Early origins of allergy and asthma (ARIES): study protocol for a prospective prenatal birth cohort in Chile.
Growing evidence shows that atopic dermatitis (AD), food allergy (FA), allergic rhinitis, and asthma are largely determined during the first 1000 days (time elapsed from conception to the 2nd birthday). The ARIES birth cohort aims to determine prenatal and perinatal conditions, as well as genetic and epigenetic factors, that participate in the early setting of immune responses, and the role of these in the later determination of the risk of allergic diseases and asthma in the offspring. We have designed a birth cohort of 250 families with prenatal recruitment (~ 14 weeks). We will genotype relevant allergy/asthma-associated variants in trios and will perform immunophenotyping and evaluation of allergy biomarkers in cord blood. At 1 and 2 years of age we will assess if infants have developed allergic sensitization, AD, FA, as well as biomarkers of asthma including the asthma predictive index. We will also evaluate how maternal conditions modify immune programming through epigenetic modifications and will then depict newborn epigenetic cues of allergy/asthma risk. Next, we will assess composition/diversity of maternal gut, placenta, breastmilk and infant gut microbiome and their association with immunophenotype and biomarkers at birth, and clinical outcomes at age 1 and 2. Finally, we plan to assess how environmental exposures (perinatal outdoor and indoor pollution, allergens and endotoxin) affect the incidence of allergic sensitization, AD, FA, and risk of asthma. The in-depth study of the ARIES birth cohort shall provide crucial information to understand the rising incidence of allergies and asthma in developing countries, and hopefully provide cues on how to prevent and treat these diseases. clinicaltrials.gov NCT04186949, retrospectively registered on December 5, 2019.


Total synthesis and absolute stereochemical assignment of (-)-communesin F.
A concise asymmetric total synthesis of (-)-communesin F (∼6% overall yield in the longest linear sequence of 19 steps) is described. It features an unprecedented intramolecular oxidative coupling strategy for the elaboration of the requisite spiro-fused indoline moiety. Other notable elements are the use of TBS-protected (S)-phenylglycinol as a chiral auxiliary to induce the asymmetric formation of the spiro-fused indoline part, the mesylate-mediated formation of its G ring, and the introduction of the A ring at the final stage via intramolecular Staudinger reaction. This intramolecular Staudinger reaction proceeded smoothly at 80 °C, providing an additional example illustrating that twisted amides are more reactive than simple amides. Along with the total synthesis, we were able to assign the absolute configuration of natural communesin F as 6R,7R,8R,9S,11R.


[Effect of notoginseng extracts and their components on lipopolysaccharide and galactosamine mixture-induced impaired hepatic function in mice].
The protective effects of notoginseng against hepatic damage were investigated in mice. To prepare a model animal of hepatitis, a mixture of lipopolysaccharide and galactosamine (LPS/GAlN) was administered intraperitoneally, leading to the impairment of hepatic function. Extracts of notoginseng or its components (ginsenoside Rb1 and ginsenoside Rg1) were orally administered 2 h before LPS/GalN injection. Eight hours after LPS/GalN injection, blood and liver tissue samples were collected. The levels of serum aspartate amino transferase (AST), alanine aminotransferase (ALT), tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured using commercial assay kits. Histologic changes in the tissue samples were also observed after hematoxylin-eosin staining. LPS/GalN administration increased the serum levels of AST and ALT, and histologic changes were noted, indicating hepatic cell damage. Prior to the increase in ALT, the serum levels of TNF-α and IFN-γ were elevated after LPS/GalN injection. Pretreatment of the mice with either notoginseng extract or gensenoside Rb1 and Rg1 attenuated the LPS/GalN-induced hepatic damage markedly. The protective effects of the components against hepatic damage appeared to be less potent than those of the crude extract and prescription of notoginseng. Notoginseng may be clinically useful in patients with hepatitis.


Genetic Biomarkers in Association with Depressive Disorder in UAE Residents: A Pilot Case Study.
We sought to explore the expression of genes associated with depressive disorder in patients with depression compared to control patients. A large body of research in the area of genetics has shown familial aggregation for depressive disorders. The purpose of this study was to identify genetic risk factors in developing depression, particularly among the population residing in the UAE. We investigated five associated genes (PPARGC1A, CAMKMT, HSD11B1, SLC6A4, and MAOA) previously linked to depression and anxiety in other populations. The study was carried out in Al Ain, although participants were from different nationalities. Blood samples were collected over a period of seven months, and lab work was carried out over a period of two months from September 1, 2018 to May 30, 2019. We screened the prevalence of the PPARGC1A, CAMKMT, HSD11B1, SLC6A4, and MAOA in 29 patients with depressive disorder and 30 controls using the quantitative real-time polymerase chain reaction method. The expression of the PPARGC1A gene, studied for the first time in the UAE population. The independent t-test was used to check the significance of difference between the expression levels of target genes where the control was set at a reference level of 1.0. PPARGC1A gene is lower among the depressed group which showed mean difference: 0.4 and p-value: 0.02, indicating a strong association with depression. No significant difference was found in the genes' expression of CAMKMT with p-value 0.150, MAOA p-value 0.070, SLC6A4 p-value 0.750, and HSD11B1 p-value 0.100 in two groups in comparison with (p < 0.050). These results open several possibilities for further research to study the role of this gene as a protective factor against developing depression.


Contact allergy to the preservative Kathon CG.
Of 976 patients routinely patch tested with Kathon CG (Rohm & Haas), 300 ppm, 43 (4.4%) gave a positive reaction. Of 170 patients routinely tested with Kathon CG 250 ppm, 10 (5.9%) gave a positive reaction. Out of 34 patients tested with serial dilutions of Kathon CG, 17 (50%) reacted to 100 ppm, 8 to 30 ppm and 2 to 10 ppm. The concentration of 1000 ppm of Kathon CG was irritant in some cases, but 300 ppm was not irritant. Of the 976 patients tested with Kathon CG 300 ppm, 8 (0.8%) showed a "flare-up" reaction, indicating patch test sensitization. Of the 170 tested with Kathon CG 250 ppm, 2 (1.2%) were sensitized. When the patch-test-sensitized patients were retested with serial dilutions, they showed the same pattern as the other patients. 13 sensitized patients were use tested and 7 (54%) gave responses. In the literature, Kathon CG 100 ppm is recommended as the routine patch test concentration. However, 50% of the sensitive persons may then be overlooked. In our clinics, Kathon CG has become the second most common contact sensitizer, but the sensitivity cannot be traced in all patients with clinically relevant allergy without an unacceptable risk of patch test sensitization.


Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high'.
Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's high', which may function to encourage habitual aerobic exercise. Endocannabinoids (eCBs) are endogenous neurotransmitters that appear to play a major role in generating these rewards by activating cannabinoid receptors in brain reward regions during and after exercise. Other species also regularly engage in endurance exercise (cursorial mammals), and as humans share many morphological traits with these taxa, it is possible that exercise-induced eCB signaling motivates habitual high-intensity locomotor behaviors in cursorial mammals. If true, then neurobiological rewards may explain variation in habitual locomotor activity and performance across mammals. We measured circulating eCBs in humans, dogs (a cursorial mammal) and ferrets (a non-cursorial mammal) before and after treadmill exercise to test the hypothesis that neurobiological rewards are linked to high-intensity exercise in cursorial mammals. We show that humans and dogs share significantly increased exercise-induced eCB signaling following high-intensity endurance running. eCB signaling does not significantly increase following low-intensity walking in these taxa, and eCB signaling does not significantly increase in the non-cursorial ferrets following exercise at any intensity. This study provides the first evidence that inter-specific variation in neurotransmitter signaling may explain differences in locomotor behavior among mammals. Thus, a neurobiological reward for endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks, and why non-cursorial mammals avoid such locomotor behaviors.


Specific labeling of synaptic schwann cells reveals unique cellular and molecular features.
Perisynaptic Schwann cells (PSCs) are specialized, non-myelinating, synaptic glia of the neuromuscular junction (NMJ), that participate in synapse development, function, maintenance, and repair. The study of PSCs has relied on an anatomy-based approach, as the identities of cell-specific PSC molecular markers have remained elusive. This limited approach has precluded our ability to isolate and genetically manipulate PSCs in a cell specific manner. We have identified neuron-glia antigen 2 (NG2) as a unique molecular marker of S100β+ PSCs in skeletal muscle. NG2 is expressed in Schwann cells already associated with the NMJ, indicating that it is a marker of differentiated PSCs. Using a newly generated transgenic mouse in which PSCs are specifically labeled, we show that PSCs have a unique molecular signature that includes genes known to play critical roles in PSCs and synapses. These findings will serve as a springboard for revealing drivers of PSC differentiation and function.


A multi-criteria approach to evaluate the sustainability performances of wines: the Italian red wine case study.
The wine industry has faced two significant environmental problems in recent years: productivity is challenged by environmental trends such as global warming, and buyers are becoming more environmentally conscious. From an environmental standpoint, the food industry is one of the most impacting sectors and wine results as one of the most studied agri-food products in the scientific literature. In general, comprehensive studies that consider an application of set of indicators to evaluate the overall sustainability of wine sector are lacking in literature. This paper aims to carry out a sustainable assessment using different indicators for fifteen Italian red wines: Water Footprint (WF), Carbon Footprint (CF), Vineyard Indicator (VI), and Territory Indicator (TI). VI is an indicator of the vineyard's agronomic management's sustainability at plot level with values ranging from 0 (fully sustainable) to 1 (fully not sustainable), while TI covers the socio-economical aspects of sustainability. Considering system boundaries from cradle to grave, at 90% confidence interval, CF results ranged between 0.97 kg CO2 eq./functional unit and 1.97 kg CO2 eq./functional unit, with an average estimated at 1.47 kg CO2 eq./functional unit, while the WF of a 0.75 L bottle of wine from cradle to gate is 666.7 L/functional unit on average, out of which 86.75% is green, 1.92% is blue and 11.34% is grey water. Concerning the VI, at 90% confidence interval VI results were between 0.117 and 0.498 with an average estimated at 0.307. The results of the correlation analyses confirmed that each indicator is not statistically correlated with each other. Concerning the sub-indicators, a positive correlation has been found between the total CF and the sum of blue and grey WF. The application of a multi-criteria analysis for sustainability performances evaluation of the wine sector presented in this study can be used by wine companies' experts to better assess sustainability performances.


