Reactive oxygen species and matrix remodeling in diabetic kidney.
Excessive deposition of extracellular matrix (ECM) in the kidney is the hallmark of diabetic nephropathy. Although the amount of ECM deposited in the kidney depends on the balance between the synthesis and degradation of ECM, the role of ECM degradation in matrix remodeling has been less well appreciated. High glucose, advanced glycation end products, angiotensin II, and TGF-beta1 all increase intracellular reactive oxygen species (ROS) in renal cells and contribute to the development and progression of diabetic renal injury. The role of ROS in increased ECM synthesis has been well documented. ROS may also play a critical role in decreased ECM degradation by mediating high glucose- and TGF-beta1-induced inhibition of the proteolytic system, plasmin, and matrix metalloproteinases in the glomeruli. A recent observation suggests that ROS play an important role in tubulointerstitial fibrosis by mediating TGF-beta1-induced epithelial-mesenchymal transition (EMT). Accelerated ECM degradation is required to disrupt tubular basement membrane and complete EMT. ROS thus seem to be involved in both decreased and increased ECM degradation. It is not clear how cells determine when and where to increase or decrease ECM degradation in response to ROS. Precise definition of ROS-activated signaling pathways leading to ECM remodeling in the kidney will provide new strategies to prevent or treat diabetic renal injury.


A three-dimensional molecular template for substrates of human cytochrome P450 involved in debrisoquine 4-hydroxylation.
A three-dimensional molecular template has been generated for substrates of human debrisoquine 4-hydroxylase cytochrome P450 (CYP2D6). This template defines the stereochemical requirements for CYP2D6 substrates in terms of the volume occupied and positions of key atoms. The modelling was based on the X-ray crystallographic coordinates of the location of the attacked C5 atom of camphor in relation to the haem in cytochrome P450 cam. Interactive molecular graphics combined with energy calculations were used to identify allowed conformers to superpose known CYP2D6 substrates to yield a molecular template. This model takes into account the site of attack of the known substrates and the requirement for a protonated nitrogen atom to interact with an anion site of the protein. A nitrogen-anion distance of between 2.5 and 4.5 A was allowed for the interaction. The substrates modelled were cardiovascular drugs (debrisoquine, sparteine, guanoxan and perhexiline), beta-adrenergic blocking agents (bufuralol and propranolol), tricyclic anti-depressants (desipramine, amitriptyline and nortriptyline) and other miscellaneous compounds (phenformin, methoxy-amphetamine, codeine and dextromethorphan). The template generated in this manner was then used to determine the likelihood that certain other compounds were substrates for CYP2D6. A carcinogenic protein pyrolysate product, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), did not fit the template and is therefore unlikely to be activated by this enzyme. A potent carcinogen in tobacco smoke, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), fitted the template but could not be modelled to form a favourable nitrogen-anion interaction. Experimental substrate competition studies also showed that NNK is unlikely to be a CYP2D6 substrate. It was also shown that the widely used drug for treatment of breast cancer, trans-1-(4-beta-dimethylaminoethoxyphenyl)-,2-diphenyl-1-ene (tamoxifen), did not fit the molecular template and is unlikely to be metabolized by CYP2D6. Coordinates of the template are available.


Dose dependent side effect of superparamagnetic iron oxide nanoparticle labeling on cell motility in two fetal stem cell populations.
Multipotent stem cells (SCs) could substitute damaged cells and also rescue degeneration through the secretion of trophic factors able to activate the endogenous SC compartment. Therefore, fetal SCs, characterized by high proliferation rate and devoid of ethical concern, appear promising candidate, particularly for the treatment of neurodegenerative diseases. Super Paramagnetic Iron Oxide nanoparticles (SPIOn), routinely used for pre-clinical cell imaging and already approved for clinical practice, allow tracking of transplanted SCs and characterization of their fate within the host tissue, when combined with Magnetic Resonance Imaging (MRI). In this work we investigated how SPIOn could influence cell migration after internalization in two fetal SC populations: human amniotic fluid and chorial villi SCs were labeled with SPIOn and their motility was evaluated. We found that SPIOn loading significantly reduced SC movements without increasing production of Reactive Oxygen Species (ROS). Moreover, motility impairment was directly proportional to the amount of loaded SPIOn while a chemoattractant-induced recovery was obtained by increasing serum levels. Interestingly, the migration rate of SPIOn labeled cells was also significantly influenced by a degenerative surrounding. In conclusion, this work highlights how SPIOn labeling affects SC motility in vitro in a dose-dependent manner, shedding the light on an important parameter for the creation of clinical protocols. Establishment of an optimal SPIOn dose that enables both a good visualization of grafted cells by MRI and the physiological migration rate is a main step in order to maximize the effects of SC therapy in both animal models of neurodegeneration and clinical studies.


CD14 influences host immune responses and alternative activation of macrophages during Schistosoma mansoni infection.
Antigen-presenting cell (APC) plasticity is critical for controlling inflammation in metabolic diseases and infections. The roles that pattern recognition receptors (PRRs) play in regulating APC phenotypes are just now being defined. We evaluated the expression of PRRs on APCs in mice infected with the helminth parasite Schistosoma mansoni and observed an upregulation of CD14 expression on macrophages. Schistosome-infected Cd14(-/-) mice showed significantly increased alternative activation of (M2) macrophages in the livers compared to infected wild-type (wt) mice. In addition, splenocytes from infected Cd14(-/-) mice exhibited increased production of CD4(+)-specific interleukin-4 (IL-4), IL-5, and IL-13 and CD4(+)Foxp3(+)IL-10(+) regulatory T cells compared to cells from infected wt mice. S. mansoni-infected Cd14(-/-) mice also presented with smaller liver egg granulomas associated with increased collagen deposition compared to granulomas in infected wt mice. The highest expression of CD14 was found on liver macrophages in infected mice. To determine if the Cd14(-/-) phenotype was in part due to increased M2 macrophages, we adoptively transferred wt macrophages into Cd14(-/-) mice and normalized the M2 and CD4(+) Th cell balance close to that observed in infected wt mice. Finally, we demonstrated that CD14 regulates STAT6 activation, as Cd14(-/-) mice had increased STAT6 activation in vivo, suggesting that lack of CD14 impacts the IL-4Rα-STAT6 pathway, altering macrophage polarization during parasite infection. Collectively, these data identify a previously unrecognized role for CD14 in regulating macrophage plasticity and CD4(+) T cell biasing during helminth infection.


Effects of dietary dimethylarsinic acid on the urine and urothelium of rats.
Dimethylarsinic acid (DMA), fed to rats for 2 years, produced bladder hyperplasia and tumors at doses of 40 and 100 p.p.m., more in females than males. No urothelial proliferation was seen in mice. Our objectives were to investigate the mode of action of bladder tumor formation, evaluate the dose-response and the role of diet and to determine if the urothelial effects were reversible. The study included groups of female F344 rats fed DMA in Purina 5002 diet at doses of 0, 2, 10, 40 or 100 p.p.m. for 10 weeks; two groups of females fed DMA (0 and 100 p.p.m.) in Altromin 1321 for 10 weeks; two groups of males fed DMA (0 and 100 p.p.m.) in Purina 5002 for 10 weeks; a female high-dose recovery group (100 p.p.m. in Purina 5002 diet for 10 weeks followed by control diet for 10 weeks); and two female groups (0 and 100 p.p.m.) in Purina diet for 20 weeks. Urothelial toxicity and hyperplasia were detected by light and scanning electron microscopy (SEM), and the bromodeoxyuridine labeling index was increased in the female 40 and 100 p.p.m. groups. The effects were less in males, but were similar in females fed DMA in Altromin 1321. SEM detected no abnormal urinary solids related to treatment in any group. Urinary calcium was increased in the females fed 40 and 100 p.p.m. in Purina diet, despite overall urinary dilution. Calcification was increased in kidneys of female rats fed Purina diet. The urothelial effects of DMA were reversible. The findings support a non-DNA reactive mechanism for DMA rat bladder carcinogenicity related to urothelial toxicity and regeneration. The toxicity is probably not due to urinary solids. The toxicity and regeneration are produced in a dose-responsive manner in female rats, are greater in female than in male rats, and are reversible.


Synthesis of OmpA protein of Escherichia coli K12 in Bacillus subtilis.
We have inserted a C-terminally truncated gene of the major outer membrane protein OmpA of Escherichia coli downstream from the promoter and signal sequence of the secretory alpha-amylase of Bacillus amyloliquefaciens in a secretion vector of Bacillus subtilis. B. subtilis transformed with the hybrid plasmid synthesized a protein that was immunologically identified as OmpA. All the protein was present in the particulate fraction. The size of the protein compared to the peptide synthesized in vitro from the same template indicated that the alpha-amylase derived signal peptide was not removed; this was verified by N-terminal amino acid sequence determination. The lack of cleavage suggests that there was little or no translocation of OmpA protein across the cytoplasmic membrane. This is an unexpected difference compared with periplasmic proteins, which were both secreted and processed when fused to the same signal peptide. A requirement of a specific component for the export of outer membrane proteins is suggested.


Effect of epoetin alpha therapy on cognitive function in anaemic patients with solid tumours undergoing chemotherapy.
The primary aim of this study was to assess whether epoetin alpha (Ea) would improve cognitive performance in a group of anaemic cancer patients receiving chemotherapy. The secondary aim was to confirm the positive impact of Ea on haematological parameters, and quality of life (QOL). Fifty patients with solid tumours and haemoglobin (Hb) <11.0 g/dL received Ea 40,000 units once weekly for 12 weeks and were administered the Mini-Mental State Examination and the European Organization for Research and Treatment of Cancer (QLQ-C30) questionnaire prior to Ea therapy and at study completion. No clinically significant alterations were observed on cognitive function during Ea treatment. Changes in cognitive function were unrelated to Hb change and there were no significant differences in cognitive performance between Ea responders and non-responders. The analyses revealed clinically significant improvements in Hb levels, physical and role function, and clinically meaningful reductions in fatigue. Hb changes were significantly associated with the magnitude of improvement in QOL parameters. The lack of a clinical benefit in cognition observed in this study during Ea treatment may redirect the focus of research from enhancing to maintaining cognitive function, since stability in cognitive performance through time may be as well clinically important.


