Lungs on fire.
A 50-year-old man was diagnosed as classical Hodgkin's lymphoma stage III B. He had been a reformed smoker and has had a coronary artery disease as his comorbidity. He was started on adriamycin, bleomycin, vinblastine, dacarbazine (ABVD)-based chemotherapy. An interim disease evaluation was suggestive of metabolic complete response after four cycles of ABVD. After completion of his sixth cycle, he presented with low-grade fever, dry cough, generalised malaise and increasing dyspnoea on exertion. FDG (18 fluoro-deoxyglucose) positron emission tomography (PET)-CT revealed intensely FDG avid diffuse activity in mid and lower zone both lung fields. He was started on intravenous steroids along with broad spectrum antibiotic and antifungal cover. Clinical, radiological and laboratory assays did not reveal any infective pathology. He was diagnosed as bleomycin-induced pulmonary toxicity (BIP). Despite best supportive care, his pulmonary functions deteriorated and he developed cardiac arrhythmias. He finally succumbed to the irreversible chemotherapy toxicity of a curable malignancy.


Binaural interaction in human auditory brainstem evoked potentials.
Binaural interaction was examined by recording human auditory brainstem responses to clicks from scalp electrodes. Deviations of binaurally evoked responses from the sum of monaurally evoked potentials were observed during waves IV through VI. Amplitude and latency of the interactions depended on click polarity: condensation clicks produced interactions of larger magnitude and longer latency than did rarefaction clicks. Latency differences cannot be accounted for by small latency shifts of the components of monaurally or binaurally evoked potentials resulting from changes in click polarity. Binaural interaction amplitude decreased as click intensity decreased and interaural delay increased. Attenuation of binaural interaction with interaural time differences was maximal at an interaural delay of 900 microseconds. Latency of interaction was prolonged in one subject with low- and high-frequency hearing loss; latency of binaural interaction in subjects with only high-frequency hearing loss was normal. These results suggest that binaural interaction in these potentials reflects binaural processing of low-frequency acoustic stimulation.


Kinetics of triscarbonato uranyl reduction by aqueous ferrous iron: a theoretical study.
Uranium is a pollutant whose mobility is strongly dependent on its oxidation state. While U(VI) in the form of the uranyl cation is readily reduced by a range of natural reductants, by contrast complexation of uranyl by carbonate greatly reduces its reduction potential and imposes increased electron transfer (ET) distances. Very little is known about the elementary processes involved in uranium reduction from U(VI) to U(V) to U(IV) in general. In this study, we examine the theoretical kinetics of ET from ferrous iron to triscarbonato uranyl in aqueous solution. A combination of molecular dynamics (MD) simulations and density functional theory (DFT) electronic structure calculations is employed to compute the parameters that enter into Marcus' ET model, including the thermodynamic driving forces, reorganization energies, and electronic coupling matrix elements. MD simulations predict that two ferrous iron atoms will bind in an inner-sphere fashion to the three-membered carbonate ring of triscarbonato uranyl, forming the charge-neutral ternary Fe(2)UO(2)(CO(3))(3)(H(2)O)(8) complex. Through a sequential proton-coupled electron-transfer mechanism (PCET), the first ET step converting U(VI) to U(V) is predicted by DFT to occur with an electronic barrier that corresponds to a rate on the order of approximately 1 s(-1). The second ET step converting U(V) to U(IV) is predicted to be significantly endergonic. Therefore, U(V) is a stabilized end product in this ET system, in agreement with experiment.


