Effects of training on odor judges scoring intensity.
This pilot study was intended to test whether a training protocol improved validity of odor judges (OJs), with or without experience, and whether odorant types differed in error proneness. The OJs (four experienced, two inexperienced) completed a 4-phase training protocol based on the American Society of Testing and Materials standards (ASTM): (i) introduction to sensory scales, n-butanol reference, sniffing techniques; (ii) pretraining measurements; 20 samples of varying intensities of four unpleasant and three pleasant odorants; (iii) exercises assessing quality, intensity, ranking, and matching; and (iv) post-training measurements. Subjects' intensity scores were analyzed as the absolute difference from the 'true' intensity (ASTM n-butanol standard) using repeated measures ANOVA. Training significantly (P = 0.02) reduced OJ errors. Experienced and novice judges did not differ in average errors (P = 0.99), or in improvement in error from pre- to post-training (P = 0.94). Improvement was consistent from pre- to post-training for all odorants except dimethylsulfide for which errors worsened (P = 0.01). Unpleasant and pleasant odorants differed (P = 0.006) in error. After removing water the effects of water control scores from the pleasant odorants, the difference was not significant (P = 0.26). The OJs improved in their ability to assess odor intensity irrespective of previous experience. Training is recommended for all OJs prior to research trials.


Public health matters: Innovative approaches for engaging medical students.
Public health faces the paradox of being increasingly emphasized by the key health and social care regulators and stakeholders, while remaining a largely under-represented discipline in the context of medical curricula. Enhancing medical student engagement in public health teaching is one way to address this concern. We discuss four key solutions to the challenges faced by public health educators in medical schools, and present five case studies which demonstrate innovative approaches to engaging medical students in our discipline. Four different approaches have been piloted by members of the Public Health Educators in Medical Schools (PHEMS) network: (i) ensuring social accountability, (ii) demonstrating clinical relevance, (iii) mapping the core curriculum, and (iv) using technology enhanced learning. Preliminary student feedback suggests that these approaches can be used to position public health as an enabler of modern medical practice, and promote a more holistic understanding of medicine by linking patient-centred care to the population level. The zeitgeist in both academia and the healthcare system supports the teaching of public health within the medical curriculum; there is also consensus at the political and pedagogical level. The challenge of ensuring engagement now needs to be met at the student-teacher interface.


Targeting double stranded DNA with peptide nucleic acid (PNA).
PNA (peptide nucleic acid) is a DNA mimic with a pseudopeptide (polyamide) backbone which can be used to target double stranded DNA with high sequence specificity. PNA therefore has great potential in the development of biomolecular tools for manipulation of DNA as well as for the development of DNA targeted gene therapeutic drugs. The status of this field is discussed in terms of PNA binding modes and mechanism as well as applications.


Pro/con debate: should PaCO2 be tightly controlled in all patients with acute brain injuries?
You are the attending intensivist in a neurointensive care unit caring for a woman five days post-rupture of a cerebral aneurysm (World Federation of Neurological Surgeons Grade 4 and Fisher Grade 3). She is intubated for airway protection and mild hypoxemia related to an aspiration event at the time of aneurysm rupture, but is breathing spontaneously on the ventilator. Your patient is spontaneously hyperventilating with high tidal volumes despite minimal support and has developed significant hypocapnia. She has not yet developed the acute respiratory distress syndrome. You debate whether to tightly control her partial pressure of arterial carbon dioxide, weighing the known risks of acute hypocapnia in other forms of brain injury against the potential loss of clinical neuromonitoring associated with deep sedation and neuromuscular blockade in this patient who is at high risk of delayed ischemia from vasospasm. You are also aware of the potential implications of tidal volume control if this patient were to develop the acute respiratory distress syndrome and the effect of permissive hypercapnia on her intracranial pressure. In this paper we provide a detailed and balanced examination of the issues pertaining to this clinical scenario, including suggestions for clinical management of ventilation, sedation and neuromonitoring. Until more definitive clinical trial evidence is available to guide practice, clinicians are forced to carefully weigh the potential benefits of tight carbon dioxide control against the potential risks in each individual patient based on the clinical issues at hand.


A clinical pathologic reappraisal of kernicterus.
Kernicterus at autopsy, traditionally associated with hyperbilirubinemia, is now often observed in the absence of markedly elevated levels of serum bilirubin. Attempts to document clinically predictive risk factors for kernicterus have been largely unsuccessful in the current population of sick neonates. In a study of 32 pairs of newborns with and without kernicterus at autopsy and matched for gestational age, weight, length of survival, and year of birth, no differences were found when multiple clinical factors thought to potentiate risk for kernicterus were compared. Microscopic sections of brains from these matched pairs were then evaluated without knowledge of the clinical or gross findings according to prearranged criteria. Statistic analysis of the microscopic findings was done, comparing each observed change in each anatomic site, all changes in each site, and each change in all sites. Although the gross pattern of staining followed that of classic kernicterus, the expected, specific histologic changes characteristic of kernicterus were found in only three patients. Spongy change, or edema, was significantly more common in the grossly stained brains (P less than .0005), but other findings were similar in both groups. Gross bilirubin staining of the neonatal brain with neither hyperbilirubinemia nor specific microscopic changes is probably not the same clinicopathologic entity as classic kernicterus.


Intrinsically Stretchable and Conductive Textile by a Scalable Process for Elastic Wearable Electronics.
The prosperous development of stretchable electronics poses a great demand on stretchable conductive materials that could maintain their electrical conductivity under tensile strain. Previously reported strategies to obtain stretchable conductors usually involve complex structure-fabricating processes or utilization of high-cost nanomaterials. It remains a great challenge to produce stretchable and conductive materials via a scalable and cost-effective process. Herein, a large-scalable pyrolysis strategy is developed for the fabrication of intrinsically stretchable and conductive textile in utilizing low-cost and mass-produced weft-knitted textiles as raw materials. Due to the intrinsic stretchability of the weft-knitted structure and the excellent mechanical and electrical properties of the as-obtained carbonized fibers, the obtained flexible and durable textile could sustain tensile strains up to 125% while keeping a stable electrical conductivity (as shown by a Modal-based textile), thus ensuring its applications in elastic electronics. For demonstration purposes, stretchable supercapacitors and wearable thermal-therapy devices that showed stable performance with the loading of tensile strains have been fabricated. Considering the simplicity and large scalability of the process, the low-cost and mass production of the raw materials, and the superior performances of the as-obtained elastic and conductive textile, this strategy would contribute to the development and industrial production of wearable electronics.


Microwave-assisted solid-state synthesis of NaRE(MO4)2 phosphors (RE = La, Pr, Eu, Dy; M = Mo, W).
A synthetic method was developed to enable the microwave-assisted solid-state preparation of double molybdate and double tungstate scheelite-type phosphors of formula NaRE(MO4)2 (RE = La, Pr, Eu, Dy; M = Mo, W). Starting from subgram-scale stoichiometric mixtures of metal carbonates and oxides and with the aid of granular activated charcoal as a microwave susceptor, ternary (NaEu(MO4)2), quaternary (NaLa0.95Eu0.05(MO4)2), and quinary phosphors (NaLa0.95Pr0.025Dy0.025(MO4)2) were obtained upon heating in a countertop microwave oven. The synthesis of crystalline and phase-pure materials required heating times ranging from 18 to 27 min, significantly shorter than those typically encountered in solid-state reactions assisted by conventional heating. Depending on chemical composition, the speed-up factor ranged from 30 to 40. More importantly, photoluminescence studies performed on the compositionally complex quinary molybdate NaLa0.95Pr0.025Dy0.025(MoO4)2 showed that phosphors synthesized using microwave and conventional heating have nearly identical luminescence responses. The synthetic method described in this contribution is robust, fast, simple, and ideally suited for exploratory synthesis and rapid screening of group VI metalate phosphors, as well as for the preparation of binary precursors to these materials (e.g., Na2MoO4 and Na2WO4).


Partnership trajectories and cardiovascular health in late life of older adults in England and Germany.
Previous studies have shown marital status differences in incidence and prevalence of cardiovascular disease and cardiovascular mortality. This study examines the consequences of partnership on biomarkers related to cardiovascular health of older men and women in Germany and England (C-reactive protein, HbA1c, systolic and diastolic blood pressure; and total cholesterol). Data used is from older adults (60 +) from the German Survey of Health and Retirement Europe SHARE (n=955) and the English Longitudinal Study of Ageing ELSA (n=9707). Life course partnership is measured using the timing (age at first partnership), quantum (number of partnerships) and partnership trajectory. OLS for C-reactive protein, logistic regressions for systolic and diastolic blood pressure, and multinomial logistic regressions for cholesterol are used to investigate the associations between life course partnership characteristics and biomarkers, accounting for early age socioeconomic and health conditions. Timing of first partnership is associated with poor cardiovascular health in England, number of partnership transitions with poor health in Germany, and partnership trajectories are associated with cardiovascular health both in Germany and England. Men in trajectories with multiple marriages have higher CRP, and are more likely to have elevated systolic and diastolic BP. Trajectories containing single marital disruption for men and women are no longer associated with poor health after accounting for selection effects of childhood conditions. Respondents in widowed partnership trajectories have poorer cardiovascular health compared to those in intact committed relationships, whereas cohabitation trajectories do not differ in the associations with biomarkers from those in intact marriage. The results offer better understanding of the pathways through which family events and processes are linked to health and support the hypothesis that adversity related to partnerships over the life course accumulates and contributes to worse cardiovascular health in later life measured by objective health measures.