Validation and clinical application of a molecular method for identification of Histoplasma capsulatum in human specimens in Colombia, South America.
The conventional means of diagnosis of histoplasmosis presents difficulties because of the delay to the time that the diagnosis is made, indicating the need for the implementation of molecular assays. We evaluated 146 clinical samples from 135 patients suspected of having histoplasmosis using a previously reported nested PCR assay for the Histoplasma capsulatum-specific 100-kDa protein (the Hc100 PCR). In order to determine the specificity of this molecular test, we also used samples from healthy individuals (n = 20), patients suspected of having respiratory disease with negative fungal cultures (n = 29), and patients with other proven infections (n = 60). Additionally, a sizable collection of DNA from cultures of H. capsulatum and other medically relevant pathogens was studied. A panfungal PCR assay that amplified the internal transcribed spacer 2 region was also used to identify all fungal DNAs. All PCR-amplified products were sequenced. Of the 146 clinical samples, 67 (45.9%) were positive by culture and PCR, while 9 samples negative by culture were positive by PCR. All the sequences corresponding to the 76 amplified products presented > or =98% identity with H. capsulatum. The Hc100 PCR exhibited a sensitivity of 100% and specificities of 92.4% and 95.2% when the results were compared to those for the negative controls and samples from other proven clinical entities, respectively; the positive predictive value was 83% and the negative predictive value was 100%; the positive and negative likelihood rates were 25 and 0, respectively. These results suggest that the Hc100 nested PCR assay for the detection of H. capsulatum DNA is a useful test in areas where mycosis caused by this organism is endemic.


The Contribution of Endothelial Dysfunction in Systemic Injury Subsequent to SARS-Cov-2 Infection.
SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection is associated, alongside with lung infection and respiratory disease, to cardiovascular dysfunction that occurs at any stage of the disease. This includes ischemic heart disease, arrhythmias, and cardiomyopathies. The common pathophysiological link between SARS-CoV-2 infection and the cardiovascular events is represented by coagulation abnormalities and disruption of factors released by endothelial cells, which contribute in maintaining the blood vessels into an anti-thrombotic state. Thus, early alteration of the functionality of endothelial cells, which may be found soon after SARS-CoV-2 infection, seems to represent the major target of a SARS CoV-2 disease state and accounts for the systemic vascular dysfunction that leads to a detrimental effect in terms of hospitalization and death accompanying the disease. In particular, the molecular interaction of SARS-CoV-2 with the ACE2 receptor located in the endothelial cell surface, either at the pulmonary and systemic level, leads to early impairment of endothelial function, which, in turn, is followed by vascular inflammation and thrombosis of peripheral blood vessels. This highlights systemic hypoxia and further aggravates the vicious circle that compromises the development of the disease, leading to irreversible tissue damage and death of people with SARS CoV-2 infection. The review aims to assess some recent advances to define the crucial role of endothelial dysfunction in the pathogenesis of vascular complications accompanying SARS-CoV-2 infection. In particular, the molecular mechanisms associated with the interaction of SARS CoV-2 with the ACE2 receptor located on the endothelial cells are highlighted to support its role in compromising endothelial cell functionality. Finally, the consequences of endothelial dysfunction in enhancing pro-inflammatory and pro-thrombotic effects of SARS-CoV-2 infection are assessed in order to identify early therapeutic interventions able to reduce the impact of the disease in high-risk patients.


Rubredoxin from the green sulfur bacterium Chlorobium tepidum functions as an electron acceptor for pyruvate ferredoxin oxidoreductase.
Rubredoxin (Rd) from the moderately thermophilic green sulfur bacterium Chlorobium tepidum was found to function as an electron acceptor for pyruvate ferredoxin oxidoreductase (PFOR). This enzyme, which catalyzes the conversion of pyruvate to acetyl-CoA and CO(2), exhibited an absolute dependence upon the presence of Rd. However, Rd was incapable of participating in the pyruvate synthase or CO(2) fixation reaction of C. tepidum PFOR, for which two different reduced ferredoxins are employed as electron donors. These results suggest a specific functional role for Rd in pyruvate oxidation and provide the initial indication that the two important physiological reactions catalyzed by PFOR/pyruvate synthase are dependent on different electron carriers in the cell. The UV-visible spectrum of oxidized Rd, with a monomer molecular weight of 6500, gave a molar absorption coefficient at 492 nm of 6.89 mM(-1) cm(-1) with an A(492)/A(280) ratio of 0.343 and contained one iron atom/molecule. Further spectroscopic studies indicated that the CD spectrum of oxidized C. tepidum Rd exhibited a unique absorption maximum at 385 nm and a shoulder at 420 nm. The EPR spectrum of oxidized Rd also exhibited unusual anisotropic resonances at g = 9.675 and g = 4.322, which is composed of a narrow central feature with broader shoulders to high and low field. The midpoint reduction potential of C. tepidum Rd was determined to be -87 mV, which is the most electronegative value reported for Rd from any source.


Metagenomic analyses and genetic diversity of Tomato leaf curl Arusha virus affecting tomato plants in Kenya.
Tomato production is threatened worldwide by the occurrence of begomoviruses which are associated with tomato leaf curl diseases. There is little information on the molecular properties of tomato begomoviruses in Kenya, hence we investigated the population and genetic diversity of begomoviruses associated with tomato leaf curl in Kenya. Tomato leaf samples with virus-like symptoms were obtained from farmers' field across the country in 2018 and Illumina sequencing undertaken to determine the genetic diversity of associated begomoviruses. Additionally, the occurrence of selection pressure and recombinant isolates within the population were also evaluated. Twelve complete begomovirus genomes were obtained from our samples with an average coverage of 99.9%. The sequences showed 95.7-99.7% identity among each other and 95.9-98.9% similarities with a Tomato leaf curl virus Arusha virus (ToLCArV) isolate from Tanzania. Analysis of amino acid sequences showed the highest identities in the regions coding for the coat protein gene (98.5-100%) within the isolates, and 97.1-100% identity with the C4 gene of ToLCArV. Phylogenetic algorithms clustered all Kenyan isolates in the same clades with ToLCArV, thus confirming the isolates to be a variant of the virus. There was no evidence of recombination within our isolates. Estimation of selection pressure within the virus population revealed the occurrence of negative or purifying selection in five out of the six coding regions of the sequences. The begomovirus associated with tomato leaf curl diseases of tomato in Kenya is a variant of ToLCArV, possibly originating from Tanzania. There is low genetic diversity within the virus population and this information is useful in the development of appropriate management strategies for the disease in the country.


Effects of hormone replacement therapy on bone mineral density in postmenopausal women with primary hyperparathyroidism: four-year follow-up and comparison with healthy postmenopausal women.
Long-term treatment of patients with asymptomatic primary hyperparathyroidism remains controversial, but the presence of osteoporosis is regarded as an indication for parathyroidectomy. Hormone replacement therapy (HRT) is a possible alternative therapy in osteopenic postmenopausal women with the disorder, and results of short-term studies suggest a beneficial effect on bone mass comparable to that achieved by parathyroidectomy. Longer-term data are required to further assess the efficacy of this treatment in chronic stable primary hyperparathyroidism. We report the results of the extension from 2 to 4 years of a randomized, placebo-controlled trial of HRT in postmenopausal women with primary hyperparathyroidism. Of 23 postmenopausal women with primary hyperparathyroidism, 11 received active HRT with conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 5 mg/d, and 12 received placebo. Bone mineral density was measured throughout the skeleton at 6-month intervals using dual-energy x-ray absorptiometry in these women and in 50 normocalcemic age-matched control subjects. None of the 23 patients withdrew during the extension period. Changes in bone mineral density were more positive in those taking HRT than placebo, with the between-group differences at 4 years being 4.6% in the total body, 7.5% in the lumbar spine, 7.4% in the femoral neck, 8.2% in the femoral trochanter, 6.8% in the legs, and 7.0% in the forearm (P<.01). At skeletal sites composed predominantly of cortical bone, there was a progressive divergence of the 2 groups. Biochemical markers of bone turnover remained lower throughout the study in women taking HRT. When rates of bone loss were compared between the placebo group and healthy women of comparable age, bone loss tended to be more marked throughout the skeleton in women with hyperparathyroidism, but only in the total body and its legs subregion was this difference significant. Hormone replacement therapy is efficacious in the long-term management of osteopenia in postmenopausal women with primary hyperparathyroidism and thus represents an important new therapeutic option for asymptomatic patients who do not have other indications for surgery. Bone loss seems to be accelerated in untreated primary hyperparathyroidism.


Laser lithotripsy in the treatment of renal stones in children. A single-center experience.
To evaluate the effectiveness and safety of laser lithotripsy in the treatment of renal stones in children in a single center. We retrospectively analysed patients (n=36) who were treated with laser nephrolithotripsy (LL group) between 2011 and 2014. We compared those results with results of pneumatic nephrolithotripsy in patients (n=32) who were treated from 2007 to 2011 (PL group). The patients were evaluated in respect of gender, age, stone location, stone size, complications and stone-free rate. The duration of anesthesia, the need for retreatment, the mean hospitalization and the occurrence of minor complications (perirenal haematoma, urinoma, minimal ureteral perforation) were significantly lower in LL group (p < 0.05). We found statistically significant difference in stone-free rate between two groups - stone-free rate was significantly higher in LL group (LL: 94.4% vs. PL: 62.5%) (p < 0.05). Analyzing the stone-free rate after lithotripsy and the occurrence of complications, it is shown that the laser lithotripsy is more efficient than pneumatic lithotripsy and that endoscopic procedure proved safer, in terms of complications. Majority of the studies showed different successful rate after laser lithotripsy for stones located in the kidney. In particular cases, there is the need for ureteral orifice dilatation and ureteral stent insertion. Laser endoscopic lithotripsy is minimally invasive, effective and safe surgical procedure for the treatment of renal stones in children with minimal complication rate. The effectiveness is partially limited to stones in lower pole calices of the kidney. Laser lithotripsy, Urolithiasis, Ureterorenoscopy.