The effect of dry period length and postpartum level of concentrate on milk production, energy balance, and plasma metabolites of dairy cows across the dry period and in early lactation.
Shortening or omitting the dry period (DP) improves energy balance (EB) in early lactation because of a reduction in milk yield. Lower milk yield results in lower energy demands and requires less energy intake. The aim of this study was to evaluate the effects of DP length and concentrate level postpartum on milk yield, feed intake, EB, and plasma metabolites between wk -4 and 7 relative to calving of cows of second parity or higher. Holstein-Friesian dairy cows (n = 123) were assigned randomly to 1 of 2 DP lengths: 0-d DP (n = 81) or 30-d DP (n = 42). Prepartum, cows with a 0-d DP received a lactation ration based on grass silage and corn silage (6.4 MJ of net energy for lactation/kg of dry matter). Cows with a 30-d DP received a dry cow ration based on grass silage, corn silage, and straw (5.4 MJ of net energy for lactation/kg of dry matter). Postpartum, all cows received the same basal lactation ration as provided to lactating cows prepartum. Cows with a 0-d DP were fed a low level of concentrate up to 6.7 kg/d based on the requirement for their expected milk yield (0-d DP-L; n = 40) or the standard level of concentrate up to 8.5 kg/d (0-d DP-S; n = 41), which was equal to the concentrate level for cows with a 30-d DP (30-d DP-S; n = 42) based on requirements for their expected milk yield. Prepartum dry matter intake, concentrate intake, basal ration intake, energy intake, plasma β-hydroxybutyrate (BHB), and insulin concentrations were greater and plasma free fatty acids (FFA) and glucose concentrations were lower, but EB was not different in cows with a 0-d DP compared with cows with a 30-d DP. During wk 1 to 3 postpartum, milk fat yield and plasma BHB concentration were lower and dry matter intake and concentrate intake were greater in cows with a 0-d DP compared with cows with a 30-d DP. During wk 4 to 7 postpartum, fat- and protein-corrected milk (FPCM), lactose content, and lactose and fat yield were lower in 0-d DP-L or 0-d DP-S cows compared with 30-d DP-S cows. Basal ration intake, EB, body weight, plasma glucose, and insulin and insulin-like growth factor-1 concentrations were greater and plasma FFA and BHB concentrations were lower in 0-d DP-L and 0-d DP-S cows compared with 30-d DP-S cows. Concentrate and energy intake were lower in 0-d DP-L cows than in 0-d DP-S or 30-d DP-S cows. Milk yield and concentrations of plasma metabolites did not differ in wk 4 to 7, although EB was lower in wk 6 and 7 postpartum in 0-d DP-L cows than in 0-d DP-S cows. In conclusion, a 0-d DP reduced milk yield and improved EB and metabolic status of cows in early lactation compared with a 30-d DP. Reducing the postpartum level of concentrate of cows with a 0-d DP did not affect fat- and protein-corrected milk yield or plasma FFA and BHB concentrations in early lactation but did reduce EB in wk 6 and 7 postpartum.


Long-term angiographic follow up, cardiac events, and survival in patients undergoing percutaneous transluminal coronary angioplasty.
The results of percutaneous transluminal coronary angioplasty were studied in 1352 consecutive patients. The angioplasty procedure was angiographically successful in 1163 (86%) patients and the success rate increased gradually with time. There were no significant differences in success rates in different vessels or indications. The success rate for repeat coronary angioplasty was 92%. In 85% of the patients the clinical course was uncomplicated. Myocardial infarction occurred in 3.6%, emergency coronary bypass grafting in 2.6%, elective bypass surgery in 4.6%, and there were 10 deaths (0.7%). There were 16 deaths (10 non-cardiac) during follow up in the 1163 patients in whom the first procedure was successful. Actuarial analysis showed that after a first angioplasty 77.9% remained free of symptoms and cardiac events for five years and that after a second angioplasty 76% did so. Angiographic follow up showed restenosis in 24% of patients but the overall clinical success rate was 86.2%. On the basis of the intention to treat the procedure was successful in 74.3% of all 1352 patients. Coronary artery bypass surgery was eventually performed in 11.6% of all patients. The long term angiographic success rate of coronary angioplasty is higher than previously suggested.