Heat and mass transfer scale-up issues during freeze drying: II. Control and characterization of the degree of supercooling.
This study aims to investigate the effect of the ice nucleation temperature on the primary drying process using an ice fog technique for temperature-controlled nucleation. In order to facilitate scale up of the freeze-drying process, this research seeks to find a correlation of the product resistance and the degree of supercooling with the specific surface area of the product. Freeze-drying experiments were performed using 5% wt/vol solutions of sucrose, dextran, hydroxyethyl starch (HES), and mannitol. Temperature-controlled nucleation was achieved using the ice fog technique where cold nitrogen gas was introduced into the chamber to form an "ice fog," thereby facilitating nucleation of samples at the temperature of interest. Manometric temperature measurement (MTM) was used during primary drying to evaluate the product resistance as a function of cake thickness. Specific surface areas (SSA) of the freeze-dried cakes were determined. The ice fog technique was refined to successfully control the ice nucleation temperature of solutions within 1 degrees C. A significant increase in product resistance was produced by a decrease in nucleation temperature. The SSA was found to increase with decreasing nucleation temperature, and the product resistance increased with increasing SSA. The ice fog technique can be refined into a viable method for nucleation temperature control. The SSA of the product correlates well with the degree of supercooling and with the resistance of the product to mass transfer (ie, flow of water vapor through the dry layer). Using this correlation and SSA measurements, one could predict scale-up drying differences and accordingly alter the freeze-drying process so as to bring about equivalence of product temperature history during lyophilization.


Behavioral changes along escape learning in toads.
Current learning theories consider escape learning as a variation in response dominance into a "habit family". These responses would integrate a repertory of "species-specific reactions" which is displayed when an aggressive or sudden stimulus is presented. We have found that toads (Bufo arenarum Hensel) show a clear correlation between escape learning performance and different rates of responses. Burrowing responses diminished, and orientation responses towards the door increased along trials, concomitantly with correct responses acquisition.


[Methods of assessing postoperative pain in children].
A study of the evaluation of postoperative pain in 210 children using physiological, reference and observation methods. A comparison with other methods leads to the conclusion that observation is the best choice and that some children do not need analgesics during the postoperative period.


Identifying new diseases and their causes: the dilemma of illnesses in Gulf War veterans.
Since the Gulf War, investigation continues of symptoms and illnesses among its veterans. Yet, identifying a specific "Gulf War Syndrome" remains elusive. With new disease entities, causal associations are relatively easily established when the condition is serious, verifiable, and has excess disease rates in specific groups. In common conditions, many excess cases are required to establish association with a specific exposure. Establishing causality in syndromes with variable symptoms is difficult because specific diagnostic algorithms must be established before causal factors can be properly investigated. Searching for an environmental cause is futile in the absence of an operational disease case definition. Common subjective symptoms (without objective physical or laboratory findings) account for over one-half of all medical outpatient visits, yet these symptoms lack an identified physical cause at least one-third of the time. Our medical care system has difficulty dealing with disorders where there is no identified anatomic abnormality or documented metabolic/physiological dysfunction.


Pressurised hot water extraction in continuous flow mode for thermolabile compounds: extraction of polyphenols in red onions.
Extraction and analysis of labile compounds in complex sample matrices, such as plants, is often a big analytical challenge. In this work, the use of a "green and clean" pressurised hot water extraction (PHWE) approach performed in continuous flow mode is explored. Experimental data for extraction and degradation kinetics of selected compounds were utilised to develop a continuous flow extraction (CFE) method targeting thermolabile polyphenols in red onions, with detection by high-performance liquid chromatography (HPLC)-diode array detection (DAD)-mass spectrometry (MS). Water containing ethanol and formic acid was used as extraction solvent. Method performance was focused on extraction yield with minimal analyte degradation. By adjusting the flow rate of the extraction solvent, degradation effects were minimised, and complete extraction could be achieved within 60 min. The CFE extraction yields of the polyphenols investigated were 80-90 % of the theoretically calculated quantitative yields and were significantly higher than the yields obtained by conventional methanol extraction and static batch extraction (70-79 and 58-67 % of the theoretical yields, respectively). The precision of the developed method was lower than 8 % expressed as relative standard deviation.


Genomic impact of CRISPR immunization against bacteriophages.
CRISPR (clustered regularly interspaced short palindromic repeats) together with CAS (RISPR-associated) genes form the CRISPR-Cas immune system, which provides sequence-specific adaptive immunity against foreign genetic elements in bacteria and archaea. Immunity is acquired by the integration of short stretches of invasive DNA as novel 'spacers' into CRISPR loci. Subsequently, these immune markers are transcribed and generate small non-coding interfering RNAs that specifically guide nucleases for sequence-specific cleavage of complementary sequences. Among the four CRISPR-Cas systems present in Streptococcus thermophilus, CRISPR1 and CRISPR3 have the ability to readily acquire new spacers following bacteriophage or plasmid exposure. In order to investigate the impact of building CRISPR-encoded immunity on the host chromosome, we determined the genome sequence of a BIM (bacteriophage-insensitive mutant) derived from the DGCC7710 model organism, after four consecutive rounds of bacteriophage challenge. As expected, active CRISPR loci evolved via polarized addition of several novel spacers following exposure to bacteriophages. Although analysis of the draft genome sequence revealed a variety of SNPs (single nucleotide polymorphisms) and INDELs (insertions/deletions), most of the in silico differences were not validated by Sanger re-sequencing. In addition, two SNPs and two small INDELs were identified and tracked in the intermediate variants. Overall, building CRISPR-encoded immunity does not significantly affect the genome, which allows the maintenance of important functional properties in isogenic CRISPR mutants. This is critical for the development and formulation of sustainable and robust next-generation starter cultures with increased industrial lifespans.


Bursting Heart Syndrome: A Rare Case Of Aortocaval Fistula Repair.
In this case report we will discuss the case of a 47-year-old woman who presented with abdominal pain, nausea, oliguria and right heart failure. A Computed Tomography (CT) aortogram revealed a fistulous abdominal aortic aneurysm. The objective of this study is to discuss the haemodynamic changes regarding aortocaval fistula and consider various management options. A literature search was undertaken on PubMed using appropriate search terms. Case series and reviews reporting presentation, diagnosis and operative management of aortocaval fistula were selected and discussed. We reached a conclusion that early identification improves surgical planning and reduces mortality. Major abdominal arteriovenous fistula repair appears to be a safer and more successful therapy with positive short and midterm outcomes. Aortocaval fistula care requires a more extensive patient series, so even better conclusions can be drawn.


Role of percutaneous nephrostomy in advanced cervical carcinoma with obstructive uropathy: a case series.
Over 70% of the cases present in advanced stages of the disease and are associated with poor prognosis and high mortality rates. In many of them, it is difficult to offer definitive treatment as they present in uremia due to associated obstructive uropathy. There are no clear-cut guidelines for performing percutaneous nephrostomy (PCN) in patients of advanced cervical cancer. The results are unpredictable in terms of benefits achieved in these cases. Thus, we evaluated our experiences with PCN in the management of cervical cancer patients presenting with obstructive uropathy. 15 patients of cervical cancer with obstructive uropathy and deranged renal functions were retrospectively evaluated for the role of PCN in their management PCN was done in 15 patients of advanced cervical cancer. The mean age of patients was 44.5 years. Twelve (80%) patients presented primarily with advanced cervical carcinoma and obstructive uropathy. Three (20%) were already treated. Symptomatic improvement and significant fall of mean serum creatinine value from 7.5 mg% to 0.9 mg% over a period of 1-3 weeks was noted post PCN. Out of 12 patient with primary untreated advanced disease, curative treatment was possible in 3, palliative radiotherapy/chemo-therapy in 7 and only symptomatic treatment in 2 cases, after obstructive uropathy was managed with PCN insertion. Out of 3 already treated patients, 2 were disease free after curative radiotherapy/surgery. PCN was done to prevent permanent kidney damage in them. One patient was defaulter of curative radiotherapy. She had progressive residual disease. Complications like hemorrhage (20%), infection (26%), reinsertion for dislodgment/misplacement (53%), percutaneous leak or perinephric leak (20%), blockage of PCN (33%) were noticed. In spite of inherent, albeit manageable complications, PCN is a simple and safe technique. One of the major benefits observed was ability to administer either curative/palliative radiotherapy or chemotherapy in 85% of patients (11 out of 13 with disease). There was no active disease in remaining 2 patients. Therefore, the decision to attempt PCN in carefully selected cervical cancer patients is justified.


Neuroendocrine prostate cancer: long noncoding RNAs to treat an incurable cancer - an interview with Dr Francesco Crea.
Francesco Crea speaks to Lucy Chard, Commissioning Editor. Dr Crea's lab studies the role of epigenetic factors and noncoding RNA in cancer initiation and progression. While working at the National Cancer Institute (USA), Dr Crea has demonstrated that polycomb-targeting drugs eradicate prostate cancer stem cells. While working at the BC Cancer Agency (Canada), Dr Crea discovered and patented PCAT18, a long noncoding RNA involved in prostate cancer metastasis. Dr Crea has received awards from the American Society of Clinical Oncology, from the Prostate Cancer Program and from Prostate Cancer Foundation BC. He is also an Editorial Board member for Epigenomics. His team is currently working on developing new biomarkers and therapeutic targets for incurable prostate and breast cancers.


Atorvastatin treatment prevents alterations in coronary smooth muscle nuclear Ca2+ signaling in diabetic dyslipidemia.
Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, alters bulk myoplasmic Ca2+ regulation and inhibits phenotypic modulation and proliferation of vascular smooth muscle in culture. Nuclear Ca2+ (Ca(n)) signaling is tightly coupled to transcriptional events and cell growth. Therefore, we hypothesized that in vivo treatment with atorvastatin would attenuate alterations in mitogen-induced Ca(n) signaling associated with coronary atherosclerosis. Three groups of male Yucatan pigs were treated for 20 weeks: controls, alloxan-induced diabetics fed an atherogenic diet and diabetics fed an atherogenic diet plus atorvastatin (80 mg/day). Right coronary artery single-cell cytosolic Ca2+ (Ca(c)) and Ca(n) responses to the mitogen endothelin-1 (5 x 10(-8) M) were measured by laser confocal microscopy using the calcium indicator Fluo-4. We observed a 39% increase in Ca(c) and a 52% increase in Ca(n) responses to endothelin-1 in cells from diabetic dyslipidemic arteries compared to control. These alterations were prevented in animals treated with atorvastatin. We show that during proliferation, the nucleus of a smooth muscle cell becomes rounded and loses the characteristic multilobular shape, clefts and invaginations. Consistent with this, a redistribution of Ca2+ stores from a transnuclear morphology in controls to a more perinuclear morphology occurred in cells from diabetic dyslipidemic arteries and was prevented by atorvastatin. In addition, the peak Ca(n) responses to endothelin-1 were inversely correlated (r = 0.712) with the extent of the transnuclear distribution of Ca2+ stores and directly correlated (r = 0.874) with the extent of atherosclerosis, as assessed in vivo by intravascular ultrasound. These findings indicate that chronic treatment with atorvastatin directly decreases mitogen-induced Ca(n) mobilization, which we suggest is related to the spatial localization of Ca(n) stores.