Amniocentesis before 14 completed weeks as an alternative to transabdominal chorionic villus sampling: a controlled trial with infant follow-up.
A (semi-) randomized controlled study with long-term follow-up was conducted to compare the effects of transabdominal chorionic villus sampling and early amniocentesis on fetal mortality and child morbidity. Women requesting early prenatal diagnosis for advanced maternal age were allocated to early amniocentesis or transabdominal chorionic villus sampling either by randomization or, if they declined randomization, by their own choice. Of the 212 women who entered the study, 117 were randomized, 70 chose early amniocentesis and 25 chose transabdominal chorionic villus sampling. Overall, 130 women underwent early amniocentesis and 74 underwent transabdominal chorionic villus sampling at a median gestation of 12 weeks. Two women were excluded because of fetal death before the procedure. Mosaic karyotypes were found in 5.4 per cent of the early amniocenteses and in none of the chorionic villus samples. All unintended fetal losses occurred after early amniocentesis with a frequency of 6.2 per cent (95 per cent confidence interval: 2.7 per cent to 11.8 per cent). Talipes equinovarus was only observed after early amniocentesis with a frequency of 3.1 per cent (95 per cent confidence interval: 0.8 per cent to 7.7 per cent). We conclude that chorionic villus sampling remains the method of choice if prenatal diagnosis is needed in the first trimester of pregnancy.


Demographic analysis of benign paroxysmal positional vertigo as a common public health problem.
Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular problem. However, demographic analysis is few. The aim of this study was to document the demographic data of patients with BPPV regarding distribution of gender, age, associated problems, most common form, symptom duration, severity of nystagmus and cure rate. A total of 263 patients with video-nystagmography confirmed BPPV were enrolled in this retrospective study (2009-2013). The data were collected in Anadolu Medical Center. Distribution of gender, age and affected side were reviewed. Associated problems were noted. Patients were analyzed according to the canal involvement, age, duration of symptoms, duration of nystagmus and recurrence. Mean values and standard deviations were calculated. One-way ANOVA test was used for the analysis of the data (Statistical Package for the Social Sciences 17.0 version, IBM, Chicago, III, USA). Statistical significance was set at P < 0.05. Women were affected more frequently than men (1:1.5). Comparative analysis of average age between the two gender groups was not statistically significant (P = 0.84). BPPV was common at middle age group. The incidence of affected side was not significant (P = 0.74). Posterior canal-BPPV (PC-BPPV) was the most leading one (129/263; 49%) followed by lateral canal (LC)-canalolithiasis (60/263; 22.8%), LC-cupulolithiasis (38/263; 14.5%) and superior canal-BPPV (9/263; 3.4%). 55.1% of patients were defined as idiopathic (145/263). Associated problems were migraine (31/263; 11.8%), trauma (19/263; 7.2%), inner ear disorders (18/263; 6.8%) and other systemic problems (50/263; 19.1%). 72.6% of patients had symptoms <2 months (191/263). 23,6% of patients had intensive nystagmus lasting more than a minute regardless of canal involvement (62/263). 33% of patients required two or more maneuvers for the relief of symptoms (87/263). Symptoms are prone to recur in those of traumatic origin, associated inner ear problems and systemic disorders. As the prognostic factors are illuminated, preventive measures will be more effective and more patients will be cured properly.


The Clinician as Leader: Why, How, and When.
Clinicians are inveterate leaders. We lead patients through the difficult maze of illness, families through the travails of ill loved ones, and physicians-in-training through the gauntlet of learning medicine. Yet, in the context of a range of leadership styles that effective leaders must be able to deploy situationally, physician leaders have traditionally defaulted to a "command and control" style that fosters the concept of physicians as "Viking warriors" or "heroic lone healers." The perverse effects of "command and control" are that this style conspires against collaboration and tends to be perpetuated as aspiring leaders emulate their predecessors. Because healthcare faces challenges of cost, access, and quality and is in the throes of change, the current landscape requires effective leadership. Though still relatively uncommon among healthcare organizations, frontrunner organizations are offering leadership development programs. The design of such programs requires clarity about requisite leadership competencies and about how and when to best to deliver such curricula. As one example, the American Thoracic Society has launched its Emerging Leaders Program (ELP), which is currently offering a leadership development curriculum to 18 selected emerging leaders. The ATS ELP curriculum focuses on awareness of self and system and incorporates highly participatory sessions on emotional intelligence, teambuilding, change management, situational leadership, appreciative inquiry, process and quality improvement, strategic planning, and organizational culture. Short-term deliverables are the development and presentation of business plans for innovations proposed by the group. Hoped for longer-term outcomes include an enhanced leadership pipeline for global respiratory health.


The Role of Extracellular Vesicles in the Pathogenesis and Treatment of Rheumatoid Arthritis and Osteoarthritis.
Cells can communicate with each other through extracellular vesicles (EVs), which are membrane-bound structures that transport proteins, lipids and nucleic acids. These structures have been found to mediate cellular differentiation and proliferation apoptosis, as well as inflammatory responses and senescence, among others. The cargo of these vesicles may include immunomodulatory molecules, which can then contribute to the pathogenesis of various diseases. By contrast, EVs secreted by mesenchymal stem cells (MSCs) have shown important immunosuppressive and regenerative properties. Moreover, EVs can be modified and used as drug carriers to precisely deliver therapeutic agents. In this review, we aim to summarize the current evidence on the roles of EVs in the progression and treatment of rheumatoid arthritis (RA) and osteoarthritis (OA), which are important and prevalent joint diseases with a significant global burden.


Reduction of acute and reactivated colitis in rats by an inhibitor of neutrophil activation.
Neutrophils have been implicated as major contributors to tissue injury in inflammatory bowel disease. In this study, we have assessed the effects of an inhibitor of neutrophil activation and adherence, NPC-18915 (4-¿2-[2-(2-benzofuranyl)phenyl]-(E)-ethenyl¿benzoic acid sodium salt), in models of both acute and reactivated colitis. Acute colitis was induced by intracolonic administration of a hapten. In other rats, colitis was reactivated 6 wk after a bout of acute colitis by subcutaneous administration of the hapten. NPC-18915 given during the first 4 days after induction of acute colitis significantly reduced tissue injury and the incidence of diarrhea and adhesions. When treatment of NPC-18915 was initiated after colitis was firmly established (48 h posthapten), it did not produce a significant effect. NPC-18915 was effective at significantly reducing colonic injury and granulocyte infiltration in the reactivated colitis model, and a similar effect could be observed in rats treated with antineutrophil serum. These results demonstrate that an inhibitor of neutrophil activation is effective in both acute and reactivated colitis, although in the former case, effectiveness is only seen when the drug is given before full establishment of colitis. These results also suggest that neutrophils, are a critical effector cell of hapten-induced colitis in the rat, particularly in the case of reactivated colitis.


The normal optic nerve head on Heidelberg Retina Tomograph II.
To study the characteristics of the optic nerve head using a scanning laser ophthalmoscope, the Heidelberg Retina Tomograph II (HRT II), in a normal population and to determine the specificity of HRT II diagnostic indices in the study population. The optic nerve heads from 275 consecutive, randomly selected normal subjects were imaged on HRT II. Stereometric parameters were studied with respect to baseline variables such as age, gender, refractive error and disc size. The stereometric parameters and the results of Moorfields regression analysis (MRA) and discriminant function analysis were recorded. The average disc size in the population under study was 2.34 +/- 0.47 mm2. Age and gender had no significant effect on stereometric parameters. Myopic discs were larger than hypermetropic discs. MRA had a specificity varying between 85.5% and 98.2% depending upon the criteria used to define an abnormal disc. The specificity of MRA decreased with increasing disc size. The RB (R Bathija) and FSM (F S Mikelberg) discriminant functions had specificities of 96.4% and 87.3% respectively. Estimation of stereometric parameters of a normal disc can be used to indicate an abnormal one. Moorfields regression analysis and discriminant functions have a high specificity in our normal population; however caution must be exercised in interpreting the results for a disc area larger than 3 mm2.


A malignant cause of hypoglycaemia: a metastatic insulin-secreting pancreatic neuroendocrine carcinoma.
Most cases of insulinomas are benign. We report a case of a malignant form of insulinoma. A 46-year-old man presented with behavioural changes associated with hypoglycaemia. Diagnostic work up revealed high serum insulin, high C-peptide and low glucose levels, compatible with endogenous hyperinsulinaemic hypoglycaemia. CT imaging of the abdomen revealed a pancreatic head mass and multiple liver masses. Biopsy of the pancreatic mass revealed a grade three pancreatic neuroendocrine carcinoma. Histological analysis of a liver mass showed that it was identical to the pancreatic mass, confirming its metastatic nature. The patient underwent distal pancreatectomy with en bloc splenectomy. There was persistence of hypoglycaemic symptoms after removal of the pancreatic mass, suggesting that the liver metastases were also functioning. Symptoms were controlled by diazoxide and octreotide long-acting release. The patient is already 1 year postsurgery with no recurrence of severe hypoglycaemia, and he has good functional capacity and has returned to his office job.


Cyclic AMP-dependent protein kinase decreases gamma-aminobutyric acidA receptor-mediated 36Cl- uptake by brain microsacs.
The effect of cyclic AMP (cAMP)-dependent protein phosphorylation on gamma-aminobutyric acidA (GABAA) receptor function was examined using isolated brain membrane vesicles (microsacs). Muscimol-stimulated 36Cl- uptake was studied in mouse brain microsacs permeabilized to introduce the catalytic subunit of cAMP-dependent protein kinase (PKA). At both submaximal and maximally effective concentrations of muscimol, PKA inhibited muscimol-stimulated 36Cl- uptake by approximately 25%. In parallel experiments, PKA and [gamma-32P]ATP were introduced into the microsacs, and we attempted to immunoprecipitate the entire GABAA receptor complex, under nondenaturing conditions, using an anti-alpha 1-subunit antibody. Data from such experiments show that PKA increases the phosphorylation of several microsac proteins, including a 66-kDa polypeptide specifically immunoprecipitated with the GABAA receptor anti-alpha 1 subunit antibody. Phosphopeptide mapping of the 66-kDa polypeptide demonstrated a 14-kDa fragment similar to that obtained with the purified, PKA-phosphorylated GABAA receptor. These results provide evidence that the catalytic subunit of PKA inhibits the function of brain GABAA receptors and demonstrate that this functional change is concomitant with an increase in protein phosphorylation.