Performance of the experimental resins and dental nanocomposites at varying deformation rates.
The aim of the present study was to evaluate the bi-axial flexural strength of experimental unfilled resins and resin-based composites at varying deformation rates following 1-week dry, 1-week wet, and 13-week wet storage regimes. A total of 270 disc-shaped specimens (12 mm diameter, 1 mm thickness) of either unfilled resins or experimental resin-based composites comprising of three groups (n = 90) were fabricated. Three groups of each unfilled resin and resin-based composites (n = 90) were stored for 1 week under dry conditions, and at 1 and 13 weeks under wet conditions (37 ± 1°C) before testing. The bi-axial flexural strength of each unfilled resin and resin-based composites group was determined at a 0.1, 1, and 10 mm/min deformation rate (n = 30). The unfilled resins revealed a deformation rate dependence following all storage regimes; however, the addition of fillers in the unfilled resins modified such reliance following the 1-week dry and 13-week wet storage regimes. In contrast, a lower bi-axial flexural strength of the 1-week wet resin-based composites specimens at a 0.1 mm/min deformation rate was identified. A lower bi-axial flexural strength of the 1-week wet resin-based composites specimens at a low deformation rate suggests that premature failure of resin-based composites restorations might occur in patients with parafunctional habits, such as bruxism.


Inhibition of Angiopoietin-Like Protein 3 or 3/8 Complex and ApoC-III in Severe Hypertriglyceridemia.
The role of the inhibition of ANGPTL3 in severe or refractory hypercholesterolemia is well documented, less in severe hyperTG. This review focuses on the preclinical and clinical development of ApoC-III inhibitors and ANGPTL3, 4, and 3/8 complex inhibitors for the treatment of severe or refractory forms of hypertriglyceridemia to prevent cardiovascular disease or other morbidities. APOC3 and ANGPTL3 became targets for drug development following the identification of naturally occurring loss of function variants in families with a favorable lipid profile and low cardiovascular risk. The inhibition of ANGPTL3 covers a broad spectrum of lipid disorders from severe hypercholesterolemia to severe hypertriglyceridemia, while the inhibition of ApoC-III can treat hypertriglyceridemia regardless of the severity. Preclinical and clinical data suggest that ApoC-III inhibitors, ANGPTL3 inhibitors, and inhibitors of the ANGPTL3/8 complex that is formed postprandially are highly effective for the treatment of severe or refractory hypertriglyceridemia. Inhibition of ANGPTL3 or the ANGPTL3/8 complex upregulates LPL and facilitates the hydrolysis and clearance of triglyceride-rich lipoproteins (TRL) (LPL-dependent mechanisms), whereas ApoC-III inhibitors contribute to the management and clearance of TRL through both LPL-dependent and LPL-independent mechanisms making it possible to successfully lower TG in subjects completely lacking LPL (familial chylomicronemia syndrome). Most of these agents are biologicals including monoclonal antibodies (mAb), antisense nucleotides (ASO), small interfering RNA (siRNA), or CRISPR-cas gene editing strategies.


Validation of Model-Basis Transfer Learning for a Personalized Electroencephalogram-Based Emotion-Classification Model.
The electroencephalogram (EEG)-based affective brain-computer interface (aBCI) has attracted extensive attention in multidisciplinary fields in the past decade. However, the inherent variability of emotional responses recorded in EEG signals increases the vulnerability of pre-trained machine-learning models and impedes the applicability of aBCIs with real-life settings. To overcome the shortcomings associated with the limited personal data in affective modeling, this study proposes a model-basis transfer learning (TL) approach and verifies its feasibility to construct a personalized model using less emotion-annotated data in a longitudinal eight-day dataset comprising data on 10 subjects. By performing daily reliability testing, the proposed TL approach outperformed the subject-dependent counterpart (using limited data only) by ~6% in binary valence classification after recycling a compact set of the eight most transferable models from other subjects. These empirical findings practically contribute to progress in applying TL in realistic aBCI applications.Clinical Relevance- The proposed model-basis TL approach overcomes the shortcoming of inherent variability in EEG signals, supporting realistic aBCI applications.


