[Factors that affect time delays to fibrinolytic treatment in ischaemic stroke].
Extending the thrombolytic therapy window in ischaemic stroke to 4.5 hours has proved to be useful and safe, but a prompt response remains a decisive factor. To analyse the factors that delay treatment. After activating the Stroke Code procedure, the consecutive cases of stroke attended in the emergency department throughout the year 2006 were recorded; data included their clinical and epidemiological features, origin, means of transport and delay times in the process. Of the total number of patients with ischaemic stroke, 10.1% finished the emergency study with a median of 1 hour to decide to carry out treatment within 3 hours, and 13.1% of them between 3 and 4.5 hours, with a median of 2 hours and 6 minutes. For the analysis of all the variables, 498 patients were selected; 39% were admitted to hospital within the first 3 hours and 11.2% between 3 and 4.5 hours of the onset of symptoms. The use of the emergency telephone system, transport by mobile ICU or ambulance and an impaired level of consciousness, sight or, to a lesser extent, language or speech were related to shorter delay times. The factors that depended on the actual patient, in general, did not shorten the delay time. Clinical severity, the presence of informants and activating the emergency system shortened intervention times.


Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene.
Disagreements about the phenotype of estrogen receptor β (ERβ) knockout mouse, created by removing the DNA-binding domain of the ERβ gene or interruption of the gene with a neocassette (Oliver Smithies ERβ knockout mice [ERβOS-/-]), prompted us to create an ERβ knockout mouse by deleting the ERβ gene with the use of CRISPR/Cas9 technology. We confirmed that the ERβ gene was eliminated from the mouse genome and that no ERβ mRNA or protein was detectable in tissues of this mouse. Overall the phenotype of the ventral prostate (VP) and mammary gland (MG) in ERβcrispr-/- mice was similar to, but more severe than, that in the ERβOS-/-mice. In the VP of 6-mo-old ERβcrispr-/- mice there was epithelial hyperplasia, fibroplasia, inflammation, stromal overgrowth, and intraductal cancer-like lesions. This was accompanied by an increase in Ki67 and P63 and loss in DACH1 and PURα, two androgen receptor (AR) repressors. In the MG there was overexpression of estrogen receptor α and progesterone receptor, loss of collagen, increase in proliferation and expression of metalloproteases, and invasive epithelium. Surprisingly, by 18 mo of age, the number of hyperplastic foci was reduced, the ducts of the VP and MG became atrophic, and, in the VP, there was massive immune infiltration and massive desquamation of the luminal epithelial cells. These changes were coincident with reduced levels of androgens in males and estrogens in females. We conclude that ERβ is a tumor suppressor gene in the VP and MG where its loss increases the activity AR and ERα, respectively.


Antimicrobial resistance of Shigellae isolated in Michigan.
Patterns of antimicrobial resistance were studied for 213 strains of shigellae isolated in rural and urban areas of Michigan by quantitative techniques: 66% of these organisms were resistant to ampicillin, tetracycline, cephalexin, or chloramphenicol or had multiple resistance to various combinations of these antibiotics. The incidence of resistant organisms was higher in the Detroit-Wayne County area, which is the most urban part of the state. Nalidixic acid and oxolinic acid were noted to be quite effective in vitro against shigellae and perhaps warrant further clinical study as potential agents for therapy of shigellosis, especially in view of the appearance of isolates with multiple resistance. Sulfamethoxazole alone was effective against only 62% of the Shigella isolates tested, but mixture with trimethoprim in a 20:1 ratio yielded a highly active in vitro combination.


Experimental lung collapse following deployment of a self-expandable bronchial occluder in a rabbit model.
Closure of a bronchopleural fistula is required to prevent fatal empyema or aspiration pneumonia. The purpose of this study was to determine the feasibility and efficacy of bronchial occlusion with a self-expandable occluder to induce experimental lung collapse in a rabbit model. 10 bronchial occluders (wine glass appearance; 8 mm in diameter and 15 mm in length) were implanted in the native left main bronchi of 10 rabbits via an endotracheal route. We analysed the following: (1) diameters and morphological changes of the bronchial occluders during follow-up; (2) percentage volume of the collapsed lung during follow-up; and (3) complications and gross pathology. 1-day and 2-week follow-up CT scans were routinely obtained. Rabbits were sacrificed 4 weeks after the experiment. In all 10 rabbits, the bronchial occluders were successfully implanted and were completely expanded within 2 weeks. Complete collapse of the left lung occurred in three rabbits on day 1 and in an additional two rabbits 2 weeks following implantation. Two other rabbits maintained the percentage volume of the collapsed lung between 51% and 99% during follow-up; the other three rabbits had <50% during follow-up. Pneumothoraces occurred in nine rabbits, but completely resolved at the 2-week follow-up. Right lung herniation across the midline progressed 2 weeks after occluder implantation. Placement of self-expandable occluders in a rabbit bronchus model was feasible and showed a potential to induce artificial lung collapse. While pneumothoraces were common, they resolved during follow-up.


Gemcitabine hydrochloride-loaded liposomes and nanoparticles: comparison of encapsulation efficiency, drug release, particle size, and cytotoxicity.
The aim of this study is to formulate and compare the physicochemical properties of negatively charged liposomes and poly(lactide-co-glycolide) (PLGA) nanoparticles loaded with gemcitabine hydrochloride. The influence of the formulation variables on the liposome and nanoparticle properties on particle size, zeta potential, encapsulation efficiency, and drug release was evaluated. Although the PEGylated nanoparticles and PEGylated liposomes were of the same size (∼200 nm), the encapsulation efficiency was 1.4 times higher for PEGylated liposomes than for PEGylated nanoparticles. The optimized formulation of PEGylated liposomes and PEGylated nanoparticles had 26.1 ± 0.18 and 18.8 ± 1.52% encapsulation efficiency, respectively. The release of drug from the PEGylated liposomes and PEGylated nanoparticles exhibited a biphasic pattern that was characterized by a fast initial release during the first 2 h followed by a slower continuous release. Transmission electron microscopy (TEM) images identified separate circular structures of the liposomes and nanoparticles. The in vitro cytotoxicity of the optimized formulations was assessed in MCF-7 and MDA-MB-231 cells, and the results showed that the cytotoxicity effect of the gemcitabine hydrochloride-loaded liposomes and nanoparticles was more than commercial product Gemko® and gemcitabine hydrochloride solution.


Neurologic side effects in neuroleptic-naive patients treated with haloperidol or risperidone.
To compare the side effect profile of risperidone with that of oral haloperidol in patients with no previous exposure to antipsychotic drugs (APDs). Early studies suggested that the APD risperidone may have a side effect profile comparable with that of placebo. These early studies involved patients with chronic schizophrenia and a long history of APD use. Very little information is available regarding the neurologic side effects of risperidone in patients without previous APD exposure. The authors prospectively studied 350 consecutive neuroleptic-naive patients admitted to their acute-care psychiatry service; 34 of these were treated with risperidone (mean dose, 3.2 mg/d) and 212 were treated with low-dose haloperidol (mean dose 3.7 mg/d). All patients were assessed on admission and twice weekly thereafter using rating scales for dystonia, parkinsonism, akathisia, and dyskinesia. The incidence and severity of dystonic reactions, akathisia, parkinsonism, and dyskinesia were comparable in the risperidone- and haloperidol-treated groups. The neurologic side effect profile of low-dose risperidone is comparable with that of haloperidol in patients receiving APDs for the first time. Risperidone may not be a useful alternative to typical APDs for patients with PD and psychosis.


Photoconductively loaded plasmonic nanoantenna as building block for ultracompact optical switches.
We propose and explore theoretically a new concept of ultrafast optical switches based on nonlinear plasmonic nanoantennas. The antenna nanoswitch operates on the transition from the capacitive to conductive coupling regimes between two closely spaced metal nanorods. By filling the antenna gap with amorphous silicon, progressive antenna-gap loading is achieved due to variations in the free-carrier density in the semiconductor. Strong modification of the antenna response is observed both in the far-field response and in the local near-field intensity. The large modulation depth, low switching threshold, and potentially ultrafast time response of antenna switches holds promise for applications ranging from integrated nanophotonic circuits to quantum information devices.


Colonoscopy polypectomy management in Glanzmann's thrombasthenia.
Glanzmann's thrombasthenia (GT) is a rare autosomal recessive bleeding syndrome characterized by abnormal Glycoprotein IIb/IIIa complex (GIIb/IIIa) on platelets with resultant abnormality in platelet aggregation. There is very little information regarding polypectomy management in GT. We report a single patient with this rare disease, who underwent sequential endoscopic management of large colon polyps. Polypectomy in our GT patient was complicated by immediate and delayed bleeding. Multiple clips used after standard cautery polypectomy for a polyp 10 mm or larger in our GT patient, was most effective in preventing immediate and delayed post-polypectomy bleeding than other known therapeutic approaches. We favor preemptive use of multiple clips in large polypectomy defects for GT patients and we may argue the added cost may be offset by the reduction in the need for blood products, and by averting or shortening potential hospitalizations.


Strong Plasmon Enhancement of the Saturation Photon Count Rate of Single Molecules.
Plasmon resonances have appeared as a promising method to boost the fluorescence intensity of single emitters. However, because research has focused on the enhancement at low excitation intensity, little is known about plasmon-fluorophore coupling near the point where the dye saturates. Here we study plasmon-enhanced fluorescence at a broad range of excitation intensities up to saturation. We adopt a novel DNA-mediated approach wherein dynamic single-molecule binding provides a controlled particle-fluorophore spacing, and dynamic rebinding circumvents artifacts due to photobleaching. We find that near saturation the maximum photon count rate is enhanced by more than 2 orders of magnitude at the optimal particle-fluorophore spacing, even for a dye with a high intrinsic quantum yield. We compare our results to a numerical model taking into account dye saturation. These experiments provide design rules to maximize the photon output of single emitters, which will open the door to studying fast dynamics in real time using single-molecule fluorescence.