Sevoflurane in intraoperative and postoperative cardiac surgery patients. Our experience in intensive care unit with sevoflurane sedation.
Recently, many studies have shown a decrease in myocardial damage in patients undergoing coronary artery bypass surgery where the anesthetic agent used was sevoflurane compared with propofol. The basis for this protective effect of the myocardium occurs through the mechanisms of preconditioning and postconditioning of halogenated agents. Both relate to the benefit of prior or subsequent administration of the drug (halogenated anesthetic agent) to the harmful stimulus for myocardial cells. The two mechanisms have similar effector mechanisms. The intraoperative administration of sevoflurane is common in anesthetic practice, but the continuation of the administration in the first postoperative hours is made possible by the AnaConDa ® device (ACD; Sedana Medical AB, Uppsala, Sweden) designed for halogenated sedation of patients admitted to intensive care units (ICU). This device has proven useful to facilitate the treatment of pathological conditions. The object of our review is to determine if there are beneficial effects to extending exposure to halogenated agents in the immediate post-operative period . In the post-operative phase, the pathological myocardium is in a reperfusion process in the coronary microcirculation and expression of certain receptors and chemical mediators can reduce potential injury secondary to reperfusion of previously hibernating and/or stunned tissue.


Oncological and Functional Outcomes of Laparoscopic Radiofrequency Ablation and Partial Nephrectomy for T1a Renal Masses: A Retrospective Single-center 60 Month Follow-up Cohort Study.
It remains unclear whether laparoscopic radiofrequency ablation (RFA) for primary treatment of small renal masses is similar to partial nephrectomy (PN) in terms of long-term oncological and renal function outcomes. We reviewed the long-term outcomes for patients with T1a renal masses treated with either laparoscopic RFA orPN. This retrospective single-center study on 115 patients who were treated by laparoscopic RFA or PN for small (<4 cm) renal masses between January 2005 and October 2014 at Chungnam National University Hospital. Estimated glomerular filtration rate (eGFR) was measured before and 1-2 weeks after surgery and at last follow-up. The laparoscopic RFA and PN groups were compared in terms of clinical characteristics data and change in eGFR after surgery using the Chi-squared test or Student's t-test. Survival data were analyzed using theKaplan-Meier method and the log-rank test. Of the 115 patients, 62 and 53 underwent laparoscopic RFA and PN, respectively. Their mean (range) follow-up duration was 60 (30-104) and 68 (30-149) months, respectively (P = 0.092). The RFA patients were older (P = 0.023) and had smaller tumors (P = 0.000). RFA associated with shorter operation and hospitalization times and less perioperative blood loss (all P<0.001). The groups did not differ in terms of change in eGFR 1-2 weeks after surgery (P = 0.252) or at the last follow-up (P = 0.395) or 5 year survival rates (P = 0.360). Laparoscopic RFA for small renal masses was comparable to PN in terms of oncological and functional outcomes and associated with shorter operative and hospitalization times and less perioperative bleeding.


A subset of synaptic transmission events is coupled to acetyl coenzyme A production.
Biological principles sustain the inference that synaptic function is coupled to neural metabolism, but the precise relationship between these two activities is not known. For example, it is unclear whether all synaptic transmission events are uniformly dependent on metabolic flux. Most synapses use glutamate, and the principal metabolic function of the brain is glucose oxidation, which starts with glycolysis. Thus, we asked how glutamatergic synaptic currents are modified by partial deficiency of the main glycolytic enzyme pyruvate dehydrogenase (PDH), which generates the intermediary metabolism product acetyl coenzyme A (acetyl-CoA). Using brain slices obtained from mice that were genetically modified to harbor a behaviorally relevant degree of PDH suppression, we also asked whether such impact is indeed metabolic via the bypassing of PDH with a glycolysis-independent acetyl-CoA substrate. We analyzed spontaneous synaptic currents under recording conditions that minimize artificial metabolic augmentation. Principal component analysis identified synaptic charge transfer as the major difference between a subset of wild-type and PDH-deficiency (PDHD) postsynaptic currents. This was due to reduced charge transfer as well as diminished current rise and decay times. The alternate acetyl-CoA source acetate rapidly restored these features but only for events of large amplitude as revealed by correlational and kernel density analyses. Application of tetrodotoxin to block large-amplitude events evoked by action potentials removed synaptic event charge transfer and decay-time differences between wild-type and PDHD neurons. These results suggest that glucose metabolic flux and excitatory transmission are intimately coupled for synaptic events characterized by large current amplitude.NEW & NOTEWORTHY In all tissues, metabolism and excitation are coupled but the details of this relationship remain elusive. Using a brain-targeted genetic approach in mice, reduction of pyruvate dehydrogenase, a major gateway in glucose metabolism, leads to changes that affect the synaptic event charge associated primarily with large excitatory (i.e., glutamate mediated) synaptic potentials. This can be modified in the direction of normal using the alternative fuel acetate, indicating that this phenomenon depends on rapid metabolic flux.


[Nucleotide sequence of the genome region of the tick-borne encephalitis virus coding for structural virion proteins].
RNA of a flavivirus-tick-borne encephalitis virus (strain Sofjin) was subjected to reverse transcription and the DNA copy was transformed into double-stranded DNA by action of E. coli DNA-polymerase I (Klenow's fragment). This DNA was annealed with pBR322 plasmid. The recombinant plasmids were cloned in E. coli K802. The nucleotide sequence of the inserts of the clones coding for region of structural proteins C, pre-M, E and nonstructural protein ns1 was determined by the Maxam-Gilbert method. The nucleotide sequence of these regions is translatable into an amino acid sequence of proteins without interruption. The amino acid sequences of proteins and nucleotide sequence of genome of the tick-borne encephalitis virus are extensively homologous to that found for the flaviviruses Yellow Fever and West Nile.


Efficacy and safety of abemaciclib alone and with PI3K/mTOR inhibitor LY3023414 or galunisertib versus chemotherapy in previously treated metastatic pancreatic adenocarcinoma: A randomized controlled trial.
Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFβ inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC. This Phase 2 open-label study enrolled patients with metastatic PDAC who progressed after 1-2 prior therapies. Patients were enrolled in a safety lead-in (abemaciclib plus galunisertib) followed by a 2-stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib-containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression-free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics. One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4-1.8), 1.8 months (95% CI: 1.3-1.9), and 3.3 months (95% CI: 1.1-5.7), respectively. No arms advanced to Stage 2. No new safety signals were identified. In patients with pretreated metastatic PDAC, abemaciclib-based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC.


Brain Aneurysms in the Pediatric Population of Slovenia: A Case Series.
Brain aneurysms are rare in the pediatric population. The diagnosis of a brain aneurysm in a child may be difficult because of its infrequency and often subtle or nonspecific clinical presentation. Endovascular therapy and microsurgical treatment are increasingly used approaches in treating children, possibly contributing to favorable outcomes if patients are treated in a timely manner. We were interested in the clinical presentation, symptoms, diagnostics, treatment, and follow-up of pediatric patients with brain aneurysms in Slovenia. This was a retrospective review of medical documentation of children with intracranial aneurysms treated at the University Children's Hospital in Ljubljana, Slovenia, from January 1998 to December 2017. We identified a cohort of eight children (median age: 14.9 years; range: 2.8-17.7). The estimated incidence of pediatric brain aneurysms in Slovenia is 0.12/100,000 children per year. We observed a male predominance (1.7:1). Half of the patients presented with acute onset of neurologic symptoms and three with subarachnoid hemorrhage. One of the patients had a related stroke. The presenting symptoms were tonic-clonic seizures, hemiparesis, paresthesias, speech disturbance, and cranial nerve palsy. The other half of aneurysms were identified incidentally. Five patients had anterior circulation aneurysms; the most prevalent location was the internal carotid artery. One patient was treated with surgical procedures, four patients were treated with endovascular procedures, and three patients were treated conservatively. Outcome was excellent in all patients. Endovascular interventions and microsurgical procedures appear to be safe and effective in the treatment of brain aneurysms in the pediatric population. Asymptomatic patients with brain aneurysms need close follow-up.


Models of visual categorization.
Visual categorization refers to our ability to organize objects and visual scenes into discrete categories. It is an essential skill as it allows us to distinguish friend from foe or edible versus poisonous food. Understanding how the visual system categorizes objects and scenes is a challenge because it requires bridging the gap between different levels of understanding-from the level of neural circuits and neural networks to the level of information processing and, ultimately, behavior. Computational models have become powerful tools for integrating knowledge across these levels of analysis. We review recent progress in our understanding of the computational mechanisms underlying visual categorization and discuss some of the remaining challenges.


Determination of Some Elements in Legumes Using ICP-MS and EDXRF Methodology Applications.
The current study involves two analytical research techniques, inductively coupled plasma-mass spectrometry (ICP-MS) and energy dispersive X-ray fluorescence (EDXRF) spectroscopy, used to determine the elemental composition of different legumes usually produced and consumed in Slovenia. Results indicate that data obtained using these methods are in agreement with certified reference materials. In total, nineteen elements were determined from twenty legume samples. An intercomparison between four macro- (P, S, K, Ca) and three microelements (Fe, Zn, Mo) measured using ICP-MS and EDXRF methods showed a strong correlation. The EDXRF was found to be a cheaper, simpler and more environmentally friendly method for determination of elements P, S, Cl, K, Ca, Fe, Zn, Mo, Sr, Rb, Ti and Br in legumes, while for the identification and determination of Na, Mg, V, Cr, Mn, Co and Cu content ICP-MS was the method of choice due to its excellent sensitivity and accuracy. Using principal component analysis (PCA), the samples of the studied legumes were classified into four groups according to their elemental composition.


Production of digoxigenin-labelled RNA probes and the detection of cytokine mRNA in rat spleen and brain by in situ hybridization.
Non-radioactive in situ hybridization is a sensitive method for determining the site of production for secretory molecules such as cytokines. We report here on the central and peripheral induction of proinflammatory cytokines by endotoxin, and outline procedures for the generation and application of rat-specific digoxigenin (Dig)-labelled RNA probes for the localization of mRNA by in situ hybridization. Rats were injected either intravenously (i.v.) or intracerebroventricularly (i.c.v.) with vehicle or lipopolysaccharide (LPS) and sacrificed at various time intervals post-injection. Rats were then perfused with 4% paraformaldehyde and the spleens and brains were removed and cryoprotected in 30% sucrose. Dig-labelled, rat-specific, antisense and sense RNA probes were generated by in vitro transcription from PCR-derived templates. Positive staining with all the antisense probes was cytoplasmic, whereas the sense probes showed no staining. Numerous tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) mRNA positive cells were observed in the marginal zone and in the red pulp of the spleen after iv LPS injections, whereas sections from saline-treated animals showed minimal cytokine mRNA expression. Cells positive for TNF-alpha and IL-1beta mRNA were detectable in the brain after i.c.v. injections of LPS, but not after icv injection of vehicle. An antisense probe for c-fos was utilized in these studies as a positive control for our procedure due to its anatomically specific expression in the rat brain after LPS. In conclusion we have demonstrated that in situ hybridization with Dig-labelled RNA probes is an efficient, sensitive and reliable tool to localize cytokine mRNA production in rat tissue.