Effect of estrogen replacement therapy on endothelial function in peripheral resistance arteries in normotensive and hypertensive postmenopausal women.
Both menopause and hypertension are associated with endothelial dysfunction and are risk factors for coronary heart disease. We evaluated forearm resistance artery endothelial function in hypertensive postmenopausal women (HPW, n=57) and compared it with endothelial function in normotensive postmenopausal women (NPW, n=67). In addition, we evaluated the effects of long-term estrogen replacement therapy (ERT, conjugated equine estrogen at a dose of 0.625 mg daily for 12 weeks) on endothelial function in HPW (n=10) and NPW (n=35). Forearm blood flow (FBF) was measured by strain-gauge plethysmography during reactive hyperemia to assess endothelium-dependent vasodilation and after sublingual nitroglycerin (NTG) administration to assess endothelium-independent vasodilation. Basal FBF was similar in the NPW and HPW groups. The FBF in the HPW group during reactive hyperemia was significantly lower than that in the NPW group. Increases in FBF after NTG were similar in the 2 groups. ERT decreased the LDL cholesterol concentration and circulating ACE activity and increased estradiol and HDL cholesterol in both groups. Basal blood pressures, heart rate, FBF, and body weight did not change with ERT. After 12 weeks of ERT, the maximal FBF response during reactive hyperemia increased significantly in both groups. The improvement in reactive hyperemia after ERT was significantly greater in the HPW group than in the NPW group (49+/-8 versus 17+/-5%, P<0.05). Changes in FBF after sublingual NTG administration were similar before and after 12 weeks of ERT. These findings suggest that continued ERT improves forearm resistance artery endothelial function in postmenopausal women and that this beneficial effect is greater in patients that are hypertensive.


Longitudinal Analysis of Opioid Analgesic Dose and Diabetes Quality of Care Measures.
To examine associations of opioid analgesic dose with quality of care for diabetes mellitus. Longitudinal statewide cohort. Subjects with diabetes filled one or more prescriptions for Schedule II/III opioids for noncancer pain in Blue Cross Blue Shield of Texas from 2008 through 2012. Opioid dose and outcomes were assessed in 6-month intervals after first filled prescription. Two morphine equivalent dose measures were daily dose and quartiles of total dose from all filled prescriptions. In fixed effects models adjusted for clinical and treatment variables, associations of opioid measures were examined for five outcomes: hemoglobin A1c (HbA1c) test, low density lipoprotein cholesterol (LDL) test, any hospitalization, any diabetes-related preventable hospitalization, and any emergency department (ED) visit. All daily and total opioid doses were associated (P < 0.05) with poorer outcomes for all five measures. For HbA1c testing, adjusted odds ratios (AORs) were reduced by 19% for high daily dose (≥100 mg) and highest quartile total dose (>900 mg), respectively, vs no opioids but >900 mg total dose had the lowest AOR for LDL testing (0.74 [CI 0.68, 0.80]). The AORs of any hospitalization or diabetes-related hospitalization were, respectively, 8.19 (CI 7.21, 9.30) and 2.76 (CI 2.19, 3.48) for >900 mg total dose but only 6.22 (CI 4.94, 7.83) and 2.16 (CI 1.34, 3.48) for >100 mg daily dose. Both opioid measures had nonmonotonic associations with ED use. Daily opioid dose but especially total dose of opioids was strongly associated with poorer diabetes quality of care in a statewide cohort.


[Echographic exploration of the portal system. Echo-anatomy and symptomatology (author's transl)].
The authors describe the extra- and intra-hepatic echographic images of the portal system in the foetus and the adult on the basis of data from literature and their personal experience with angiographic comparisons and investigation of anatomical specimens. The knowledge gained by echography provides the means for a sure approach to systematisation of the liver and thus accurately identifies the site of focal processes (tumour, abscess, etc.) furnishes very useful information in a large number of pathological cases (foetal hypotrophy, portal hypertension, etc.), facilitates diagnostic and therapeutic instrumental exploration and will soon make it possible to carry out haemodynamic studies of the portal system through the addition of pulsed Doppler to the present echographs.


Objective B wave analysis in 55 patients with non-communicating and communicating hydrocephalus.
B waves, slow and rhythmic oscillations in intracranial pressure (ICP), are claimed to be one of the best predictors of outcome after surgery for normal pressure hydrocephalus (NPH). To determine the relation between the percentage of B waves and outcome in patients with hydrocephalus, and also the diurnal variation of B waves. ICP and patient behaviour were recorded overnight (17 to 26 hours) in 29 patients with non-communicating hydrocephalus and 26 with NPH. The B wave activity, measured with an amplitude threshold of 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, and 5.0 mm Hg, was estimated as the percentage of total monitoring time (% B waves) using a computer algorithm, and correlated with postoperative outcome, defined as changes in 12 standardised symptoms and signs. There was no linear correlation between improvement after surgery in the 55 patients and total % B waves, but a correlation was found between improvement and % B waves during sleep (r = 0.39, p = 0.04). The percentage of B waves was the same during sleep and wakefulness, and patients with NPH had the same proportion of B waves as the non-communicating patients. B waves are commonly observed in patients with both communicating and non-communicating hydrocephalus, but are only weakly related to the degree of postsurgical improvement.


Differences in the metabolism and metabolic effects of the carbocyclic adenosine analogs, neplanocin A and aristeromycin.
Neplanocin A and aristeromycin are carbocyclic adenosine analogs that differ only in that neplanocin A contains a double bond in the carbocyclic ring, whereas this ring in aristeromycin is saturated. We have compared the metabolism and some of the metabolic effects of neplanocin A and synthetic (+/-)-aristeromycin (C-Ado) in murine leukemia L1210 cells in culture. C-Ado, as shown earlier, was not only converted to its own phosphates but also was metabolized to phosphates of carbocyclic guanosine. Both rapidly proliferating and slowly proliferating or resting cells phosphorylated C-Ado, but C-Ado was not converted to phosphates of carbocyclic guanosine in detectable amounts in cells whose growth had reached a plateau. When the metabolism of neplanocin and C-Ado was examined in the same experiment, both analogs were converted to the triphosphate analogs of ATP; no conversion of neplanocin A to the corresponding carbocyclic analogs of guanine nucleotides was detected, whereas C-Ado was converted to the carbocyclic analog of GTP in amounts that approximated the GTP pool. This difference in metabolism was associated with a marked difference in effects of the two analogs on the utilization of hypoxanthine and guanine which was inhibited by C-Ado but not by neplanocin. The failure of neplanocin A to be converted to analogs of guanine nucleotides apparently is the result of poor capacity of its monophosphate to serve as a substrate for AMP deaminase; the Vmax for deamination of neplanocin-5'-monophosphate by this enzyme was only 5% of that for C-Ado monophosphate. In contrast, neplanocin A was a better substrate than C-Ado for adenosine deaminase.


Formulation and characterization of a compacted multiparticulate system for modified release of water-soluble drugs--part 1--acetaminophen.
The aim of this study was to characterize and evaluate a modified release, multiparticulate tablet formulation consisting of placebo beads and drug-loaded beads. Acetaminophen (APAP) bead formulations containing ethylcellulose (EC) from 40-60% and placebo beads containing 30% calcium silicate and prepared using 0-20% alcohol were developed using extrusion-spheronization and studied using a central composite experimental design. Particle size and true density of beads were measured. Segregation testing was performed using the novel ASTM D6940-04 method on a 50:50 blend of uncoated APAP beads (60%EC) : calcium silicate placebo beads (10% alcohol). Tablets were prepared using an instrumented Stokes-B2 rotary tablet press and evaluated for crushing strength and dissolution rate. Compared with drug beads (60%EC), placebo beads (10% alcohol) were smaller but had higher true densities: 864.8 mum and 1.27 g/cm(3), and 787.1 mum and 1.73 g/cm(3), respectively. Segregation testing revealed that there was approximately a 20% difference in drug content (as measured by the coefficient of variation) between initial and final blend samples. Although calcium silicate-based placebo beads were shown to be ineffective cushioning agents in blends with Surelease(R)-coated APAP beads, they were found to be very compactibile when used alone and gave tablet crushing strength values between 14 and 17 kP. The EC in the APAP bead matrix minimally suppressed the drug release from uncoated beads (t(100%) = 2 h). However, while tablets containing placebo beads reformulated with glycerol monostearate (GMS) showed a slower release rate (t(60%)= 5 h) compared with calcium silicate-based placebos, some coating damage ( approximately 30%) still occurred on compression as release was faster than coated APAP beads alone. While tablets containing coated drug beads can be produced with practical crushing strengths (>8 kP) and low compression pressures (10-35 MPa), dissolution studies revealed that calcium silicate-based placebos are ineffective as cushioning agents. Blend segregation was likely observed due to the particle size and the density differences between APAP beads and calcium silicate-based placebo beads; placebo bead percolation can perhaps be minimized by increasing their size during the extrusion-spheronization process. The GMS- based placebos offer greater promise as cushioning agents for compacted, coated drug beads; however, this requires an optimized compression pressure range and drug bead : placebo bead ratio (i.e., 50:50).


Establishment of a new cell line of canine inflammatory mammary cancer: IMC-118.
Canine inflammatory mammary cancer (IMC) has long been regarded as an attractive animal model for research into human inflammatory breast cancer (IBC), Although some canine mammary tumour cell lines corresponding to human mammary cancer cell lines have been established, there is still a need to supplement the canine mammary tumour cell bank. The goal of this study was to create a new type of IMC cell line. The primary tumour, IMC-118, was identified as IMC by pathology examination. Immunohistochemistry analysis revealed negative immunoreactivity to oestrogen receptor (ER), but positive immunoreactivity to progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2). Immunofluorescence (IF) analysis revealed that the IMC-118 cell line from this primary tumour was negative for ER but positive for PR and HER-2, and was also positive for epithelial and mesenchymal cell markers. This cell line was cultured stably for more than 50 passages and grew well after cryopreservation. In vivo, tumour masses and metastases in the lungs were discovered after inoculating the IMC-118 cells into the nude mice model. As a result, a novel canine IMC cell line, IMC-118, was effectively established, and could be employed as a promising model for immunotherapy and epithelial-mesenchymal transition mechanism of IMC research in both dogs and humans.