A Cross-Sectional Survey of the Zika Virus and its Prevention: The Knowledge, Thoughts, and Beliefs of a Community of Residents in Caguas, Puerto Rico.
The objective of this study was to explore the knowledge, thoughts, and beliefs regarding the Zika virus and its prevention in a community of residents in the municipality of Caguas, Puerto Rico, and elicit their concerns and perceptions of risk. A quantitative, non experimental, descriptive, cross-sectional correlational study was conducted in a community in Caguas, Puerto Rico. A structured questionnaire was administered to a sample of 158 residents, aged 21 and older, who participated voluntarily. The data were analyzed using SPSS version 17 via univariate and bivariate analysis. Of 158 surveyed, 64.6% were women; with a population average of 53.85 years. Of the respondents who believed that they would be affected in some way if they were infected by the Zika virus, over half (52.3%) felt that the virus represented a significant threat to their emotional stability. Of those who perceived emotional threat, 39.5% (n=32) continued to study after completing high school (X2=9.217, p=0.027), 57.9% (n=55) had private health insurance (X2=6.325; p=0.042), and 67.9% (n=55) reported it was little or unlikely to become infected (X2= 6.783; p=0.034). Out of those concerned, 57.4% (n=54) considered Zika very or extremely severe (X2=22.827, p<0.001) and 98.9% (n=93) clean the house surroundings as a preventive measure (X2 = 4.951, p=0.026). Lack of interest was the most common reason identified for not complying with preventive actions by the residents (89.2%). The underestimation both of the risk concerning the Zika virus and of its consequences was evident. This study reaffirms the need to develop a network that effectively and constantly communicates risk estimates, doing so while addressing the specific needs within the communities served by that network. Community interventions aimed at improving the benefits of and reducing the risks associated with and the perceived barriers to preventive behaviors are needed.


Relapse to cocaine use persists following extinction of drug-primed craving.
Craving often precedes relapse into cocaine addiction. This explains why considerable research effort is being expended to try to develop anti-craving strategies for relapse prevention. Recently, we discovered using the classic reinstatement model of cocaine craving that the reinstating or priming effect of cocaine can be extinguished with repeated priming in rats - a phenomenon dubbed extinction of cocaine priming because it is thought to involve extinction of the conditioned interoceptive cues of the drug. Here we measured the effect of this extinction strategy on subsequent relapse-like behavior in rats (i.e., return to the pre-extinction pattern of cocaine self-administration once the drug is made again available after extinction). We found that extensive extinction of the conditioned priming effects of cocaine had no major impact on relapse-like behavior. This lack of effect occurred despite evidence for post-extinction loss of neuronal responses to cocaine priming in brain regions causally involved in cocaine reinstatement (i.e., the dorsomedial prefrontal cortex and the core of the nucleus accumbens). These findings suggest that the conditioned priming effects of cocaine can be dissociated from and are thus not essential for relapse-like behavior, and that extinction of these effects is unlikely to represent a viable approach to relapse prevention. Overall, these findings are in general agreement with previous neurobiological dissociation studies and with research on extinction of exteroceptive drug cues.


New insights into the use of magnetic force microscopy to discriminate between magnetic and nonmagnetic nanoparticles.
Magnetic force microscopy (MFM) is a very powerful technique, which can potentially be used to detect and localize the magnetic fields arising from nanoscopic magnetic domains, such as magnetic nanoparticles. However, in order to achieve this, we must be able to use MFM to discriminate between magnetic forces arising from the magnetic nanoparticles and nonmagnetic forces from other particles and sample features. Unfortunately, MFM can show a significant response even for nonmagnetic nanoparticles, giving rise to potentially misleading results. The literature to date lacks evidence for MFM detection of magnetic nanoparticles with nonmagnetic nanoparticles as a control. In this work, we studied magnetite particles of two sizes and with a silica shell, and compared them to nonmagnetic metallic and silica nanoparticles. We found that even on conducting, grounded substrates, significant electrostatic interaction between atomic force microscopy probes and nanoparticles can be detected, causing nonmagnetic signals that might be mistaken for a true MFM response. Nevertheless, we show that MFM can be used to discriminate between magnetic and nonmagnetic nanoparticles by using an electromagnetic shielding technique or by analysis of the phase shift data. On the basis of our experimental evidence we propose a methodology that enables MFM to be reliably used to study unknown samples containing magnetic nanoparticles, and correctly interpret the data obtained.


[Percutaneous endoscopic gastrostomy: 5-year experience at out center (1997-2002)].
Gauderer and Ponsky first described percutaneous endoscopic gastrostomy (PEG) in 1979. It was introduced as a routine method in the Division of Gastroenterology, University Hospital Rebro, Zagreb, in 1995. Over the years the number of PEG insertions has increased significantly. We reviewed the available literature and compared the results with our experience according to indications, complications and efficacy of the procedure. We inserted PEG in 86 patients from January 1, 1997 until January 31, 2002. There were 40 females and 46 males. The most frequent indication for PEG insertion was a neurological condition (60/86). There were no deaths directly related to the procedure. One patient had a leakage of PEG feeding into the peritoneal cavity that caused severe peritonitis and required urgent laparatomy within 24 hours of the PEG insertion. Two patients had local infection and the tube had to be removed. The antibiotic prophylaxis has been given to 65 patients. Our experience confirms that PEG is a relatively safe and well tolerated procedure.


Preoperative radiographic assessment of hepatic steatosis with histologic correlation.
The adverse impact of hepatic steatosis on perioperative outcomes after liver resection is gaining recognition. But the accuracy of preoperative radiologic assessment of fatty liver disease remains unclear. The objective of this study was to correlate preoperative radiologic estimation with postoperative histologic measurement of steatosis. Patients who underwent partial hepatectomy between 1997 and 2001, with complete preoperative radiographic imaging and postoperative pathologic assessment of steatosis, were retrospectively analyzed. The presence of steatosis was assessed radiographically using noncontrast-enhanced CT (NCCT), contrast-enhanced CT (CCT), or MRI, using standard quantitative radiologic criteria. Repeat histologic analysis was used to quantify the extent of hepatic steatosis. One hundred thirty-one patients were studied. The overall sensitivity and specificity for all imaging modalities in detecting pathologically confirmed hepatic steatosis were 56% and 82%, respectively. Sensitivity and specificity for NCCT, CCT, and MRI using standard quantitative criteria were 33% and 100%, 50% and 83%, and 88%, and 63%, respectively. Increasing body mass indices adversely affected the accuracy of NCCT (p=0.002). Preoperative chemotherapy did not notably affect radiologic accuracy. The presence of a fatty-appearing liver on NCCT scans indicates clinically significant steatosis, but steatosis cannot be excluded based on a normal NCCT scan, particularly in obese patients. Conversely, normal MRI helps to exclude hepatic steatosis, but abnormal MRI is not a reliable indicator of fatty change. CCT is not an effective means of identifying steatosis. We conclude that, when used alone, conventional cross-sectional imaging does not consistently permit accurate identification of hepatic steatosis.


Surface modification of titanium based biomaterials by ion beam.
Ion beam enhanced deposition (IBED) was adopted to synthesize biocompatible titanium oxide film. Structure characteristics of titanium oxide film were investigated by RBS, AES, and XRD. The blood compatibility of the titanium oxide film was studied by measurements of blood clotting time and platelet adhesion. The results show that the anticoagulation property of titanium oxide film is improved significantly. The mechanism of anticoagulation of the titanium oxide film was discussed.


Bridging the translational gap: adenosine as a modulator of neuropathic pain in preclinical models and humans.
This review aims to analyse the published data on preclinical and human experimental and clinical adenosine modulation for pain management. We summarise the translatability of the adenosine pathway for further drug development and aim to reveal subgroups of pain patients that could benefit from targeting the pathway. Chronic pain patients suffer from inadequate treatment options and drug development is generally impaired by the low translatability of preclinical pain models. Therefore, validating the predictability of drug targets is of high importance. Modulation of the endogenous neurotransmitter adenosine gained significant traction in the early 2000s but the drug development efforts were later abandoned. With the emergence of new drug modalities, there is a renewed interest in adenosine modulation in pain management. In both preclinical, human experimental and clinical research, enhancing adenosine signalling through the adenosine receptors, has shown therapeutic promise. A special focus has been on the A1 and A3 receptors both of which have shown great promise and predictive validity in neuropathic pain conditions. Adenosine modulation shows predictive validity across preclinical, human experimental and clinical investigations. The most compelling evidence is in the field of neuropathic pain, where adenosine has been found to alleviate hyperexcitability and has the potential to be disease-modifying. Adenosine modulation show therapeutic potential in neuropathic pain if selective and safe drugs can be developed. New drug modalities such as RNA therapeutics and cell therapies may provide new options.


Update: vinorelbine (navelbine) in non-small cell lung cancer.
Vinorelbine (navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France), a novel semisynthetic vinca alkaloid, is the first drug approved by the Food and Drug Administration in over 20 years for the first-line treatment of ambulatory patients with unresectable advanced non-small cell lung cancer (NSCLS). In a multicenter, randomized US trial, single-agent vinorelbine produced response rates of 12%, compared with prior single-center studies demonstrating a response rate of 30%. Furthermore, in the US trial, median survival for patients receiving vinorelbine was 30 weeks, with a 1-year survival rate of 25%, compared with 22 weeks for 5-fluorouracil and leucovorin, with a 1-year survival rate of 16%. This impact on survival was confirmed in a European multicenter randomized trial. In this study, vinorelbine as a single agent demonstrated a median survival of 31 weeks, with a 1-year survival rate of 30%. Single-agent vinorelbine was comparable to the combination of vindesine/cisplatin, which had a median survival of 32 weeks and a 1-year survival rate of 27%. By contrast, the combination of vinorelbine/cisplatin produced a medial survival of 40 weeks and a 1-year survival rate of 35%. The major dose-limiting toxic effect of vinorelbine is granulocytopenia. Vinorelbine has demonstrated a survival advantage in patients with advanced NSCLC in two controlled clinical trials and has been associated with a favorable safety profile associated with a low incidence of hospitalization. These findings would suggest that vinorelbine alone or in combination with cisplatin may be a cost-effective treatment for appropriate patients with advanced NSCLC.