N-acetyl-L-cysteine combined with mesalamine in the treatment of ulcerative colitis: randomized, placebo-controlled pilot study.
To evaluate the effectiveness and safety of oral N-acetyl-L-cysteine (NAC) co-administration with mesalamine in ulcerative colitis (UC) patients. Thirty seven patients with mild to moderate UC were randomized to receive a four-wk course of oral mesalamine (2.4 g/d) plus N-acetyl-L-cysteine (0.8 g/d) (group A) or mesalamine plus placebo (group B). Patients were monitored using the Modified Truelove-Witts Severity Index (MTWSI). The primary endpoint was clinical remission (MTWSI < or = 2) at 4 wk. Secondary endpoints were clinical response (defined as a reduction from baseline in the MTWSI of > or = 2 points) and drug safety. The serum TNF-alpha, interleukin-6, interleukin-8 and MCP-1 were evaluated at baseline and at 4 wk of treatment. Analysis per-protocol criteria showed clinical remission rates of 63% and 50% after 4 wk treatment with mesalamine plus N-acetyl-L-cysteine (group A) and mesalamine plus placebo (group B) respectively (OR = 1.71; 95% CI: 0.46 to 6.36; P = 0.19; NNT = 7.7). Analysis of variance (ANOVA) of data indicated a significant reduction of MTWSI in group A (P = 0.046) with respect to basal condition without significant changes in the group B (P = 0.735) during treatment. Clinical responses were 66% (group A) vs 44% (group B) after 4 wk of treatment (OR = 2.5; 95% CI: 0.64 to 9.65; P = 0.11; NNT = 4.5). Clinical improvement in group A correlated with a decrease of IL-8 and MCP-1. Rates of adverse events did not differ significantly between both groups. In group A (oral NAC combined with mesalamine) contrarily to group B (mesalamine alone), the clinical improvement correlates with a decrease of chemokines such as MCP-1 and IL-8. NAC addition not produced any side effects.


Interruption of the tricuspid regurgitant jet: A possible consequence of reflected waves.
Reflected pressure waves can impact central aortic pressure, and can cause notching of the pulmonic valve Doppler signal. However, reflected waves in the venous system usually do not achieve a high enough velocity to alter Doppler flow patterns. Herein we report a case of systolic notching of the tricuspid regurgitant signal that likely resulted from reflected venous waves.


Use of carotid artery cannulation during redo sternotomy in congenital cardiac surgery: a single-centre experience.
Management of resternotomy is often a difficult challenge in patients with congenital diseases who have undergone multiple sternotomies. Our goal was to report our single-centre experience with carotid cannulation using a graft interposed during redo sternotomy in complex cardiac reintervention procedures. We performed a retrospective review of all patients who had undergone complex redo sternotomies between January 2019 and May 2020 utilizing a cervical cannulation technique with a Gore-Tex graft interposed on the carotid artery. We classified our population study on the basis of the primary diagnosis and the type of surgery. The primary outcomes of our analysis were the evaluation of the safety of the procedure in terms of survival and freedom from neurological events. We analysed 22 patients who had undergone previous complex operations. The median age and weight at the time of reintervention were 130.35 (range 0.46-435) months and 31.5 (range 2.2-85) kg, respectively. Composite graft carotid cannulation provided adequate arterial flow in all patients with a median arterial flow of 3.5 l/min/m2 (range 0.6-6). One major cardiac injury occurred during sternotomy when emergency cardiopulmonary bypass (CPB) was initiated. Moreover, during their hospital stays, all patients had an uneventful recovery without neurological or vascular complications and no cervical wound infections. Carotid cannulation using interposition of a side graft on the common carotid artery for arterial inflow is a reliable and safe method for initiation of CPB in complex redo surgeries in patients with congenital disease. Complications directly associated with this type of cannulation are uncommon and allow surgical re-entry with overall low risks.


Enhanced Biological Phosphorus Removal at low Sludge Retention Time in view of its integration in A-stage systems.
The two-stage A/B WWTP configuration is being studied as a possible wastewater treatment with low energy consumption or even with a net energy generation. The first phase, A-stage, is designed to remove organic matter at very short Sludge Retention Time (SRT), while the B-stage is based on autotrophic nitrogen removal. However, P-removal in the A/B process usually only relies on precipitation. This work studies the potential inclusion of Enhanced Biological Phosphorus Removal (EBPR) in the A-stage phase. For this aim, the long-term operation of three different Sequencing Batch Reactors (SBR) enriched in Accumulibacter at low SRT was thoroughly monitored for more than three months each one. This work shows that EBPR can be sustained with a minimal SRT of 3.6 d at 25 °C. Lower values, SRT = 3 d, led to the PAO washout because of a reduction in P-release and P-uptake, an increase of the VSS/TSS ratio and a decrease of the P/C ratio. The Yobs could be related to the SRT with the parameters Y = 0.39 ± 0.05 gCODX·g-1CODS and kD = 0.06 ± 0.04 d-1 which leads to a 24% increase of biomass yield when SRT was reduced from 10 to 4 d.


Patch test results in paediatric patients with atopic dermatitis in Laos.
Dermatological services in Laos, South East Asia are limited mainly to the capital and patch testing is currently not available, so no data exists regarding the common cutaneous allergens in this population. The aim of this study was to document common allergens in paediatric patients with atopic dermatitis attending the allergy clinic in the capital, Vientiane. Fifty paediatric patients with atopic dermatitis were patch tested using TRUE Test® panels 1 to 3 (35 allergens). Readings were taken at Days 2 and 4. Twenty-six positive patch tests were recorded on Day 4 in 15 children (30%). The most common allergens were: gold (18%), nickel (10%), formaldehyde (6%) and p-Phenylenediamine (6%). Other positive allergens were potassium dichromate (2%), cobalt dichloride (2%), Bronopol (2%), paraben mix (2%), fragrance mix 1 (2%) and neomycin (2%). The majority of the patients with positive reactions were female. This study represents the first documented patch test results in the Lao population. It is hoped that these findings will help clinicians to advise the families of children with atopic dermatitis on common allergens to avoid and inform future work on contact dermatitis in this population.


Phenotype and genotype analysis in patients with macular corneal dystrophy.
The aim of this study was to analyse corneal morphological organisation and identify mutations in the carbohydrate sulfotransferase 6 gene (CHST6) in patients with macular corneal dystrophy originating in a Polish population. Macular corneal dystrophy was diagnosed in 24 patients based on the slit-lamp exam, confocal microscopy, 1310 nm time domain and 840 nm spectral domain optical coherence tomography. 10 corneal buttons obtained from penetrating keratoplasty were processed for light microscopy. Genetic analysis of the CHST6 gene was performed, followed by a study of the sequencing results. Highly reflective, diffuse corneal deposits and a general increase in reflectivity were revealed with optical coherence tomography and confocal microscopy. The deposits extended from the Bowman layer to the Descemet membrane and correlated with the Alcian blue-positive granular-filamentous material into and around the stromal keratocytes confirmed by structural analysis of the corneal buttons. The genetic analysis of the blood samples identified the following mutations and single nucleotide polymorphisms: novel P64L (heterozygous), Y110C (homozygous), R162G and L200R, and M1L (heterozygous and homozygous). Genetic mutation heterogeneity was revealed. No phenotype heterogeneity was revealed among patients with in vivo corneal morphology assessment or histological analysis.


Gene flow between species of Lake Victoria haplochromine fishes.
The haplochromine cichlid fishes of Lake Victoria (LV), East Africa, are a textbook example of adaptive radiation-a rapid divergence of multiple morphologically distinguishable forms from a few founding lineages. The forms are generally believed to constitute a "flock" of several hundred reproductively isolated species in a dozen or so genera. This belief has, until now, not been subjected to a test, however. Here, we compare genetic variation at 11 loci in 10 haplochromine populations of 6 different species. Although the genetic diversity in the populations is quite high, using a variety of statistical tests, we find no evidence of genetic differentiation among the populations of LV haplochromines. On genetic distance trees, populations of the same species intermingle with those of different species. At the molecular level, the species are indistinguishable from one another. Genetic comparisons with closely related species in 2 crater lakes indicate that the species within LV continue exchanging genes. These observations have important implications for phylogenetic reconstruction. The approach used in this study is applicable to other instances of adaptive radiation.


Epidemiology of coronavirus respiratory infections.
Human coronaviruses were found by enzyme linked immunosorbent assay in upper respiratory tract secretions taken during 30% of 108 acute respiratory infections experienced by 30 children under age 6 years with recurrent respiratory infections (index group), and during 29% of 51 acute infections experienced by their siblings. Lower respiratory tract infection--predominantly wheezy bronchitis--occurred in 30% of the index children's coronavirus positive infections but in none of their siblings' infections. Reinfections were common. Two peaks of infection were seen each year in the late autumn/early winter and in the early summer.


Effect of three alcohol doses on breathing during sleep in 30-49 year old nonobese snorers and nonsnorers.
To test the effect of alcohol ingestion and snoring on sleep-disordered breathing (SDB), the sleep and respiration of 31 nonobese healthy males ages 30-49 (15 snorers, 16 nonsnorers) were studied overnight after alcohol ingestion. Subjects received placebo, 0.32, 0.65, and 0.81 g alcohol/kg body weight prior to their evening bedtime, with each dose given on one of four nonconsecutive nights in a repeated-measures counterbalanced design. On each night, respiration was assessed by recording respiratory effort from intercostal surface electromyography (EMG), ventilation from oral and nasal thermistors, and arterial oxygen saturation (SaO2) from an ear oximeter (BIOX III). Snorers had significantly: (a) more total SDB, (b) more obstructive sleep apnea (OSA), and (c) lower minimum SaO2 than nonsnorers after the placebo and each alcohol dose. Snorers had more hypoxic events than nonsnorers after each alcohol dose but not after placebo. Increasing alcohol dose caused a statistically significant (p = 0.0004) decrease in minimum SaO2 in snorers only, but this decrease was small and probably not clinically important. Alcohol did not cause significant increases in SDB and hypoxic events, and did not have different effects on SDB and hypoxic events for snorers versus nonsnorers. Because this experiment included only nonobese 30-49-year-old males, these results do not imply that alcohol has no significant effects on obese subjects or those older than 50.