Psychological treatment of depression in inpatients: a systematic review and meta-analysis.
Research on psychological treatment of depression in inpatients is not conclusive, with some studies finding clear positive effects and other studies finding no significant benefit compared to usual care or structured pharmacotherapy. The results of a meta-analysis investigating how effective psychological treatment is for depressed inpatients are presented. A systematic search in bibliographical databases resulted in 12 studies with a total of 570 respondents. This set of studies had sufficient statistical power to detect small effect sizes. Psychological treatments had a small (g=0.29), but statistically significant additional effect on depression compared to usual care and structured pharmacological treatments only. This corresponded with a numbers-needed-to-be-treated of 6.17. Heterogeneity was zero in most analyses, and not significant in all analyses. There was no indication for significant publication bias. Effects were not associated with characteristics of the population, the interventions and the design of the studies. Although the number of studies was small, and the quality of many studies was not optimal, it seems safe to conclude that psychological treatments have a small but robust effect on depression in depressed inpatients. More high-quality research is needed to verify these results.


An evaluation of maximum likelihood-expectation maximization reconstruction for SPECT by ROC analysis.
A ROC study was performed in order to evaluate whether the maximum likelihood expectation maximization (ML-EM) reconstruction algorithm improves diagnostic performance compared to the conventional filtered backprojection method in SPECT. Several implementations of the algorithm were tested including 25 and 50 iteration stopping points, with and without nonuniform attenuation compensation, and with and without Metz filtering. Filtered backprojection was with Metz filter and without attenuation compensation. The test data were computer simulated to model cardiac 201Tl SPECT. The data incorporated the effects of nonuniform attenuation, distance-dependent collimator response, and scatter. Patient CT images provided realistic anatomy and attenuation information for the data simulation. Four observers each viewed 120 images for each of the reconstruction methods. Lesion detectability with ML-EM increased with Metz filtering and decreased with nonuniform attenuation compensation. The best MIL-EM implementation, 50 iterations with Metz filtering and without attenuation compensation, was not statistically better than filtered backprojection.


Association of QRS narrowing with response to cardiac resynchronization therapy-a systematic review and meta-analysis of observational studies.
Prolonged QRS duration, which reflects a higher degree of mechanical dysynchrony, is a predictor of response to CRT. However, the association of QRS narrowing after biventricular pacing with CRT response rates is not clear. Our aim was to conduct a systematic review and meta-analysis on the association between QRS narrowing after cardiac resynchronization therapy (CRT) and clinical and echocardiographic response to CRT in patients with heart failure. Two independent investigators searched MedLine and EMBASE databases through July 2018 without any limitations. Studies providing estimates (continuous data) on the association of QRS shortening with either clinical (defined as New York Heart Association (NYHA) reduction ≥ 1) or echocardiographic (defined as left ventricular end-systolic volume (LVESV) reduction ≥ 15%) response to CRT were finally included in the quantitative synthesis. We included 32 studies (14 studies (1274 patients mean age 64 years old, males 79.3%) using clinical CRT response and 18 studies (1270 patients, mean age 64 years old, males 69.1%) using echocardiographic CRT response). A significant association between QRS narrowing and shorter attained QRS duration with clinical and echocardiographic CRT response was observed. The observed association was independent of the timing of QRS width measurement after CRT implantation. Acute and late improvement of electrical dysynchrony as depicted by QRS narrowing following biventricular pacing is associated with clinical and echocardiographic response to CRT. However, large prospective studies are needed to further examine our findings.


Intranuclear aggregates of ferritin in liver cells of mice treated with saccharated iron oxide. Their possible relation to nuclear protein synthesis.
Several months following parenteral injections of saccharated iron oxide into DBA/2J mice, granules rich in iron were found in nuclei of scattered parenchymal liver cells as well as in the cytoplasm. As seen in the light microscope, the intranuclear granules were brown; most of them measured between 0.5 micro and 1 micro in cross-section. They gave positive Prussian blue tests, and were not selectively stainable with pyronine. Electron micrographs of the granules showed closely packed aggregates of ferritin molecules, occasionally in paracrystalline order. The intranuclear collections were often surrounded by bands of material of moderate opacity. Scattered ferritin molecules and collections of such molecules were also present in the cytoplasm of many liver cells, but there seemed to be no quantitative relationship between intranuclear and cytoplasmic ferritin. Liver cells from untreated control mice failed to reveal intranuclear deposits of ferritin. Although the site of origin of the intranuclear aggregates of ferritin is unknown, the findings suggest the possibility that under suitable circumstances ferritin synthesis may take place within nuclei of liver cells-perhaps induced by the presence of colloidal iron.


[Humoral factors of general and local immunity in diabetes mellitus].
Considerable changes in the humoral factors of the general and local immunity were revealed during examination of 53 patients. A raised IgA and IgM level and a lowered titer of normal antibodies to antitoxins of diphtheria and tetanus and to staphylococcus antigen were revealed in the patients' blood. The content for IgG, lysozyme and normal antibodies to the antigens of dysentery and whooping cough was normal. A significant rise of the level of IgA, IgG, titers of normal antibodies and a decrease in the lysozyme activity were observed in the saliva.


Molecular basis for active Na,K-transport by Na,K-ATPase from outer renal medulla.
Active transcellular transport of NaCl in thick ascending limb of Henle's loop (TAL) consists of primary active transport of Na+ and secondary active transport of Cl-. The Na,K-pump maintains a low electrochemical potential for Na+ in the cytoplasm. The Na,K,Cl-cotransport system couples the entry of Cl- across the lumen membrane to entry of Na+ along its gradient. In mammalian kidney the TAL is concentrated in the red outer medulla and this tissue has exceedingly high concentrations of Na,K-pump sites, comparable with those in salt glands of birds and fishes. With the red outer medulla as starting material we developed procedures for purification of the Na,K-pump in membrane-bound form. The pump protein can be immobilized in two-dimensional membrane crystals by stabilization of the E2 form with vanadate or phosphate. The minimum functional protein unit of both membrane-bound and soluble Na,K-ATPase is an alpha beta-dimer (alpha-subunit Mr 84,000-106,000 and beta-subunit Mr 32,000-38,000 plus carbohydrate). Binding data, proteolytic digestion and fluorescence analysis show that both Na,K-induced and ATP-dependent conformational transitions of the alpha-subunit can be demonstrated in preparations consisting of soluble and fully active alpha beta-units. This is consistent with the notion that a single alpha beta-unit can catalyse the whole series of intermediary reactions and cation transport in the membrane. The Na,K,Cl-cotransport system can be identified by assaying bumethanide-sensitive ion fluxes in membrane vesicles from the outer renal medulla. Using equilibrium binding with [3H]bumethanide as an assay the cotransporter has been partially purified to capacities of 600-1,000 pmol/mg of protein. A polypeptide of Mr 34,000 is covalently labelled with [3H]bumethanide by direct photolysis. The [3H]bumethanide binding protein is not extracted by nonionic detergent except at high ionic strength, suggesting that the Na,K,Cl-cotransport protein is associated with cytoskeleton components. This association may be important for control of the entry of NaCl into the cytoplasm and for cellular regulation of the rate of active transport of NaCl across the tubule cells in the TAL.


Demonstration of bend-induced nonlinearities in large-mode-area fibers.
We present what we believe to be the first direct measurements of enhanced nonlinearities in large-mode-area fibers due to bend induced reductions in effective area. Both Raman scattering and self-phase modulation are observed to increase in tightly coiled fibers. The measured increase in nonlinearity compares well with predictions from simulations of the modal effective area.


Explaining Intentions to Seek Help for Depressive Symptoms in the Context of Responsibility Message Framing.
U.S. college students are disproportionally affected by depression but typically do not seek help. To advance understanding of the role of health messages in shaping college students' help-seeking intentions, we used a reasoned action approach to experimentally investigate help-seeking intentions for depressive symptoms. Due to negative interpretation biases among those who suffer from depression, scholars have previously warned against attempts to decrease feelings of responsibility for one's depression in health messages. We tested the determinants of help-seeking intentions as a function of exposure to depression help-seeking messages that differed in responsibility cues. Findings revealed that in our sample low responsibility health message framing did not affect determinants of help-seeking intentions. We identified instrumental attitude (β = .53) and descriptive norms (β = .24) as determinants of intentions to seek help (R2 = .42) across message conditions and across levels of depression. These findings indicate potentially important targets for messages that seek to increase help-seeking among depressed college students.


Cell adhesion molecules expression pattern indicates that somatic cells arbitrate gonadal sex of differentiating bipotential fetal mouse gonad.
Unlike other organ anlagens, the primordial gonad is sexually bipotential in all animals. In mouse, the bipotential gonad differentiates into testis or ovary depending on the genetic sex (XY or XX) of the fetus. During gonad development cells segregate, depending on genetic sex, into distinct compartments: testis cords and interstitium form in XY gonad, and germ cell cysts and stroma in XX gonad. However, our knowledge of mechanisms governing gonadal sex differentiation remains very vague. Because it is known that adhesion molecules (CAMs) play a key role in organogenesis, we suspected that diversified expression of CAMs should also play a crucial role in gonad development. Using microarray analysis we identified 129 CAMs and factors regulating cell adhesion during sexual differentiation of mouse gonad. To identify genes expressed differentially in three cell lines in XY and XX gonads: i) supporting (Sertoli or follicular cells), ii) interstitial or stromal cells, and iii) germ cells, we used transgenic mice expressing EGFP reporter gene and FACS cell sorting. Although a large number of CAMs expressed ubiquitously, expression of certain genes was cell line- and genetic sex-specific. The sets of CAMs differentially expressed in supporting versus interstitial/stromal cells may be responsible for segregation of these two cell lines during gonadal development. There was also a significant difference in CAMs expression pattern between XY supporting (Sertoli) and XX supporting (follicular) cells but not between XY and XX germ cells. This indicates that differential CAMs expression pattern in the somatic cells but not in the germ line arbitrates structural organization of gonadal anlagen into testis or ovary.