Human HSP70-escort protein 1 (hHep1) interacts with negatively charged lipid bilayers and cell membranes.
Human Hsp70-escort protein 1 (hHep1) is a cochaperone that assists in the function and stability of mitochondrial HSPA9. Similar to HSPA9, hHep1 is located outside the mitochondria and can interact with liposomes. In this study, we further investigated the structural and thermodynamic behavior of interactions between hHep1 and negatively charged liposomes, as well as interactions with cellular membranes. Our results showed that hHep1 interacts peripherally with liposomes formed by phosphatidylserine and cardiolipin and remains partially structured, exhibiting similar affinities for both. In addition, after being added to the cell membrane, recombinant hHep1 was incorporated by cells in a dose-dependent manner. Interestingly, the association of HSPA9 with hHep1 improved the incorporation of these proteins into the lipid bilayer. These results demonstrated that hHep1 can interact with lipids also present in the plasma membrane, indicating roles for this cochaperone outside of mitochondria.


Delisting eye examinations from public health insurance: Empirical evidence from Canada regarding impacts on patients and providers.
This paper examines the impacts of delisting routine eye exam services on patient eye care utilization and on providers' labour market outcomes in a public healthcare system. Provincial governments in Canada started to de-insure routine eye examinations from the basket of publicly insured healthcare services in the early 1990s. We explore these policy changes across Canadian provinces to estimate the impacts of delisting from the supply- and demand-sides. Demand side analysis suggests that, on average, for the working age population delisting decreased the probability of using eye care. However, the number of visits among those who continued to use eye care services did not change. Additionally, the delisting may have had unintended consequences by causing a large negative impact among low-income individuals, and there is suggestive evidence of a positive spillover on utilization by publicly-funded patients over age 64. On the supply side, using Canadian census data we find that delisting eye exams decreased optometrists' weekly work hours, raised their annual work weeks and had little effect on their income.


Coronary Sinus Catheter-Induced Heart Block During Aortic Valve Replacement: A Case Report.
Conduction abnormalities after cardiac surgery are common as is spontaneous resolution of these abnormalities. However, 1%-3% of patients will require placement of a permanent pacemaker. Patients with preexisting conduction abnormalities, undergoing reoperation, preexisting pulmonary hypertension and undergoing mitral or aortic valve operations are at a higher risk for requiring a permanent pacemaker. We present the first case described in the literature of a patient with a preexisting left bundle branch block, and heart failure with a reduced left ventricular ejection fraction of 25% who developed complete heart block after placement of a coronary sinus catheter.


Transcriptional regulation of the flavohemoglobin gene for aerobic nitric oxide detoxification by the second nitric oxide-responsive regulator of Pseudomonas aeruginosa.
The regulatory gene for a sigma54-dependent-type transcriptional regulator, fhpR, is located upstream of the fhp gene for flavohemoglobin in Pseudomonas aeruginosa. Transcription of fhp was induced by nitrate, nitrite, nitric oxide (NO), and NO-generating reagents. Analysis of the fhp promoter activity in mutant strains deficient in the denitrification enzymes indicated that the promoter was regulated by NO or related reactive nitrogen species. The NO-responsive regulation was operative in a mutant strain deficient in DNR (dissimilatory nitrate respiration regulator), which is the NO-responsive regulator required for expression of the denitrification genes. A binding motif for sigma54 was found in the promoter region of fhp, but an FNR (fumarate nitrate reductase regulator) box was not. The fhp promoter was inactive in the fhpR or rpoN mutant strain, suggesting that the NO-sensing regulation of the fhp promoter was mediated by FhpR. The DNR-dependent denitrification promoters (nirS, norC, and nosR) were active in the fhpR or rpoN mutants. These results indicated that P. aeruginosa has at least two independent NO-responsive regulatory systems. The fhp or fhpR mutant strains showed sensitivity to NO-generating reagents under aerobic conditions but not under anaerobic conditions. These mutants also showed significantly low aerobic NO consumption activity, indicating that the physiological role of flavohemoglobin in P. aeruginosa is detoxification of NO under aerobic conditions.


Neonates living with enterostomy following necrotising enterocolitis are at high risk of becoming severely underweight.
Necrotising enterocolitis (NEC) is often managed with a temporary enterostomy. Neonates with enterostomy are at risk of growth retardation during critical neurodevelopment. We examined their growth using z-score. We identified all patients with enterostomy from NEC in two neonatal surgical units (NSU) during January 2012-December 2016. Weight-for-age z-score was calculated at birth, stoma formation and closure, noting severely underweight as z < - 3. We compared those kept in NSU until stoma closure with those discharged to local units or home (LU/H) with a stoma. A total of 74 patients were included. By stoma closure, 66 (89%) had deteriorated in z-score with 31 (42%) being severely underweight. There was no difference in z-score at stoma closure between NSU and LU/H despite babies sent to LU/H having a more distal stoma, higher birth weight and gestational age. Babies in LU/H spent a much shorter period on parenteral nutrition while living with their stoma for longer, many needing readmission.Conclusion: Growth failure is a common and severe problem in babies living with enterostomy following NEC. z-score allowed growth trajectory to be accounted for in nutrition prescription and timing of stoma closure. Care during this period should be focused on minimising harm.What is Known:• Necrotising enterocolitis (NEC) is a life-threatening condition affecting predominately premature and very low birth weight neonates. Emergency treatment with temporary enterostomy often leads to growth failure.• There is no consensus on the optimal timing for stoma reversal, hence prolonging impact on growth during crucial developmental periods. Both malnutrition and surgical NEC are independently associated with poor neurodevelopment outcome.What is New:• Our study found growth in 89% of babies deteriorated while living with a stoma, with 42% having a weight-for-age z-score < - 3, meeting the WHO criteria of being severely underweight, despite judicial use of parenteral nutrition. Applying z-score to weight measurements will allow growth trajectory to be accounted for in clinical decisions, including nutrition prescription (both enteral and parenteral), and guide timing of stoma closure.• Surgeons who target stoma closure at a certain weight risk waiting for an indefinite period of time, during which babies' growth may falter.


adPEO mutations in ANT1 impair ADP-ATP translocation in muscle mitochondria.
Mutations in the heart and muscle isoform of adenine nucleotide translocator 1 (ANT1) are associated with autosomal-dominant progressive external opthalmoplegia (adPEO) clinically characterized by exercise intolerance, ptosis and muscle weakness. The pathogenic mechanisms underlying the mitochondrial myopathy caused by ANT1 mutations remain largely unknown. In yeast, expression of ANT1 carrying mutations corresponding to the human adPEO ones causes a wide range of mitochondrial abnormalities. However, functional studies of ANT1 mutations in mammalian cells are lacking, because they have been hindered by the fact that ANT1 expression leads to apoptotic cell death in commonly utilized replicating cell lines. Here, we successfully express functional ANT1 in differentiated mouse myotubes, which naturally contain high levels of ANT1, without causing cell death. We demonstrate, for the first time in these disease-relevant mammalian cells, that mutant human ANT1 causes dominant mitochondrial defects characterized by decreased ADP-ATP exchange function and abnormal translocator reversal potential. These abnormalities are not due to ANT1 loss of function, because knocking down Ant1 in myotubes causes functional changes different from ANT1 mutants. Under certain physiological conditions, mitochondria consume ATP to maintain membrane potential by reversing the ADP-ATP transport. The modified properties of mutant ANT1 can be responsible for disease pathogenesis in adPEO, because exchange reversal occurring at higher than normal membrane potential can cause excessive energy depletion and nucleotide imbalance in ANT1 mutant muscle cells.


ZnO-Ag hybrids for ultrasensitive detection of trinitrotoluene by surface-enhanced Raman spectroscopy.
An efficient and green approach was used to fabricate novel and low-cost surface-enhanced Raman scattering (SERS) spectroscopy sensors based on 4-aminothiophenol (4-ATP) functionalized ZnO-Ag hybrid nanoflowers for the detection of explosives. Such SERS sensors exhibited high sensitivity to rhodamine 6G (R6G) at a low concentration of 10(-12) M and an enhancement factor of over 4.12 × 10(6) was achieved. Moreover, the Raman-inactive trinitrotoluene (TNT) initiated the high Raman scattering of non-resonated 4-ATP through the formation of a π-donor-π-acceptor interaction between the π-acceptor, TNT, and the π-donor, the 4-ATP-Ag-ZnO complex, on the flower-like hybrids. Because this π-donor-π-acceptor interaction could effectively induce the "hot spots" for SERS, TNT concentrations as low as 5 × 10(-9) M could be detected. Furthermore, other derivatives of TNT were also explored, and this sensor exhibited better selectivity for TNT than other similarly structured explosives. The low-cost hybrid SERS substrates presented good sensitivity and reproducibility for the analytes employed, demonstrating promising application in forensic science and homeland security.


Decreased expression of the human carbonyl reductase 2 gene HCR2 in hepatocellular carcinoma.
Altered gene expression was associated with the induction and maintenance of hepatocellular carcinoma (HCC). To determine the significance of HCR2 in HCC, here we compare the expression levels of HCR2 in carcinoma and in paired non-carcinoma tissues using semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), Western blot analysis, and immunohistochemical staining. The expression ratio (ER) of HCR2 between the tumor and paired tumor-free tissues was calculated for each case and the data was clinicopathologically analyzed. The expression of HCR2 mRNA was found to be significantly decreased in HCC tissues compared with paired normal tissues (P < 0.001). HCR2 was downregulated in 58% (n = 22) of 38 HCC patients. The ER of HCR2 was higher in Edmondson's grade I/II carcinomas than that in Edmondson's grade III/IV carcinomas (P < 0.05). Western blot analysis showed HCR2 to be notably depressed in carcinoma tissues in 3 out of 4 HCC patients. Immunohistochemical staining indicated most HCR2 protein accumulated in non-carcinoma cells. These results suggested that altered HCR2 expression might play roles in the carcinogenesis and progression of HCC, and it could be a clinical marker for prognosis, and a molecular target for screening potential anti-HCC drugs.


