPSCs from patients with heart disease and subsequently differentiating these hiPSCs to cardiomyocytes, it is feasible to study cardiac biology in vitro and model cardiac diseases. While there are many different methods for deriving hiPSCs, clinical use of these hiPSCs will require derivation by methods that do not involve modification of the original genome (non-integrative) or incorporate xeno-derived products (such as bovine serum albumin) which may contain xeno-agents. Ideally, this derivation would be carried out under chemically defined conditions to prevent lot-to-lot variability and enhance reproducibility. Additionally, derivation from cell types such as fibroblasts requires extended culture (4-6 weeks), greatly increasing the time required to progress from biopsy to hiPSC. Herein, we outline a method of culturing peripheral blood mononuclear cells (PBMCs) and reprogramming PBMCs into hiPSCs using a non-integrative Sendai virus.


Heat stroke and cytokines.
Heat stroke is a life-threatening illness that affects all segments of society, including the young, aged, sick, and healthy. The recent high death toll in France (Dorozynski, 2003) and the death of high-profile athletes has increased public awareness of the adverse effects of heat injury. However, the etiology of the long-term consequences of this syndrome remains poorly understood such that preventive/treatment strategies are needed to mitigate its debilitating effects. Cytokines are important modulators of the acute phase response (APR) to stress, infection, and inflammation. Current data implicating cytokines in heat stroke responses are mainly from correlation studies showing elevated plasma levels in heat stroke patients and experimental animal models. Correlation data fall far short of revealing the mechanisms of cytokine actions such that additional research to determine the role of these endogenous substances in the heat stroke syndrome is required. Furthermore, cytokine determinations have occurred mainly at end-stage heat stroke, such that the role of these substances in progression and long-term recovery is poorly understood. Despite several studies implicating cytokines in heat stroke pathophysiology, few studies have examined the protective effect(s) of cytokine antagonism on the morbidity and mortality of heat stroke. This is particularly surprising since heat stroke responses resemble those observed in the endotoxemic syndrome, for which a role for endogenous cytokines has been strongly implicated. The implication of cytokines as mediators of endotoxemia and the presence of circulating endotoxin in heat stroke patients suggests that much knowledge can be gained from applying our current understanding of endotoxemic pathophysiology to the study of heat stroke. Heat shock proteins (HSPs) are highly conserved proteins that function as molecular chaperones for denatured proteins and reciprocally modulate cytokine production in response to stressful stimuli. HSPs have been shown repeatedly to confer protection in heat stroke and injury models. Interactions between HSPs and cytokines have received considerable attention in the literature within the last decade such that a complex pathway of interactions between cytokines, HSPs, and endotoxin is thought to be occurring in vivo in the orchestration of the APR to heat injury. These data suggest that much of the pathophysiologic changes observed with heat stroke are not a consequence of heat exposure, per se, but are representative of interactions among these three (and presumably additional) components of the innate immune response. This chapter will provide an overview of current knowledge regarding cytokine, HSP, and endotoxin interactions in heat stroke pathophysiology. Insight is provided into the potential therapeutic benefit of cytokine neutralization for mitigation of heat stroke morbidity and mortality based on our current understanding of their role in this syndrome.


A racial bias test with tertiary cancer centre employees: why anti-racist measures are required for First Nations Australians cancer care equity.
Objective To examine implicit bias in employees at a cancer centre using an Australian race (Aboriginal-white) Implicit Association Test (IAT), in an attempt to understand a potential factor for inequitable outcomes of First Nations Australians cancer patients. Methods All employees at an Australian cancer centre were invited to take part in a web-based, cross-sectional study using an Australian race IAT. The results were analysed using Welch t-tests, linear regression and ANOVA. Results Overall, 538/2871 participants (19%) completed the IAT between January and June 2020. The mean IAT was 0.147 (s.d. 0.43, P < 0.001, 95% CI 0.11-0.18), and 60% had a preference for white over First Nations Australians. There was no significant mean difference in IAT scores between sub-groups of gender, age or clinical/non-clinical employees. 21% of employees (95% CI 17.65-24.53) had moderate to strong preference for white over First Nations Australians, compared to 7.1% with moderate to strong preference for First Nations over white Australians (95% CI 5.01-9.09). Conclusions Inequitable cancer survival for First Nations patients has been well established and cancer is now the leading cause of mortality. This paper documents the presence of racial bias in employees at one cancer centre. We argue that this cannot be understood outside the history of colonialism and its effects on First Nations Australians, healthcare workers and our society. Further research is required to evaluate measures of racism, its effect on health care, and how to eliminate it.