Erosion of empathy during medical training by gender. A cross-sectional study.
Empathy erosion may be defined as a sudden decline in the levels of empathy that occurs as of the third year of medical school and continues until the fifth year. According to some authors, this process is normal during medical training and may be considered a model of empathic behavior. The objective of this study was to verify whether empathy erosion is a general phenomenon in the schools of medicine included in the study and its relation to gender. Exploratory, cross-sectional study. Students from first through sixth year of the School of Medicine of Universidad del Azuay (Cuenca, Ecuador) and from first through fifth year of the School of Medicine of Corporación Universitaria Rafael Nuñez (Colombia). The levels of overall empathy and of each component were estimated using the Jefferson Scale of Empathy, which was administered in both schools during July and August of 2016. The significance level was established at α < 0.05. Results. Universidad del Azuay: n= 278 (98% of all students); women= 112; men= 166; Corporación Universitaria Rafael Nuñez: n= 756 (77.86% of all students); women= 434; men= 322. The model of erosion of empathy is not fulfilled at the level of overall empathy or of each studied component according to gender. Empathy erosion is a specific element of several different models of empathic response (and of its components). Men and women do not have the same empathic response. Such response, in the studied conditions, is variable.


GIBA: a clustering tool for detecting protein complexes.
During the last years, high throughput experimental methods have been developed which generate large datasets of protein - protein interactions (PPIs). However, due to the experimental methodologies these datasets contain errors mainly in terms of false positive data sets and reducing therefore the quality of any derived information. Typically these datasets can be modeled as graphs, where vertices represent proteins and edges the pairwise PPIs, making it easy to apply automated clustering methods to detect protein complexes or other biological significant functional groupings. In this paper, a clustering tool, called GIBA (named by the first characters of its developers' nicknames), is presented. GIBA implements a two step procedure to a given dataset of protein-protein interaction data. First, a clustering algorithm is applied to the interaction data, which is then followed by a filtering step to generate the final candidate list of predicted complexes. The efficiency of GIBA is demonstrated through the analysis of 6 different yeast protein interaction datasets in comparison to four other available algorithms. We compared the results of the different methods by applying five different performance measurement metrices. Moreover, the parameters of the methods that constitute the filter have been checked on how they affect the final results. GIBA is an effective and easy to use tool for the detection of protein complexes out of experimentally measured protein - protein interaction networks. The results show that GIBA has superior prediction accuracy than previously published methods.


Identification of a point mutation in the topoisomerase II gene from a human leukemia cell line containing an amsacrine-resistant form of topoisomerase II.
HL-60/AMSA is a human leukemia cell line that is 50- to 100-fold more resistant to the cytotoxic actions of the topoisomerase II-reactive intercalator amsacrine than is its drug-sensitive HL-60 parent line. Previously, we have shown that the topoisomerase II from HL-60/AMSA is also resistant to inhibition by amsacrine and other intercalating agents. We therefore sought the molecular basis for the resistance of the topoisomerase II of HL-60/AMSA and, by inference, of the HL-60/AMSA line itself. We report the cloning and sequencing of the topoisomerase II genes from both the sensitive and resistant leukemia cell lines using polymerase chain reaction technology. We have identified a single base change associated with the drug-resistant form of topoisomerase II. This mutation is present in both cloned HL-60/AMSA complementary DNA and extracted HL-60/AMSA genomic DNA. A rapid assay for this mutation in clinical samples has been developed and applied to the DNA of cells from both normal volunteers and leukemia patients. Thus far, the HL-60/AMSA genotype has not been identified in the cells from any individual, suggesting that this genotype is indeed a mutation and not an allelic form of topoisomerase II. The novel assay developed will allow a rapid search for the prevalence of this mutation in clinical samples from patients with leukemia who have relapsed following intercalator therapy.


Photoelectron trapping in N2O 7sigma-->ksigma resonant ionization.
Vibrationally resolved photoelectron spectroscopy of the N2O+(A 2Sigma+) state is used to compare the dependence of the photoelectron dynamics on molecular geometry for two shape resonances in the same ionization channel. Spectra are acquired over the photon energy range of 18< or =hv< or =55 eV. There are three single-channel resonances in this range, two in the 7sigma-->ksigma channel and one in the 7sigma-->kpi channel. Vibrational branching ratio curves are determined by measuring vibrationally resolved photoelectron spectra as a function of photon energy, and theoretical branching ratio curves are generated via Schwinger variational scattering calculations. In the region 30< or =hv< or =40 eV, there are two shape resonances (ksigma and kpi). The ksigma ionization resonance is clearly visible in vibrationally resolved measurements at hv=35 eV, even though the total cross section in this channel is dwarfed by the cross section in the degenerate, more slowly varying 7sigma-->kpi channel. This ksigma resonance is manifested in non-Franck-Condon behavior in the approximately antisymmetric v3 stretching mode, but it is not visible in the branching ratio curve for the approximately symmetric v1 stretch. The behavior of the 35-eV ksigma resonance is compared to a previously studied N2O 7sigma-->ksigma shape resonance at lower energy. The mode sensitivity of the 35-eV ksigma resonance is the opposite of what was observed for the lower-energy resonance. The contrasting mode-specific behavior observed for the high- and low-energy 7sigma-->ksigma resonances can be explained on the basis of the "approximate" symmetry of the quasibound photoelectron resonant wave function, and the contrasting behavior reflects differences in the continuum electron trapping. An examination of the geometry dependence of the photoelectron dipole matrix elements shows that the ksigma resonances have qualitatively different dependences on the individual bond lengths. The low-energy resonance is influenced only by changes in the end-to-end length of the molecule, whereas the higher-energy resonance depends on the individual N-N and N-O bond lengths. Branching ratios are determined for several vibrational levels, including the symmetry-forbidden bending mode, and all of the observed behavior is explained in the context of an independent particle, Born-Oppenheimer framework.


Proven and probable invasive fungal infections in children with acute lymphoblastic leukaemia: results from an university hospital, 2005-2013.
Despite improvements in diagnosis and treatment, invasive fungal infections (IFIs) are still a major cause of morbidity and mortality in immunocompromised patients. The data on IFI among children with acute lymphoblastic leukaemia (ALL) are still scarce, and our aim was to estimate the risk, aetiology and outcome of proven and probable IFIs in children with ALL who did not receive primary prophylaxis over an 8-year period. Between January 2005 and February 2013, 125 children who were treated for ALL at the Pediatric Hematology Department of the Medical School of Ege University were retrospectively reviewed. Proven and probable IFIs were defined according to revised definitions of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group. The proven and probable IFI incidence was 30/125 (24%). Profound neutropenia was detected in 18 (60%) patients, and prolonged neutropenia was detected in 16 (53.3%) of the patients. The most isolated agents were non-albicans Candida spp. The crude and attributable mortality was 20% and 13.3% respectively. Profound neutropenia was associated with mortality (P < 0.05). The younger patients were especially at risk for proven IFI. Prolonged neutropenia, to be in the induction phase of chemotherapy, and profound neutropenia were found to be the most common predisposing factors for IFI episodes.


Judicialization of access to medicines in four Latin American countries: a comparative qualitative analysis.
The valuation of medicines as health needs vary depending on the stakeholders involved (users, prescribers, managers, etc.) and their expectations. These factors modulate the role of medicines as a health need and influence access to medicines, and could be useful to explain the rising of Judicialization of access to medicines. To conduct a comparative analysis of the causes and consequences of judicialization of access to medicines in Argentina, Brazil, Colombia and Chile from the perspective of medicines as health needs. A qualitative, cross-country study was carried out in these 4 countries. Semi-structured interviews were conducted with 50 representatives of the different stakeholders involved in the judicialization of access to medicines, including Executive branch, Judiciary, health system managers, patient organizations. The interviews were audio-recorded and transcribed verbatim. Thematic analysis used a framework approach based on the theoretical model for medicines as health needs. Representatives from Argentina, Brazil and Colombia considered judicialization of access to medicines as a widespread phenomenon in their respective countries. Meanwhile in Chile, the respondents highlighted that most lawsuits related to the right to health were filed against private insurers because of unjustified increases in the insurance premiums. The comparative analysis showed that judicialization of access to medicines emerged in the four countries regardless of the constitutional protection or the health system population coverage. Among the causes were mentioned difficulties in guaranteeing access to covered medicines and the influence of pharmaceutical marketing on needs assessment and prescription behaviours. The interviewees highlighted the pressure to health system managers to fulfil their responsibilities as a positive impact of litigation. In contrast, the funding of medicines without evidence of efficacy or safety was considered a negative impact. Only in Brazil, judicialization has had impact on R&D policies. In Colombia, litigation also encouraged the recognition of the right to health as a fundamental right and the development of policies for controlling medicines prices. The results suggest that applying the adopted theoretical model creates the possibility of identifying critical points to guide policy makers to improve the health systems performances and to control lawsuits for access to medicines.


Rebuilding a planarian: from early signaling to final shape.
Why some animals can regenerate and others not has fascinated biologists since the first examples of regeneration were reported. Although many animal phyla include species with some regenerative ability, mainly restricted to particular cell types or tissues, there are some other species capable of regenerating complex structures, such as the vertebrate limb and heart. More remarkably, there are some examples of animals that can regenerate the whole body from a tiny piece of them. Understanding how regeneration is triggered and achieved in these animals is fundamental not only to understand this fascinating primary biological question, but also because of its implications for the field of regenerative medicine. Here, we discuss one of the models with higher regenerative capabilities: the freshwater planarians. Two key features make planarians an attractive model to study regeneration: the presence of adult pluripotent stem cells and the permanent activation of the morphogenetic mechanisms that instruct cell fate. Here, we revise our current knowledge of key events that lead to successful regeneration including: how heterogeneous is the stem cell population; what are the immediate changes at the gene level after amputation and what triggers the regenerative response; how is axial polarity re-established; how do the different cell types differentiate from lineage-committed progenitors and how is size and organ proportionality controlled. Finally, we point out some open questions that the field needs to address in the near future.