Photodynamic therapy with pyropheophorbide-a methyl ester in human lung carcinoma cancer cell: efficacy, localization and apoptosis.
Pyropheophorbide-a methyl ester (MPPa) is a semisynthetic photosensitizer derived from chlorophyll a. The absorption peak of MPPa in organic solvent and in cells was at 667 and 674 nm, respectively. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay showed that MPPa had no dark cytotoxicity. In vitro photodynamic activity was extensively evaluated using a human lung carcinoma cancer cell line (NCI-h446). MPPa exhibited no genotoxicity, as assayed by single-cell gel electrophoresis. Using confocal laser scanning microscopy and organelle-specific fluorescent probes, MPPa was found to localize in the intracellular membrane system, namely the endoplasmic reticulum, Golgi apparatus, lysosomes and mitochondria, in the NCI-h446 cells. Furthermore, nuclear staining and DNA gel electrophoresis revealed that DNA condensation and fragmentation occurred post-photodynamic therapy, indicating the cell death was in the apoptotic mode.


Prolonged Delayed Renal Graft Function Secondary to Venous Hypertension.
The case of a 39-year-old highly sensitized woman who underwent second renal transplantation after being on warfarin because of a history of frequent thromboses of her left femoral arteriovenous graft (AVG) is reported here. The patient received a flow cytometric positive crossmatch kidney transplant from a deceased donor. Her posttransplant course was complicated by prolonged delayed graft function (DGF) lasting for 9 months. Antibody-mediated rejection occurred in the immediate postoperative period. This resolved after treatment, and resolution was confirmed by repeat biopsy. Despite this, she had persistent DGF and remained dialysis dependent. A computed tomography scan due to the development of perinephric hematoma after posttransplant biopsy demonstrated venous collateralization around the allograft. At 7 months posttransplant, a venogram during declotting of AVG revealed chronic thrombus in the inferior vena cava (IVC) above the level of native renal veins with a venous gradient of 26 mmHg. After declotting of the graft, iliac venoplasty, and subsequent IVC stent, her renal function continues to improve with a most recent creatinine of 1.4 mg/dL at 36 months posttransplant. Venous hypertension secondary to IVC thrombosis in presence of patent femoral AVG should be considered as a rare cause of prolonged DGF.


["Interventional radiology" in breast examination].
The data on such highly-effective invasive diagnostico-therapeutic procedures as ductography, sclerosing-solution cystography, X-ray-controled puncture biopsy, stereotactical computer technique, sonography and preoperative maging of nonpalpable lesions were analyzed following a complex mammographic examination of 20,000 patients with different breast pathologies. Advantages offered by complex breast examination are discussed. Among them were the use of optimal effects of each invasive procedure, an accuracy of preoperative diagnosis reaching 95-98% (nonpalpable breast lesions included) and a significantly reduced extent of breast surgery.


Feeding ecology of Cobitis paludica and Cobitis calderoni in Central Spain.
In total, 253 specimens of Cobitis paludica and 163 Cobitis calderoni were collected in the Lozoya River (Madrid, Spain) in April, May, July, September and December 1990. Both species showed high percentages of empty guts in all months. C. paludica fed mainly on detritus and invertebrates while Cobitis calderoni fed on invertebrates and unicellular algae. Preferred prey items were the larvae of Dipterans (Chironomidae, Simuliidae) and micro crustaceans, with Ephemeroptera (Caenis) in summer. Cobitis calderoni fed on the most abundant prey except in April and July, when it selected invertebrates. C. paludica selected invertebrates throughout all the months. Diet overlapping (Horn's Index) was complete except in September, when the abundance of invertebrates in both diets was similar. For the remaining months, food type (invertebrates, unicellular algae and detritus) abundance differed, minimizing the interspecific competition.


Modulation of neuronal sodium channels by the sea anemone peptide BDS-I.
Blood-depressing substance I (BDS-I), a 43 amino-acid peptide from sea anemone venom, is used as a specific inhibitor of Kv3-family potassium channels. We found that BDS-I acts with even higher potency to modulate specific types of voltage-dependent sodium channels. In rat dorsal root ganglion (DRG) neurons, 3 μM BDS-I strongly enhanced tetrodotoxin (TTX)-sensitive sodium current but weakly inhibited TTX-resistant sodium current. In rat superior cervical ganglion (SCG) neurons, which express only TTX-sensitive sodium current, BDS-I enhanced current elicited by small depolarizations and slowed decay of currents at all voltages (EC(50) ∼ 300 nM). BDS-I acted with exceptionally high potency and efficacy on cloned human Nav1.7 channels, slowing inactivation by 6-fold, with an EC(50) of approximately 3 nM. BDS-I also slowed inactivation of sodium currents in N1E-115 neuroblastoma cells (mainly from Nav1.3 channels), with an EC(50) ∼ 600 nM. In hippocampal CA3 pyramidal neurons (mouse) and cerebellar Purkinje neurons (mouse and rat), BDS-I had only small effects on current decay (slowing inactivation by 20-50%), suggesting relatively weak sensitivity of Nav1.1 and Nav1.6 channels. The biggest effect of BDS-I in central neurons was to enhance resurgent current in Purkinje neurons, an effect reflected in enhancement of sodium current during the repolarization phase of Purkinje neuron action potentials. Overall, these results show that BDS-I acts to modulate sodium channel gating in a manner similar to previously known neurotoxin receptor site 3 anemone toxins but with different isoform sensitivity. Most notably, BDS-I acts with very high potency on human Nav1.7 channels.


Melanoma Cell Adhesion and Migration Is Modulated by the Uronyl 2-O Sulfotransferase.
Although the vast majority of melanomas are characterized by a high metastatic potential, if detected early, melanoma can have a good prognostic outcome. However, once metastasised, the prognosis is bleak. We showed previously that uronyl-2-O sulfotransferase (Ust) and 2-O sulfation of chondroitin/dermatan sulfate (CS/DS) are involved in cell migration. To demonstrate an impact of 2-O sulfation in metastasis we knocked-down Ust in mouse melanoma cells. This significantly reduced the amount of Ust protein and enzyme activity. Furthermore, in vitro cell motility and adhesion were significantly reduced correlating with the decrease of cellular Ust protein. Single cell migration of B16VshUst(16) cells showed a decreased cell movement phenotype. The adhesion of B16V cells to fibronectin depended on α5β1 but not αvβ3 integrin. Inhibition of glycosaminoglycan sulfation or blocking fibroblast growth factor receptor (FgfR) reduced α5 integrin in B16V cell lines. Interestingly, FgfR1 expression and activation was reduced in Ust knock-down cells. In vivo, pulmonary metastasis of B16VshUst cells was prevented due to a reduction of α5 integrin. As a proof of concept UST knock-down in human melanoma cells also showed a reduction in ITGa5 and adhesion. This is the first study showing that Ust, and consequently 2-O sulfation of the low affinity receptor for FgfR CS/DS, reduces Itga5 and leads to an impaired adhesion and migration of melanoma cells.


Robust EEG Based Biomarkers to Detect Alzheimer's Disease.
Biomarkers to detect Alzheimer's disease (AD) would enable patients to gain access to appropriate services and may facilitate the development of new therapies. Given the large numbers of people affected by AD, there is a need for a low-cost, easy to use method to detect AD patients. Potentially, the electroencephalogram (EEG) can play a valuable role in this, but at present no single EEG biomarker is robust enough for use in practice. This study aims to provide a methodological framework for the development of robust EEG biomarkers to detect AD with a clinically acceptable performance by exploiting the combined strengths of key biomarkers. A large number of existing and novel EEG biomarkers associated with slowing of EEG, reduction in EEG complexity and decrease in EEG connectivity were investigated. Support vector machine and linear discriminate analysis methods were used to find the best combination of the EEG biomarkers to detect AD with significant performance. A total of 325,567 EEG biomarkers were investigated, and a panel of six biomarkers was identified and used to create a diagnostic model with high performance (≥85% for sensitivity and 100% for specificity).


TRIPPD: a practice-based network effectiveness study of postpartum depression screening and management.
Postpartum depression is common but inadequately recognized and undertreated. Continuing depressive symptoms are associated with adverse outcomes for the woman, her infant, and family. We wanted to determine the effect of a practice-based training program for screening, diagnosis, and management of depression in postpartum mothers. In this practice-based effectiveness study, 28 practices were randomized to usual care (n = 14) or intervention (n = 14), and 2,343 women were enrolled between 5 and 12 weeks' postpartum. The intervention sites received education and tools for postpartum depression screening, diagnosis, initiation of therapy, and follow-up within their practices. Usual-care practices received a 30-minute presentation about postpartum depression. Screening information for the usual care was obtained from baseline surveys sent directly to the central site but was not available for patient care. Outcomes were based on patient-reported outcomes (level of depressive symptoms) from surveys at 6 and 12 months, plus medical record review (diagnosis and therapy initiation). Among the 2,343 women enrolled, 1,897 (80.1%) provided outcome information, and were included in the analysis. Overall, 654 (34.5% of 1,897) women had elevated screening scores indicative of depression, with comparable rates in the intervention and usual-care groups. Among the 654 women with elevated postpartum depression screening scores, those in the intervention practices were more likely to receive a diagnosis (P = .0006) and therapy for postpartum depression (P = .002). They also had lower depressive symptom levels at 6 (P = .07) and 12 months' (P=.001) postpartum. Primary care-based screening, diagnosis, and management improved mother's depression outcomes at 12 months. This practical approach could be implemented widely with modest resources.