Bioactivation of dimethylnitrosamine in intrasanguinous host-mediated assay and its association with in vitro mutagenesis assays.
These studies have revealed the usefulness of in vivo intrasanguine host-mediated assay (HMA) to detect point mutations. Mutations were found to occur at a significant rate in Salmonella typhimurium G-46 employed as indicator organisms recovered from liver, lung, kidney and spleen of DMN-treated animals compared to negative control animals. These differences were true for both male and female animals. The number of Salmonella typhimurium G-46 recovered from the testes was not large enough to make a valid judgment about mutations occurring in testes. The results from in vitro studies do not match with the in vivo host-mediated assay results for mutants occurring in spleen from the male and the female mice. The results also do not correlate for in vitro and in vivo studies involving female kidneys. These results suggest there may be no one-to-one correlation between the organ bioactivation in vitro and in vivo, and predictions of in vivo target organ cannot always be made from in vitro studies with isolated microsomal enzymes.


[Relation between chronic hepatitis and cirrhosis in the type of differentiation of symptoms and signs and endocrine hormone].
In order to investigate the objective index of the type of differentiation of symptoms and signs between chronic hepatitis and cirrhosis, the levels of serum Tes, ALD, HCT, INS, GR, gastrin, T3, T4, TSH were tested in the chronic hepatitis and cirrhosis of 27 cases of sthenia-syndrome and 61 cases of asthenia-syndrome. Meanwhile, 30 cases of healthy people were taken as the control. The results indicated that the levels of serum Tes, T3, T4, gastrin in the group of asthenia-syndrome (P less than 0.01, P less than 0.05). The levels of serum T4 and gastrin were increased in the group of sthenia-syndrome than in the groups of asthenia-syndrome and control (P less than 0.01). The levels of serum ALT, HCT, INS, and GR were significantly different between the group of asthenia-syndrome and that of sthenia-syndrome. This suggests that clinic symptoms were concerned with the level of serum endocrine on chronic hepatitis and cirrhosis, such as the function of genital, thyroid, adrenal gland and pancrease. The observation of the levels of serum Tes, T3, T4, ALT, INS, GR and gastrin may be an objective index to differentiate the chronic hepatitis and cirrhosis.


The biochemical status of metabolites of alkane-utilizing Pseudomonas organisms.
Examination of the metabolic products formed by five alkane-utilizing Pseudomonas organisms during growth on various alkanes and on glucose as sole carbon sources indicates that many metabolites may be of predominantly synthetic origin rather than intermediary metabolites of alkane breakdown. This conclusion is supported by an examination of the effect of fluoroacetate on such fermentations.


A novel prognostic prediction model for recurrence in patients with stage II colon cancer after curative resection.
The present study aimed to clarify the risk factors for recurrence of stage II colon cancer in patients and to determine possible treatment options for postoperative adjuvant chemotherapy. A prediction model for recurrence in patients with stage II colon cancer after curative surgical resection was developed. The present study retrospectively investigated 436 patients who underwent curative resection for stage II colon cancer at Osaka International Cancer Institute and Yao Municipal Hospital between 2004 and 2012. Several clinicopathological factors were examined and the Cox regression model was used to develop a prediction model for recurrence. The prediction model was validated in an independent group of 213 patients who underwent surgery at Osaka University Hospital between 2001 and 2012. Univariate analysis revealed that preoperative serum carcinoembryonic antigen level, preoperative obstruction, tumor invasion, lymphatic invasion and venous invasion were significantly correlated with disease-free survival. Using these variables, a classification and regression tree was constructed as a prediction model. The prediction models were validated by external datasets in an independent patient group. The concordance indices for DFS after current surgical resection were 0.675 in the learning set and 0.552 in the validation set. To conclude, a novel, reliable and personalized prognostic model was developed to predict recurrence in patients with stage II colon cancer, which may help clinicians to determine and perform adjuvant chemotherapy.


The relationships between message passing, pairwise, Kermack-McKendrick and stochastic SIR epidemic models.
We consider a very general stochastic model for an SIR epidemic on a network which allows an individual's infectious period, and the time it takes to contact each of its neighbours after becoming infected, to be correlated. We write down the message passing system of equations for this model and prove, for the first time, that it has a unique feasible solution. We also generalise an earlier result by proving that this solution provides a rigorous upper bound for the expected epidemic size (cumulative number of infection events) at any fixed time [Formula: see text]. We specialise these results to a homogeneous special case where the graph (network) is symmetric. The message passing system here reduces to just four equations. We prove that cycles in the network inhibit the spread of infection, and derive important epidemiological results concerning the final epidemic size and threshold behaviour for a major outbreak. For Poisson contact processes, this message passing system is equivalent to a non-Markovian pair approximation model, which we show has well-known pairwise models as special cases. We show further that a sequence of message passing systems, starting with the homogeneous one just described, converges to the deterministic Kermack-McKendrick equations for this stochastic model. For Poisson contact and recovery, we show that this convergence is monotone, from which it follows that the message passing system (and hence also the pairwise model) here provides a better approximation to the expected epidemic size at time [Formula: see text] than the Kermack-McKendrick model.


Factors associated with nicotine dependence during methadone maintenance treatment: findings from a multisite survey in Vietnam.
Smoking is associated with adverse health outcomes among drug users, including those in treatment. To date, however, there has been little evidence about smoking patterns among people receiving opioid-dependence treatment in developing countries. We examined self-reported nicotine dependence and associated factors in a large sample of opioid-dependent patients receiving methadone maintenance treatment (MMT) in northern Vietnam. Five clinics in Hanoi (urban area) and Nam Dinh (rural area). Patients receiving MMT in the settings during the study period. We collected data about smoking patterns, levels of nicotine dependence and other covariates such as socioeconomic status, health status, alcohol use and drug use. The Fagerström test was used to measure nicotine dependence (FTND). Logistic regression and Tobit regression were employed to examine relationships between the smoking rate, nicotine dependence and potentially associated variables. Among 1016 drug users undergoing MMT (98.7% male), 87.2% were current smokers. The mean FTND score was 4.5 (SD 2.4). Longer duration of MMT (OR 0.98, 95% CI 0.96 to 0.99) and being HIV-positive (OR 0.46, 95% CI 0.24 to 0.88) were associated with lower likelihood of smoking. Being employed, older age at first drug injection and having long duration of MMT were inversely related with FTND scores. Higher age and continuing drug and alcohol use were significantly associated with higher FTND scores. Smoking prevalence is high among methadone maintenance drug users. Enhanced smoking cessation support should be integrated into MMT programmes in order to reduce risk factors for cigarette smoking and improve the health and well-being of people recovering from opiate dependence.


[Interest of tiapride in digestive endoscopy (author's transl)].
Used in monotherapy in 20 patients as a premedication for a high digestive endoscopy, tiapride gave results quite comparable to those of substances used till now (anticholinergic, anxiolytic) with tolerance on the whole excellent.


No heritability of temporomandibular joint signs and symptoms.
The causes of temporomandibular joint (TMJ)-related signs and symptoms are largely unknown. We tested the hypotheses that these signs and symptoms, as well as oral parafunctional habits, are substantially heritable. Questionnaire and clinical data were collected from 494 twins, including pairs of reared-apart and reared-together monozygotic (MZ) and dizygotic (DZ) twins. A history of joint-area pain, joint noises, and clenching and grinding habits was scored as present or absent. Twenty-nine percent of the population experienced at least one sign or symptom. Nearly one-quarter of subjects clenched or ground their teeth, and 8.7% reported a history of joint-area pain. Pain was associated with clenching, grinding, and joint noises. MZ twins were no more similar than DZ twins for any outcome, suggesting that genetic factors do not influence these traits in the population. Reared-together MZ twins were no more similar than reared-apart MZ twins, suggesting a negligible effect of the family environment on these outcomes. Environmental factors unique to each twin appeared to be the major determinants of variation in this population.


A telepresence mobile robot controlled with a noninvasive brain-computer interface.
This paper reports an electroencephalogram-based brain-actuated telepresence system to provide a user with presence in remote environments through a mobile robot, with access to the Internet. This system relies on a P300-based brain-computer interface (BCI) and a mobile robot with autonomous navigation and camera orientation capabilities. The shared-control strategy is built by the BCI decoding of task-related orders (selection of visible target destinations or exploration areas), which can be autonomously executed by the robot. The system was evaluated using five healthy participants in two consecutive steps: 1) screening and training of participants and 2) preestablished navigation and visual exploration telepresence tasks. On the basis of the results, the following evaluation studies are reported: 1) technical evaluation of the device and its main functionalities and 2) the users' behavior study. The overall result was that all participants were able to complete the designed tasks, reporting no failures, which shows the robustness of the system and its feasibility to solve tasks in real settings where joint navigation and visual exploration were needed. Furthermore, the participants showed great adaptation to the telepresence system.


Mammalian tolerance to humans is predicted by body mass: evidence from long-term archives.
Humans are implicated as a major driver of species extinctions from the Late Pleistocene to the present. However, our predictive understanding of human-caused extinction remains poor due to the restricted temporal and spatial scales at which this process is typically assessed, and the risks of bias due to "extinction filters" resulting from a poor understanding of past species declines. We develop a novel continent-wide data set containing country-level last-occurrence records for 31 European terrestrial mammals across the Holocene (c.11,500 yr BP to present), an epoch of relative climatic stability that captures major transitions in human demography. We analyze regional extirpations against a high-resolution database of human population density (HPD) estimates to identify species-specific tolerances to changing HPD through the Holocene. Mammalian thresholds to HPD scale strongly with body mass, with larger-bodied mammals experiencing regional population losses at lower HPDs than smaller-bodied mammals. Our analysis enables us to identify levels of tolerance to HPD for different species, and therefore has wide applicability for determining biotic vulnerability to human impacts. This ecological pattern is confirmed across wide spatiotemporal scales, providing insights into the dynamics of prehistoric extinctions and the modern biodiversity crisis, and emphasizing the role of long-term archives in understanding human-caused biodiversity loss.