Decorin levels in early- and late-onset preeclampsia.
Preeclampsia (PE) is a pregnancy complication caused by typically limited proliferation, apoptosis, migration, and invasion of extra-trophoblast cells. Decorin (DCN) is a decidua-derived transforming growth factor (TGF)-binding proteoglycan which exerts multiple physiological functions such as collagen fibrillogenesis, myogenesis, angiostasis, and restraining placental invasiveness by adversely regulate proliferation, migration, and invasiveness of human extravillous trophoblast cells. Preeclampsia is mainly classified as early- and late-onset PE according to the timing of the disease onset. In the present study, we aimed to investigate the DCN levels in early-onset PE (EOPE, < 34 weeks) and late-onset severe PE (LOPE, ≥ 34 weeks) and uncomplicated pregnancies. In this case-control study, serum samples were obtained from 21 pregnant women with EOPE and 29 pregnant women with LOPE, as well as from 38 healthy controls (n = 12 early-onset controls and n = 26 late-onset controls) with uncomplicated pregnancies. The mean DCN level was statistically significantly higher in the early-onset PE controls than late-onset PE controls (p = 0.040). Although the mean DCN level was higher in the early-onset PE controls than EOPE and LOPE groups, it did not reach statistical significance (p = 0.119 and p = 0.117, respectively). Although DCN has been thought to play a role in the pathophysiology of PE, our study results show that DCN is not a useful predictive marker of EOPE and LOPE. Further large-scale studies are needed to draw a definitive conclusion.


Thyroid peroxidase autoantibodies and perinatal depression risk: A systematic review.
While thyroid autoantibodies have been linked to depression in general population samples, it is unclear if the immunological milieu of pregnancy alters this association. As a result, we systematically reviewed the literature to determine if abnormal levels of autoantibodies that target thyroperoxidase (TPO-AB) during the perinatal period are associated with an increased risk of antenatal and postnatal depression. MEDLINE, EMBASE, PsycINFO, and CINAHL databases were searched through February 2016. Primary studies that examined TPO-AB titers during pregnancy or the postpartum period, and antenatal or postnatal depression were eligible. The quality of each study was assessed using the Newcastle-Ottawa Scale. Among the eleven articles selected for synthesis, three of these examined associations between TPO-AB and depression both during pregnancy and in the postpartum period. Three of five studies reported statistically significant associations between elevated TPO-AB titers (TPO-AB+) and concurrent depression at 12-25 weeks gestation. Four of five studies found significant associations between TPO-AB+ status at 12-25 weeks gestation and depression in the postpartum period. Two of four studies found links between postpartum TPO-AB and depression concurrently in the puerperium. Lack of adjustment for confounding variables limits causal inference and conclusions about the predictive power of TPO-AB. Studies suggest that TPO-AB+ in early to mid-pregnancy is associated with concurrent depression and may be predictive of depression in the postpartum period. Future studies with improved methodology are required to better understand the full pathophysiological implications and predictive utility of TPO-AB in perinatal depression.


Go with the FLO? A novel approach to quality and safety.
In their paper "Front-Line Ownership: Generating a Cure Mindset for Patient Safety," Zimmerman and her colleagues introduce us to the novel concept of FLO - front-line ownership - within the quality and safety arena. Based on their 18-month study of nosocomial infections within five Canadian hospitals, the authors highlight the benefits of allowing front-line staff to own and manage patient safety problems as opposed to imposing programs on them that were created by leaders who did not consult them in developing appropriate solutions.Their paper highlights many of the benefits of FLO, particularly around social networking, interdisciplinary team work and clinician engagement. But how does FLO measure up in the context of other more technical methods of managing adverse events within healthcare organizations? What are the benefits and weakness of FLO? Is FLO consistent with external accreditation requirements and the drive for greater standardization? Will its necessarily longer time frame consign it to a few small-scale research projects or is there real potential to use FLO techniques for other quality and safety problems beyond nosocomial infections?


Egg marketing in national supermarkets: specialty eggs--part 2.
Large eggs promoted as having one or more features beyond conventional white or brown shell eggs (specialty eggs) were evaluated for quality and price in a national retail study. Subtypes of specialty eggs included: nutritionally altered eggs, organic eggs, fertile eggs, eggs from welfare-managed hens, or hens fed all-vegetable diets. Extension Poultry Specialists in California (CA), Connecticut, Illinois, North Carolina, Pennsylvania and Texas conducted a survey of egg quality and price and compared 246 dozen specialty eggs with 390 dozen conventional white shell eggs during the summer of 1996. Age of the eggs based on carton dating indicated specialty eggs were older (16.5 d) than white eggs (11.7 d). Average egg weights for specialty compared to white were 60.2 and 59.6 g, respectively. Interior egg quality evaluations including albumen height, Haugh units (HU), and percentage HU <55, indicated white eggs were superior (5.0 mm, 67.5, and 10.6%, respectively) compared to specialty eggs (4.7 mm, 63.8, and 16.3%). Although the percentage of cracked eggs was similar between specialty and white eggs (5.4 and 5.7%), the percentage of leakers was threefold higher for the specialty eggs (1.0 vs. 0.3%). Egg price was substantially higher for the specialty eggs, averaging $2.18/dozen with a range from 0.88 to $4.38, compared to white eggs, averaging $1.23/dozen and ranging from 0.39 to $2.35.


Solvent Effects in the Homogeneous Catalytic Reduction of Propionaldehyde with Aluminium Isopropoxide Catalyst: New Insights from PFG NMR and NMR Relaxation Studies.
Solvent effects in homogeneous catalysis are known to affect catalytic activity. Whilst these effects are often described using qualitative features, such as Kamlet-Taft parameters, experimental tools able to quantify and reveal in more depth such effects have remained unexplored. In this work, PFG NMR diffusion and T1 relaxation measurements have been carried out to probe solvent effects in the homogeneous catalytic reduction of propionaldehyde to 1-propanol in the presence of aluminium isopropoxide catalyst. Using data on diffusion coefficients it was possible to estimate trends in aggregation of different solvents. The results show that solvents with a high hydrogen-bond accepting ability, such as ethers, tend to form larger aggregates, which slow down the molecular dynamics of aldehyde molecules, as also suggested by T1 measurements, and preventing their access to the catalytic sites, which results in the observed decrease of catalytic activity. Conversely, weakly interacting solvents, such as alkanes, do not lead to the formation of such aggregates, hence allowing easy access of the aldehyde molecules to the catalytic sites, resulting in higher catalytic activity. The work reported here is a clear example on how combining traditional catalyst screening in homogeneous catalysis with NMR diffusion and relaxation time measurements can lead to new physico-chemical insights into such systems by providing data able to quantify aggregation phenomena and molecular dynamics.


CBF alpha3 (AML2) is induced by TGF-beta1 to bind and activate the mouse germline Ig alpha promoter.
TGF-beta1 directs class switching to IgA by splenic B cells and by the surface IgM+ B cell line, I.29mu, by inducing germline (GL) Ig alpha transcripts. The promoter segment between -130 and +46, relative to the first initiation site for mouse GL alpha transcripts, is sufficient for expression and TGF-beta1 inducibility of a reporter gene in B cell lines. Within this segment resides a TGF-beta1-responsive element (TbetaRE) that is required for induction of the promoter by TGF-beta1 and, when multimerized, is sufficient to transfer TGF-beta1 inducibility to another promoter. In this report we show that a TGF-beta1-inducible complex binds the TbetaRE and contains the transcription factor core-binding factor (CBF; also known as acute myeloid leukemia, AML). Although all three CBF alpha family members activate the GL alpha promoter, only CBF alpha3 (AML-2) is induced by TGF-beta1 in splenic B and I.29mu cells. The TbetaRE contains two CBF binding sites. Mutation of both sites reduces but does not eliminate induction of the GL alpha promoter by TGF-beta1 or by overexpression of CBF, possibly due to the presence of an additional CBF site in the promoter. In addition, the TbetaRE contains two copies of another sequence motif. Mutation of these motifs eliminates TGF-beta1 induction of the GL alpha promoter. Together the data indicate that TGF-beta1 induction of the alpha promoter involves induction of CBF alpha3, which binds to the TbetaRE of the promoter along with one or more proteins.


A Patient-Centered Information System (myED) for Emergency Care Journeys: Design, Development, and Initial Adoption.
Medical care is highly complex in that it addresses patient-centered health goals that require the coordination of multiple care providers. Emergency department (ED) patients currently lack a sense of predictability about ED procedures. This increases frustration and aggression. Herein, we describe a system for providing real-time information to ED patients regarding the procedures in their ED medical journey. This study aimed to develop a system that provides patients with dynamically updated information about the specific procedures and expected waiting times in their personal ED journey, and to report initial evaluations of this system. To develop the myED system, we extracted information from hospital databases and translated it using process mining and user interface design into a language that is accessible and comprehensible to patients. We evaluated the system using a mixed methods approach that combined observations, interviews, and online records. Interviews with patients, accompanying family members, and health care providers (HCPs) confirmed patients' needs for information about their personal ED journey. The system developed enables patients to access this information on their personal mobile phones through a responsive website. In the third month after deployment, 492 of 1614 (30.48%) patients used myED. Patients' understanding of their ED journey improved significantly (F8,299=2.519; P=.01), and patients showed positive reactions to the system. We identified future challenges, including achieving quick engagement without delaying medical care. Salient reasons for poor system adoption were patients' medical state and technological illiteracy. HCPs confirmed the potential of myED and identified means that could improve patient experience and staff cooperation. Our iterative work with ED patients, HCPs, and a multidisciplinary team of developers yielded a system that provides personal information to patients about their ED journey in a secure, effective, and user-friendly way. MyED communicates this information through mobile technology. This improves health care by addressing patients' psychological needs for information and understanding, which are often overlooked. We continue to test and refine the system and expect to find positive effects of myED on patients' ED experience and hospital operations.