Persistence of DNA damage in the freshwater mussel Unio pictorum upon exposure to ethyl methanesulphonate and hydrogen peroxide.
An important endpoint in assessing pollution-related toxicity is genotoxicity. To obtain insight into the time-course of oxidative- and alkylation-induced DNA damage in the freshwater mussel, Unio pictorum, mussels were exposed for 24 hr to concentration gradients of pro-oxidant hydrogen peroxide (H(2)O(2)) and a mono-functional alkylating agent, ethyl methanesulfonate (EMS). DNA damage was assessed in haemocytes immediately upon exposure and over the recovery period of up to 72 days by means of comet and micronucleus assays. Following exposure to H(2)O(2), DNA damage as detected by the comet assay returned to control values after one day, except for the mussels exposed to the highest dose when damage was detectable for the next 3 days. In contrast, alkylation-induced DNA damage was detectable even after 72 days of recovery in de-chlorinated water, with a dose-response relationship observable throughout the whole recovery period. Micronucleus frequency was the highest on Day 3 after exposure to EMS; it decreased considerably by Day 7 and returned almost to the control levels 19 days after exposure, while no significant induction of micronuclei was observed in mussels exposed to H(2)O(2). Although the comet assay is considered a biomarker of recent genotoxic exposure, detecting DNA damage of shorter longevity than with the micronucleus assay, results presented here show that in the case of alkylation damage the comet assay reveals genotoxic exposure of U. pictorum in a dose-dependent manner even after 2 months.


[Distribution and enrichment characteristics of organic carbon and total nitrogen in mollisols under long-term fertilization].
The characteristics and changes of soil organic carbon (SOC) and total nitrogen (TN) in different size particles of soil under different agricultural practices are the basis for better understanding soil carbon sequestration of mollisols. Based on a 31-year long-term field experiment located at the Heilongjiang Academy of Agricultural Sciences (Harbin) , soil samples under six treatments were separated by size-fractionation method to explore changes and distribution of SOC and TN in coarse sand, fine sand, silt and clay from the top layer (0-20 cm) and subsurface layer (20-40 cm). Results showed that long-term application of manure (M) increased the percentages of SOC and TN in coarse sand and clay size fractions. In the top layer, application of nitrogen, phosphorus and potassium fertilizers combined with manure (NPKM) increased the percentages of SOC and TN in coarse sand by 191.3% and 179.3% compared with the control (CK), whereas M application increased the percentages of SOC and TN in clay by 45% and 47% respectively. For subsurface layers, the increase rates of SOC and TN in corresponding parts were lower than that in top layer. In the surface and subsurface layers, the percentages of SOC storage in silt size fraction accounted for 42%-63% and 48%-54%, TN storage accounted for 34%-59% and 41%-47%, respectively. The enrichment factors of SOC and TN in coarse sand and clay fractions of surface layers increased significantly under the treatments with manure. The SOC and TN enrichment factors were highest in the NPKM, being 2.30 and 1.88, respectively, while that in the clay fraction changed little in the subsurface layer.


Assessment of trace metal distribution and contamination in surface soils of Hong Kong.
An intensive investigation was conducted to study the distribution of trace metals in surface soils of Hong Kong and to assess the soil environmental quality. From results of cluster analysis, and comparisons among soil types and areas, it is clearly shown that increases in trace metal concentrations in the soils were generally extensive and obvious in urban and orchard soils, less so in vegetable soils, whilst rural and forest soils were subjected to the least impact of anthropogenic sources of trace metals. However, some of the forest soils also contained elevated levels of As, Cu, and Pb. Urban soils in Hong Kong were heavily polluted by Pb from gasoline combustion. Agricultural soils, both orchard and vegetable soils, usually accumulated As, Cd, Cu, and Zn originating from applications of pesticides, animal manures, and fertilizers. In general, trace metal pollution in soils of the industrial areas and Pb pollution in the soils of the commercial and residential areas were obvious.


Hemostatic parameters predict 90-day mortality in hospitalized cirrhotic patients with acute decompensation: a prospective cohort study.
Hemostatic disturbances are common in patients with cirrhosis. Few studies have evaluated the prognostic role of hemostatic parameters in cirrhosis with acute decompensation. This study aims to determine the prognostic ability of standard hemostatic parameters in hospitalized cirrhotic patients with acute decompensation. Cirrhotic patients admitted with acute decompensation were prospectively enrolled. Hemostatic parameters were determined within 24 h, and the DIC (disseminated intravascular coagulation) score was calculated based on platelet count, prothrombin time (PT), fibrinogen, and D- dimer. New onset of in-hospital major bleeding and 90-day mortality were assessed. Eighty-nine patients were included (MELD 13.6 ± 5.7). The indications of admission were infection (38.2%), and portal hypertension-related bleeding (31.5%). 14.6% developed in-hospital major bleeding, and 90-day mortality rate was 21.3%. Major bleeding group and 90-day nonsurvivors had significantly higher activated partial thromboplastin time (aPTT), PT, and DIC score. The 90-day mortality rate was higher in major bleeding group (46.2 vs. 17.1%, P = 0.029). By multivariate logistic regression analysis, DIC score was associated with 90-day mortality. The AUROC of DIC score for 90-day mortality prediction was significantly higher than of MELD score (0.78 vs. 0.59, P = 0.04). DIC score at least 4 predicted 90-day mortality with a sensitivity of 88.9%. The cumulative 90-day survival was significantly lower in patients with DIC score at least 4 (57.2 vs. 93.6%, P = 0.0003). The development of in-hospital major bleeding significantly increases mortality in cirrhotic patients with acute decompensation. The DIC score within 24 h can be used as a simple and reliable predictor for 90-day mortality in these patients.


Strong Surface Orientation Dependent Thermal Transport in Si Nanowires.
Thermoelectrics, which convert waste heat to electricity, offer an attractive pathway for addressing an important niche in the globally growing landscape of energy demand. Research to date has focused on reducing the thermal conductivity relative to the bulk. Si nanowires (NWs) have received exceptional attention due to their low-dimensionality, abundance of availability, and high carrier mobility. From thermal transport point of view, the thermal conductivity of Si NWs strongly depends on the detailed surface structure, such as roughness and surface orientation. Here, direct molecular dynamics simulations and theoretical models are used to investigate the thermal transport in Si NWs with diverse surface orientations. Our results show that the thermal conductivity of Si NWs with different surface orientation can differ by as large as 2.7~4.2 times, which suggests a new route to boost the thermoelectric performance. Using the full spectrum theory, we find that the surface orientation, which alters the distribution of atoms on the surface and determines the degree of phonon coupling between the core and the surface, is the dominant mechanism. Furthermore, using spectral thermal conductivity, the remarkable difference in the thermal conductivity for different surface orientation is found to only stem from the phonons in the medium frequency range, with minor contribution from low and high frequency phonons.


Cystic thyroid and parathyroid lesions in cats.
Reports of cystic thyroid and parathyroid masses in cats are uncommon. Herein, the authors describe a series of four cats with cystic ventral cervical lesions, among them thyroid cyst (n=1), thyroid cystadenoma (n=2), and parathyroid adenocarcinoma (n=1). Presentations ranged from completely asymptomatic cervical swellings to signs related to local compression of adjacent structures (e.g., trachea). Ultrasonographic evaluation was helpful in localization of the mass in two cases. Hormone analysis and concentration of cystic fluid were performed in one cat. Surgical excision was performed successfully in three cases. Histopathological examination was performed in all four cases. Long-term prognosis was excellent for those cases in which follow-up was available.


Maternal stress programs a demasculinization of glutamatergic transmission in stress-related brain regions of aged rats.
Brain aging may be programmed by early-life stress. Aging affects males and females differently, but how perinatal stress (PRS) affects brain aging between sexes is unknown. We showed behavioral and neurobiological sex differences in non-stressed control rats that were strongly reduced or inverted in PRS rats. In particular, PRS decreased risk-taking behavior, spatial memory, exploratory behavior, and fine motor behavior in male aged rats. In contrast, female aged PRS rats displayed only increased risk-taking behavior and reduced exploratory behavior. PRS induced large reductions in the expression of glutamate receptors in the ventral and dorsal hippocampus and prefrontal cortex only in male rats. PRS also reduced the expression of synaptic vesicle-associated proteins, glucocorticoid receptors (GR), and mineralocorticoid receptors (MR) in the ventral hippocampus of aged male rats. In contrast, in female aged rats, PRS enhanced the expression of MRs and brain-derived neurotrophic factor (BDNF) in the ventral hippocampus and the expression of glial fibrillary acidic protein (GFAP) and BDNF in the prefrontal cortex. A common PRS effect in both sexes was a reduction in exploratory behavior and metabotropic glutamate (mGlu2/3) receptors in the ventral hippocampus and prefrontal cortex. A multidimensional analysis revealed that PRS induced a demasculinization profile in glutamate-related proteins in the ventral and dorsal hippocampus and prefrontal cortex, as well as a demasculinization profile of stress markers only in the dorsal hippocampus. In contrast, defeminization was observed only in the ventral hippocampus. Measurements of testosterone and 17-β-estradiol in the plasma and aromatase in the dorsal hippocampus were consistent with a demasculinizing action of PRS. These findings confirm that the brains of males and females differentially respond to PRS and aging suggesting that females might be more protected against early stress and age-related inflammation and neurodegeneration. Taken together, these results may contribute to understanding how early environmental factors shape vulnerability to brain aging in both sexes and may lay the groundwork for future studies aimed at identifying new treatment strategies to improve the quality of life of older individuals, which is of particular interest given that there is a high growth of aging in populations around the world.


Draining pus from the cornea.
Thirteen patients with varying grades of suppurative keratitis were studied with regard to their response to keratoplasty. In all patients there was a rapid improvement in symptoms and signs. In eight of the 13 there was restoration at least of previous function: one patient lost all vision due to secondary closed-angle glaucoma, because he refused further surgery. Corneal graft opacification occurred in three eyes; one other became partially opaque; whilst in a fourth, the lamellar graft remained clear while the original autograft failed. At last follow-up, all eyes were normotensive and free of symptoms. Keratoplasty should assume an important part of the management of suppurative keratitis, from both theoretical and practical considerations.