Screening, Expression and Identification of Nanobody Against Monkeypox Virus A35R.
The monkeypox (Mpox) virus epidemic presents a significant risk to global public health security. A35R, a crucial constituent of EEV, plays a pivotal role in virus transmission, serves as a vital target for vaccine development, and has potential for serological detection. Currently, there is a dearth of research on nanobodies targeting A35R. The purpose of this study is to identify specific nanobodies target A35R, so as to provide new antibody candidates for Mpox vaccine development and diagnostic kit development. Three nanobodies specific to the monkeypox virus protein A35R were screened from a naïve phage display library. After four rounds of panning, positive phage clones were identified by enzyme-linked immunosorbent assay (ELISA). Further, the nanobody fusion protein was constructed in pNFCG1-IgG1-Fc vector and expressed in HEK293F cells and purified by affinity chromatography. The specificity and affinity of the nanobodies were identified by ELISA. The binding kinetics of the VHH antibody to A35R were assessed via employment of a bio-layer interferometry (BLI) apparatus, thereby determining the nanobodies affinity. The three purified nanobodies showed specific high-affinity binding MPXV A35R, of them, VHH-1 had the best antigen binding affinity (EC50 = 0.010 ug/mL). In addition, VHH-1 on Protein A biosensor can bind Mpox virus A35R, with an affinity constant of 54 nM as determined in BLI assay. In sum, we has obtained three nanobody strains against Mpox virus A35R with significant affinity and specificity, therefore laying an essential foundation for further research as well as the applications of diagnostic and therapeutic tools of Mpox virus.


Chest tube drainage of transudative pleural effusions hastens liberation from mechanical ventilation.
Pleural effusions occur frequently in patients requiring mechanical ventilatory support. Treatment of the precipitating cause and resolution of the pleural effusion may take considerable time. We retrospectively studied the effect of chest tube drainage of transudative pleural effusions on the liberation of patients from mechanical ventilatory support. Patients in the medical ICU (MICU) at Maimonides Medical Center between January 1, 2009, and October 31, 2009, requiring mechanical ventilatory support with a transudative pleural effusion, were studied retrospectively. They were divided into two groups: standard care and standard care plus chest tube drainage. Chest tubes were placed under ultrasound guidance by trained intensivists. Duration of mechanical ventilatory support was the primary end point. Secondary end points included measures of oxygenation, amount of fluid drained, and complications associated with the chest tube. A total of 168 patients were studied; 88 were treated with standard care and 80 underwent chest tube drainage. Total duration of mechanical ventilatory support was significantly shorter for patients who had chest tube drainage: 3.8±0.5 days vs 6.5±1.1 days for the standard group (P=.03). No differences in oxygenation were noted between the two groups. The average amount of fluid drained was 1,220 mL. No significant complications were caused by chest tube drainage. Chest tube drainage of transudative pleural effusions resulted in more rapid liberation from mechanical ventilatory support. It is a very safe procedure when performed under ultrasound guidance by experienced personnel. ClinicalTrials.gov; Identifier: NCT0114285; URL: www.clinicaltrials.gov.


Cardiovascular radiology. Cardiac alterations during intravenous urography.
Electrocardiographic monitoring of 406 patients undergoing intravenous urography was performed before, during, and after the examination. Major cardiac arrhythmias and ischemia were encountered frequently (18%) in those with cardiac disease but also occurred (5%) in the healthy individual with no history of heart disease. Rapid higher dose (28-g iodine) bolus injections result in more cardiac alterations than the slower but larger (42-g iodine) infusion method, whereas the smaller (14-g iodine) bolus injections have the least cardiac effect. Ectopic ventricular beats, the most common abnormality, are usually transient but remain the most potentially lethal of the effects of intravenous contrast media on the heart.


Spatial Release from Masking Using Clinical Corpora: Sentence Recognition in a Colocated or Spatially Separated Speech Masker.
Speech recognition in complex multisource environments is challenging, particularly for listeners with hearing loss. One source of difficulty is the reduced ability of listeners with hearing loss to benefit from spatial separation of the target and masker, an effect called spatial release from masking (SRM). Despite the prevalence of complex multisource environments in everyday life, SRM is not routinely evaluated in the audiology clinic. The purpose of this study was to demonstrate the feasibility of assessing SRM in adults using widely available tests of speech-in-speech recognition that can be conducted using standard clinical equipment. Participants were 22 young adults with normal hearing. The task was masked sentence recognition, using each of five clinically available corpora with speech maskers. The target always sounded like it originated from directly in front of the listener, and the masker either sounded like it originated from the front (colocated with the target) or from the side (separated from the target). In the real spatial manipulation conditions, source location was manipulated by routing the target and masker to either a single speaker or to two speakers: one directly in front of the participant, and one mounted in an adjacent corner, 90° to the right. In the perceived spatial separation conditions, the target and masker were presented from both speakers with delays that made them sound as if they were either colocated or separated. With real spatial manipulations, the mean SRM ranged from 7.1 to 11.4 dB, depending on the speech corpus. With perceived spatial manipulations, the mean SRM ranged from 1.8 to 3.1 dB. Whereas real separation improves the signal-to-noise ratio in the ear contralateral to the masker, SRM in the perceived spatial separation conditions is based solely on interaural timing cues. The finding of robust SRM with widely available speech corpora supports the feasibility of measuring this important aspect of hearing in the audiology clinic. The finding of a small but significant SRM in the perceived spatial separation conditions suggests that modified materials could be used to evaluate the use of interaural timing cues specifically.