Protein Structure Prediction in Drug Discovery.
When the results of DeepMind's AlphaFold2 at CASP were announced in 2020, the scientific world was so amazed by how effectively it performed that "it will change everything" became the motto for this revolution [...].


[Etidronate and calcitonin to PTH (1-84) in postmenopausal osteoporosis].
Postmenopausal osteoporosis is now a major health problem. The advancement of knowledge on the role preferred cellular osteocytes, osteoblasts and osteoclasts in bone tissue, the biochemical activity and gene expression, interaction with physical activity, diet and nutritional measures, as well as various currently available drugs are disclosed in interaction with clinical studies of etidronate and calcitonin, parathyroid hormone and recombinant 1-84. It is concluded in relation to its activity at eighteen months of the administration and its assessment by bone mineral density, biochemical markers and production of fractures.


Heart rate and posttraumatic stress in injured children.
Elevated, acute heart rate has been related to later posttraumatic stress disorder (PTSD) development in injured adults, but this has not been examined in children and adolescents. Better understanding of the relationship between acute physiological arousal and later child PTSD could help elucidate the etiology of posttrauma responses in children and might identify useful markers for PTSD risk. To evaluate the relationship between heart rate assessed in the emergency department (ED) during normal clinical care and later PTSD outcome in traumatically injured children. Prospective cohort study assessed heart rate at ED triage and PTSD an average of 6 months' postinjury. Large, urban pediatric academic medical center in the northeastern United States. One hundred ninety children and adolescents (aged 8-17 years) hospitalized for traffic-related injury.Main Outcome Measure Clinician-Administered PTSD Scale for Children and Adolescents. The group of children who developed partial or full PTSD had a higher mean +/- SD heart rate at ED triage than those who did not go on to have PTSD (109.6 +/- 22.3 vs 99.7 +/- 18.0 beats per minute). Children with an elevated heart rate (defined as >/=2 SDs higher than the normal resting heart rate for their age and sex) at ED triage were more likely to meet criteria for partial or full PTSD at follow-up, even after adjusting for age, sex, and injury (adjusted odds ratio, 2.4 [95% confidence interval, 1.1-5.4]). These results suggest an association between early physiological arousal and the development or persistence of PTSD symptoms in injured children and point to the importance of better understanding the interplay between physiological and psychological functioning after a traumatic stressor.


Efficacy of a Hybrid Closed-Loop Solution in Patients With Excessive Time in Hypoglycaemia: A Post Hoc Analysis of Trials With DBLG1 System.
Automated insulin delivery is an efficient treatment for patients with type 1 diabetes. Little is known on its impact on patients with excessive time in hypoglycaemia. We performed a post hoc analysis of three randomized control trials that used the DBLG1 (Diabeloop Generation 1) hybrid closed-loop solution. Patients whose time below 70 mg/dL during baseline, open-loop phase exceeded 5% were selected. The outcomes were the differences between the closed-loop and the open-loop phases in time in various ranges and Glycemia Risk Index (GRI). We identified 45 patients exhibiting ≥5% of time below 70 mg/dL during the open-loop phase. Under closed-loop, the time in hypoglycaemia (54 to <70 mg/dL) dropped from 7.9% (SD 2.4) to 3.2% (SD 1.6) (difference -4.7% [-5.3; -4.1], P < 10-4). The time below 54 mg/dL decreased from 1.9% (SD 1.3) to 0.8% (SD 0.7) (difference -0.9% [-1.4; -0.8], P < 10-4). The time in range (TIR 70-180 mg/dL) improved from 63.3 (SD 9.5) to 68.2% (SD 8.2) (difference 5.1% [2.9; 7.0], P < 10-4). The GRI improved from 51.2 (SD 12.4) to 38.0 (SD 10.9) (difference 13.2 [10.4; 16.0], P < 10-4). DBLG1 decreased time in hypoglycaemia by more than 50% even in patients with excessive time in hypoglycaemia at baseline, while also improving both TIR and GRI, under real-life conditions. The improvement in GRI (13.2%) exceeded that of the improvement in TIR (5.1%) indicating that in this data set, GRI was more sensitive than TIR to the improvement in glycaemia achieved with closed-loop. These results support the safety and efficacy of this treatment.


Giant Cell Tumour of the Talus: A Rare Case Report.
Giant-cell tumor constitutes 4-20% of all primary bone tumors in south East Asian population. They are benign locally aggressive bone tumour first described by cooper in 1818. These tumors occur predominantly in meta-epiphyseal region. Most often they are located around the knee joint. Although most of the tumors are diagnosed on plain radiograph alone, varying CT and MRI presentations of these tumors are essential to narrow down the differentials has an extended pre operative assessment.


New drugs of 2002.
To provide information regarding the most important properties of the new therapeutic agents marketed in 2002. Published studies, drug information reference sources, and product labeling. In 2002, 26 new therapeutic agents were marketed. The indications and information on dosage and administration for the new agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. Where possible, the properties of the new drugs are compared with those of other drugs marketed for the same indications. A number of the new therapeutic agents marketed in 2002 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.


IDENTIFYING GAPS IN PELVIC PAIN EDUCATION: A SCOPING REVIEW AND STRUCTURED ANALYSIS OF OBSTETRICS AND GYNECOLOGY TRAINING MILESTONES.
Several clinical practice guidelines on the evaluation and management (EM) of chronic pelvic pain (CPP) are published; however, it is not known whether obstetrics and gynecology (OBGYN) educational milestones are aligned with current practice recommendations. Therefore, this scoping review and structured analysis aims to identify gaps between clinical guidelines for the EM of CPP, and OBGYN training milestones published by educational authorities like the ACGME and the AAGL. The literature search was performed in MEDLINE, PubMed Central, and Bookshelf on the PubMed interface from January 2018 to September 2022. Peer-reviewed publications were included if they were a systematic review of recent practice guidelines and focused on female CPP. Publications that focused on a single pelvic pain condition or focused on a specific treatment were excluded. Two reviewers extracted the data and appraised the study quality following the Critical Appraisal Skills Programme Checklist for systematic reviews. Four articles met inclusion criteria for thematic analysis. A reflexive thematic analysis via the inductive approach was performed to develop clinical themes common to all review articles and presumed important in the EM of CPP. Pelvic pain experts and Delphi methodology was used to assess validity and relevance of each theme in OBGYN training. Validated themes were used in a SWOT analysis of the ACGME and the AAGL Milestones used for training OBGYN residents and fellows. A SWOT analysis is an organizational tool used to analyze processes in terms of strengths, weaknesses, opportunities for improvement and threats to implementing a potential change. Twelve clinical themes were conceptualized and achieved ≥ 90% consensus as being important in the EM of CPP. Clinical themes pertained to pathophysiology, biopsychosocial approach, trauma informed care, history and physical examination, diagnostic testing, multimodal/multidisciplinary management, pain education, and medical and surgical management. SWOT analysis showed that the ACGME Milestones lacked milestones specific to CPP, while the AAGL Milestones had 6 CPP focused competencies with multiple milestones. Milestones on trauma informed care and application of biopsychosocial assessment were notably absent. OBGYN educational milestones published by the ACGME and the AAGL are not yet aligned with current clinical guidelines for the EM of CPP.


Birth timing generates reproductive trade-offs in a non-seasonal breeding primate.
The evolutionary benefits of reproductive seasonality are often measured by a single-fitness component, namely offspring survival. Yet different fitness components may be maximized by different birth timings. This may generate fitness trade-offs that could be critical to understanding variation in reproductive timing across individuals, populations and species. Here, we use long-term demographic and behavioural data from wild chacma baboons (Papio ursinus) living in a seasonal environment to test the adaptive significance of seasonal variation in birth frequencies. We identify two distinct optimal birth timings in the annual cycle, located four-month apart, which maximize offspring survival or minimize maternal interbirth intervals (IBIs), by respectively matching the annual food peak with late or early weaning. Observed births are the most frequent between these optima, supporting an adaptive trade-off between current and future reproduction. Furthermore, infants born closer to the optimal timing favouring maternal IBIs (instead of offspring survival) throw more tantrums, a typical manifestation of mother-offspring conflict. Maternal trade-offs over birth timing, which extend into mother-offspring conflict after birth, may commonly occur in long-lived species where development from birth to independence spans multiple seasons. Our findings therefore open new avenues to understanding the evolution of breeding phenology in long-lived animals, including humans.


Correlates of fruit, vegetable, soft drink, and snack intake among adolescents: the ESSENS study.
Identifying modifiable correlates of dietary behaviors is of utmost importance for the promotion of healthy dietary behaviors. This study explores individual, home, and school/neighborhood environmental correlates of dietary behaviors (intake of fruits, vegetables, soft drinks, and unhealthy snacks) among adolescents. In total, 742 adolescents with a mean age of 13.6 (SD=0.3) were included in this cross-sectional study conducted in 11 secondary schools located in the eastern part of Norway. A web-based questionnaire was used to collect data. Univariable and multivariable linear regression analyses were used to explore factors associated with the dietary behaviors included. A higher frequency of food/drink purchase in the school canteen was related to a higher consumption of soft drinks and snacks. A higher frequency of food/drink purchase in shops around schools during break or recess was related to a higher consumption of snacks. A higher frequency of food/drink purchase in shops around the neighborhood on the way to and from school was related to a higher consumption of soft drinks. Perceived parental modeling and perceived accessibility at home were found to be positively associated with all dietary behaviors. Perceived parental rules were inversely associated with soft drink and snack consumption; self-efficacy related to healthy eating was positively associated with fruit and vegetable consumption. Other included school and neighborhood environmental correlates were not associated with the dietary behaviors. There is a need to address the food purchasing behavior of the adolescents using different approaches. The findings also highlight the important role of parents and the home environment for healthy and unhealthy dietary behaviors of adolescents.