Nicaraguan Sign Language and Theory of Mind: the issue of critical periods and abilities.
Previous studies in the literature report that deaf individuals who experience late access to language perform poorly on false belief tests of Theory of Mind (ToM) compared with age-matched deaf and hearing controls exposed to language early. A group of 22 deaf Nicaraguans (aged 7 to 39 years) who learned Nicaraguan Sign Language (ISN) at different ages were tested on a false belief and a nonverbal cartoon retell task designed to elicit talk about the contents of character's mental states. Access to sign language by 10 years of age with possible advantages in language fluency was a strong predictor of performance on both the false belief task and mental state narrative task. However, a comparison of performance on the two tests indicated that children and adults who learned sign after the age of 10 were still able to demonstrate a more general ability to use mental state expressions in narratives. Results are discussed in terms of late access to language and critical periods for the parallel development of Theory of Mind and language. The findings point to age 10 years as a crucial period when lack of language exposure can lead to long-lasting deficits in false belief abilities. Late exposure to sign language does not, however, rule out all aspects of the ability to consider others' mental states. This paper also highlights the need to take into consideration a variety of communication responses when evaluating deaf children's ToM reasoning.


[Current problems of combined use of vaccination and non-immunological methods for infection control].
Based on data analysis on the morbidity rates and dynamics of the vaccine-preventable infectious diseases in Russia in comparison with those, immune-prophylaxis methods of which have not been developed yet, the need is shown to intensify efforts on generation and application disinfectological technologies and non-specific prophylactic means in addition to the missing vaccinological ones. First of all, this is necessary to control salmonella infections, different hemorrhagic fevers, sexually transmitted diseases, lice and, especially, mass acute respiratory diseases, upper respiratory infections, multiple unrecorded localization and etiology, annual contribution of which to total infection morbidity is 86-93%. Studies and development of this area of prevention and control of "uncontrolled" infections requires efforts both of disinfectologists and professionals in hygiene, epidemiology, microbiology, chemistry, bio-technology, entomology etc. Under these conditions, all infections can and shall become "controlled" through combined application of immunological and non-immunological methods and means generated and assessed on the basis of principles of the evidence-based medicine.


Dual Responsive Block Copolymer Micelles Functionalized by NIPAM and Azobenzene.
A novel amphiphilic diblock copolymer composed of a hydrophilic poly(ethylene oxide) block and a hydrophobic block copolymerized by azobenzene-containing methacrylate and N-isopropylacrylamide was synthesized using ATRP. The polymer micelles showed dual responsiveness to heat and light. The size of the micelles was dependent on temperature and the encapsulated substance in the hydrophobic cores was released during heating and cooling processes. The hydrophobicity of the micellar cores appeared as a reversible change in response to light with neither disruption of the micelles nor leakage of the encapsulated substance while H-aggregation of the azobenzene moieties was detected.


Domiciliary comparison of terbutaline treatment by metered dose inhaler with and without conical spacer in severe and moderately severe chronic asthma.
The bronchodilator response to cumulative doses of terbutaline administered by metered dose inhaler with and without a conical spacer device and by Acorn nebuliser has been compared in groups of patients with chronic severe and moderately severe asthma. After laboratory studies the patients undertook a randomised domiciliary crossover comparison of bronchodilator response to terbutaline given by metered dose inhaler with and without a spacer device, during which the severity of asthma was assessed by thrice daily recordings of peak expiratory flow (PEF) and symptom score. Improvement in FEV1 produced in the laboratory by the metered dose inhaler with spacer device was significantly greater than by metered dose inhaler alone (p less than 0.001) and similar to that from the nebuliser in both asthmatic groups throughout a range of terbutaline doses. In the domiciliary comparison mean midday and evening PEF rates were significantly higher with the use of the spacer device both in those with severe (p less than 0.01) and in those with moderately severe (p less than 0.05) asthma, and mean morning PEF was significantly higher in the severe group (p less than 0.05). The spacer device also produced a significant improvement in symptom score in both the severe and the moderately severe groups (p less than 0.05). Regular domiciliary use of the spacer device with the metered dose inhaler improves bronchodilator response, particularly in patients with chronic severe asthma, and may be a useful alternative to nebuliser treatment.


Translation and validation of the Self-care of Heart Failure Index into Persian.
Chronic heart failure (CHF) is a common burdensome health problem worldwide. Self-care improves outcomes in patients with CHF. The Self-care of Heart Failure Index (SCHFI) is a well-known scale for assessing self-care. A reliable, valid, and culturally acceptable instrument is needed to develop and test self-care interventions in Iran. We sought to translate and validate the Persian version of SCHFI v 6.2 (pSCHFI). We translated the SCHFI into Persian (pSCHFI) using standardized methods. The reliability was evaluated by assessing Cronbach's α coefficient. Expert opinion, discussion with patients, and confirmatory factor analysis were used to assess face validity, content validity, and construct validity, respectively. The analysis, using 184 participants, showed acceptable internal consistency and construct validity for the 3 subscales of pSCHFI-self-care maintenance, self-care management, and self-care self-confidence. The pSCHFI is a valid instrument with an acceptable reliability for evaluating self-care in Persian patients with heart failure.


Perinatal intracranial hemorrhage and retinopathy of prematurity: currently nonpreventable complications of premature birth?
There is now considerable evidence that the control of cerebral circulation in sick small infants is sometimes seriously deranged and subject to wide fluctuations during neonatal care. Our current preoccupation with looking at oxygen administration and peripheral arterial oxygen tensions as the only cause of ROP is not likely to be productive. Until we know more about the causes of cerebral blood flow fluctuation, IVH, asphyxia, and their effects on the retinal circulation, we are not apt to make much progress. There is a strong association between retinopathy and IVH in premature infants. With our current knowledge, we are unable to prevent or to treat either IVH or ROP. The public should be better informed that both of these conditions are usually unavoidable complications of premature birth.


The Role of Prophylactic Intraventricular Antibiotics in Reducing the Incidence of Infection and Revision Surgery in Pediatric Patients Undergoing Shunt Placement.
Ventriculoperitoneal shunt placement remains the primary treatment modality for children with hydrocephalus. However, morbidity and revision surgery secondary to infection remains high, even while using antibiotic-impregnated shunts. To determine whether intraoperative injection of antibiotics is independently associated with reduced rates of infection and revision surgery in children undergoing shunt placement. This is an analysis of a prospectively collected, multicenter, shunt-specific neurosurgical registry consisting of data from over 100 hospitals collected between 2016 and 2017. All patients under 18 yr of age undergoing first-time shunt placement for the definitive treatment of hydrocephalus were included. The primary exposure of interest was injection of intraventricular antibiotics into the shunt catheter following shunt placement and prior to closure. The use of additional surgical adjuncts, such as antibiotic-impregnated shunts, stereotactic guidance, and endoscopy was collected. The primary outcome metric was the need for additional intervention because of an infection. A total of 2007 pediatric patients undergoing shunt placement for hydrocephalus were identified. Postoperatively, 97 (4.8%) patients had additional intervention secondary to infection. In a multivariable regression model controlling for patient characteristics, etiology of hydrocephalus, prior temporizing measures, and placement of an antibiotic-impregnated shunt, injection of intraventricular antibiotics was associated with a significant reduction in postoperative infections (odds ratio = 0.29, 95% CI: 0.04-0.89, P = .038). Of those receiving intraventricular antibiotics, only 2 (0.38%) went on to undergo re-intervention due to infection. These data suggest that for this select group of patients, use of intraventricular antibiotics was associated with decreased rates of re-intervention secondary to infection.


NK-lysin, dicentracin and hepcidin antimicrobial peptides in European sea bass. Ontogenetic development and modulation in juveniles by nodavirus.
Antimicrobial peptides (AMPs) are considered to be amongst the most powerful tools for the fight against pathogens in fish, since they form part of the innate immune response, which is especially vital in eggs and early larval stages, when the immune system is developing. The fish responsible for a large part of the profits in Mediterranean aquaculture is European sea bass (Dicentrarchus labrax), a species greatly susceptible to nodavirus (NNV), especially in the larval and juvenile stages. In this work, polyclonal antibodies were developed and used to detect and quantify NK-lysin, dicentracin and hepcidin AMPs in European sea bass eggs and during larval development, as well as to evaluate their regulation in juvenile specimens upon NNV infection. Basal and detectable levels of all the AMPs studied were present in eggs, confirming the maternal transfer of peptides, which increased in one or two waves during larval development up to 69 days post-fertilization. After NNV infection, the mRNA of all the AMPs analysed was up-regulated five days after infection in most of the tissues, whilst peptide quantification of all three AMPs decreased in the brain, the target tissue for NNV, but increased in the head-kidney 5 days after infection. Further research should be carried out to ascertain the role of AMPs in fish innate immunity and to understand how NNV evades the immune response to be disseminated.


Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer's Disease Dementia.
While the angiotensin-converting enzyme degrades amyloid-β, angiotensinconverting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer's disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. For 193 patients, minor allele frequencies were 0.497 for rs1800764 - C (44.6% heterozygotes) and 0.345 for rs4291 - T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 - T and rs4291 - A, or for APOE4- carriers of rs1800764 - T or rs4291 - T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.


Spatial cohesion of adult male chimpanzees (Pan troglodytes verus) in Taï National Park, Côte d'Ivoire.
Group living animals can exhibit fission-fusion behavior whereby individuals temporarily separate to reduce the costs of living in large groups. Primates living in groups with fission-fusion dynamics face numerous challenges in maintaining spatial cohesion, especially in environments with limited visibility. Here we investigated the spatial cohesion of adult male chimpanzees (Pan troglodytes verus) living in Taï National Park, Côte d'Ivoire, to better understand the mechanisms by which individuals maintain group cohesion during fission-fusion events. Over a 3-year period, we simultaneously tracked the movements of 2-4 males for 4-12 hr on up to 12 consecutive days using handheld GPS devices that recorded locations at one-minute intervals. Analyses of the male's inter-individual distance (IID) showed that the maximum, median, and mean IID values across all observations were 7.2 km, 73 m, and 483 m, respectively. These males (a) had maximum daily IID values below the limits of auditory communication (<1 km) for 63% of the observation time, (b) remained out of visual range (≥100 m) for 46% of observation time, and (c) remained within auditory range for 70% of the time when they were in different parties. We compared the observed distribution of IIDs with a random distribution obtained from permutations of the individuals' travel paths using Kolmogorov-Smirnov tests. Observation IID values were significantly smaller than those generated by the permutation procedure. We conclude that these male chimpanzees actively maintain cohesion when out of sight, and that auditory communication is one likely mechanism by which they do so. We discuss mechanisms by which chimpanzees may maintain the level of cohesion observed. This study provides a first analysis of spatial group cohesion over large distances in forest chimpanzees using high-resolution tracking, and illustrates the utility of such data for quantifying socio-ecological processes in primate ecology.