Nutritional value of midday meals of senior schoolchildren.
A survey of 565 senior schoolchildren showed that 41% took the school meal. It provided 27% of the daily recommended energy intake and 35% of the daily protein intake set by the Department of Health and Social Security. Of the children who did not take the school meal 4% had a meal which compared favourably with it, though an equal number ate no lunch at all. The remainder either brought snacks from home or bought foods which were found to be both low in protein, iron, and calcium, and high in sugar. Sweets and chips provided the main source of energy for 9% of the subjects.


Cemetery vase breeding of dengue vectors in Manila, Republic of the Philippines.
Aedes albopictus and Ae. aegypti were found breeding abundantly in cement vases within cemeteries in Manila. Aedes albopictus dominated in cemeteries containing vegetation which provided both shade and plant debris for the vase water. The highest larval densities for both species were found from August to December, which is from mid-to-late rainy season. Aedes albopictus is unable to compete successfully with Ae. aegypti in residential areas with sparce vegetation and thus is very limited in its distribution within the city. Biting activity of both species is similar, with peaks occurring between 0530-0600 h and 1730-1800 h.


Shaping Tomorrow's Liver Organoids: A Journey Toward Integrating Bile Ducts.
Liver tissue engineering has undergone remarkable developments since the late 20th century, transitioning from simple two-dimensional cultures to sophisticated three-dimensional organoid models for drug toxicity assessments. Stem cell innovations have enabled the creation of liver organoids for disease modelling and tissue engineering. However, a key limitation is the absence of functional bile ducts in these organoids, crucial for replicating bile-duct related diseases. Bile, synthesized by hepatocytes, plays a vital role in digesting fats and expelling lipid-soluble wastes, including drug byproducts. Diseases impeding bile flow are responsible for many liver transplants and can cause severe conditions such as liver cirrhosis, causing over 50,000 annual deaths in the US. Current liver organoids, while bile-producing, are devoid of bile ducts, limiting their efficacy in mimicking diseases related to bile flow. This article underscores the pressing need to incorporate bile ducts in engineered liver tissues, delves into the challenges faced in this effort, and highlights potential solutions through biomaterial and bioengineering techniques. Such advancements will offer researchers enhanced insights into bile duct disorders and pave the way for exploring innovative therapeutic strategies.


Brain mitochondrial dysfunction and driving simulator performance in untreated obstructive sleep apnea.
It is challenging to determine which patients with obstructive sleep apnea (OSA) have impaired driving ability. Vulnerability to this neurobehavioral impairment may be explained by lower brain metabolites levels involved in mitochondrial metabolism. This study compared markers of brain energy metabolism in OSA patients identified as vulnerable vs resistant to driving impairment following extended wakefulness. 44 patients with moderate-severe OSA underwent 28hr extended wakefulness with three 90min driving simulation assessments. Using a two-step cluster analysis, objective driving data (steering deviation and crashes) from the 2nd driving assessment (22.5 h awake) was used to categorise patients into vulnerable (poor driving, n = 21) or resistant groups (good driving, n = 23). 1 H magnetic resonance spectra were acquired at baseline using two scan sequences (short echo PRESS and longer echo-time asymmetric PRESS), focusing on key metabolites, creatine, glutamate, N-acetylaspartate (NAA) in the hippocampus, anterior cingulate cortex and left orbito-frontal cortex. Based on cluster analysis, the vulnerable group had impaired driving performance compared with the resistant group and had lower levels of creatine (PRESS p = ns, APRESS p = 0.039), glutamate, (PRESS p < 0.01, APRESS p < 0.01), NAA (PRESS p = 0.038, APRESS p = 0.035) exclusively in the left orbito-frontal cortex. Adjusted analysis, higher glutamate was associated with a 21% (PRESS) and 36% (APRESS) reduced risk of vulnerable classification. Brain mitochondrial bioenergetics in the frontal brain regions are impaired in OSA patients who are vulnerable to driving impairment following sleep loss. These findings provide a potential way to identify at risk OSA phenotype when assessing fitness to drive, but this requires confirmation in larger future studies.