Treatment of periodontitis reduces systemic inflammation in type 2 diabetes.
To assess the impact of periodontal treatment on systemic inflammation in type 2 diabetes. Adults with type 2 diabetes (n = 83) and without diabetes (controls, n = 75) were recruited, and participants with periodontitis received periodontal treatment and 12 months' follow-up. Biomarkers for periodontal inflammation (gingival crevicular fluid interleukin-6, tumour necrosis factor-α, interleukin-1β, interferon-γ, matrix metalloproteinase-8, matrix metalloproteinase-9, adiponectin) and serum markers of inflammation and diabetes control (glycated haemoglobin, high sensitivity C-reactive protein, interleukin-6, tumour necrosis factor-α, interleukin-1β, interferon-γ, leptin, adiponectin) were measured. Structural equation modelling was used to evaluate periodontal treatment effects on oral and systemic inflammation. Periodontal treatment resulted in significant improvements in clinical status and reductions in gingival crevicular fluid biomarkers from baseline to month 12. Structural equation modelling identified that, at baseline, individuals with diabetes and periodontitis had significantly higher systemic inflammation than non-diabetic controls with periodontitis (Δ = 0.20, p = .002), with no significant differences between groups for oral inflammation. There was a greater reduction in systemic inflammation following periodontal treatment in individuals with diabetes and periodontitis compared to those with periodontitis but not diabetes (Δ = -0.25, p = .01). Diabetes and periodontitis together appear to increase systemic inflammation, with evidence of reductions following periodontal treatment.


An outbreak of herpes gladiatorum at a high-school wrestling camp.
Herpes simplex virus type 1 (HSV-1) has been identified as a cause of cutaneous or ocular infection among athletes involved in contact sports; in this context it is known as herpes gladiatorum. In July 1989, we investigated an outbreak among 175 high-school wrestlers attending a four-week intensive-training camp. Cases of infection were identified by review of medical records, interview and examination of the wrestlers, and culture of skin lesions. Oropharyngeal swabs were obtained for HSV-1 culture, and serum samples for HSV-1 serologic studies. HSV-1 isolates were compared by restriction-endonuclease analysis. HSV-1 infection was diagnosed in 60 wrestlers (34 percent). The lesions were on the head in 73 percent of the wrestlers, the extremities in 42 percent, and the trunk in 28 percent. HSV-1 was isolated from 21 wrestlers (35 percent), and in 39 (65 percent) infection was identified by clinical criteria. Five had conjunctivitis or blepharitis; none had keratitis. Constitutional symptoms were common, including fever (25 percent), chills (27 percent), sore throat (40 percent), and headache (22 percent). The attack rate varied significantly among the three practice groups, ranging from 25 percent for practice group 1 (lightweights) to 67 percent for group 3 (heavyweights). Restriction-endonuclease analysis identified four strains of HSV-1 among the 21 isolates. All 10 isolates from practice group 3 were identical (strain A), and 5 of 7 isolates from practice group 2 (middleweights) were identical (strain B), which suggested concurrent transmission of different strains within different groups. HSV-1 was not isolated from any oropharyngeal swabs. Herpes gladiatorum may cause substantial morbidity among wrestlers, and it is primarily transmitted by direct skin-to-skin contact. Prompt identification and exclusion of wrestlers with skin lesions may reduce transmission.


Surgical management of lumbar degenerative spinal stenosis with spondylolisthesis via posterior reduction with minimal laminectomy.
Degenerative lumbar spondylolisthesis with spinal stenosis is commonly treated with laminectomy. Recent reports have consistently supported the incremental clinical benefit of associated in situ arthrodesis with or without instrumentation. Resection of the lamina may result in intraoperative dural tear or epidural scar formation. Fifty-six consecutive patients with back pain, neuroclaudication, or both, in addition to degenerative spondylolisthesis with spinal stenosis, underwent a surgical procedure that incorporated fusion after reduction of the spondylolisthesis deformity with preservation of the lamina and the balance of the posterior elements. Clinical records were reviewed and patients interviewed at a mean of 33 months after surgery. Oswestry Disability Index scores were obtained independently at baseline and at a late review. Late imaging was available a mean of 28 months after operation. Clinical and imaging analyses and Oswestry scoring confirmed results comparable to the published outcomes of in situ fusion after formal laminectomy. Resection of the lamina may not be necessary in the treatment of degenerative lumbar spinal stenosis with spondylolisthesis.


Vandetanib for the treatment of medullary thyroid cancer.
Vandetanib (ZD6474, Caprelsa, AstraZeneca), an oral small-molecule tyrosine kinase inhibitor (TKI) that targets the rearranged during transfection receptor (RET), VEGF receptor (VEGFR2-3), and EGF receptor (EGFR), is the first systemic therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of symptomatic or progressive advanced medullary thyroid cancer (MTC). In a randomized phase III trial of patients with unresectable, locally advanced, or metastatic MTC, vandetanib improved progression-free survival compared with placebo [HR, 0.46; 95% confidence interval (CI), 0.31-0.69; P < 0.001]. However, the benefits in delaying disease progression need to be balanced against the associated and potentially serious toxicities, including diarrhea, hypertension, and QTc prolongation. Here, we review the clinical development of vandetanib leading to its integration into the current treatment paradigm and highlight the ongoing and future challenges in TKI use in MTC.


Diagnosis and treatment of bowel perforation following pediatric orthotopic liver transplantation.
Bowel perforation is a frequent cause of mortality after pediatric orthotopic liver transplantation. The aims of this study were to identify the cause of this phenomenon and to examine current methods of treatment. This is a retrospective analysis of 246 pediatric patients who underwent orthotopic liver transplantation at a large, urban, tertiary care medical center between 1984 and 1992. We examined the frequency of bowel perforations after transplantation and identified predisposing factors and signs. In this series, bowel perforations occurred in 24 of 246 recipients and were common in those who had previous liver-related surgery (22 patients). Clinical signs included fever (13 patients), leukocytosis (14 patients), and free air on abdominal roentgenograms (11 patients). Perforation occurred at the Roux-en-Y limb in 15 of 24 recipients as well as in the right transverse colon (five patients), terminal ileum (three patients), and duodenum (one patient). The repair was resection and/or primary closure (18 patients), or diversion (six patients). Recurrent perforations (nine patients) could not be attributed to the method of the repair. Perforation-related sepsis was the primary cause of death in 12 patients (50%) and was more common among patients who developed recurrent perforation (seven [78%] of nine patients). The occurrence and location of bowel perforation after pediatric orthotopic liver transplantation suggests that the cause is related to bowel injury during difficult hepatectomy. Mortality may be reduced by early second-look operations in high-risk patients.


Long-term treatment outcome after only popliteal lymph node dissection for nodal metastasis in malignant melanoma of the heel: the only "interval node" dissection can be an adequate surgical treatment.
We present a patient with malignant melanoma on his heel. Wide local excision was performed, along with sentinel lymph node biopsy of the inguinal and popliteal lesions. The primary site was clear of tumor at all margins; the inguinal nodes were negative, but the popliteal node was positive for metastatic melanoma. Only radical popliteal lymph node dissection was performed. The patient went on to receive adjuvant chemoimmunotherapy. There was no recurrence or complication until the long-term followup. Popliteal drainage from below the knee is uncommon, and the rate of popliteal-positive and inguinal-negative cases is estimated to be less than 1% of all melanomas. There is no established evidence about how to treat lymph nodes in these cases. Because we considered popliteal nodes as a regional, not interval, lymph node basin, only popliteal lymph node dissection was performed, and good postoperative course was achieved. The first site of drainage is the sentinel node, and the popliteal node can be a sentinel node. The inguinal node is not a sentinel node in all lower extremity melanomas. This case illustrates the importance of individual detailed investigation of lymphatic drainage patterns from foot to inguinal and popliteal nodes.


Increased healthcare utilisation among atopic children in a general practice database: a nested index-control study.
Atopic eczema, asthma, and allergic rhinitis (AR) create a serious burden on general practice resources. To investigate the use of general practice resources (that is, consultation visits, telephone contacts, and home visits) in children with physician-diagnosed atopic disorders (ADs). In a nested index-control study design, all children (here defined as individuals aged 2-18 years) listed in a representative general practice database were selected in 2014. Children diagnosed with ADs were matched on age and sex with non-atopic controls within the same practice. For all the different groups, the number and frequency of children contacting the GP were calculated. Of the children with atopic eczema (n = 15 202), 80% consulted the GP in 2014 (controls = 67%). Of the children with asthma (n = 7754), 80% consulted the GP (controls = 65%), and for children with AR (n = 6710), this was 82% (controls = 66%). Of the children with all three ADs, 91% consulted the GP (controls = 68%). On average, a child with atopic eczema contacted the GP 2.8 times/year (controls = 1.9); for children with asthma, the contact frequency was 3.0 (controls = 1.9); and for AR, 3.2 (controls = 1.9). For children with all three ADs, the contact frequency was 4.3 (controls = 2.0). Consultations related to the ADs investigated only explain a smaller part of the increased healthcare utilisation in atopic children. Atopic children use more general practice resources compared to non-atopic children, yet frequently for morbidity or other health-related questions not related to one of the ADs.


A multiphasic screening survey in San Jose.
In the interest of economy and of better service to the persons examined, three screening tests of a kind usually made separately were combined and applied in a single examination of 945 employees in four industrial establishments. Miniature x-ray films of the chest were taken, blood specimens drawn and urine samples obtained so that studies and tests might be made to determine the presence of pulmonary or cardiac disease, syphilis, kidney disease, or diabetes. The history of each person examined was taken. Through this multiphasic survey, 13 cases of significant disease previously unknown to the patient were discovered. Sixteen cases of significant disease, previously known, were also disclosed; and in several such cases treatment was begun or resumed. The results in case finding were considerably greater than those of the customary screening for a single disease.


Dimethyl Ferrocene-Induced Ambient-Processed High-Quality Films toward Efficient Perovskite Solar Cells for Industrial Application.
Metal halide perovskite solar cells (PSCs) have recently made significant progress with power conversion efficiencies (PCEs) boosted from 3.8% to a certified one over 26.1%, partially benefiting from the high-quality perovskite film enabled by the effective one-step spin-coating route. However, an extra antisolvent step with poor controllability and producibility is often involved in such a process, and some intrinsic defects are generated inevitably, especially in ambient atmospheric conditions, thus fundamentally limiting the commercialization of PSCs. Here, we introduce 1,1'dimethyl ferrocene into methylammonium lead halide precursor, which could not only recover the defects within perovskite film but also simplify the process without the extra antisolvent step. Accordingly, a dense and uniform perovskite film with large grains has been obtained under ambient conditions, which has much lower defect density, better stability against moisture penetration, and enhanced thermal tolerance than the control one, delivering a champion PCE of 16.92%. Current work sheds light on the simplified air-processed strategy for high-quality perovskite films, which might pave the way for exploring efficient and stable PSCs toward industrial applications.