Relation of Reduction of Antibodies against Hepatitis B Virus to Hepatocellular Carcinoma Recurrence in the Patients with Resolved Hepatitis B Virus Infection Following Direct-acting Antiviral Therapy for Hepatitis C Virus Infection.
A possible interaction of hepatitis viruses at cellular and molecular levels has been suggested. Eradication of hepatitis C virus (HCV) has been reported to induce activation of hepatitis B virus (HBV)-related liver diseases. The present study examined association of HBV markers with recurrence of hepatocellular carcinoma (HCC) in patients with resolved HCV infection by direct-acting antiviral (DAA) therapy. In a patient pool of 378 patients with sustained virologic response (SVR) by DAA, the antibody to the hepatitis B surface antigen (anti-HBs), the antibody to the hepatitis B core antigen (anti-HBc), and HBV-DNA levels were estimated before and at the end of DAA therapy. These patients were HBsAg negative. Eighty-nine patients had a history of curative treatment of HCC by resection or radiofrequency ablation. A Cox proportional hazards model was used to identify risk factors for HCC recurrence, including the change ratio of the antibody against HBV proteins. Although 188 patients had resolved HBV infection, no patient showed HBV reactivation, but anti-HBs and anti-HBc levels decreased significantly. No significant difference in the HCC recurrence rate was evident between patients with and without resolved HBV infection. Changes of immune responses to HBV proteins did not affect HCC recurrence after DAA therapy for HCV infection in this cohort. The mechanisms underlying diverse roles of DAA-induced SVR of HCV on HBV kinetics need to be resolved in future. Joko K, Mashiba T, Ochi H, et al. Relation of Reduction of Antibodies against Hepatitis B Virus to Hepatocellular Carcinoma Recurrence in the Patients with Resolved Hepatitis B Virus Infection Following Direct-acting Antiviral Therapy for Hepatitis C Virus Infection. Euroasian J Hepato-Gastroenterol 2019;9(2):78-83.


Aorto-caval fistula clinically presenting as left renal colic. Findings of multislice computed tomography.
Spontaneous aorto-caval fistula is a rare complication of abdominal aortic aneurysm. A definitive diagnosis is sometimes difficult, as the classic diagnostic signs (pulsatile abdominal mass with bruit, high-output hearth failure, and acute dyspnea) are present in about half of the patients. Diagnosis may be suspected from clinical symptoms, but sometimes atypical clinical features may obscure the actual situation. Computed tomography findings include early detection of contrast medium in the dilated inferior vena cava, which is isodense with the adjacent aorta, an associated aortic aneurysm, loss of normal anatomic space between aorta and vena cava, and rarely one can even visualize the abnormal communication between aorta and vena cava. Prompt radiological diagnosis is of key importance in the management of these patients. We describe findings of multislice computed tomography of the patient with dissecting aortic aneurysm and aortocaval fistula, clinically presenting as left renal colic. Multislice computed tomography is the imaging modality of choice for diagnosis of abdominal vascular pathology as it is noninvasive, fast and demonstrates a high diagnostic accuracy.


Analysis of GPIIb/IIIa receptor number by quantification of 7E3 binding to human platelets.
A large number of glycoprotein (GP) IIb/IIIa receptors are present on the surface of platelets. Studies to define precisely the number of GPIIb/IIIa receptors using specific monoclonal antibodies (MoAbs) or fibrinogen binding have, however, yielded varying estimates of receptor number. To refine the quantitative estimation of GPIIb/IIIa receptors on resting platelets, we have used the MoAb 7E3, which has high affinity for GPIIb/IIIa. Quantitative binding studies were performed using radiolabeled conjugates of 7E3 IgG, as well as fragments and derivatives of 7E3. For platelets obtained from any single individual, the numbers of 7E3 F(ab')2 and IgG molecules bound per platelet were equivalent (approximately 40,000), whereas the number of Fab molecules bound per platelet was consistently approximately twofold higher (approximately 80,000). To investigate the basis of the quantitative disparity in binding of intact 7E3 and 7E3 F(ab')2 versus 7E3 Fab, we studied the binding of a newly constructed, bispecific (Fab')2 molecule containing only a single 7E3 combining site. Because this construct bound to the same extent as the Fab species, the larger size of the intact 7E3 and 7E3 F(ab')2 molecules could not explain the reduced number of molecules that bound per platelet compared to the Fab fragment. Rather, it appears that the valency of the antibody is the critical factor determining the number of antibody molecules bound per platelet. Thus, we conclude that the binding of 7E3 Fab corresponds most closely with surface GPIIb/IIIa number and that the number of GPIIb/IIIa receptors is approximately 80,000 per platelet.


On the use of the Lloyd's Mirror effect to infer the depth of vocalizing fin whales.
The interference between the direct path and the sea surface reflection of a signal as measured by a receiver is called Lloyd's Mirror effect (LME). It results in a frequency-dependent interference pattern that can be observed in a spectrogram. LME depends on the receiver depth, signal source depth, signal frequency, and slant range between source and receiver. Knowing three of these parameters a priori, LME can be used to estimate the third parameter, such as source depth. Here, the work in Pereira et al. (2016) was expanded to estimate the depth of a vocalizing fin whale recorded by an ocean-bottom seismometer (OBS). In Pereira et al. (2016), the depth of a vocalizing fin whale was inferred by manually comparing spectrograms of LME transmission loss models with observed LME. This study developed an automated procedure to perform the same task using the LME interference pattern observed in the spectrograms of the hydrophone and the vertical channel of the OBS. The results show that the joint use of the two channels was the best approach to estimate a source depth using LME. LME provides a non-intrusive approach for estimating the depth at which a fin whale was vocalizing.


The role of volatile organic compounds, morphology and pigments of globeflowers in the attraction of their specific pollinating flies.
• Floral scents and visual cues of the globeflower Trollius europaeus may play a key role in the attraction of Chiastocheta flies, involved in a highly specific nursery pollination mutualism. • Here, headspace collection and GC-MS were used to identify and quantify the volatile organic compounds emitted by the globeflower. • Scents are produced in three different floral parts by four structures: secretory glands and flat epidermis cells in the abaxial sepal epidermis, conical cells in the adaxial sepal epidermis, and pollen. The blend is made up of 16 compounds commonly found in floral scents. Geographical variation among populations is low compared with variation amongst individuals within populations. Electroantenno-graphic analyses revealed that six compounds emitted by both anthers and sepals are detected by Chiastocheta flies. Removing the anthers hidden inside the globe from flowers in the field decreased the number of fly visits to globeflowers. • A multivariate analysis of the effect of several floral traits on pollinator visitation rate conducted in the field showed that both floral scents and visual flower cues play a role in pollinator attraction. However, their relative roles and the intensity of the selective pressures exerted on floral traits by pollinators appear to vary in time and space.


Predictive simulation of the subsidence of venice.
Land subsidence at Venice is the result of sediment compaction in the unconsolidated, aquifer-aquitard system that underlies the Venetian Lagoon. Compaction is caused by extensive groundwater withdrawals at the nearby industrial port of Marghera. The total subsidence at Venice for the period from 1930 through 1973 has been about 15 centimeters. Predictive simulations with a calibrated mathematical model were hampered by the sparseness of available data, but, as a first estimate, they suggest that, if withdrawals are kept constant in the future as they have been since 1969, about 3 centimeters of further subsidence can be expected.


Gemcitabine and cisplatin treatment of advanced-stage non-small-cell lung cancer in patients given cisplatin on day 8.
Gemcitabine and cisplatin treatment were administered to patients with advanced-stage, non-small-cell lung cancer. During phase II studies, the treatment is performed using a 28-day cycle, with gemcitabine administered on days 1, 8, and 15. Although it is advised that cisplatin not be administered on the first day, gemcitabine and cisplatin treatment is usually performed using a 21-day cycle, with gemcitabine administered on days 1 and 8, and cisplatin is given on the first day in most phase III studies. In contrast with previous phase III studies, cisplatin was administered on day 8 in our study. Dose density, drug toxicity, and efficacy were analyzed. Chemonaive patients with stage IIIB or stage IV nonsmall-cell lung cancer received gemcitabine (1250 mg/m2) on days 1 and 8 plus cisplatin (75 mg/m2) on day 8 every 3 weeks (1 cycle contained 2 applications). Sixty-seven patients received a total of 293 applications. Dose densities were 92.3% for gemcitabine and 93.9% for cisplatin. The types and rates of grade 3 and grade 4 hematologic toxicities were anemia (6%), granulocytopenia (46%), and thrombocytopenia (6%). Complete remission was seen in 2 patients (3%); partial remission was 40%, stable disease was 39%, and progression of disease, 10%. The median overall survival time was 13 months. The median progression-free survival time was 9.5 months. One-year survival rate was 54% and 2-year survival, 10.4%. In this 21-day treatment regimen, overall survival was longer than 1 year and the 1-year survival rate was more than 50%. Both the severity and rate of observed thrombocytopenia in the study were very low. Other adverse effects in the current study were comparable to those reported in the literature.


Expandable metallic esophageal stents in benign disease: a cause for concern.
Over a 2-year period at our institution, 6 patients underwent metallic stent treatment, 5 for malignant conditions and 1 for a benign condition of the esophagus. The use of expandable metallic stents for benign strictures has paralleled malignant indications but is limited and less understood from a clinical standpoint. A review of current literature in the treatment of benign strictures is presented. Treatment of benign strictures is associated with high morbidity and mortality as demonstrated by the cumulative experience of 21 patients. Migration, hyperplastic tissue obstruction at the terminal ends, reflux, and complications of perforation occur at a prohibitive rate. We conclude that expandable metallic stents should be reserved for palliative treatment of esophageal malignant obstructions and tracheoesophageal fistulas. Pharmacological management, necessary dilatations and operative corrections (antireflux procedures, esophagectomy) are recommended treatments for benign strictures.


Efficacy and safety of dietary supplements containing CLA for the treatment of obesity: evidence from animal and human studies.
Dietary supplements containing conjugated linoleic acid (CLA) are widely promoted as weight loss agents available over the counter and via the Internet. In this review, we evaluate the efficacy and safety of CLA supplementation based on peer-reviewed published results from randomized, placebo-controlled, human intervention trials lasting more than 4 weeks. We also review findings from experimental studies in animals and studies performed in vitro. CLA appears to produce loss of fat mass and increase of lean tissue mass in rodents, but the results from 13 randomized, controlled, short-term (<6 months) trials in humans find little evidence to support that CLA reduces body weight or promotes repartitioning of body fat and fat-free mass in man. However, there is increasing evidence from mice and human studies that the CLA isomer trans-10, cis-12 may produce liver hypertrophy and insulin resistance via a redistribution of fat deposition that resembles lipodystrophy. CLA also decreases the fat content of both human and bovine milk. In conclusion, although CLA appears to attenuate increases in body weight and body fat in several animal models, CLA isomers sold as dietary supplements are not effective as weight loss agents in humans and may actually have adverse effects on human health.