The biosynthesis of (+)- -pinene in Pinus species.
1. The degradation of (+)-alpha-pinene biosynthesized from 3RS-[2-(14)C]mevalonate by Pinus radiata or Pinus nigra revealed an asymmetrical labelling pattern whereby the moiety derived from isopentenyl pyrophosphate contained at least 90% of the incorporated tracer. This pattern differed both in asymmetry and position of labelling from previous results obtained with P. nigra, but is consistent with the generally accepted hypothetical mechanism for the biosynthesis of the pinane skeleton. 2. (+)-alpha-Pinene biosynthesized in Pinus attenuata and in the previously named two species from 3RS-[2-(14)C,(4R)-4-(3)H(1)]mevalonate and its (4S)-isomer retained all the 4R hydrogen atoms (within the experimental error) but lost all the 4S hydrogen atoms of the precursor. This stereospecificity of hydrogen loss is the same as that previously found for the formation of geraniol and nerol in other plant species, and the result may be reasonably inferred to be general for monoterpenes.


[The effect of trifluoroperazine on cAMP levels in the rat myocardium during various phases of heart cycle].
Trifluoperazine, a calmodulin inhibitor, has been studied for its effect on cAMP content in rat heart tissue at various cardiac cycle stages with beta-adrenoreceptors stimulation by izadrine. When trifluoperazine is absent, the cAMP level is found to be decreased at the beginning of the cardiac cycle in comparison with the middle of the cardiac cycle. Trifluoperazine (6 X 10(-6) M) induces an increase of the content of cyclic nucleotides at the beginning of the cardiac cycle and has no effect on its level in the middle of the cardiac cycle. This leads to a decrease of the difference between cAMP concentrations in the defined cardiac cycle regions. The calmodulin-dependent reactions might be expected to play an important role in the regulation of the myocardium cAMP concentration change during the cardiac cycle.


Predicting interresidue contacts using templates and pathways.
We present a novel method, HMMSTR-CM, for protein contact map predictions. Contact potentials were calculated by using HMMSTR, a hidden Markov model for local sequence structure correlations. Targets were aligned against protein templates using a Bayesian method, and contact maps were generated by using these alignments. Contact potentials then were used to evaluate these templates. An ab initio method based on the target contact potentials using a rule-based strategy to model the protein-folding pathway was developed. Fold recognition and ab initio methods were combined to produce accurate, protein-like contact maps. Pathways sometimes led to an unambiguous prediction of topology, even without using templates. The results on CASP5 targets are discussed. Also included is a brief update on the quality of fully automated ab initio predictions using the I-sites server.


Active buoyancy adjustment increases dispersal potential in benthic marine animals.
While the study of dispersal and connectivity in the ocean typically centres on pelagic species and planktonic larval stages of benthic species, the present work explores an overlooked locomotor means in post-settlement benthic stages that redefines their dispersal potential. Members of the echinoderm class Holothuroidea colonize a diversity of marine environments world-wide, where they play key ecological and economical roles, making their conservation a priority. Holothuroids are commonly called sea cucumbers or sea slugs to reflect their slow movements and are assumed to disperse chiefly through pelagic larvae. The present study documents and explores their unexpected ability to actively modify their buoyancy, leading them to tumble or float at speeds orders of magnitudes faster than through benthic crawling. Two focal species representing different taxonomic orders, geographic distributions and reproductive strategies were studied over several years. Active buoyancy adjustment (ABA) was achieved through a rapid increase in water-to-flesh ratio by up to 740%, leading to bloating, and simultaneously detachment from the substrate. It occurred as early as 6 months post settlement in juveniles and was recorded in wild adult populations. In experimental trials, ABA was triggered by high conspecific density, decreasing salinity and increasing water turbidity. Based on field video footage, ABA-assisted movements generated speeds of up to 90 km/day. These findings imply that displacement during planktonic larval stages may not supersede the locomotor capacity of benthic stages, challenging the notion of sedentarity. Combining the present results and anecdotal reports, ABA emerges as a generalized means of dispersal among benthic animals, with critical implications for world-wide management and conservation of commercially and ecologically significant species.