An ecological framework for temporal and individual differences in color preferences.
There are well-known and extensive differences in color preferences between individuals, but there are also within-individual differences from one time to another. Despite the seeming independence between these individual and temporal effects, we propose that they have the same underlying cause: people's ecological experiences with color-associated objects and events. Our approach is motivated by the Ecological Valence Theory (EVT; Palmer & Schloss, 2010) which states that preference for a given color is determined by the combined valence (liking/disliking) of all objects and events associated with that color. We define three ecologically-based hypotheses for explaining temporal and individual differences in color preferences concerning: (1) differences in object valences, (2) differences in color-object associations, and (3) differences in object activations in the mind when preferences are measured. We review prior studies that support these hypotheses and raise open research questions about untested predictions. We also extend the computational framework of the EVT by defining a single weighted average equation that captures both individual and temporal differences in color preferences. Finally, we consider other factors that potentially contribute to color preferences, including abstract symbolic associations, color in design, and psychophysical and/or physiological factors.


Spatially organized multicellular immune hubs in human colorectal cancer.
Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.


Electronic consultations (E-consults) and their outcomes: a systematic review.
Electronic consultations (e-consults) are clinician-to-clinician communications that may obviate face-to-face specialist visits. E-consult programs have spread within the US and internationally despite limited data on outcomes. We conducted a systematic review of the recent peer-reviewed literature on the effect of e-consults on access, cost, quality, and patient and clinician experience and identified the gaps in existing research on these outcomes. We searched 4 databases for empirical studies published between 1/1/2015 and 2/28/2019 that reported on one or more outcomes of interest. Two investigators reviewed titles and abstracts. One investigator abstracted information from each relevant article, and another confirmed the abstraction. We applied the GRADE criteria for the strength of evidence for each outcome. We found only modest empirical evidence for effectiveness of e-consults on important outcomes. Most studies are observational and within a single health care system, and comprehensive assessments are lacking. For those outcomes that have been reported, findings are generally positive, with mixed results for clinician experience. These findings reassure but also raise concern for publication bias. Despite stakeholder enthusiasm and encouraging results in the literature to date, more rigorous study designs applied across all outcomes are needed. Policy makers need to know what benefits may be expected in what contexts, so they can define appropriate measures of success and determine how to achieve them.


Seasonal change and prolonged anoxia affect the kinetic properties of phosphofructokinase and pyruvate kinase in oysters.
The effects of seasonal change, November versus July, and prolonged anoxia (96 h under N2 gas) on the properties of phosphofructokinase and pyruvate kinase from five tissues (gill, mantle, hepatopancreas, phasic adductor, catch adductor) of the oyster, Crassostrea virginica were investigated. Both enzymes showed tissue-specific and season-specific changes in kinetic properties; for pyruvate kinase this correlated with seasonal differences in enzyme elution patterns on hydroxylapatite chromatography. Kinetic properties of both enzymes in winter were consistent with primarily catabolic roles in glycolysis with responsiveness to cellular energy demands, whereas in summer these enzymes may be more closely regulated with respect to the biosynthetic and gluconeogenic functions of the tissues. Anoxia-induced changes in phosphofructokinase properties were relatively minor but anoxia stimulated changes in pyruvate kinase properties and elution profiles on hydroxylapatite in all tissues except mantle, with much greater effects seen for the enzyme from winter versus summer animals. For example, anoxia-induced changes in pyruvate kinase from winter gill included a fourfold rise in the substrate affinity constant for phosphoenolpyruvate, a sevenfold increase in the concentration of fructose-1,6-bisphosphate needed to activate the enzyme by 50%, and a 50% decrease in the concentration of L-alanine that inhibits activity by 50%. Changes in pyruvate kinase kinetics and hydroxylapatite elution patterns during prolonged anoxia are consistent with covalent modification of pyruvate kinase but contrary to results for many other mollusc species, anoxia exposure appears to induce a dephosphorylation of the enzyme.


Youth who use e-cigarettes regularly: A qualitative study of behavior, attitudes, and familial norms.
Limited research exists describing youth who use e-cigarettes on a regular basis, including knowledge of nicotine levels, health effects, and plans for future use. This qualitative study explored the patterns of use, social and familial norms, and perceptions of health effects among this group. Youth (N = 43), 14-17 years old, who described themselves as regular e-cigarette users, participated in 4 focus group discussions in Miami, Florida, and Raleigh, North Carolina in February 2016. Youth often initiated or continued e-cigarette use with a device obtained from a friend or family member, and often do not own their own device. They cite the flavors and doing tricks as the two main reasons they initially used e-cigarettes. Many reported that their family members are aware they use e-cigarettes, and that they have received implicit and explicit messages from family members that are positive toward ecigarette use. They are aware of the negative effects of nicotine, including addiction, but not confident that they are using e-liquids without nicotine. Participants reported they will stop using e-cigarettes when they become aware of reported negative health effects. Parents and family members are an important target audience for prevention campaigns and health messaging, given that their own use and acceptance could be encouraging initiation and continuation. Youth are using products containing nicotine and may be becoming addicted, even if they would not choose to use nicotine-containing e-juice. Increased awareness of negative health effects may encourage prevention and cessation of e-cigarette use among youth.


Precise intensity correlation measurement for atomic resonance fluorescence from optical molasses.
We measured the intensity correlation of true thermal light scattered from cold atoms in an optical molasses. Using a single-mode fiber as a transverse mode filter, measurement with maximally high spatial coherence was realized, allowing us to observe ideal photon bunching with unprecedented precision. The measured intensity correlation functions showed a definite bimodal structure with fast damped oscillation from the maximum value of 2.02(3) and slow monotonic decay toward unity. The oscillation can be understood as an interference between elastic and inelastic scattering fields in resonance fluorescence.


Short term benefits for laparoscopic colorectal resection.
Colorectal resections are common surgical procedures all over the world. Laparoscopic colorectal surgery is technically feasible in a considerable amount of patients under elective conditions. Several short-term benefits of the laparoscopic approach to colorectal resection (less pain, less morbidity, improved reconvalescence and better quality of life) have been proposed. This review compares laparoscopic and conventional colorectal resection with regards to possible benefits of the laparoscopic method in the short-term postoperative period (up to 3 months post surgery). We searched MEDLINE, EMBASE, CancerLit, and the Cochrane Central Register of Controlled Trials for the years 1991 to 2004. We also handsearched the following journals from 1991 to 2004: British Journal of Surgery, Archives of Surgery, Annals of Surgery, Surgery, World Journal of Surgery, Disease of Colon and Rectum, Surgical Endoscopy, International Journal of Colorectal Disease, Langenbeck's Archives of Surgery, Der Chirurg, Zentralblatt für Chirurgie, Aktuelle Chirurgie/Viszeralchirurgie. Handsearch of abstracts from the following society meetings from 1991 to 2004: American College of Surgeons, American Society of Colorectal Surgeons, Royal Society of Surgeons, British Assocation of Coloproctology, Surgical Association of Endoscopic Surgeons, European Association of Endoscopic Surgeons, Asian Society of Endoscopic Surgeons. All randomised-controlled trial were included regardless of the language of publication. No- or pseudorandomised trials as well as studies that followed patient's preferences towards one of the two interventions were excluded, but listed separately. RCT presented as only an abstract were excluded. Results were extracted from papers by three observers independently on a predefined data sheet. Disagreements were solved by discussion. 'REVMAN 4.2' was used for statistical analysis. Mean differences (95% confidence intervals) were used for analysing continuous variables. If studies reported medians and ranges instead of means and standard deviations, we assumed the difference of medians to be equal to the difference of means. If no measure of dispersion was given, we tried to obtain these data from the authors or estimated SD as the mean or median. Data were pooled and rate differences as well as weighted mean differences with their 95% confidence intervals were calculated using random effects models. 25 RCT were included and analysed. Methodological quality of most of these trials was only moderate and perioperative treatment was very traditional in most studies. Operative time was longer in laparoscopic surgery, but intraoperative blood was less than in conventional surgery. Intensity of postoperative pain and duration of postoperative ileus was shorter after laparoscopic colorectal resection and pulmonary function was improved after a laparoscopic approach. Total morbidity and local (surgical) morbidity was decreased in the laparoscopic groups. General morbidity and mortality was not different between both groups. Until the 30th postoperative day, quality of life was better in laparoscopic patients. Postoperative hospital stay was less in laparoscopic patients. Under traditional perioperative treatment, laparoscopic colonic resections show clinically relevant advantages in selected patients. If the long-term oncological results of laparoscopic and conventional resection of colonic carcinoma show equivalent results, the laparoscopic approach should be preferred in patients suitable for this approach to colectomy.


Responses of gut and pancreatic hormones, bile acids, and fibroblast growth factor-21 differ to glucose, protein, and fat ingestion after gastric bypass surgery.
Postprandial gut hormone responses change after Roux-en-Y gastric bypass (RYGB), and we investigated the impact of glucose, protein, and fat (with and without pancreas lipase inhibition) on plasma responses of gut and pancreas hormones, bile acids, and fibroblast growth factor 21 (FGF-21) after RYGB and in nonoperated control subjects. In a randomized, crossover study 10 RYGB operated and 8 healthy weight-matched control subjects were administered 4 different 4-h isocaloric (200 kcal) liquid meal tests containing >90 energy (E)% of either glucose, protein (whey protein), or fat (butter with and without orlistat). The primary outcome was glucagon-like peptide-1 (GLP-1) secretion (area under the curve above baseline). Secondary outcomes included responses of peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glicentin, neurotensin, ghrelin, insulin, glucagon, bile acids, and FGF-21. In the RYGB group the responses of GLP-1, GIP, glicentin, FGF-21, and C-peptide were increased after glucose compared with the other meals. The neurotensin and bile acids responses were greater after fat, while the glucagon and CCK responses were greater after protein ingestion. Furthermore, compared with control subjects, RYGB subjects had greater responses of total PYY after glucose, glucagon after glucose and fat, glicentin after glucose and protein, and GLP-1 and neurotensin after all meals, while GIP and CCK responses were lower after fat. Ghrelin responses did not differ between meals or between groups. Orlistat reduced all hormone responses to fat ingestion, except for ghrelin in the RYGB group. In conclusion, after RYGB glucose is a more potent stimulator of most gut hormones, especially for the marked increased secretion of GLP-1 compared with fat and protein.NEW & NOTEWORTHY We investigated the impact of glucose, protein, and fat meals on intestinal and pancreatic hormones, bile acid, and fibroblast growth factor 21 (FGF-21) secretion in gastric bypass-operated patients compared with matched nonoperated individuals. The fat meal was administered with and without a pancreas lipase inhibitor. We found that the impact of the different meals on gut hormones, bile, and FGF 21 secretion differ and was different from the responses observed in nonoperated control subjects.