Squamous cell carcinoma of the penis: a clinicopathological study from a population with late circumcision.
Squamous cell carcinoma (SCC) of the penis has been subject to only a few studies in populations where late childhood circumcision is performed. To asses clinicopathological features and human papillomavirus (HPV) status of penile SCC in men with late circumcision, eight institutions in the country volunteered to collaborate and 15 cases of penile SCC were collected from their pathology archives. The presence and genotype of HPV were determined in addition to clinicopathological features of the tumors. Findings were correlated with disease outcome. The mean age of the patients evaluated was 66.5 years. Histological subtypes were usual SCC (6∕15), papillary (2∕15), mixed (2∕15), basaloid (2∕15), acantholytic (1∕15), pseudohyperplastic (1∕15), and warty-basaloid (1∕15) carcinomas. HPV was identified in 33.3% of samples; HPV16 was detected in 60% of positive cases and was associated with basaloid and/or warty morphology. Cause-specific 1-year and 2-year survivals were 76.9% and 54.5%, respectively. The usual subtype and nodal metastasis were associated with worse outcome (p=0.045 and p=0.047, respectively). As a conclusion, our results suggest an inclination for penile SCC to develop at a later age in a population with late circumcision than the patients from the regions of high penile cancer incidence. These men seem to have less frequent HPV association and their outcome appears poorer than other populations, although reaching substantial provision is not possible due to our limited case number.


Observations on Prostaglandin Orbitopathy.
To present the various orbital soft-tissue changes that can result from the use of topical prostaglandin analogs. A case series of patients seen in a referral oculoplastic practice with presumed prostaglandin orbitopathy. Thirty-five patients were found to have a variety of disorders, including deepening of the superior sulci (24/35), hypertrichosis (32/35), periocular erythema (24/35), and meibomian gland dysfunction (18/35). Marginal eyelid thinning with posterior migration of the lash line was commonly present (34/35). Increased eyelid margin tension with horizontal eyelid shortening (32/35) was often associated with lateral canthal deformity or displacement (15/35). Lower eyelid retraction (18/35) seemed to contribute to ptosis in some patients, secondary to apparent tethering at the lateral canthus. Functional conditions resulting from the above structural abnormalities included tractional ptosis (n = 4), cicatricial entropion (n = 3), cicatricial ectropion (n = 2), trichiasis (n = 2), eyelid subluxation (n = 1), and chalazia (n = 1). While topical prostaglandin analogs are well-tolerated by many patients with glaucoma, some individuals using these medications develop structural changes of the orbital soft tissue resulting in a variety of cosmetic and functional eyelid disorders. The eyelid margins can thin, causing posterior migration of the lashes. Increased horizontal tension of the eyelids may result in acquired blepharophimosis and upper or lower eyelid malposition. These orbital changes may be partially reversible in some patients. When possible, it is reasonable to withhold the prostaglandin and allow a period of observation before proceeding with surgical correction.


Decreased osmotic pressure via interfacial charge clustering.
Behaviors of a model interfacial system featuring the clustering of discrete, mobile wall charges and a counterion solution are investigated. The results demonstrate that even very small localized charge clusters produce significant effects for the osmotic pressure, effects that are not adequately represented in common colloidal models. We observe a pronounced decrease in osmotic pressure where a certain level of clustering is attained, with potentially significant implications for theories of colloidal stability and biochemical processes at microscopic length scales. The stable level of wall charge clustering, and thus the osmotic pressure, is found to be variable in the addition of an attractive potential, as measured via the excess free energy of clustering.


Interplay between HDAC6 and its interacting partners: essential roles in the aggresome-autophagy pathway and neurodegenerative diseases.
Cytoplasmic localization and possession of two deacetylase domains and a ubiquitin-binding domain make histone deacetylase 6 (HDAC6) a unique histone deacetylase. HDAC6 interacts with a number of proteins in the cytoplasm. Some of these proteins can be deacetylated by HDAC6 deacetylase activity. Others can affect HDAC6 functions by modulating its catalytic activity or ubiquitin-binding capability. Over the last decade, HDAC6 has been shown to play important roles in the aggresome-autophagy pathway, which selectively targets on protein aggregates or damaged organelles for their accumulation and clearance in cells. HDAC6-interacting partners are integral components in this pathway with regard to their regulatory roles through interaction with HDAC6. The aggresome-autophagy pathway appears to be an attractive therapeutic target for the treatment of neurodegenerative diseases as accumulation of protein aggregates are hallmarks in these diseases. In the current review, I discuss the molecular details of how HDAC6 and its interacting partners regulate each individual step in the aggresome-autophagy pathway and also provide perspectives of how HDAC6 can be targeted in treating neurodegenerative diseases.