Pretreatment Liver Injury Predicts Poor Prognosis of DLBCL Patients.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of lymphoma, with different clinical manifestation and prognosis. The International Prognostic Index (IPI), an index designed during the prerituximab era for aggressive lymphoma, showed variable values in the prediction of patient clinical outcomes. The aim of this study was to analyze the prognostic value and causes of pretreatment liver injury in 363 de novo DLBCL patients in our institution. Pretreatment liver impairment, commonly detected in lymphoma patients, showed significant association with poor outcomes and increased serum inflammatory cytokines in DLBCL patients but had no relation to hepatitis B virus replication nor lymphomatous hepatic infiltration. Multivariate analysis revealed that liver dysfunction, advanced Ann Arbor stage, and elevated lactate dehydrogenase (LDH) were independent adverse prognostic factors of both PFS and OS. Accordingly, a new liver-IPI prognostic model was designed by adding liver injury as an important factor in determining IPI score. Based on Kaplan-Meier curves for PFS and OS, the liver-IPI showed better stratification in DLBCL patients than either the IPI or the revised IPI in survival prediction.


Effect of acute exposure to high ambient temperature on the thermal, metabolic and hygric physiology of a small desert bird.
The intensity and frequency of extreme weather events, such as heat waves, are increasing as a consequence of global warming. Acute periods of extreme heat can be more problematic for wildlife than a chronic increase in mean temperature, to which animals can potentially acclimatise. Predicting effects of heat exposure requires a clear understanding of the capacity of individuals to respond to heat waves, so we examined the physiological response of a small desert bird, the zebra finch (Taeniopygia guttata), after acute previous exposure to high ambient temperature, simulating heatwave-like conditions. The standard physiology of the zebra finches was unaffected by prior exposure to heatwave-type conditions, suggesting that periodic exposure to heatwaves is unlikely to impact their longer-term day-to-day energy and water requirements. When finches were thermally challenged, prior experience of heatwave-like conditions did not impact overall body temperature and evaporative water loss, but birds previously experiencing high temperatures did reduce their metabolic heat production, and the variance in water loss and metabolism between individuals was significantly lower. This suggests that some individuals are more likely to become dehydrated if they have not had prior experience of high temperatures, and do not prioritise water conservation over thermoregulation. However, our observations overall suggest that acute periods of heat exposure do little to modify the general physiology of small birds, supporting the hypothesis that periodic extreme heat events may be more problematic for them than chronic warming.


Ultraviolet night airglow of venus.
The night airglow spectrum of Venus in the ultraviolet is dominated by the v' = 0 progressions of the gamma and delta bands of nitric oxide. The bands are produced by two-body radiative recombination of nitrogen and oxygen atoms. Since the source of these atoms is in the dayside thermosphere, the night airglow is a tracer of the day-to-night thermospheric circulation. The airglow is brightest at equatorial latitudes, and at longitudes on the morning side of the antisolar meridian.


Automatic segmentation of fluorescence lifetime microscopy images of cells using multiresolution community detection--a first study.
Inspired by a multiresolution community detection based network segmentation method, we suggest an automatic method for segmenting fluorescence lifetime (FLT) imaging microscopy (FLIM) images of cells in a first pilot investigation on two selected images. The image processing problem is framed as identifying segments with respective average FLTs against the background in FLIM images. The proposed method segments a FLIM image for a given resolution of the network defined using image pixels as the nodes and similarity between the FLTs of the pixels as the edges. In the resulting segmentation, low network resolution leads to larger segments, and high network resolution leads to smaller segments. Furthermore, using the proposed method, the mean-square error in estimating the FLT segments in a FLIM image was found to consistently decrease with increasing resolution of the corresponding network. The multiresolution community detection method appeared to perform better than a popular spectral clustering-based method in performing FLIM image segmentation. At high resolution, the spectral segmentation method introduced noisy segments in its output, and it was unable to achieve a consistent decrease in mean-square error with increasing resolution.


Anti-tumor effect of hot aqueous extracts from Sonchus oleraceus (L.) L. and Juniperus sabina L - Two traditional medicinal plants in China.
Sonchus oleraceus (L.) L (SO) and Juniperus sabina L (JS) are traditional medicinal plants in China. And the aqueous extracts of them have been used to treat tumor, inflammatory diseases, infection and so on in Chinese folk culture. However, the underlying mechanisms of their anti-tumor activities have not been illustrated yet. This study aims to evaluate the inhibitory effects of aqueous extracts from SO and JS on tumor cells. The prepared aqueous extracts of SO and JS were used to treat HepG-2 and K562 tumor cells, while the human peripheral blood mononuclear cells (PBMCs) were set as normal control. The viabilities, cell cycle and apoptosis of tumor cells after extracts treatment were assessed, in addition the expression of apoptosis-related genes (FasL, caspase 3, 6, 7, 8, 9, and 10) were analyzed. Meanwhile, the adherence and migration of HepG-2 were tested, and the expression levels of MMPs and ICAM-1 were analyzed. On top of that, the pSTAT in the two cells were also analyzed and suggested the related signaling pathway that the extracts acted on with in these tumor cells. Results showed that aqueous extracts of SO and JS have inhibitory effects on HepG-2 and K562 cells by decreasing cell viability and inducing apoptosis via up-regulation of the expression of the apoptosis-related genes FasL, caspase 3 and caspase 9. The extracts had different IC50 on tumor cells and PBMCs, which could block the tumor cell cycle at the G(0)/G(1) stage and significantly inhibit the adherence of HepG-2 cells. The extracts inhibited migration of these cells by inhibiting the expression of ICAM-1, MMP-2 and MMP-9. Further study indicated that the inhibition of pSTAT1 and 3 might be responsible for the inhibitory effects of the extracts on tumor cells. The results of this study indicated that SO and JS extracts had the anti-tumor effects, which may be developed as novel anti-tumor drugs and used in cancer therapy.