Phase synchronization analysis of EEG signals: an evaluation based on surrogate tests.
Phase synchronization (PS) analysis has been demonstrated to be a useful method to infer functional connectivity with multichannel neural signals, e.g., electroencephalography (EEG). Methodological problems on quantifying functional connectivity with PS analysis have been investigated extensively, but some of them have not been fully solved yet. For example, how long a segment of EEG signal should be used in estimating PS index? Which methods are more suitable to infer the significant level of estimated PS index? To address these questions, this paper performs an intensive computation study on PS analysis based on surrogate tests with 1) artificial surrogate data generated by shuffling the rank order, the phase spectra, or the instantaneous frequency of original EEG signals, and 2) intersubject EEG pairs under the assumption that the EEG signals of different subjects are independent. Results show that 1) the phase-shuffled surrogate method is workable for significance test of estimated PS index and yields results similar to those by intersubject EEG surrogate test; 2) generally, a duration of EEG waves covering about 3 16 cycles is suitable for PS analysis; and 3) the PS index based on mean phase coherence is more suitable for PS analysis of EEG signals recorded at relatively low sampling rate.


A temperature-controlled amplicon system derived from Plum pox potyvirus.
The control of replication can facilitate a viral amplicon to reach high expression levels by enabling the virus to escape host defence mechanisms and reducing the deleterious effects of viral infection. We have developed a novel system to regulate amplicon expression by controlling the temperature of plant growth. Nicotiana benthamiana plants were transformed at two different temperatures with a cDNA copy of the Plum pox potyvirus genome harbouring the open reading frame 2 of Porcine circovirus 2 between the nuclear inclusion protein b and coat protein coding sequences. Although transformation at 27 degrees C mainly yielded nonexpressing amplicons, lines with a tight control of amplicon expression were obtained. Viral replication was not detected in these plants when germinated at 28 degrees C, but was observed when the plants were shifted to 20 degrees C. In lines transformed at 24 degrees C, although the amplicon was expressed at 28 degrees C, viral accumulation was low and caused only minor growing defects. Viral replication was enhanced in these plants by shifting the temperature to 20 degrees C; under such conditions, the amplicon reached higher and more persistent expression levels than in plants transformed at 27 degrees C. These results demonstrate the utility of temperature regulation to control viral amplicon expression.


Single Transmitter Direction Finding Using a Single Moving Omnidirectional Antenna.
Traditional direction-finding systems are based on processing the outputs of multiple spatially separated antennas. The impinging signal Angle-of-Arrival (AOA) is estimated using the relative phase and amplitude of the multiple outputs that are sampled simultaneously. Here, we explore the potential of a single moving antenna to provide useful direction finding of a single transmitter. If the transmitted signal frequency is steady enough during the collection of data, a single antenna can be moved while tracking the phase changes to provide an Angle-of-Arrival measurement. The advantages of a single-antenna sensor include the sensor size, the lack of a need for multiple-receiver synchronization in time and frequency, the lack of mutual antenna coupling, and the cost of the system. However, a single-antenna sensor requires an accurate knowledge of its position during the data collection and it is challenged by transmitter phase instability, signal modulation, and transmitter movement during the measurement integration time. We analyze the performance of the proposed sensor, support the analysis with simulations and finally, present measurements performed by hardware configured to check the validity of the proposed single-antenna sensor.


Chylomicronemia due to apolipoprotein CIII overexpression in apolipoprotein E-null mice. Apolipoprotein CIII-induced hypertriglyceridemia is not mediated by effects on apolipoprotein E.
The mechanism of apolipoprotein (apo) CIII-induced hypertriglyceridemia remains uncertain. We crossed apoCIII transgenic and apoE gene knockout (apoE0) mice, and observed severe hypertriglyceridemia with plasma triglyceride levels of 4,521+/-6, 394 mg/dl vs. 423+/-106 mg/dl in apoE0 mice, P < 0.00001 for log(triglycerides [TG]). Cholesterols were 1,181+/-487 mg/dl vs. 658+/-151 mg/dl, P < 0.0001. Lipoprotein fractionation showed a marked increase in triglyceride-enriched chylomicrons+VLDL. This increase was limited to the lowest density (chylomicrons and Sf 100-400) subfractions. Intermediate density lipoproteins (IDL)+LDL increased moderately, and HDL decreased. There was no significant increase in triglyceride production in apoCIII transgenic/apoE0 mice. The clearance of VLDL triglycerides, however, was significantly decreased. Lipoprotein lipase in postheparin plasma was elevated, but activation studies suggested LPL inhibition by both apoCIII transgenic and apoCIII transgenic/apoE0 plasma. ApoCIII overexpression also produced a marked decrease in VLDL glycosaminoglycan binding which was independent of apoE. The predominant mechanism of apoCIII-induced hypertriglyceridemia appears to be decreased lipolysis at the cell surface. The altered lipoprotein profile that was produced also allowed us to address the question of the direct atherogenicity of chylomicrons and large VLDL. Quantitative arteriosclerosis studies showed identical results in both apoCIII transgenic/apoE0 and apoE0 mice, supporting the view that very large triglyceride-enriched particles are not directly atherogenic.


Adaptive aging in the context of evolutionary theory.
Compelling evidence for an adaptive origin of aging has clashed with traditional evolutionary theory based on exclusively individual selection. The consensus view has been to try to understand aging in the context of a narrow, restrictive evolutionary paradigm, called the Modern Synthesis, or neo-Darwinism. But neo-Darwinism has shown itself to be inadequate in other ways, failing to account for stable ecosystems, for the evolution of sex and the maintenance of diversity and the architecture of the genome, which appears to be optimized for evolvability. Thus aging is not the only reason to consider overhauling the standard theoretical framework. Selection for stable ecosystems is rapid and efficient, and so it is the easiest modification of the neo-Darwinian paradigm to understand and to model. Aging may be understood in this context. More profound and more mysterious are the ways in which the process of evolution itself has been transformed in a bootstrapping process of selection for evolvability. Evolving organisms have learned to channel their variation in ways that are likely to enhance their long-term prospects. This is an expanded notion of fitness. Only in this context can the full spectrum of sophisticated adaptations be understood, including aging, sex, diversity, ecological interdependence, and the structure of the genome.


Epigenetic Regulation of GABAergic Neurotransmission and Neurosteroid Biosynthesis in Alcohol Use Disorder.
Alcohol use disorder (AUD) is a chronic relapsing brain disorder. GABAA receptor (GABAAR) subunits are a target for the pharmacological effects of alcohol. Neurosteroids play an important role in the fine-tuning of GABAAR function in the brain. Recently, we have shown that AUD is associated with changes in DNA methylation mechanisms. However, the role of DNA methylation in the regulation of neurosteroid biosynthesis and GABAergic neurotransmission in AUD patients remains under-investigated. In a cohort of postmortem brains from 20 male controls and AUD patients, we investigated the expression of GABAAR subunits and neurosteroid biosynthetic enzymes and their regulation by DNA methylation mechanisms. Neurosteroid levels were quantified by gas chromatography-mass spectrometry. The α 2 subunit expression was reduced due to increased DNA methylation at the gene promoter region in the cerebellum of AUD patients, a brain area particularly sensitive to the effects of alcohol. Alcohol-induced alteration in GABAAR subunits was also observed in the prefrontal cortex. Neurosteroid biosynthesis was also affected with reduced cerebellar expression of the 18kDa translocator protein and 3α-hydroxysteroid dehydrogenase mRNAs. Notably, increased DNA methylation levels were observed at the promoter region of 3α-hydroxysteroid dehydrogenase. These changes were associated with markedly reduced levels of allopregnanolone and pregnanolone in the cerebellum. Given the key role of neurosteroids in modulating the strength of GABAAR-mediated inhibition, our data suggest that alcohol-induced impairments in GABAergic neurotransmission might be profoundly impacted by reduced neurosteroid biosynthesis most likely via DNA hypermethylation.


[Diagnostic laparoscopy in pregnant women].
54 laparoscopic examinations were performed in 52 pregnant women when acute surgical diseases of the abdomen were suspected. When the suspicions of acute surgical diseases in pregnant women are substantiated, diagnostic laparoscopy has high diagnostic potential and is safe for the mother and fetus. This method permits to avoid unnecessary open operations, and also to perform simple operations through laparoscope.


Impact of mitomycin C on the mRNA expression signatures of immunological biomarkers in eosinophilic nasal polyposis.
The topical application of mitomycin C has been evaluated as a complementary therapy for eosinophilic nasal polyposis (ENP). However, the mechanism underlying the additional benefits of mitomycin C for the control of eosinophilic inflammation and prevention of posttherapeutic relapse remains to be elucidated. In this work, the aim was to characterize the gene expression profile by quantitative real-time polymerase chain reaction (qPCR) of proinflammatory and regulatory biomarkers that are typically associated with ENP and to assess the impact of the topical application of mitomycin C on the nasal mucosal tissue immunologic milieu after ENP surgery. We have selected 20 patients with ENP that were recommended to undergo surgical intervention. Normal mucosal tissue was obtained from healthy nasal mucosa from six patients with absence of eosinophilic infiltration. To test the effect of mitomycin C, one side of the maxillary sinus mucosa was selected for topical application of this drug and the other received no further treatment and acted as the control. The genes interleukin-4 (IL-4), IL-5, IL-10, IL-13, chemokine (C-C motif) ligand 5 (CCL5), CCL24, colony-stimulating factor 2 (CSF2), transforming growth factor beta 1 (TGFB1), tumor necrosis factor alpha (TNF-alpha), and beta actin (ACTB) were selected for gene expression analysis by qPCR. The data showed higher expression of proinflammatory biomarkers and lower levels of regulatory TGFB1 transcripts in ENP mucosal tissue. Surgery with topical application of mitomycin C induced a prominent transcriptional down-regulation of the immunologic biomarkers, CCL24, TNF-alpha, CSF2, and IL-5, in ENP mucosal tissue. Additionally, this treatment restored the levels of chemokines and cytokines to those observed in the nasal mucosal tissue of control subjects, except for TGFB1, which remained below the reference pattern. Moreover, CSF2 was identified as a putative biomarker with significant predictive value for complementary prophylactic purposes after surgery in ENP patients. After the characterization of the expression signatures of immunologic biomarkers in ENP, we observed that the topical use of mitomycin C is important for the reestablishment of the immunologic microenvironment of a normal expression profile of biomarkers involved in ENP mucosal tissue.