[The analysis of the association of the polymorphic variants of the TPMT, COMT, and ABCC3 genes with the development of hearing disorders induced by the cisplatin treatment].
Cisplatin and its derivatives are widely used chemotherapeutic agents for the treatment of many cancers, including hepatoblastoma, brain tumors, and germ-cell tumors. This therapy contributed to the dramatic increase in the survival rate. However, its use is restricted by the high incidence of irreversible ototoxicity associated with cisplatin application (in more than 60% of the children receiving it). Some studies have reported that genetic variants of TPMT (rs 12201199), COMT (rs4646316), and ABCC3 (rs 1051640) are conferring increased risk of developing cisplatin-induced hearing loss. However, in other studies the results were not replicated. In the present study, we replicated the previous studies based on an independent cohort of Russian patients. SNP genotypes for rs 12201199, rs4646316 and rs 1051640 were determined in DNA samples obtained from 16 patients who developed hearing loss and a group of 34 patients whose hearing was retained. The association between TPMT (rs 12201199), COMT (rs4646316), and ABCC3 (rs 1051640) variants and the hearing loss was not observed in our cohort.


Investigating the Effect of Data Length on the Performance of Frequency-Domain fNIRS Functional Connectivity Measures.
Resting-state functional connectivity is a promising tool for understanding and characterizing brain network architecture. However, obtaining uninterrupted long recording of resting-state data is challenging in many clinically relevant populations. Moreover, the interpretation of connectivity results may heavily depend on the data length and functional connectivity measure used. We compared the performance of three frequency-domain connectivity measures: magnitude-squared, wavelet and multitaper coherence; and the effect of data length ranging from 3 to 9 minutes. Performance was characterized by distinguishing two groups of channel pairs with known different connectivity strengths. While all methods considered improved the ability to distinguish the two groups with increasing data lengths, wavelet coherence performed best for the shortest time window of 3 minutes. Knowledge of which measure is more reliably used when shorter fNIRS recordings are available could make the utility of functional connectivity biomarkers more feasible in clinical populations of interest.


Serotonin 2A receptors contribute to the regulation of risk-averse decisions.
Pharmacological studies point to a role of the neurotransmitter serotonin (5-HT) in regulating the preference for risky decisions, yet the functional contribution of specific 5-HT receptors remains to be clarified. We used pharmacological fMRI to investigate the role of the 5-HT2A receptors in processing negative outcomes and regulating risk-averse behavior. During fMRI, twenty healthy volunteers performed a gambling task under two conditions: with or without blocking the 5-HT2A receptors. The volunteers repeatedly chose between small, likely rewards and large, unlikely rewards. Choices were balanced in terms of expected utility and potential loss. Acute blockade of the 5-HT2A receptors with ketanserin made participants more risk-averse. Ketanserin selectively reduced the neural response of the frontopolar cortex to negative outcomes that were caused by low-risk choices and were associated with large missed rewards. In the context of normal 5-HT2A receptor function, ventral striatum displayed a stronger response to low-risk negative outcomes in risk-taking as opposed to risk-averse individuals. This (negative) correlation between the striatal response to low-risk negative outcomes and risk-averse choice behavior was abolished by 5-HT2A receptor blockade. The results provide the first evidence for a critical role of 5-HT2A receptor function in regulating risk-averse behavior. We suggest that the 5-HT2A receptor system facilitates risk-taking behavior by modulating the outcome evaluation of "missed" reward. These results have implications for understanding the neural basis of abnormal risk-taking behavior, for instance in pathological gamblers.


Do estuaries pose a toxic contamination risk for wading birds?
The impact of potentially toxic chemicals on wildlife is commonly assessed by comparing the intake of the contaminant with the "no observable effects level" (NOAEL) of intake. It is known, however, that there are considerable uncertainties inherent in this method. This study presents a Monte-Carlo based model to assess the degree of risk posed to birds (dunlin, Calidris alpina) from important estuarine habitats, and to show the limitations of such risk assessments, particularly with regard to data availability. The model was applied to predict the uptake of metals (Hg, Pb) in this shorebird species in Poole Harbour and the Severn Estuary/Bristol Channel, UK, two internationally important shorebird habitats. The results show that in both areas, Pb and Hg concentrations may pose an ecologically relevant toxic risk to wading birds. For Pb, uncertainty in NOAEL values dominates the overall uncertainty. Use of lethal toxicity data (LD50/100) was investigated as a method for assessing sub-lethal impacts from Hg. It was found that this method led to a significant under-estimate of the potential impact of Hg contamination, compared with direct estimation of NOAEL.