Compositional Shift of Bacterial, Archaeal, and Fungal Communities Is Dependent on Trophic Lifestyles in Rice Paddy Soil.
The soil environment determines plants' health and performance during their life cycle. Therefore, ecological understanding on variations in soil environments, including physical, chemical, and biological properties, is crucial for managing agricultural fields. Here, we present a comprehensive and extensive blueprint of the bacterial, archaeal, and fungal communities in rice paddy soils with differing soil types and chemical properties. We discovered that natural variations of soil nutrients are important factors shaping microbial diversity. The responses of microbial diversity to soil nutrients were related to the distribution of microbial trophic lifestyles (oligotrophy and copiotrophy) in each community. The compositional changes of bacterial and archaeal communities in response to soil nutrients were mainly governed by oligotrophs, whereas copiotrophs were mainly involved in fungal compositional changes. Compositional shift of microbial communities by fertilization is linked to switching of microbial trophic lifestyles. Random forest models demonstrated that depletion of prokaryotic oligotrophs and enrichment of fungal copiotrophs are the dominant responses to fertilization in low-nutrient conditions, whereas enrichment of putative copiotrophs was important in high-nutrient conditions. Network inference also revealed that trophic lifestyle switching appertains to decreases in intra- and inter-kingdom microbial associations, diminished network connectivity, and switching of hub nodes from oligotrophs to copiotrophs. Our work provides ecological insight into how soil nutrient-driven variations in microbial communities affect soil health in modern agricultural systems.


Impact of tumor characteristics and pre- and postoperative hormone levels on hormonal remission following endoscopic transsphenoidal surgery in patients with acromegaly.
Acromegaly is a disease of acral enlargement and elevated serum levels of insulin-like growth factor-1 (IGF-1) and growth hormone (GH), usually caused by a pituitary adenoma. A lack of consensus on factors that reliably predict outcomes in acromegalic patients following endoscopic endonasal transsphenoidal surgery (EETS) warrants additional investigation. The authors identified 52 patients with acromegaly who underwent an endoscopic endonasal approach (EEA) for resection of a GH-secreting pituitary adenoma. Preoperative and postoperative tumor and endocrinological characteristics such as tumor size, invasiveness, and GH/IGF-1 levels were evaluated as potential indicators of postoperative hormonal remission. Endocrinological remission was defined as postoperative IGF-1 levels at or below the age- and sex-normalized values. The 52 patients had a mean age of 50.7 ± 13.4 years and a mean follow-up duration of 24.4 ± 19.1 months. Ten patients (19%) had microadenomas and 42 (81%) had macroadenomas. Five patients (9.6%) had giant adenomas. Forty-four tumors (85%) had extrasellar extension, with 40 (77%) exhibiting infrasellar invasion, 18 (35%) extending above the sella, and 7 (13%) invading the cavernous sinuses. Thirty-six patients (69%) underwent gross-total resection (GTR; mean maximal tumor diameter 1.47 cm), and 16 (31%) underwent subtotal resection (STR; mean maximal tumor diameter 2.74 cm). Invasive tumors were significantly larger, and Knosp scores were negatively correlated with GTR. Thirty-eight patients (73%) achieved hormonal remission after EEA resection alone, which increased to 87% with adjunctive medical therapy. Ninety percent of patients with microadenomas and 86% of patients with macroadenomas achieved hormonal remission. Preoperative IGF-1 and postoperative day 1 (POD1) GH levels were inversely correlated with hormonal remission. Postoperative CSF leakage occurred in 2 patients (4%), and none experienced vision loss, death, or injury to internal carotid arteries or cranial nerves. Endoscopic transsphenoidal resection of GH-secreting pituitary adenomas is a safe and highly effective treatment for achieving hormonal remission and tumor control in up to 87% of patients with acromegaly when combined with postoperative medical therapy. Patients with lower preoperative IGF-1 and POD1 GH levels, with less invasive pituitary adenomas, and who undergo GTR are more likely to achieve postoperative biochemical remission.


Climate and ecosystem linkages explain widespread declines in North American Atlantic salmon populations.
North American Atlantic salmon (Salmo salar) populations experienced substantial declines in the early 1990s, and many populations have persisted at low abundances in recent years. Abundance and productivity declined in a coherent manner across major regions of North America, and this coherence points toward a potential shift in marine survivorship, rather than local, river-specific factors. The major declines in Atlantic salmon populations occurred against a backdrop of physical and biological shifts in Northwest Atlantic ecosystems. Analyses of changes in climate, physical, and lower trophic level biological factors provide substantial evidence that climate conditions directly and indirectly influence the abundance and productivity of North American Atlantic salmon populations. A major decline in salmon abundance after 1990 was preceded by a series of changes across multiple levels of the ecosystem, and a subsequent population change in 1997, primarily related to salmon productivity, followed an unusually low NAO event. Pairwise correlations further demonstrate that climate and physical conditions are associated with changes in plankton communities and prey availability, which are ultimately linked to Atlantic salmon populations. Results suggest that poor trophic conditions, likely due to climate-driven environmental factors, and warmer ocean temperatures throughout their marine habitat area are constraining the productivity and recovery of North American Atlantic salmon populations.


Antipsychotic drugs rapidly induce dopamine neuron depolarization block in a developmental rat model of schizophrenia.
Repeated administration of antipsychotic drugs to normal rats has been shown to induce a state of dopamine neuron inactivation known as depolarization block, which correlates with the ability of the drugs to exhibit antipsychotic efficacy and extrapyramidal side effects in schizophrenia patients. Nonetheless, in normal rats depolarization block requires weeks of antipsychotic drug administration, whereas schizophrenia patients exhibit initial effects soon after initiating antipsychotic drug treatment. We now report that, in a developmental disruption rat model of schizophrenia [methyl-azoxymethanol acetate (20 mg/kg, i.p.) injected into G17 pregnant female rats, with offspring tested as adults], the extant hyperdopaminergic state combines with the excitatory actions of a first- (haloperidol; 0.6 mg/kg, i.p.) and a second- (sertindole; 2.5 mg/kg, i.p.) generation antipsychotic drug to rapidly induce depolarization block in ventral tegmental area dopamine neurons. Acute injection of either antipsychotic drug induced an immediate reduction in the number of spontaneously active dopamine neurons (cells per electrode track; termed population activity). Repeated administration of either antipsychotic drug for 1, 3, 7, 15, and 21 d continued to reduce dopamine neuron population activity. Both acute and repeated effects on population activity were reversed by acute apomorphine injections, which is consistent with the reversal of dopamine neuron depolarization block. Although this action may account for the effects of D2 antagonist drugs on alleviating psychosis and the lack of development of tolerance in humans, the drugs appear to do so by inducing an offsetting deficit rather than attacking the primary pathology present in schizophrenia.


Highly Selective Two-Photon Fluorescent Probe for Ratiometric Sensing and Imaging Cysteine in Mitochondria.
A novel ratiometric mitochondrial cysteine (Cys)-selective two-photon fluorescence probe has been developed on the basis of a merocyanine as the fluorophore and an acrylate moiety as the biothiol reaction site. The biocompatible and photostable acrylate-functionalized merocyanine probe shows not only a mitochondria-targeting property but also highly selective detection and monitoring of Cys over other biothiols such as homocysteine (Hcy) and glutathione (GSH) and hydrogen sulfide (H2S) in live cells. In addition, this probe exhibits ratiometric fluorescence emission characteristics (F518/F452), which are linearly proportional to Cys concentrations in the range of 0.5-40 μM. More importantly, the probe and its released fluorophore, merocyanine, exhibit strong two-photon excited fluorescence (TPEF) with two-photon action cross-section (Φσmax) of 65.2 GM at 740 nm and 72.6 GM at 760 nm in aqueous medium, respectively, which is highly desirable for high contrast and brightness ratiometric two-photon fluorescence imaging of the living samples. The probe has been successfully applied to ratiometrically image and detect mitochondrial Cys in live cells and intact tissues down to a depth of 150 μm by two-photon fluorescence microscopy. Thus, this ratiometric two-photon fluorescent probe is practically useful for an investigation of Cys in living biological systems.


The genetics of gaits in Icelandic horses goes beyond DMRT3, with RELN and STAU2 identified as two new candidate genes.
In domesticated animals, many important traits are complex and regulated by a large number of genes, genetic interactions, and environmental influences. The ability of Icelandic horses to perform the gait 'pace' is largely influenced by a single mutation in the DMRT3 gene, but genetic modifiers likely exist. The aim of this study was to identify novel genetic factors that influence pacing ability and quality of the gait through a genome-wide association study (GWAS) and correlate new findings to previously identified quantitative trait loci (QTL) and mutations. Three hundred and seventy-two Icelandic horses were genotyped with the 670 K+ Axiom Equine Genotyping Array, of which 362 had gait scores from breeding field tests. A GWAS revealed several SNPs on Equus caballus chromosomes (ECA) 4, 9, and 20 that were associated (p < 1.0 × 10-5) with the breeding field test score for pace. The two novel QTL on ECA4 and 9 were located within the RELN and STAU2 genes, respectively, which have previously been associated with locomotor behavior in mice. Haplotypes were identified and the most frequent one for each of these two QTL had a large favorable effect on pace score. The second most frequent haplotype for the RELN gene was positively correlated with scores for tölt, trot, gallop, and canter. Similarly, the second most frequent haplotype for the STAU2 gene had favorable effects on scores for trot and gallop. Different genotype ratios of the haplotypes in the RELN and STAU2 genes were also observed in groups of horses with different levels of pacing ability. Furthermore, interactions (p < 0.05) were detected for the QTL in the RELN and STAU2 genes with the DMRT3 gene. The novel QTL on ECA4, 9, and 20, along with the effects of the DMRT3 variant, were estimated to account jointly for 27.4% of the phenotypic variance of the gait pace. Our findings provide valuable information about the genetic architecture of pace beyond the contribution of the DMRT3 gene and indicate genetic interactions that contribute to the complexity of this trait. Further investigation is needed to fully understand the underlying genetic factors and interactions.