Reversing the direction in a light-driven rotary molecular motor.
Biological rotary motors can alter their mechanical function by changing the direction of rotary motion. Achieving a similar reversal of direction of rotation in artificial molecular motors presents a fundamental stereochemical challenge: how to change from clockwise to anticlockwise motion without compromising the autonomous unidirectional rotary behaviour of the system. A new molecular motor with multilevel control of rotary motion is reported here, in which the direction of light-powered rotation can be reversed by base-catalysed epimerization. The key steps are deprotonation and reprotonation of the photochemically generated less-stable isomers during the 360° unidirectional rotary cycle, with complete inversion of the configuration at the stereogenic centre. The ability to change directionality is an essential step towards mechanical molecular systems with adaptive functional behaviour.


[Surgical treatment of chronic venous insufficiency].
Patients with chronic venous insufficiency (CVI) may develop serious symptoms such as pain, oedema, venous claudication and leg ulcers. Conventional therapy includes compression therapy, elevation of the extremities, and in some cases surgical elimination of superficial varicose veins. This article presents and discusses surgical treatment (reconstructive deep venous surgery and transplantation) and endovascular therapy (percutaneous recanalization of post-thrombotic deep venous occlusions). The article is based on literature identified through non-systematic searches in the PubMed and Cochrane databases. After reconstructive deep venous surgery, ulcer healing is reported in 60-78 % of cases and clinical improvement in 90 %. After such surgery, the median ulcer-free period seems to be longer in primary (congenital, familial), 54 months, than in secondary (after deep vein thrombosis) chronic venous insufficiency (18 months). Recanalization of deep venous occlusions is successful in 90 % of patients who have undergone endovascular treatment of venous claudication and leg ulcer. Reconstructive deep venous surgery constitutes a real treatment choice for patients with chronic venous insufficiency for whom conventional measures have failed. The benefits are ulcer-free periods, clinical improvement, return to work and improved quality of life.


Development of a murine model to study the cerebral pathogenesis of Aspergillus fumigatus.
Molds are environmental fungi that can cause disease in immunocompromised individuals. The most common pathogenic mold is Aspergillus fumigatus, which is typically inhaled into the lungs and causes invasive pulmonary disease. In a subset of these patients, this infection can spread from the lungs to other organs including the brain, resulting in cerebral aspergillosis. How A. fumigatus causes brain disease is not well understood and these infections are associated with extremely high mortality rates. Thus, we developed an animal model to study the pathogenesis of cerebral aspergillosis to better understand this disease and develop better treatments for these life-threatening infections.


Growth factor-extracellular matrix synergy in the control of trophoblast invasion.
At the periphery of the human placenta, trophoblast attaches to the uterine wall. The tissue interface contains many anchoring sites, with cytotrophoblast columns that form bridges between the overlying extraembryonic (villous) mesenchyme and the maternal decidual stroma beneath. From the periphery of these columns, large numbers of trophoblast cells detach, migrate through the decidua and eventually colonize and transform maternal arteries. In this way the placenta increases and gives priority to the maternal blood supply to the conceptus. We have shown that when early villous tissue is explanted on a collagen gel in serum-free medium, anchoring-site morphogenesis occurs. Thus, in the presence of placental mesenchyme but in the absence of maternal cells, contact with a permissive extracellular matrix (ECM) is necessary and sufficient for cytotrophoblast column development. Proliferation of trophoblast occurs, followed by differentiation into a columnar cell phenotype in which cells remain attached to one another and to the ECM. At this stage, interaction between fibronectin and integrin alpha5beta1 at the cell surface stabilizes the column and the cells remain as a contiguous multilayered sheet. However, the addition of serum-free conditioned medium from first-trimester placental fibroblasts stimulates cytotrophoblast to detach from the distal column and migrate in streams across the ECM. The removal of insulin-like growth factor I (IGF-I) from the fibroblast medium decreases streaming activity, whereas the addition of exogenous IGF-I (10 ng/ml) to serum-free medium produces a streaming phenotype. In contrast, transforming growth factor beta1 (10 ng/ml) maintains the cells in a tight sheet. These results suggest the possibility of a paracrine interaction between villous mesenchyme and cytotrophoblast in anchoring sites to stimulate the infiltration of the maternal ECM by trophoblast. Such a mechanism would be self-limiting because the signal diminishes with distance from the placenta.


Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice.
Molecular mechanisms underlying learning and memory remain imprecisely understood, and restorative interventions are lacking. We report that intranasal administration of siRNAs can be used to identify targets important in cognitive processes and to improve genetically impaired learning and memory. In mice modeling the intellectual deficiency of Fragile X syndrome, intranasally administered siRNA targeting glycogen synthase kinase-3β (GSK3β), histone deacetylase-1 (HDAC1), HDAC2, or HDAC3 diminished cognitive impairments. In WT mice, intranasally administered brain-derived neurotrophic factor (BDNF) siRNA or HDAC4 siRNA impaired learning and memory, which was partially due to reduced insulin-like growth factor-2 (IGF2) levels because the BDNF siRNA- or HDAC4 siRNA-induced cognitive impairments were ameliorated by intranasal IGF2 administration. In Fmr1-/- mice, hippocampal IGF2 was deficient, and learning and memory impairments were ameliorated by IGF2 intranasal administration. Therefore intranasal siRNA administration is an effective means to identify mechanisms regulating cognition and to modulate therapeutic targets.


[Familial hydatidiform mole syndrome and genetic aspects of this disturbed trophoblast development].
A female sibship is presented, where in a total of six sisters aged 16 to 34 years three women suffered from recurrent hydatiform molar pregnancies. Until now none of them has given birth to a child. The family's pedigree and the seven molar events are shown, and cytogenetic findings of complete and incomplete (partial) hydatiform mole as described in the literature and with regard to histomorphological changes. Finally, "genomic imprinting" means that it makes a difference whether chromosomes are derived maternally or paternally (parental origin effect).


Investigation of relaxant effects of new agents affecting nitric oxide/cyclic guanosine monophosphate pathway on sheep oddi sphincter.
Nitric oxide (NO) is a potent nonadrenergic, noncholinergic mediator of gastrointestinal smooth muscle. We aimed to investigate the effects of new NO/cyclic guanosine monophosphate (cGMP) pathway-affecting agents at the sheep sphincter of Oddi (SO) in vitro. Sheep SO rings were mounted in organ baths and tested for isometric tension and cGMP levels in response to 3,3-bis(aminoethyl)-1-hydroxy-2-oxo-1-triazene; 3-morpholinosydnonimine hydrochloride (SIN-1); and BAY 41-2272 in the presence and absence of 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one (ODQ). 3,3-bis(Aminoethyl)-1-hydroxy-2-oxo-1-triazene; SIN-1; and BAY 41-2272 relaxed SO rings in a concentration-dependent manner. These relaxations were significantly decreased in the presence of ODQ (P < 0.05). All agents significantly increased the cGMP levels compared with the control group (P < 0.05). The increased cGMP levels in the 3,3-bis(aminoethyl)-1-hydroxy-2-oxo-1-triazene- and BAY 41-2272-treated groups were significantly different from both control and carbachol groups (P < 0.05), whereas the increase in the SIN-1 group was significantly different from all groups (P < 0.05). The cGMP levels were significantly lower in the presence of ODQ compared with its absence (P < 0.05). The relaxation of SO rings by these agents may be via increasing the levels of cGMP. The additional increase produced by SIN-1 may be the combined effects of NO generation and activation of guanylyl cyclase.


Ambient temperature and added heat wave effects on hospitalizations in California from 1999 to 2009.
Investigators have examined how heat waves or incremental changes in temperature affect health outcomes, but few have examined both simultaneously. We utilized distributed lag nonlinear models (DLNM) to explore temperature associations and evaluate possible added heat wave effects on hospitalizations in 16 climate zones throughout California from May through October 1999-2009. We define heat waves as a period when daily mean temperatures were above the zone- and month-specific 95th percentile for at least two consecutive days. DLNMs were used to estimate climate zone-specific non-linear temperature and heat wave effects, which were then combined using random effects meta-analysis to produce an overall estimate for each. With higher temperatures, admissions for acute renal failure, appendicitis, dehydration, ischemic stroke, mental health, non-infectious enteritis, and primary diabetes were significantly increased, with added effects from heat waves observed for acute renal failure and dehydration. Higher temperatures also predicted statistically significant decreases in hypertension admissions, respiratory admissions, and respiratory diseases with secondary diagnoses of diabetes, though heat waves independently predicted an added increase in risk for both respiratory types. Our findings provide evidence that both heat wave and temperature exposures can exert effects independently.


Lobe-specific telomerase activity in the intact adult brown Norway rat prostate and its regional distribution within the prostatic ducts.
It is generally established that telomerase activity is present in most cancer cells, germ line cells, and established cell lines but typically is not present in normal somatic cells. Among the few exceptions, telomerase activity has been detected in hematopoietic stem cells and in physiologically renewable epithelial cell populations (e.g. skin, small intestine). The adult rat prostate gland is a tissue that has the ability to regenerate in response to androgen. We hypothesized, therefore, that telomerase activity should be present in the normal adult rat prostate. In this study, using a highly sensitive PCR-based telomerase assay [the telomerase repeat amplification protocol (TRAP) assay], we tested this hypothesis by measuring telomerase activity in the ventral, dorsal, lateral, and anterior lobes of the adult rat prostate. We show herein that telomerase activity indeed is present in whole tissue extracts of the ventral, dorsal, and anterior lobes, though at differing levels, but not the lateral lobe. However, lateral lobe prostatic fluid was found to contain one or more factors inhibitory for the TRAP reaction, and therefore, telomerase activity was detected after removal of this fluid. Telomerase activities were not uniform within the prostatic ducts, but rather telomerase positive cells are regionally distributed within the distal, intermediate, and proximal ducts of the microdissected segments of each of the lobes. We speculate from these results that androgen-stimulated regeneration of rat prostate following androgen ablation may depend upon the telomerase-positive regenerating pool of cells present within specific regions of the ductal network.