A parametric solution for optimal overlapped block motion compensation.
We find the optimal window for overlapped block motion compensation (OBMC) by statistically modeling the motion field, the field of block motion estimates and their relationship. This enables us to show how the optimal OBMC window is affected by random field parameters, such as the variance of the motion field and the correlation coefficients of both the intensity field and the motion field. The OBMC window obtained in this fashion is shown to have good performance in reducing the prediction error. Furthermore, this parametric solution provides insight into motion uncertainty and the overlapped motion compensation process.


Enteral tube feeding in a cohort of chronic hemodialysis patients.
Malnutrition affects up to half of all chronic dialysis patients and is an important predictor of mortality, but the efficacy of interventions designed to improve the nutritional status of dialysis patients has been poorly studied. Specifically, although enteral tube feeding is often cited as an important option in the treatment of malnourished dialysis patients, there are few studies examining the effectiveness and complications of enteral tube feedings in adults on dialysis. We performed a retrospective analysis of a small cohort (n = 10) of chronic hemodialysis patients who received enteral tube feeding as all or part of their nutrition between January 1 and May 1, 1999, with follow-up through May 1, 2000, to assess the efficacy and complications of enteral tube feeding. Six patients received feeding via a peritoneoscopically placed (PEG) tube, 3 via nasogastric (NG) tube, and 1 patient was switched from PEG to NG feeding after an exit site infection developed at her PEG site. Seven patients received enteral feeding because of swallowing difficulties occurring after a cerebrovascular accident. Four patients were fed via enteral tube temporarily (</=4 months); the range of time on enteral feeding was 0.5 to 36 months. Five patients died by study end; only 1 recovered and no longer required enteral feeding. Patients were well dialyzed (median urea reduction rate, 73%). A significant improvement in serum albumin was seen (initial median albumin, 2.8, versus final median albumin, 3.4 g/dL, P =.04). Hypophosphatemia occurred in 8 of the 10 patients, and the nadir median phosphorus level was 1.95 mg/dL. One patient died as a result of an infected PEG. We conclude that enteral tube feeding is an important tool in the treatment of malnourished chronic hemodialysis patients and deserves formal study. Hypophosphatemia commonly occurs, and phosphorus levels should therefore be followed closely when initiating tube feedings in hemodialysis patients. In some cases, a nonrenal enteral formula may be useful for avoiding hypophosphatemia in these patients.


[A report on clinical PET activities in Germany].
Clinical diagnostic procedure using positron emission tomography (PET) requires high costs. To promote clinical use of PET, sociomedical evaluation is necessary. In this paper, sociomedical situations concerning clinical use of PET in Germany is reported. Some comparisons are made between Japan and this country putting emphases on several points such as 1) number of cyclotron and PET facilities, 2) social restriction to transportation of radioisotopes, 3) activities of satellite PET facilities, and 4) clinical indications for PET studies. Number of cyclotron was larger in Japan (29) than in Germany (17), but number of PET facilities was larger in Germany (47) than in Japan (29). The reason seems that in Germany transportation and buying of radioisotopes is less restricted. Hence, more than half of PET facilities in Germany are "satellite facilities" which do not have their own cyclotrons. Radioisotope distribution seems to serve as a backbone of "satellite concept." Additionally in Germany, list of clinical indications for PET study is almost completed and now is widely in applied to most cases. To promote clinical use of PET in Japan, the German system might serve as an important socioeconomic model in Europe instead of the United States.


The high incidence of intestinal volvulus in Iran.
The incidence of intestinal volvulus gleaned from the world's medical literature spread over the past seven decades supports the contention that this bowel disorder has distinct geographical predilections. Sigmoid volvulus, invariably superimposed upon a redundancy of this part of the bowel, probably results from a functional disturbance of the colon mediated perhaps by a high-residue vegetable diet. The same factors appear to hold for small bowel volvulus, though caecal volvulus occurs strictly on the basis of preexisting anatomical abnormalities.