Cyclic GMP-dependent protein kinase stimulates the plasmalemmal Ca2+ pump of smooth muscle via phosphorylation of phosphatidylinositol.
The effect of phosphorylation by cyclic GMP-dependent protein kinase (G-kinase) on the activity of the plasmalemmal Ca2+-transport ATPase was studied on isolated plasma membranes and on the ATPase purified from pig erythrocytes and from the smooth muscle of pig stomach and pig aorta. Incubation with G-kinase resulted, in both smooth-muscle preparations, but not in the erythrocyte ATPase, in a higher Ca2+ affinity and in an increase in the maximal rate of Ca2+ uptake. Cyclic AMP-dependent protein kinase (A-kinase) did not exert such an effect. The stimulation of the (Ca2+ + Mg2+)-dependent ATPase activity of the purified Ca2+ pump reconstituted in liposomes depended on the phospholipid used for reconstitution. The stimulation of the (Ca2+ + Mg2+)-ATPase activity by G-kinase was only observed in the presence of phosphatidylinositol (PI). G-kinase, but not A-kinase, stimulated the phosphorylation of PI to phosphatidylinositol phosphate (PIP) in a preparation of (Ca2+ + Mg2+)-ATPase obtained by calmodulin affinity chromatography from smooth muscle, but not in a similar preparation from erythrocytes. Adenosine inhibited both the phosphorylation of PI and the stimulation of the (Ca2+ + Mg2+)-ATPase by G-kinase. In the absence of G-kinase the (Ca2+ + Mg2+)-ATPase was stimulated by the addition of PIP, but not by PI. In contrast with previous results of Furukawa & Nakamura [(1987) J. Biochem (Tokyo) 101, 287-290], no convincing evidence for a phosphorylation of the (Ca2+ + Mg2+)-ATPase was found. Evidence is presented showing that the apparent phosphorylation occurs in a contaminant protein, possibly myosin light-chain kinase. It is proposed that G-kinase stimulates the plasmalemmal Ca2+ pump of smooth-muscle cells indirectly via the phosphorylation of an associated PI kinase.


Association of macrophage inhibitory factor -173 gene polymorphism with biological behavior of prostate cancer.
Chronic inflammation is an important factor in the etiology of prostate cancer. Macrophage migration inhibitory factor (MIF) plays an important regulatory role in inflammatory responses. The aim of this study was to investigate the potential association between MIF-173 G/C polymorphism, and both biological behavior and incidence of prostate cancer. Analysis of polymorphic variants for MIF was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 128 subjects with prostate cancer and 135 controls. The frequency of MIF-173 *C allele was significantly (OR = 2.18, 95% CI = 1.32-3.61) higher in patients with prostate cancer (19.5%) than in healthy individuals (10%). Prostate cancer patients with Gleason scores ? 7 had higher frequency of MIF-173 *C allele than Gleason scores < 7 (86.1% vs. 27.1%, P = 0.003, OR = 3.18, 95%CI = 1.46-6.95). The frequency of MIF-173 *C allele was significantly different in patients with T1, T2 and ?T3 clinical stages of prostate cancer (15.2% vs. 42.6% and 47.8%, P = 0.003). Our data suggest that MIF-173 polymorphisms may be associated with a higher incidence of prostate cancer compared to controls. We believe that MIF-173 GC+CC genotype can be used as a predictive factor for aggressive behavior of prostate cancer including pathological stage and Gleason scores as well as metastatic potential.


Liver transplantation for drug-induced acute liver failure.
To summarize the different clinical features of drug-induced acute liver failure, the diagnostic work-up, conservative management and the prognostic scores currently used to list patients for liver transplantation. The current review is based on an analysis of the current literature and the caseload experience of the Authors on this topic. Drug-induced liver injury is the leading cause of acute liver failure in the adult population in Western countries, with a transplant-free survival rate of less than 50%. Main subtypes include paracetamol and idiosyncratic drug-induced injury, which differ in epidemiology, clinical course, prognosis and conservative management. In cases of a high likelihood of death, urgent hepatic transplantation is indicated, but the decision whether and when to put a patient with drug-induced acute liver failure on the list for urgent liver transplant is extremely difficult and requires constant interdisciplinary exchange and continuous updating of the clinical picture. Intensive management should be done in a clinical tertiary referral center which has a specialized team of hepatologists and a liver transplant center.


Communication in Daily Life of Children With Developmental Language Disorder: Parents' and Teachers' Perspectives.
This study explores limitations in communication in daily life of children with developmental language disorder (DLD) from their parents' perspective as well as communicative abilities and social functioning in the classroom from their teacher's perspective. Furthermore, differences between children with mixed receptive-expressive disorder and children with expressive-only disorder in communication in daily life and social functioning are studied. Data were collected through questionnaires completed by parents and teachers of children (5-6 years old) who attended schools for special education for DLD. Language test scores were retrieved from school records. Parents of 60 children answered open-ended questions about situations and circumstances in which their child was most troubled by language difficulties. Teachers of 83 children rated communicative abilities, social competence, and student-teacher relationship. Parents reported communication with strangers as most troublesome and mentioned the influence of the mental state of their child. Parents considered limitations in expressing oneself and being understood and not being intelligible as core difficulties. Teachers rated the children's communicative abilities in the school context as inadequate, but their scores concerning social competence and the quality of teacher-child relationships fell within the normal range. Children with receptive-expressive disorder experienced limitations in communication in almost all situations, whereas those with expressive disorder faced limitations in specific situations. Children with receptive-expressive disorder were also significantly more limited in their communicative abilities and social competence at school than children with expressive disorder. No differences were found between the two groups in the quality of the teacher-child relationship. The results confirm that children with DLD face significant challenges in a variety of communicative situations. We found indications that children with receptive-expressive disorder experience more severe limitations than children with expressive disorder. The involvement of parents and teachers in evaluating a child's communicative ability provides valuable and clinically relevant information.


On the history of men and genocide.
A historical and psychological study of genocide is presented in which special emphasis is given to modern manifestations of this phenomenon. The policy of eradication of the Jews by the Hitler regime is considered as an example of genocide in the twentieth century. The psychopathology of genocide and the complex relationships among aggressors, victims and witnesses are elaborated. Inferences are drawn from past and present patterns of genocide that may provide some leads to the future. It is now possible to envisage an all-consuming genocide unless nations can learn to live together, not necessarily in unity but in diversity.


Use of podcast technology to facilitate education, communication and dissemination in palliative care: the development of the AmiPal podcast.
Podcasts have the potential to facilitate communication about palliative care with researchers, policymakers and the public. Some podcasts about palliative care are available; however, this is not reflected in the academic literature. Further study is needed to evaluate the utility of podcasts to facilitate knowledge-transfer about subjects related to palliative care. The aims of this paper are to (1) describe the development of a palliative care podcast according to international recommendations for podcast quality and (2) conduct an analysis of podcast listenership over a 14-month period. The podcast was designed according to internationally agreed quality indicators for medical education podcasts. The podcast was published on SoundCloud and was promoted via social media. Data were analysed for frequency of plays and geographical location between January 2015 and February 2016. 20 podcasts were developed which were listened to 3036 times (an average of 217 monthly plays). The Rich Site Summary feed was the most popular way to access the podcast (n=1937; 64%). The mean duration of each podcast was 10 min (range 3-21 min). The podcast was listened to in 68 different countries and was most popular in English-speaking areas, of which the USA (n=1372, 45.2%), UK (n=661, 21.8%) and Canada (n=221, 7.3%) were most common. A palliative care podcast is a method to facilitate palliative care discussion with global audience. Podcasts offer the potential to develop educational content and promote research dissemination. Future work should focus on content development, quality metrics and impact analysis, as this form of digital communication is likely to increase and engage wider society.


Role of interleukin (IL)-2 receptor beta-chain subdomains and Shc in p38 mitogen-activated protein (MAP) kinase and p54 MAP kinase (stress-activated protein Kinase/c-Jun N-terminal kinase) activation. IL-2-driven proliferation is independent of p38 and p54 MAP kinase activation.
We have shown recently that interleukin (IL)-2 activates the mitogen-activated protein (MAP) kinase family members p38 (HOG1/stress-activated protein kinase II) and p54 (c-Jun N-terminal kinase/stress-activated protein kinase I). Furthermore, the p38 MAP kinase inhibitor SB203580 inhibited IL-2-driven T cell proliferation, suggesting that p38 MAP kinase might be involved in mediating proliferative signals. In this study, using transfected BA/F3 cell lines, it is shown that both the acidic domain and the membrane-proximal serine-rich region of the IL-2Rbeta chain are required for p38 and p54 MAP kinase activation and that, as for p42/44 MAP kinase, this activation requires the Tyr338 residue of the acidic domain, the binding site for Shc. It is well established that the acidic domain of the IL-2Rbeta chain is dispensable for IL-2-driven proliferation, and thus our observations suggest that neither p38 nor p54 MAP kinase activation is required for IL-2-driven proliferation of BA/F3 cells. In addition, the tetravalent guanylhydrazone inhibitor of proinflammatory cytokine production, CNI-1493, can block the activation of p54 and p38 MAP kinases by IL-2 but has no effect on IL-2-driven proliferation of BA/F3 cells, activated primary T cells, or a cytotoxic T cell line. Furthermore, our observations provide evidence for the existence of an additional, unknown target of the p38 MAP kinase inhibitor SB203580, the activation of which is essential for mitogenic signaling by IL-2.


Determinants of contraceptive switching behavior in rural Sri Lanka.
This study examines the influence of a selected set of determinants of contraceptive method switching in rural Sri Lanka. Of interest is the question of how change in contraceptive practice at the individual level can account for patterns observed at the aggregate level. Based on calendar data on contraceptive use over a 3-year period, collected for more than 3,000 married women in a 1986 survey, the multivariate analysis shows that women who attain all or a significant proportion of their desired fertility tend to switch to more effective methods. Women who experience method failure tend to switch methods, usually to a type that is more effective. The woman's background determinants of age and education have small but significant effects on method switching, whereas the effect of household economic well-being is not significant. There is strong indication that rural couples are practicing contraception in a nonrandom fashion, switching methods in accordance with changes in their fertility motivations and contraceptive experience.