Route to 3-Amidino Indoles via Pd(II)-Catalyzed C-H Bond Activation.
We report a facile synthesis of 3-amidino indoles from indoles and cyanamides. The reaction is Pd(II)-catalyzed and proceeds via C-H bond activation of the indole in its 3-position followed by a 1,2-addition of the resulting indole-palladium σ-complex to a cyanamide, which provides the corresponding amidine. The preference for 4,5-diazafluoren-9-one (DAF) as the ligand is investigated using DFT calculations, and a plausible reaction pathway is presented.


[Peripheral angioplasty in patients with lower limb critical ischaemia after operations of femoropopliteal bypass grafting].
The study was aimed at retrospectively assessing the outcomes of peripheral angioplasty (PAP) in patients presenting with lower limb critical ischaemia (LLCI) after previously endured operations off emoropopliteal bypass grafting (FPBG). The PAP procedure was carried out in a total of nine patients diagnosed with LLCI meeting the criteria of the Trans-Atlantic Inter-Society Consensus (TASC), in whom repeat bypass grafting was recognized impossible owing to the absence of either shunting-fit veins or arterial segments suitable for anastomosing. Of these, eight patients had a femoropoplietal bypass graft implanted previously, and the remaining patient had a femoral-anterior-tibial one. In four cases, the patency of the shunts was preserved but all the three tibial arteries were occluded. Five patients displayed total occlusion of the shunts. In 80% of cases, the PAP procedure was performed in C and D types of morphology of the arterial lesion according to the TASC criteria. The PAP procedure was technically successful in eight (89%) patients, making it possibly to re-establish blood supply to the foot along at least one tibial artery. No clinically significant complications following PAP in the treated patients were observed. The average duration of follow up amounted to 9 months. Technically successful PAP was accompanied by clinical success in all the cases. During the follow-up period, one patient died from myocardial infarction with no signs of LLCI. A relapse of LLCI was observed in one (12.5%) patient. The obtained findings suggest that in the treated patients with LLCI after FPBG and impossibility of performing repeat bypass grafting, PAP proved to be a safe and efficient method of revascularization.


Effects of a glucocorticoid receptor agonist, dexamethasone, on fathead minnow reproduction, growth, and development.
Synthetic glucocorticoids are pharmaceutical compounds prescribed in human and veterinary medicine as anti-inflammatory agents and have the potential to contaminate natural watersheds via inputs from wastewater treatment facilities and confined animal-feeding operations. Despite this, few studies have examined the effects of this class of chemicals on aquatic vertebrates. To generate data to assess potential risk to the aquatic environment, we used fathead minnow 21-d reproduction and 29-d embryo-larvae assays to determine reproductive toxicity and early-life-stage effects of dexamethasone. Exposure to 500 µg dexamethasone/L in the 21-d test caused reductions in fathead minnow fecundity and female plasma estradiol concentrations and increased the occurrence of abnormally hatched fry. Female fish exposed to 500 µg dexamethasone/L also displayed a significant increase in plasma vitellogenin protein levels, possibly because of decreased spawning. A decrease in vitellogenin messenger ribonucleic acid (mRNA) expression in liver tissue from females exposed to the high dexamethasone concentration lends support to this hypothesis. Histological results indicate that a 29-d embryo-larval exposure to 500 µg dexamethasone/L caused a significant increase in deformed gill opercula. Fry exposed to 500 µg dexamethasone/L for 29 d also exhibited a significant reduction in weight and length compared with control fry. Taken together, these results indicate that nonlethal concentrations of a model glucocorticoid receptor agonist can impair fish reproduction, growth, and development.