Exact diagonal representation of normal mode energy, occupation number, and heat current for phonon-dominated thermal transport.
Collective excitations of crystal vibrations or normal modes are customarily described using complex normal mode coordinates. While appropriate for calculating phonon dispersion, the mixed representation involving the complex conjugates does not allow the construction of equivalent phonon occupation number or modal dynamical quantities such as the energy or heat current specific to a wave-vector direction (q). Starting from a canonical solution that includes waves going to the left and right directions, we cast the Hamiltonian, normal mode population, and heat current in an exactly diagonalizable representation using real normal mode amplitudes. We show that the use of real amplitudes obviates the need for a complex modal heat current while making the passage to second quantization more apparent. Using nonequilibrium molecular dynamics simulations, we then compute the net modal energy, heat current, and equivalent phonon population in a linear lattice subjected to a thermal gradient. Our analysis paves a tractable path for probing and computing the direction-dependent thermal-phononic modal properties of dielectric lattices using atomistic simulations.


Non-receptor protein tyrosine kinases.
The protein tyrosine kinases (PTKs) are enzymes catalyzing the transfer of the gamma-phosphate group of ATP to the hydroxyl groups of specific tyrosine residues in peptides. Although phosphotransfer reactions catalyzed by various PTKs are similar with regard to their basic mechanisms, their biological functions demonstrate a considerable degree of specificity. PTKs are divided into two groups according to the presence of transmembrane and extracellular domains. Whereas most PTKs possess these domains, which render them capable of recognizing extracellular ligands, many PTKs lack these sequences and are therefore referred to as non-receptor or non-transmembrane PTKs. Thirty-two genes encoding for non-receptor PTKs are present in the human genome. The current review focuses on the composition, structure, expression, functions and regulation of the mammalian non-receptor PTK families.


DNA damage reduces Taq DNA polymerase fidelity and PCR amplification efficiency.
DNA damage blocks DNA polymerase progression and increases miscoding. In this study, we assessed the effects of specific lesions on Taq DNA polymerase fidelity and amplification efficiency. In the presence of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), Taq DNA polymerase inserted dCMP and to a lesser extent dAMP. 8-Oxo-7,8-dihydro-2'-deoxyadenosine (8-oxodA) instructed the incorporation of dTMP and caused a pronounced n-1 deletion not observed in other systems. The presence of an abasic lesion led to dAMP incorporation and n-1 deletions. In addition, we introduce the mean modified efficiency (MME) as a more precise method for determining PCR amplification efficiency of damaged templates. Using this method, we were able to quantify reductions in amplification efficiency of templates containing 8-oxodG (single or multiple), 8-oxodA, or abasic sites. Because the MME method can detect small reductions in amplification efficiency, it may be useful in comparing the extent of damage in environmentally degraded or archival DNA specimens.


Effect of ibuprofen on the course of canine endotoxin shock.
Four groups of dogs were anesthetized, instrumented for measurement of blood pressures and flows across the liver, and, except for the control group, injected with 1 mg/kg endotoxin. The control group received only saline. One group received endotoxin only (ETOX) while animals in the other two groups received 10 mg/kg ibuprofen either 30 min before (PreIBU) or 30 min after endotoxin (PostIBU). Blood pressure, hepatic arterial and portal flow decreased after endotoxin injection in the ETOX and Post IBU animals but not in the PreIBU-injected animals. Pressure and flows returned to normal within 15 min after ibuprofen in the PostIBU animals but remained significantly lower in the ETOX animals. There was a transient increase in blood glucose concentration in the ETOX and PostIBU animals immediately after endotoxin injection, but not in the PreIBU group. Glucose then steadily decreased in all three experimental groups for the remainder of the experiment in spite of the fact that glucose production was elevated. Blood lactate and glycerol concentration increased in all three groups throughout the experiment. Ibuprofen was able to correct the pressure and flow changes caused by endotoxin, but did not prevent the hypoglycemia or accumulation of lactate and glycerol in plasma.


How the Intricate Interaction among Toll-Like Receptors, Microbiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology.
The gut is able to maintain tolerance to microbial and food antigens. The intestine minimizes the number of harmful bacteria by shaping the microbiota through a symbiotic relationship. In healthy human intestine, a constant homeostasis is maintained by the perfect regulation of microbial load and the immune response generated against it. Failure of this balance may result in various pathological conditions. Innate immune sensors, such as Toll-like receptors (TLRs), may be considered an interface among intestinal epithelial barrier, microbiota, and immune system. TLRs pathway, activated by pathogens, is involved in the pathogenesis of several infectious and inflammatory diseases. The alteration of the homeostasis between physiologic and pathogenic bacteria of intestinal flora causes a condition called dysbiosis. The breakdown of homeostasis by dysbiosis may increase susceptibility to inflammatory bowel diseases. It is evident that environment, genetics, and host immunity form a highly interactive regulatory triad that controls TLR function. Imbalanced relationships within this triad may promote aberrant TLR signaling, critically contributing to acute and chronic intestinal inflammatory processes, such as in IBD, colitis, and colorectal cancer. The study of interactions between different components of the immune systems and intestinal microbiota will open new horizons in the knowledge of gut inflammation.


Immunohistochemical profile of cytokines and growth factors expressed in vestibular schwannoma and in normal vestibular nerve tissue.
Vestibular schwannomas, also known as acoustic neuromas, are benign tumors, which originate from myelin-forming Schwann cells. They develop in the vestibular branch of the eighth cranial nerve in the internal auditory canal or cerebellopontine angle. The clinical progression of the condition involves slow and progressive growth, eventually resulting in brainstem compression. The objective of the present study was to investigate the expression level and the localization of the pro-inflammatory cytokines, transforming growth factor-β1 (TGF-β1) interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α), as well as the adhesion molecules, intracellular adhesion molecule-1 and vascular endothelial growth factor (VEGF), in order to determine whether these factors are involved in the transformation and development of human vestibular schwannoma. The present study investigated whether changes in inflammation are involved in tumor growth and if so, the mechanisms underlying this process. The results of the current study demonstrated that pro-inflammatory cytokines, including TGF-β1, IL-1β and IL-6 exhibited increased expression in human vestibular schwannoma tissue compared with normal vestibular nerve samples. TNF-α was weakly expressed in Schwann cells, confirming that a lower level of this cytokine is involved in the proliferation of Schwann cells. Neoplastic Schwann cells produce pro-inflammatory cytokines that may act in an autocrine manner, stimulating cellular proliferation. In addition, the increased expression of VEGF in vestibular schwannoma compared with that in normal vestibular nerve tissue, suggests that this factor may induce neoplastic growth via the promotion of angiogenesis. The present findings suggest that inflammation may promote angiogenesis and consequently contribute to tumor progression. In conclusion, the results of the present study indicated that VEGF and pro-inflammatory cytokines may be potential therapeutic targets in vestibular schwannoma. Further studies are necessary to confirm the involvement of these factors in the growth of neoplasms and to develop inhibitors of pro-inflammatory cytokines as a potential treatment option in the future.


Aspects of the regulation of adenylate cyclase synthesis in Escherichia coli K12.
In Escherichia coli K12 expression of the adenylate cyclase gene is subject to multiple controls. In order to gain understanding of the regulation of adenylate cyclase synthesis, operon and protein fusions were constructed by in vitro recombination either into bacteriophage lambda or low-copy-number plasmids, or directly on the chromosome at the cya locus. The fusions were used in physiological experiments as probes to study transcriptional and translational controls of cya expression. It was found that adenylate cyclase synthesis was insensitive to glucose effects. As already described by other workers, the CAP-cAMP complex had a moderate negative control on cya expression. In addition it was observed that concomitant with a severe slackening of growth rate, specific to the growth of cya strains in rich medium, cya expression was considerably enhanced. This increase of adenylate cyclase synthesis did not appear to be directly dependent on the presence of a functional cAMP receptor (CAP), and seemed to be controlled at the level of transcription. Finally, translation of the cya message was very weak when compared to cya transcription (the mRNA level was the same in protein and operon fusions.


A novel human homeobox gene lies at the chromosome 10 breakpoint in lymphoid neoplasias with chromosomal translocation t(10;14).
The translocation t(10;14)(q24;q11) is an acquired change seen in 4% to 7% of T-cell acute lymphoblastic leukemias (T-ALL). We previously demonstrated that the translocation juxtaposes the T-cell receptor (TCR) delta-chain gene in chromosome 14q11 with a novel region in chromosome 10q24 and is likely catalyzed by recombinases normally involved in the generation of immunoglobulin and TCR diversity. We now present the sequence of a gene on chromosome 10 that lies immediately telomeric of the breakpoints in nine new ALL patients with acquired rearrangements in 10q24. The gene is a novel human homeobox gene and is expressed in leukemic cells from ALL patients with rearrangements in a defined chromosome 10 breakpoint cluster region, but not in other adult tissues or cell lines. This new gene has been designated HOX11. Our results strongly support a role for homeobox genes in oncogenesis and may represent the first example of a human cancer in which deregulated expression of an unaltered homeobox gene is involved in tumorigenesis.