The thrombin receptor is a critical extracellular switch controlling myelination.
Hemorrhagic white matter injuries in the perinatal period are a growing cause of cerebral palsy yet no neuroprotective strategies exist to prevent the devastating motor and cognitive deficits that ensue. We demonstrate that the thrombin receptor (protease-activated receptor 1, PAR1) exhibits peak expression levels in the spinal cord at term and is a critical regulator of the myelination continuum from initiation to the final levels achieved. Specifically, PAR1 gene deletion resulted in earlier onset of spinal cord myelination, including substantially more Olig2-positive oligodendrocytes, more myelinated axons, and higher proteolipid protein (PLP) levels at birth. In vitro, the highest levels of PAR1 were observed in oligodendrocyte progenitor cells (OPCs), being reduced with differentiation. In parallel, the expression of PLP and myelin basic protein (MBP), in addition to Olig2, were all significantly higher in cultures of PAR1-/- oligodendroglia. Moreover, application of a small molecule inhibitor of PAR1 (SCH79797) to OPCs in vitro increased PLP and MBP expression. Enhancements in myelination associated with PAR1 genetic deletion were also observed in adulthood as evidenced by higher amounts of MBP and thickened myelin sheaths across large, medium, and small diameter axons. Enriched spinal cord myelination in PAR1-/- mice was coupled to increases in extracellular-signal-regulated kinase 1/2 and AKT signaling developmentally. Nocturnal ambulation and rearing activity were also elevated in PAR1-/- mice. These studies identify the thrombin receptor as a powerful extracellular regulatory switch that could be readily targeted to improve myelin production in the face of white matter injury and disease.


The association of blood pressure and primary open-angle glaucoma: a meta-analysis.
To conduct a systematic review and meta-analysis of the association between blood pressure levels and hypertension with primary open-angle glaucoma and intraocular pressure endpoints. Systematic review with quantitative meta-analysis. Studies were identified by searching the PubMed and EMBASE databases. Inverse-variance weighted random-effects models were used to summarize relative risks. Subgroup analyses and meta-regression were used to explore potential sources of heterogeneity across studies. Sixty observational studies were included. The pooled relative risk for primary open-angle glaucoma comparing patients with hypertension to those without hypertension was 1.16 (95% CI = 1.05-1.28), with modest heterogeneity across studies (I(2) 34.5%). Virtually all studies reported a positive association between blood pressure and intraocular pressure (IOP). The pooled average increase in IOP associated with a 10 mm Hg increase in systolic blood pressure was 0.26 mm Hg (95% CI 0.23-0.28, I(2) 30.7%), and the average increase associated with a 5 mm Hg increase in diastolic blood pressure was 0.17 mm Hg (95% CI 0.11-0.23, I(2) 90.5%). In this meta-analysis, hypertension was associated with increased intraocular pressure. The association between hypertension and primary open-angle glaucoma was stronger in cross-sectional compared with case-control and longitudinal studies. Our findings support a role of increased blood pressure in elevated intraocular pressure and possibly in the development of glaucoma.