Intracortical Causal Information Flow of Oscillatory Activity (Effective Connectivity) at the Sleep Onset Transition.
We investigated the sleep onset transition in humans from an effective connectivity perspective in a baseline condition (approx. 16 h of wakefulness) and after sleep deprivation (40 h of sustained wakefulness). Using EEG recordings (27 derivations), source localization (LORETA) allowed us to reconstruct the underlying patterns of neuronal activity in various brain regions, e.g., the default mode network (DMN), dorsolateral prefrontal cortex and hippocampus, which were defined as regions of interest (ROI). We applied isolated effective coherence (iCOH) to assess effective connectivity patterns at the sleep onset transition [2 min prior to and 10 min after sleep onset (first occurrence of stage 2)]. ICOH reveals directionality aspects and resolves the spectral characteristics of information flow in a given network of ROIs. We observed an anterior-posterior decoupling of the DMN, and moreover, a prominent role of the posterior cingulate cortex guiding the process of the sleep onset transition, particularly, by transmitting information in the low frequency range (delta and theta bands) to other nodes of DMN (including the hippocampus). In addition, the midcingulate cortex appeared as a major cortical relay station for spindle synchronization (originating from the thalamus; sigma activity). The inclusion of hippocampus indicated that this region might be functionally involved in sigma synchronization observed in the cortex after sleep onset. Furthermore, under conditions of increased homeostatic pressure, we hypothesize that an anterior-posterior decoupling of the DMN occurred at a faster rate compared to baseline overall indicating weakened connectivity strength within the DMN. Finally, we also demonstrated that cortico-cortical spindle synchronization was less effective after sleep deprivation than in baseline, thus, reflecting the reduction of spindles under increased sleep pressure.


High-throughput SNP discovery and genotyping in durum wheat (Triticum durum Desf.).
We describe the application of complexity reduction of polymorphic sequences (CRoPS(®)) technology for the discovery of SNP markers in tetraploid durum wheat (Triticum durum Desf.). A next-generation sequencing experiment was carried out on reduced representation libraries obtained from four durum cultivars. SNP validation and minor allele frequency (MAF) estimate were carried out on a panel of 12 cultivars, and the feasibility of genotyping these SNPs in segregating populations was tested using the Illumina Golden Gate (GG) technology. A total of 2,659 SNPs were identified on 1,206 consensus sequences. Among the 768 SNPs that were chosen irrespective of their genomic repetitiveness level and assayed on the Illumina BeadExpress genotyping system, 275 (35.8%) SNPs matched the expected genotypes observed in the SNP discovery phase. MAF data indicated that the overall SNP informativeness was high: a total of 196 (71.3%) SNPs had MAF >0.2, of which 76 (27.6%) showed MAF >0.4. Of these SNPs, 157 were mapped in one of two mapping populations (Meridiano × Claudio and Colosseo × Lloyd) and integrated into a common genetic map. Despite the relatively low genotyping efficiency of the GG assay, the validated CRoPS-derived SNPs showed valuable features for genomics and breeding applications such as a uniform distribution across the wheat genome, a prevailing single-locus codominant nature and a high polymorphism. Here, we report a new set of 275 highly robust genome-wide Triticum SNPs that are readily available for breeding purposes.


Cyclooxygenase-2 Is Essential for Colorectal Anastomotic Healing.
To study the effects of COX-2 on colonic surgical wound healing. Cyclooxygenase-2 (COX-2) is a key enzyme in gastrointestinal homeostasis. COX-2 inhibitors have been associated with colonic anastomotic leakage. Wildtype, COX-2 knockout and COX-2 heterozygous mice were subjected to a model of colonic anastomotic leakage, and were treated with vehicle, diclofenac, or prostaglandin E2 (PGE2), the most important COX-2 product in the intestine. We assessed anastomotic leakage, mortality, angiogenesis, and inflammation. Furthermore, we investigated the association between anastomotic leakage and a human polymorphism of the COX-2 gene resulting in low COX-2 levels. Diclofenac, a nonsteroidal anti-inflammatory drug inhibiting COX-2, increased anastomotic leakage compared to vehicle-treated mice (100% vs 25%, respectively). Similarly, 92% of COX-2-deficient mice developed anastomotic leakage (P = 0.003) compared to WT. PGE2 partly rescued this severe phenotype because only 46% of PGE2-administered COX-2 knockout mice developed anastomotic leakage (P = 0.02). This may be related to decreased neovascularization, because decreased CD31 staining, indicating less blood vessels, was observed in COX-2 mice (2 vessels/mm vs 6 vessels/mm in controls (P = 0.03)). This effect could partly be reversed by administration of PGE2 to COX-2 mice. No significant differences in inflammation were found. PTGS2-765G>C polymorphism in humans, associated with reduced COX-2 expression, was associated with higher anastomotic leakage rates. COX-2-induced PGE2 production is essential for intestinal wound healing after colonic surgery, possibly via its effects on angiogenesis. These data emphasize that COX-2 inhibitors should be avoided after colonic surgery, and administration of PGE2 might be favorable for a selection of patients.


Expression of t-DARPP mediates trastuzumab resistance in breast cancer cells.
We have investigated the role of t-DARPP in trastuzumab resistance in ERBB2-amplified and overexpressed breast cancer cell lines. We have used the HR-5 and HR-6 trastuzumab-resistant cells that were established from tumors that recurred in the presence of trastuzumab therapy following xenografts of BT-474 cells in nude mice. In addition, SKBR-3 cells, engineered for stable expression of t-DARPP, and HCC-1569 cells, which have constitutive expression of t-DARPP and are de novo resistant to trastuzumab, were used. We reported > or =15-fold up-regulation of mRNA and protein levels of t-DARPP in HR-5 and HR-6 cells compared with their progenitor BT-474 trastuzumab-sensitive cells. The t-DARPP expression was not regulated by changes in its promoter DNA methylation levels. The SKBR-3 cells stably expressing t-DARPP developed resistance to trastuzumab compared with their parental cells and empty vector controls (P < 0.01). The trastuzumab-resistant cell lines showed a significant increase in pAKT (Ser(473)) and BCL2 protein levels. The small interfering RNA knockdown of t-DARPP in all trastuzumab-resistant cells led to a significant reduction in ERBB2, pAKT (Ser(473)), and BCL2 protein levels with a significant decrease in cell viability (P < or = 0.001) and an increase in cleaved caspase-3 levels, indicating the progression of these cells toward apoptosis. The t-DARPP protein was associated with both heat shock protein 90 and ERBB2 forming a potential protein complex. This association may play a role in regulating ERBB2 protein in trastuzumab-resistant cells. We conclude that t-DARPP is a novel molecular target that can mediate the therapeutic resistance to trastuzumab in breast cancer cells.


The efficacy of Polyporus Umbellatus polysaccharide in treating hepatitis B in China.
Polyporus umbellatus polysaccharide (PUPS) has been identified as the major bioactive component in the mushroom Polyporus umbellatus that has immuno-enhancing, anti-tumor, anti-inflammatory, and hepatoprotective activities. Both PUPS capsule and injection are Chinese Food and Drug Administration (SFDA) approved drugs, which have been used alone or in combination with a variety of clinical drugs for treating Hepatitis B, lung and liver cancers in China since 1990. Our aim was to review both the efficacy and problem associated with PUPS mono- and combination therapy conducted in China and the underlying molecular mechanisms. To this end, the term Polyporus umbellatus polysaccharide both in English and in Chinese was used to conduct a systematic search of PubMed, VIP (Chongqing VIP Chinese Scientific Journals Database), CNKI (China National Knowledge Infrastructure), and Wanfang database. A total 11,703 clinically reported cases in China from over 100 publications during the past 27 years were evaluated, translated into English, and summarized into 3 figures and 13 tables to provide a general view of efficacy of PUPS during mono- and combination therapy. The published data showed the effectiveness of PUPS for treating hepatitis B in most reported cases. Moreover, the combined therapies for PUPS plus hepatitis B vaccine, PUPS plus interferon, PUPS plus acyclovir, and PUPS plus iRNA are better than when treated with either drug alone. Overall, when PUPS is used alone or in combination with other drugs for prevention and treatment of hepatitis B-affected patients, the efficacy is convincible.


Epidemiological patterns of meningococcal meningitis in Niger in 2003 and 2004: under the threat of N. meningitidis serogroup W135.
Since the Neisseria meningitidis serogroup W135 epidemic in Burkina Faso in 2002, the neighbouring countries dread undergoing outbreaks. Niger has strongly enhanced the microbiological surveillance, especially by adding the polymerase chain reaction (PCR) assay to the national framework of the surveillance system. During the 2003 epidemic season, 8113 clinically suspected cases of meningitis were notified and nine districts of the 42 crossed the epidemic threshold, while during the 2004 season, the number of cases was 3521 and four districts notified epidemics. In 2003 and 2004, serogroup A was identified in most N. meningitidis from cerebrospinal fluid (CSF) specimens (89.7% of 759 and 87.2% of 406, respectively). Although serogroup W135 represented only 8.3% of the meningococcal meningitis in 2003 and 7.9% in 2004, and was not involved in outbreaks, it was widespread in various areas of the country. In the regions that notified epidemics, the proportion of serogroup W135 was tiny while it exceeded 40% in several non-epidemic regions. Despite the wide distribution of W135 serogroup in Niger and the fears expressed in 2001, the threat of a large epidemic caused by N. meningitidis W135 seems to have been averted in Niger so far. There is no clear indication whether this serogroup will play a lasting role in the epidemiology of meningococcal meningitis or not. As early as in the 1990s, a significant but transient increase in the incidence of N. meningitidis serogroup X was observed. Close microbiological surveillance is crucial for monitoring the threat and for identifying at the earliest the serogroups involved in epidemics.