Effects of anti-reflux surgery on chronic cough and asthma in patients with gastro-oesophageal reflux disease.
This two-group prospective study evaluated the effect of anti-reflux surgery (fundoplication) on 24 patients with severe gastro-oesophageal reflux disease (GORD) and concomitant asthma (n=13) or chronic cough (n=11). Twenty-four hour oesophageal pH monitoring and lung function tests (FEV1, FVC) were done before and within 1 year after anti-reflux surgery. A diary was kept by the patient during the 4-week period prior to surgery and during 4-week periods 6 and 12 months postoperatively, with daily monitoring of peak expiratory flow rate, respiratory and reflux symptoms and medication. In non-asthmatic patients, coughing was reduced by 47% and 80% during the day and night, respectively, 12 months after surgery (P < 0.01). Concomitant hoarseness and expectoration were also significantly reduced (P<0.05). No effect on lung function was seen. In patients with asthma, small, non-significant reductions in asthma symptom scores and consumption of rescue medication were seen. Twenty-two patients were completely free from their GORD symptoms after surgery. In conclusion, anti-reflux surgery in patients with GORD had a more favourable effect on concomitant cough than concomitant asthma.


A hot, swollen joint in a cirrhotic patient.
Septic arthritis in the elderly carries a high mortality. Underlying risk factors, such as diabetes, malignancy, chronic renal failure, rheumatoid arthritis, hepatobiliary disease and AIDS, should be assessed. Rare causative organisms are occasionally encountered. Here, we describe a case of an 80-year-old diabetic patient with liver cirrhosis who developed Klebsiella pneumoniae septic arthritis, which is a rare cause of joint infection. We postulate that this case supports the notion that the patient's knee effusion seeded during a primary K pneumoniae bacteraemia of intestinal origin and related to liver cirrhosis.


T1-weighted three-dimensional magnetization transfer MR of the brain: improved lesion contrast enhancement.
We developed and evaluated clinically T1-weighted three-dimensional gradient-echo magnetization transfer (MT) sequences for contrast-enhanced MR imaging of the brain. A short-repetition-time, radio frequency-spoiled, 3-D sequence was developed with a 10-millisecond MT pulse at high MT power and narrow MT pulse-frequency offset, and the enhancing lesion-to-normal white matter background (L/B) and the contrast-to-noise (C/N) ratios on these images were compared with those on T1-weighted spin-echo images and on non-MT 3-D gradient-echo images in a prospective study of 45 patients with 62 enhancing lesions. In the 24 patients who had intracranial metastatic disease, the number of lesions was counted and compared on the three types of images. The MT ratio of normal callosal white matter was 55% on the MT 3-D gradient-echo sequences. The L/B and C/N on the MT 3-D gradient-echo images were more than double those on the 3-D gradient-echo images, and were significantly greater than those on the T1-weighted spin-echo images. In patients with metastatic disease, the MT 3-D gradient-echo images showed significantly more lesions than did the T1-weighted spin-echo or 3-D gradient-echo images. MT 3-D gradient-echo MR imaging improves the contrast between enhancing lesion and background white matter over that obtained with conventional T1-weighted 3-D gradient-echo and spin-echo imaging. MT 3-D gradient-echo imaging provides practical sampling, image coverage, and spatial resolution, attributes that may be advantageous over MT T1-weighted spin-echo techniques.


[Glycogen content in gerbil's liver following the spacecraft Foton-M3 mission].
Glycogen cytochemistry and distribution in hepatocytes of the classic liver lobules were studied in three groups of gerbils Meriones unguiculatus: vivarium, synchronous control and flown in the 12-d Foton-M3 mission. The control animals were shown to have the central glycogen distribution with a large pool of polysaccharides found in hepatocytes of the pericentral and intermediate lobules and a small pool in the periportal area. Glycogen in hepatocyte plasm was within the physiological norm in the alpha- and beta-granules, typically localized on the cell periphery. Exposure to the spaceflight conditions decreased significantly glycogen concentrations in each functional region of the hepatic lobules and reduced the gradient of polysaccharide distribution from the portal triads toward the central vein. In parallel, high glycogen heterogeneity formed in adjacent hepatocytes and loci. The presence of glycosomes evidenced disturbance of carbohydrates metabolism. In addition, intracellular topography of glycogen granules in cytoplasm was altered. Trends of glycogen in gerbils of the synchronous control were similar to the space flown animals but much less pronounced.


Changing the subcellular location of the oncoprotein Bcr-Abl using rationally designed capture motifs.
Bcr-Abl, the causative agent of chronic myelogenous leukemia (CML), localizes in the cytoplasm where its oncogenic signaling leads to proliferation of cells. If forced into the nucleus Bcr-Abl causes apoptosis. To achieve nuclear translocation, binding domains for capture of Bcr-Abl were generated and attached to proteins with signals destined for the nucleus. These resulting proteins would be capable of binding and translocating endogenous Bcr-Abl to the nucleus. Bcr-Abl was targeted at 3 distinct domains for capture: by construction of high affinity intracellular antibody domains (iDabs) to regions of Bcr-Abl known to promote cytoplasmic retention, via its coiled coil domain (CC), and through a naturally occurring protein-protein interaction domain (RIN1). These binding domains were then tested for their ability to escort Bcr-Abl into the nucleus using a "protein switch" or attachment of 4 nuclear localization signals (NLSs). Although RIN1, ABI7-iDab, and CCmut3 constructs all produced similar colocalization with Bcr-Abl, only 4NLS-CCmut3 produced efficient nuclear translocation of Bcr-Abl. We demonstrate that a small binding domain can be used to control the subcellular localization of Bcr-Abl, which may have implications for CML therapy. Our ultimate future goal is to change the location of critical proteins to alter their function.


Polarization-Sensitive Asymmetric Scattering at the Single-Particle Scale via Surface Plasmon Resonance Microscopy.
Surface plasmon resonance microscopy (SPRM), based on the scattering of single molecules at the interface, is a highly efficient analytical platform widely used in the fields of biology and chemistry. Due to the interference scattering, the imaging pattern exhibits typical parabolic tail and phase transition features, providing a quantitative means of observing the changes in the physical and chemical properties of single molecules. In this work, we reported another unique asymmetric parabolic distribution pattern resulting from polarization conversion in the experiment based on SPRM. This microscopic-level feature is derived from the switching between SPR resonant and nonresonant states. Starting from energy flux theory, we constructed an analysis model and conducted full-wave numerical simulations to verify the experimental results. Furthermore, we demonstrate that the optical rotation induced by chiral thin films can be directly measured through imaging with asymmetric features, providing valuable insights into the field of chiral materials. The quantitative interpretation of asymmetric scattering not only advances the fundamental understanding of the imaging mechanism of SPRM, but also opens up possibilities for utilizing this polarization-sensitive characteristic for single-particle detection and sensing in the future.


Restricted repair of aflatoxin B1 induced damage in alpha DNA of monkey cells.
We have investigated the processing of adducts formed by covalent binding of aflatoxin B1 (AFB1) to DNA in confluent cultures of African green monkey cells. Repair synthesis elicited by AFB1 adducts was deficient in alpha DNA sequences compared to that in bulk DNA, although the initial levels of modification were the same for these DNAs. The removal of the primary initial adduct, AFB1-N7-Guanine, was deficient in alpha DNA and the kinetics of its loss resembled those previously reported for removal from total DNA in xeroderma pigmentosum cells of complementation group A. Spontaneous loss of the AFB1 moiety or the concomitant loss of the guanine to yield an apurinic site account for these results. The formation of the more chemically stable secondary product, AFB1-triamino-Pyrimidine, occurred more rapidly and to a greater extent in alpha DNA than in bulk DNA, probably because of slower removal of the primary product. The excision repair patch size for AFB1 adducts in alpha DNA was only 10 nucleotides compared to 20 nucleotides for repair of AFB1 adducts in bulk DNA. Irradiation of cells with low doses of UV prior to or immediately after treatment with AFB1 increased the rate and extent of removal of AFB1 adducts from alpha DNA to the levels found in the bulk DNA, indicating that the formation of pyrimidine dimers or their repair may alter the chromatin structure of alpha DNA sufficiently to facilitate its repair.


Relaxin drives Wnt signaling through upregulation of PCDHY in prostate cancer.
Relaxin, a potent peptide hormone of the insulin-like family normally produced and secreted by the human prostate, is upregulated in castrate resistant prostate cancer progression. In various tissues, relaxin increases angiogenesis and cell motility through upregulation of vascular endothelial growth factor, matrix metalloproteases, and nitric oxide, and therefore maybe an attractive target for cancer therapeutics. To examine the role of relaxin in prostate cancer progression, LNCaP cells stably transfected with relaxin (LNCaP(RLN)) were used to form xenograft tumors, and microarray expression analysis was subsequently performed to determine novel pathways regulated by relaxin. Prostate cancer tissue microarrays from patient samples were stained by immunohistochemistry for further validation and correlation of the findings. Expression analysis identified novel relaxin regulated pathways, including the ProtocadherinY (PCDHY)/Wnt pathway. PCDHY, which upregulates Wnt11, has previously been shown to stabilize beta-catenin, causing beta-catenin to translocate from the cytoplasmic membrane to the nucleus and initiate TCF-mediated signaling. LNCaP(RLN) xenografts exhibit increased PCDHY expression and increased cytoplasmic localization of beta-catenin, suggesting relaxin directs Wnt11 overexpression through PCDHY upregulation. Similarly, prostate cancer samples from patients who have undergone androgen ablation have increased Wnt11 expression, which is further upregulated in castrate resistant tissues. Like relaxin, Wnt11, and PCDHY are negatively regulated by androgens, and further analysis indicated that the overexpression of relaxin results in dysregulation of androgen-regulated genes. These data suggest that prostate cancer cell motility and altered androgen receptor activity attributed to relaxin may be mediated in part by Wnt11.


Phantom smelling.
A case of phantom smelling (phantosmia) is described in a 28-yr.-old man who developed permanent bilateral anosmia after a serious injury to olfaction-related brain structures at the age of 25 years. The findings indicate that, even years after loss of input from olfactory receptors, the neural representation of olfactory perception can still recreate olfactory sensations without any conscious recall of them. This indicates that the neural representation of olfactory sensations remains functional and implies that neuronal activity in the olfactory organ or in other brain structures gives rise to olfactory experiences perceived as originating from the perception of original odor substances. The report suggests the intriguing possibility that the olfactory perception is not a passive process that merely reflects its normal input from the olfactory system but is continuously generated by a neural representation in the olfactory organ or in other olfaction-related brain structures, based on both genetic and sensory determinants. To the author's knowledge this is the first reported case of its kind.