Roles of IL-17, Th1, and Tc1 cells in patients with IgG4-related sclerosing sialadenitis.
Immunoglobulin G4 (IgG4)-related sclerosing sialadenitis is a recently recognized disease entity characterized by high serum IgG4 concentration and IgG4-producing plasma cell expansion in affected organs, which show fibrotic or sclerotic changes. However, little is known about the roles of CD4+ and CD8+ T cells or interleukin (IL)-17 in this disease. The purpose of this study was to evaluate the characteristics of CD4+ and CD8+ T cells and IL-17 in patients with IgG4-related sclerosing sialadenitis. A retrospective clinical study at the Yamagata University School of Medicine. The patient group consisted of six males and four females with an average age of 57.9 years (range, 38 to 73 years). Subsets of T helper (Th)1, Th2, T cytotoxic type (Tc)1, and Tc2 cells from patients with IgG4-related sclerosing sialadenitis were examined by using intracellular cytokine flow cytometry. Expression of IL-17 in the patients' lesions was also investigated immunohistochemically. Six patients with IgG4-related sclerosing sialadenitis with high ratios of IgG4/IgG and prominent infiltration of IgG4-positive plasmacytes in the involved salivary glands had systemic complications, including pancreatitis, retroperitoneal fibrosis, and/or inflammatory pseudotumor of the lung after the initial swelling of the salivary glands. Populations of Th1 and Tc1 cells were significantly greater in IgG4-related sclerosing sialadenitis than in the controls (P < .05), but Th2 and Tc2 cell populations were not significantly increased. Expression of IL-17 was observed in the lesions of affected patients. Increases in Th1 and Tc1 cell populations and IL-17 expression might be involved in the mechanism of pathogenesis of IgG4-related sclerosing sialadenitis.


[The pharmacological blockade of the cardiac and gastric enteric ganglia by a new parasympatholytic].
The blocking effects of a newly synthetized compound N-decyltropine bromide (IEM-1556), on pentagastrin-, carbachol- and histamine-induced gastric secretion in chronic dogs, on stress-induced changes in gastric mucosa in rats, on vagus-induced effect in heart and on arterial blood pressure in rats were studied. The effects were compared with those produced by hexamethonium, a conventional ganglionic blocking agent. IEM-1556 inhibited gastric secretion and acid output for a much longer time than hexamethonium did. It also effectively protected gastric mucosa against stress-induced erosions and hemorrhages. IEM-1556 much more effectively blocked the vagus-induced reduction of the heart rate than hexamethonium did, and, in contrast to latter, did not reduce the arterial blood pressure. The results suggest that IEM-1556 is a highly selective blocking agent for parasympathetic and enteric ganglia versus sympathetic ganglia.


Dermal uptake directly from air under transient conditions: advances in modeling and comparisons with experimental results for human subjects.
To better understand the dermal exposure pathway, we enhance an existing mechanistic model of transdermal uptake by including skin surface lipids (SSL) and consider the impact of clothing. Addition of SSL increases the overall resistance to uptake of SVOCs from air but also allows for rapid transfer of SVOCs to sinks like clothing or clean air. We test the model by simulating di-ethyl phthalate (DEP) and di-n-butyl phthalate (DnBP) exposures of six bare-skinned (Weschler et al. 2015, Environ. Health Perspect., 123, 928) and one clothed participant (Morrison et al. 2016, J. Expo. Sci. Environ. Epidemiol., 26, 113). The model predicts total uptake values that are consistent with the measured values. For bare-skinned participants, the model predicts a normalized mass uptake of DEP of 3.1 (μg/m2 )/(μg/m3 ), whereas the experimental results range from 1.0 to 4.3 (μg/m2 )/(μg/m3 ); uptake of DnBP is somewhat overpredicted: 4.6 (μg/m2 )/(μg/m3 ) vs. the experimental range of 0.5-3.2 (μg/m2 )/(μg/m3 ). For the clothed participant, the model predicts higher than observed uptake for both species. Uncertainty in model inputs, including convective mass transfer coefficients, partition coefficients, and diffusion coefficients, could account for overpredictions. Simulations that include transfer of skin oil to clothing improve model predictions. A dynamic model that includes SSL is more sensitive to changes that impact external mass transfer such as putting on and removing clothes and bathing.


Plant genotypic diversity increases population size of a herbivorous insect.
It is critical to incorporate the process of population dynamics into community genetics studies to identify the mechanisms of the linkage between host plant genetics and associated communities. We studied the effects of plant genotypic diversity of tall goldenrod Solidago altissima on the population dynamics of the aphid Uroleucon nigrotuberculatum. We found genotypic variation in plant resistance to the aphid in our experiments. To determine the impact of plant genotypic diversity on aphid population dynamics, we compared aphid densities under conditions of three treatments: single-genotype plots, mixed-genotype plots and mixed-genotype-with-cages plots. In the latter treatment plants were individually caged to prevent natural enemy attack and aphid movement among plants. The synergistic effects of genotypes on population size were demonstrated by the greater aphid population size in the mixed-genotype treatment than expected from additive effects alone. Two non-exclusive hypotheses are proposed to explain this pattern. First, there is a source-sink relationship among plant genotypes: aphids move from plant genotypes where their reproduction is high to genotypes where their reproduction is low. Second, natural enemy mortality is reduced in mixed plots in a matrix of diverse plant genotypes.


ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29.
Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked ERAP2 with BU, an aminopeptidase which trims peptides before their presentation by HLA class I at the cell surface, which suggests that ERAP2-dependent peptide presentation by HLA-A29 drives the pathogenesis of BU. However, it remains poorly understood whether the effects of ERAP2 on the HLA-A29 peptidome are distinct from its effect on other HLA allotypes. To address this, we focused on the effects of ERAP2 on the immunopeptidome in patient-derived antigen presenting cells. Using complementary HLA-A29-based and pan-class I immunopurifications, isotope-labeled naturally processed and presented HLA-bound peptides were sequenced by mass spectrometry. We show that the effects of ERAP2 on the N-terminus of ligands of HLA-A29 are shared across endogenous HLA allotypes, but discover and replicate that one peptide motif generated in the presence of ERAP2 is specifically bound by HLA-A29. This motif can be found in the amino acid sequence of putative autoantigens. We further show evidence for internal sequence specificity for ERAP2 imprinted in the immunopeptidome. These results reveal that ERAP2 can generate an HLA-A29-specific antigen repertoire, which supports that antigen presentation is a key disease pathway in BU.


Styrene Aziridination by Iron(IV) Nitrides.
Thermolysis of the iron(IV) nitride complex [PhB(tBuIm)3Fe≡N] with styrene leads to formation of the high-spin iron(II) aziridino complex [PhB(tBuIm)3Fe-N(CH2CHPh)]. Similar aziridination occurs with both electron-rich and electron-poor styrenes, while bulky styrenes hinder the reaction. The aziridino complex [PhB(tBuIm)3Fe-N(CH2CHPh)] acts as a nitride synthon, reacting with electron-poor styrenes to generate their corresponding aziridino complexes, that is, aziridine cross-metathesis. Reaction of [PhB(tBuIm)3Fe-N(CH2CHPh)] with Me3SiCl releases the N-functionalized aziridine Me3SiN(CH2CHPh) while simultaneously generating [PhB(tBuIm)3FeCl]. This closes a synthetic cycle for styrene azirdination by a nitride complex. While the less hindered iron(IV) nitride complex [PhB(MesIm)3Fe≡N] reacts with styrenes below room temperature, only bulky styrenes lead to tractable aziridino products.


Performance of Relative Enhancement on Multiphasic MRI for the Differentiation of Clear Cell Renal Cell Carcinoma (RCC) From Papillary and Chromophobe RCC Subtypes and Oncocytoma.
The objective of our study was to investigate the performance of relative enhancement on multiphasic MRI to differentiate clear cell renal cell carcinoma (RCC) from other RCC subtypes (papillary and chromophobe) and oncocytoma. For this study, we derived a cohort of 34 clear cell RCCs, nine oncocytomas, 12 papillary RCCs, and 10 chromophobe RCCs with a preoperative multiphasic dynamic contrast-enhanced MRI study with up to four phases (i.e., unenhanced, corticomedullary, nephrographic, excretory) from 2005 to 2016. These groups were evaluated for multiphasic enhancement and were compared using Kruskal-Wallis and Mann-Whitney tests. ROC curves were constructed and logistic regression analyses were performed to evaluate the performance of multiphasic enhancement in differentiating clear cell RCCs from the other three groups. Clear cell RCCs exhibited significantly greater relative signal intensity compared with uninvolved renal cortex in the corticomedullary phase (mean, 2.9) than oncocytomas (-21.7, p = 0.001), papillary RCCs (-53.0, p < 0.001), and chromophobe RCCs (-21.0, p < 0.001). Relative signal intensity in the corticomedullary phase differentiated clear cell RCCs from oncocytomas with an AUC of 0.90 and with an accuracy of 84% (32/38), sensitivity of 90% (27/30), and specificity of 63% (5/8) after controlling for lesion size, patient age, and patient sex. Relative corticomedullary signal intensity differentiated clear cell RCCs from oncocytomas and other RCC subtypes with an AUC of 0.93 and with an accuracy of 90% (53/59), sensitivity of 90% (27/30), and specificity of 90% (26/29) after controlling for lesion size, patient age, and patient sex. Multiphasic MRI enhancement may assist in differentiating clear cell RCC from oncocytomas and other RCC subtypes, if validated in prospective studies.