Neural structures supporting spontaneous and assisted (entrained) speech fluency.
Non-fluent speech is one of the most common impairments in post-stroke aphasia. The rehabilitation of non-fluent speech in aphasia is particularly challenging as patients are rarely able to produce and practice fluent speech production. Speech entrainment is a behavioural technique that enables patients with non-fluent aphasia to speak fluently. However, its mechanisms are not well understood and the level of improved fluency with speech entrainment varies among individuals with non-fluent aphasia. In this study, we evaluated the behavioural and neuroanatomical factors associated with better speech fluency with the aid of speech entrainment during the training phase of speech entrainment. We used a lesion-symptom mapping approach to define the relationship between chronic stroke location on MRI and the number of different words per second produced during speech entrainment versus picture description spontaneous speech. The behavioural variable of interest was the speech entrainment/picture description ratio, which, if ≥1, indicated an increase in speech output during speech entrainment compared to picture description. We used machine learning (shallow neural network) to assess the statistical significance and out-of-sample predictive accuracy of the neuroanatomical model, and its regional contributors. We observed that better assisted speech (higher speech entrainment/picture description ratio) was achieved by individuals who had preservation of the posterior middle temporal gyrus, inferior fronto-occipital fasciculus and uncinate fasciculus, while exhibiting lesions in areas typically associated with non-fluent aphasia, such as the superior longitudinal fasciculus, precentral, inferior frontal, supramarginal and insular cortices. Our findings suggest that individuals with dorsal stream damage but preservation of ventral stream structures are more likely to achieve more fluent speech with the aid of speech entrainment compared to spontaneous speech. This observation provides insight into the mechanisms of non-fluent speech in aphasia and has potential implications for future research using speech entrainment for rehabilitation of non-fluent aphasia.


The effect of gold kiwifruit consumed with an iron fortified breakfast cereal meal on iron status in women with low iron stores: a 16 week randomised controlled intervention study.
Dietary treatment is often recommended as the first line of treatment for women with mild iron deficiency. Although it is well established that ascorbic acid enhances iron absorption, it is less clear whether the consumption of ascorbic acid rich foods (such as kiwifruit) with meals fortified with iron improves iron status. The aim of this study is to investigate whether the consumption of ZESPRI(R) GOLD kiwifruit (a fruit high in ascorbic acid and carotenoids) with an iron fortified breakfast cereal meal increases iron status in women with low iron stores. Eighty nine healthy women aged 18-44 years with low iron stores (serum ferritin (SF) <or= 25 microg/L, haemoglobin (Hb) >or= 115 g/L) living in Auckland, New Zealand were randomised to receive an iron fortified breakfast cereal (16 mg iron per serve) and either two ZESPRI(R) GOLD kiwifruit or a banana (low ascorbic acid and carotenoid content) to eat at breakfast time every day for 16 weeks. Iron status (SF, Hb, C-reactive protein (CRP) and soluble transferrin receptor (sTfR)), ascorbic acid and carotenoid status were measured at baseline and after 16 weeks. Anthropometric measures, dietary intake, physical activity and blood loss were measured before and after the 16 week intervention. This randomised controlled intervention study will be the first study to investigate the effect of a dietary based intervention of an iron fortified breakfast cereal meal combined with an ascorbic acid and carotenoid rich fruit on improving iron status in women with low iron stores. ACTRN12608000360314.


The bifactor model of the Maslach Burnout Inventory-Human Services Survey (MBI-HSS)--an alternative measurement model of burnout.
The purpose of the present study was to examine the construct validity of the Hungarian language version of the Maslach Burnout Inventory-Human Services Survey (MBI-HSS). A sample of 653 healthcare professionals (420 physicians and 233 nurses and nursing assistants) completed the MBI-HSS. A series of confirmatory factor analyses showed that a hierarchical bifactor model including a global burnout factor and three specific factors of emotional exhaustion, depersonalization and reduced personal accomplishment had the closest fit to the data, compared with an alternative second-order three-factor hierarchical model as well as to non-hierarchical one-factor, two-factor, three-factor, four-factor and five-factor models. However, only the global burnout factor and the specific personal accomplishment factor explained a considerable unique proportion of variance in observed scores. Our study confirms the validity of the MBI-HSS and suggests an alternative structural model, which may contribute to further understanding of the burnout construct.


Genetic architecture of adiposity and organ weight using combined generation QTL analysis.
We present here a detailed study of the genetic contributions to adult body size and adiposity in the LG,SM advanced intercross line (AIL), an obesity model. This study represents a first step in fine-mapping obesity quantitative trait loci (QTLs) in an AIL. QTLs for adiposity in this model were previously isolated to chromosomes 1, 6, 7, 8, 9, 12, 13, and 18. This study focuses on heritable contributions and the genetic architecture of fatpad and organ weights. We analyzed both the F(2) and F(3) generations of the LG,SM AIL population single-nucleotide polymorphism (SNP) genotyped with a marker density of approximately 4 cM. We replicate 88% of the previously identified obesity QTLs and identify 13 new obesity QTLs. Nearly half of the single-trait QTLs were sex-specific. Several broad QTL regions were resolved into multiple, narrower peaks. The 113 single-trait QTLs for organs and body weight clustered into 27 pleiotropic loci. A large number of epistatic interactions are described which begin to elucidate potential interacting molecular networks. We present a relatively rapid means to obtain fine-mapping details from AILs using dense marker maps and consecutive generations. Analysis of the complex genetic architecture underlying fatpad and organ weights in this model may eventually help to elucidate not only heritable contributions to obesity but also common gene sets for obesity and its comorbidities.


Detection of silent intervals between noises activating different perceptual channels: some properties of "central" auditory gap detection.
This article describes four experiments on gap detection by normal listeners, with the general goal being to examine the consequences of using noises in different perceptual channels to delimit a silent temporal gap to be detected. In experiment 1, subjects were presented with pairs of narrow-band noise sequences. The leading element in each pair had a center frequency of 2 kHz and the trailing element's center frequency was parametrically varied. Gap detection thresholds became increasingly poor, sometimes by up to an order of magnitude, as the spectral disparity was increased between the noise bursts that marked the gap. These data suggested that gap-detection performance is impoverished when the underlying perceptual timing operation requires a comparison of activity in different perceptual channels rather than a discontinuity detection within a given channel. In experiment 2, we assessed the effect of leading-element duration in within-channel and between-channel gap detection tasks. Gap detection thresholds rose when the duration of the leading element was less than about 30 ms, but only in the between-channel case. In experiment 3, the gap-detection stimulus was redesigned so that we could probe the perceptual mechanisms that might be involved in stop consonant discrimination. The leading element was a wideband noise burst, and the trailing element was a 300-ms bandpassed noise centered on 1.0 kHz. The independent variable was the duration of the leading element, and the dependent variable was the smallest detectable gap between the elements. When the leading element was short in duration (5-10 ms), gap thresholds were close to 30 ms, which is close to the voice onset time that parses some voiced from unvoiced stop consonants. In experiment 4, the generality of the leading-element duration effect in between-channel gap detection was examined. Spectrally identical noises defining the leading and trailing edges of the gap were presented to the same or to different ears. There was a leading-element duration effect only for the between channel case. The mean gap threshold was again close to 30 ms for short leading-element durations. Taken together, the data suggest that gap detection requiring a temporal correlation of activity in different perceptual channels is a fundamentally different task to the discontinuity detection used to execute gap detection performance in the traditional, within-channel paradigm.


Primary Squamous Cell Biliary Carcinoma With Liver Metastasis Is Rare but Malicious.
Primary squamous cell carcinoma (SCC) of the liver is quite rare, and to our knowledge, very few cases have been reported in the literature. The exact pathogenesis of the disease is unestablished; however, it is mostly reported to be associated with hepatic cyst, Caroli's disease, hepatolithiasis, hepatic cirrhosis, and hepatic teratoma. We report a case of a 50-year-old woman with no prior medical history initially, who presented with postprandial epigastric and right upper quadrant pain that continued to worsen and was associated with early satiety, nausea, and weight loss of 25 pounds over 2 months, which prompted further evaluation by her primary care physician. Magnetic resonance imaging (MRI) examination a month later revealed a large heterogeneous area measuring 8.5 × 2.4 × 7.4 cm in the inferior right hepatic lobe with heterogeneous enhancement and involvement of the gallbladder, concerning for cholangiocarcinoma. Given radiographic findings, she underwent a computed tomography (CT)-guided core biopsy of the liver, which showed a necrotic malignant tumor favoring adenocarcinoma and was also found to have germline BRCA mutation. A positron emission tomography (PET) scan revealed a large partially necrotic fluorodeoxyglucose (FDG) avid mass, possibly arising from the gallbladder fossa with an invasion of both lobes of the liver and probable involvement of a portion of the ascending colon. There was no gross evidence of distant metastatic disease. The patient underwent staging laparoscopy prior to initiating chemotherapy, and another biopsy was done, which returned in favor of SCC, with immunohistochemical stains being positive for cytokeratin (CK)19, Ber-EP4 (epithelial antigen recognized by Ber-EP4 antibody), and P40 (DeltaNp63); while negative for CK7, CK20, caudal-type homeobox 2 (CDX-2), paired box 8 (PAX-8), and mucicarmine. The patient started platinum-based chemotherapy due to germline BRCA mutation. However, due to complications associated with therapy and the progression of the disease, the patient eventually chose hospice. Primary SSC remains an unexplored aggressive malignancy that carries an overall poor prognosis. Diagnosis can be challenging and requires high clinical suspicion due to the scarcity in specific laboratory workup. Pathological diagnosis remains the gold standard; however, it also carries its own challenges. Treatment is usually case-oriented, and definitive protocols have yet to be established.


Human beta defensin is absent in burn blister fluid.
Defensins are a family of cationic antimicrobial peptides that participate in innate host defence. Human beta defensin-2 (HBD-2) is produced by human keratinocytes, and has a potent bactericidal activity against a wide spectrum of microorganisms. We have recently shown that expression of HBD-2 is present in normal skin and lost in the full-thickness burn wound. Defensins have been found in the blister fluid of chronic wounds. Our study was designed to examine blister fluid from partial-thickness burns for defensin content. Fluid from five patients was collected from partial-thickness burn blisters, and then analysed by sandwich Enzyme-Linked Immunosorbent Assay (ELISA) with a monoclonal antibody and rabbit polyclonal antibody to HBD-2. The assay was validated against a Western blot assay for HBD-2 in samples of bronchoalveolar lavage fluid from patients with inflammatory lung disease. No HBD-2 was detectable in any of the burn blister fluids analysed. HBD-2 is lost in the full-thickness burn wound, and we have now demonstrated its absence in burn blister fluid. This finding represents evidence of a host defence defect within the burn wound and suggests a possible therapeutic role for antimicrobial peptides in the management of burn wounds.


An introduction to medical imaging with coherent terahertz frequency radiation.
Methods have recently been developed that make use of electromagnetic radiation at terahertz (THz) frequencies, the region of the spectrum between millimetre wavelengths and the infrared, for imaging purposes. Radiation at these wavelengths is non-ionizing and subject to far less Rayleigh scatter than visible or infrared wavelengths, making it suitable for medical applications. This paper introduces THz pulsed imaging and discusses its potential for in vivo medical applications in comparison with existing modalities.