Microfluidics for cell factory and bioprocess development.
Bioindustry is expanding to an increasing variety of food, chemical and pharmaceutical products, each requiring rapid development of a dedicated cell factory and bioprocess. Microfluidic tools are, together with tools from synthetic biology and metabolic modeling, being employed in cell factory and bioprocess development to speed up development and address new products. Recent examples of microfluidics for bioprocess development range from integrated devices for DNA assembly and transformation, to high throughput screening of cell factory libraries, and micron scale bioreactors for process optimization. These improvements act to improve the biotechnological engineering cycle with tools for building, testing and evaluating cell factories and bioprocesses by increasing throughput, parallelization and automation.


Appropriate heart rate during exercise in Fontan patients.
To evaluate heart rate against workload and oxygen consumption during exercise in Fontan patients. Fontan patients (n = 27) and healthy controls (n = 25) underwent cardiopulmonary exercise testing with linear increase of load. Heart rate and oxygen uptake were measured during tests. Heart rate recovery was recorded for 10 minutes. Heart rate at midpoint (140 ± 14 versus 153 ± 11, p < 0.001) and at maximal effort (171 ± 14 versus 191 ± 10 beats per minute, p < 0.001) of test was lower for patients than controls. Heart rate recovery was similar between groups. Heart rate in relation to workload was higher for patients than controls both at midpoint and maximal effort. Heart rate in relation to oxygen uptake was similar between groups throughout test. Oxygen pulse, an indirect surrogate measure of stroke volume, was reduced at maximal effort in patients compared to controls (6.6 ± 1.1 versus 7.5 ± 1.4 ml·beat-1·m-2, p < 0.05) and increased significantly less from midpoint to maximal effort for patients than controls (p < 0.05). Heart rate is increased in relation to workload in Fontan patients compared with controls. At higher loads, Fontan patients seem to have reduced heart rate and smaller increase in oxygen pulse, which may be explained by inability to further increase stroke volume and cardiac output. Reduced ability to increase or maintain stroke volume at higher heart rates may be an important limiting factor for maximal cardiac output, oxygen uptake, and physical performance.


Presynaptic gamma-aminobutyric acid responses in the olfactory cortex.
1. Potential changes were recorded from the lateral olfactory tract in slices of rat olfactory cortex in vitro at room temperature. 2. Superfused gamma-aminobutyric acid (GABA) usually produced dose-related depolarization of the lateral olfactory tract. Muscimol and 3-aminopropanesulphonic acid appeared more potent depolarizing agents than GABA, and glycine and taurine appeared less potent. Carbachol and glutamate were virtually ineffective. 3. The GABA responses were at least partially Cl- dependent. 4. (+)-Bicuculline and higher concentrations of strychnine antagonized the GABA but not the glycine-induced depolarizations. Paradoxically, responses to high doses of GABA were sometimes potentiated by both bicuculline and strychnine. 5. It is suggested that GABA receptors could occur as widely on nerve terminals as they do postsynaptically in the CNS, where GABA could be involved in the modulation of transmitter output.


Changes in ventricular size and plasma renin activity after cardiac surgery in children.
Plasma renin activity and one-dimensional echocardiographic measurements of the left atrium and left ventricle as well as function indices were studied repeatedly in 20 children with various cardiopathies (ages: 9 months to 15 years) before and after corrective surgery. Nine children had tetralogy of Fallot, four had pulmonary stenosis, four had rheumatic heart disease, two had ventricular septal defect, and one had atrial septal defect. Plasma renin activity was normal preoperatively, but increased significantly immediately after surgery, was still significantly higher on the 12th postoperative day and returned to normal six to eight weeks after surgery. Patients with tetralogy of Fallot and pulmonary stenosis had higher plasma renin activity values than the others. There was a positive correlation between plasma renin activity and postoperative percentage change of the left ventricular dimension. In patients with tetralogy of Fallot and pulmonary stenosis, this meant that plasma renin activity became normal when the preoperatively small left ventricle reached its normal dimension. This adjustment occurred slowly over a period of two months. In rheumatic heart disease and left-to-right shunt lesions, plasma renin activities became normal when the preoperatively dilated left ventricle decreased in size towards normal values; the plasma renin activities of these patients had reached normal levels by the fifth postoperative day. The renin secretion is modulated by various factors: of these, ventricular size and pulmonary venous return seem to be of importance.


[Development of atrio-ventricular conduction pathways].
In the embryonic heart of man and mouse, four rings of specialized myocardium are present at the transitions between the different components of the heart tube. Further development produces an adult conducting system which is only composed of certain parts of these rings. The four ring concept not only explains the normal conducting system, but in addition its variations in the hearts of certain animals and in malformed human hearts are easily understood.


Latest pharmacotherapy options for benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is a very common condition in men over 50 years, often resulting in lower urinary tract symptoms (LUTS). Medical therapy aims at improving quality of life and preventing complications. The range of drugs available to treat LUTS is rapidly expanding. Silodosin is a relatively new α1-adrenoreceptor antagonist that is selective for α1A-adrenergic receptor. While causing smooth muscle relaxation in the lower urinary tract, it minimizes blood pressure-related adverse effects. Tadalafil, a PDEs type 5 inhibitor, is a drug recently approved for the treatment of BPH/LUTS that challenges the standard therapy with α1-blockers, especially in men with concomitant erectile dysfunction (ED). Mirabegron is the first β3-adrenoceptor agonist approved for the treatment of symptoms of overactive bladder. BPH-related detrusor overactivity (DO) may be successfully targeted by mirabegron. Gonadotropin-releasing hormone antagonists, intraprostatic injections with NX-1207 and vitamin D3 receptor analogues exerted beneficial effects on LUTS but need further evaluation in clinical studies. Choosing the right treatment should be guided by patients' symptoms, comorbidities and potential side effects of available drugs. Silodosin is a valid option for elderly and for people taking antihypertensive drugs. BPH patients affected by ED can target both conditions with continuous tadalafil therapy. The encouraging data on mirabegron use in BPH-DO have to be further assessed in larger prospective randomized clinical trials.


A novel chemical sensor with multiple all-solid-state electrodes and its application in freshwater environmental monitoring.
Freshwater quality detection is important for pollution control. Three important components of water quality are pH, ammonia and dissolved H2S and there is an urgent need for a high-precision sensor for simultaneous and continuous measurement. In this study, all-solid-state electrodes of Eh, pH, NH4 + and S2- were manufactured and mounted to a wireless chemical sensor with multiple parameters. Calibration indicated that the pH electrode had a Nernst response with slope of 53.174 mV; the NH4 + electrode had a detection limit of 10-5 mol/L (Nernst response slope of 53.56 mV between 10-1 to 10-4 mol/L). Ag/Ag2S has a detection limit of 10-7 mol/L (Nernst response slope of 28.439 mV). The sensor was cylindrical and small with low power consumption and low storage demand to achieve continuous in-situ monitoring for long periods. The sensor was tested for 10 days in streams at Trawsgoed Dairy farm in Aberystwyth, UK. At the intensively farmed Trawsgoed, the concentration of NH4 + in the stream rose sharply after the application of slurry to adjacent fields. Further, the stream was overhung with extensive vegetation and exhibited changes in pH, which correlated with photosynthetic activity. Measurements of S2- were stable throughout the week. Our data demonstrate the applicability of our multiple electrode sensor.


Synthesis, In-vivo and In-vitro Anti-inflammatory Evaluation of some Novel Coumarin Derivatives.
Synthetic coumarin derivatives had attracted considerable attention for their broad spectrum of biological and pharmacological activities such as; anticoagulant, antiviral, antibacterial, antitumor and anti-inflammatory activities especially as COX inhibitors. Synthesis of some new coumarin esters using different benzoyl chloride derivatives. The benzoyl chloride derivatives were selected to have different hydrophobic groups and this aims to increase the lipophilicity of the final compounds hoping to increase the bioavailability and thus improve the anti-inflammatory activity. The reaction between compound III and different aromatic acyl chloride had resulted in a series of ester derivatives 1-9. All synthesized new compounds along with compound III as a parent compound and Celecoxib as a reference, were assessed for their antiinflammatory activity both in-vivo and in-vitro using the formalin-induced hind paw edema method and inhibition of albumin denaturation and Red Blood Cells (RBCs) membrane stabilization, respectively. All synthesized new compounds 1-9 showed an improved activity compared with the parent compound III, in both in-vivo and in-vitro screening. In addition, compounds, 1, 5, 6, 7 and 8 showed significant anti-inflammatory activity compared with the standard compound Celecoxib with compound 6 has a comparable activity with Celecoxib in both invivo and in-vitro evaluation. The newly synthesized ester derivatives 1-9 showed an improved activity compared with the parent compound III, in both in-vivo and in-vitro screening which proved that the new ester derivatives improve the activity and/or bioavailability.


Influence of the polymerization process on composite resistance to chemical degradation by food-simulating liquids.
This study determined the influence of curing lights and modes on composite resistance to chemical degradation by various food-simulating liquids. Two different types of curing light (Halogen [H]-Elipar Trilight, 3M-ESPE; LED [L]-Freelight, 3M-ESPE) and two curing modes (standard [S]; exponential [E) were evaluated in the study. Forty-five composite (Z100 [3M-ESPE]) specimens were made for each light-curing mode combination (HS, HE, LS and LE). The specimens were randomly divided into five groups of nine and exposed to the following food-simulating liquids (FSL) for one week at 37 degrees C: distilled water, 50% aqueous ethanol solution, heptane and citric acid. Specimens stored in air were used as control. After the one week conditioning period, hardness testing was conducted with a digital microhardness tester (load = 500 gf; dwell time = 15 seconds). Mean hardness (HK)/hardness deterioration (deltaHK) were subsequently computed and data was subjected to analysis using ANOVA/Scheffe's test (p < 0.05). The resistance of composite to chemical degradation by FSL was light/curing mode dependent. Significant differences in HK and deltaHK were observed among the four curing techniques after conditioning in some FSL and air. After conditioning in water and citric acid, specimens polymerized with HE underwent significantly more softening compared to specimens polymerized with HS, LS and LE.