[Empathy in psychiatry and psychotherapy].
Empathy is the epicenter of the theoretical and clinical interest of many different scientific domains, constituting a common term in different fields as these of psychology, psychiatry, clinical psychopathology, neuroscience, psychotherapy and psychoanalysis. Studying the phenomenon of empathy requires distinguishing the empathy as a method of observation of psychological phenomena from the empathy as a component of the therapy of psychopathological phenomena. In this case, beyond the empathic understanding, the optimum responsiveness of the therapist is included. Empathy means sharing the psychological and emotional state of another as if you were able to sense one's private world. This emotional sharing is a temporary situation and concerns the quality but not the quantity of the emotional experience. The modern scientists of neurobiology and neurobehavior distinguish three types of empathy: the emotional, the cognitive and motivational which help the interpersonal relations occurring in complex groups of society where the transgenerational relationships between parents and offspring are essential for the survival of species. Jaspers introduces, already by the beginning of the 20th century in his monumental work ''General Psychopathology'', the notion of empathy as an interpretative and a diagnostic tool in psychiatry and psychopathology. Meanwhile psychoanalysis, mainly during its early course, was not impressed by this term. The answer to this seems to be that the term empathy is related to the intersubjectivity and the interpersonal relationship, fields that were not really attractive at this point of time for the psychoanalytical theory which during the period of the founder of the psychoanalysis was initially mainly focused on the "intrapsychic" field. However, during the course of time and chiefly with the contribution of Kohut and Greenson, the importance of the concept of empathy is emphasized in the clinical psychoanalysis and efforts are made regarding the clarification of the nature and the psychological mechanisms that operate in this complex intuitive (feeling the other through the interpersonal communication) form of knowledge. The quality of the relationship between the therapist and the patient (therapeutic alliance) plays a fundamental role in the positive outcome in any form of psychotherapy. Empathic understanding plays an important role in the quality of the therapeutic relationship. In the field of general psychiatry, the focus of research for the role of empathy and the potential of its application, has been until today limited. The lack of a model for the application of empathy in psychiatric and psychotherapeutic practice is an important challenge for the training of the new psychiatrists.


Actin-Capping Protein and the Hippo pathway regulate F-actin and tissue growth in Drosophila.
The conserved Hippo tumor suppressor pathway is a key kinase cascade that controls tissue growth by regulating the nuclear import and activity of the transcription co-activator Yorkie. Here, we report that the actin-Capping Protein αβ heterodimer, which regulates actin polymerization, also functions to suppress inappropriate tissue growth by inhibiting Yorkie activity. Loss of Capping Protein activity results in abnormal accumulation of apical F-actin, reduced Hippo pathway activity and the ectopic expression of several Yorkie target genes that promote cell survival and proliferation. Reduction of two other actin-regulatory proteins, Cofilin and the cyclase-associated protein Capulet, cause abnormal F-actin accumulation, but only the loss of Capulet, like that of Capping Protein, induces ectopic Yorkie activity. Interestingly, F-actin also accumulates abnormally when Hippo pathway activity is reduced or abolished, independently of Yorkie activity, whereas overexpression of the Hippo pathway component expanded can partially reverse the abnormal accumulation of F-actin in cells depleted for Capping Protein. Taken together, these findings indicate a novel interplay between Hippo pathway activity and actin filament dynamics that is essential for normal growth control.


Isolation and Quantification of Mimivirus-Like and Marseillevirus-Like Viruses from Soil Samples in An Aboriginal (Orang asli) Village in Peninsular Malaysia.
The giant amoebal viruses of Mimivirus and Marseillevirus are large DNA viruses and have been documented in water, soil, and sewage samples. The trend of discovering these giant amoebal viruses has been increasing throughout Asia with Japan, India, and Saudi Arabia being the latest countries to document the presence of these viruses. To date, there have been no reports of large amoebal viruses being isolated in South East Asia. In this study, we aim to discover these viruses from soil samples in an aboriginal village (Serendah village) in Peninsular -Malaysia. We successfully detected and isolated both Mimivirus-like and Marseillevirus-like viruses using Acanthamoeba castellanii. Phylogeny analysis identified them as Mimivirus and Marseillevirus, respectively. The ubiquitous nature of both Mimivirus and Marseillevirus is further confirmed in our study as they are detected in higher quantity in soil that is near to water vicinities in an aboriginal village in Peninsular Malaysia. However, this study is limited by our inability to investigate the impact of Mimivirus and Marseillevirus on the aboriginal villagers. More studies on the potential impact of these viruses on human health, especially on the aborigines, are warranted.


Nicotine and pathological angiogenesis.
This paper describes the role of endothelial nicotinic acetylcholine receptors (nAChR) in diseases where pathological angiogenesis plays a role. An extensive review of the literature was performed, focusing on studies that investigated the effect of nicotine upon angiogenesis. Nicotine induces pathological angiogenesis at clinically relevant concentrations (i.e. at tissue and plasma concentrations similar to those of a light to moderate smoker). Nicotine promotes endothelial cell migration, proliferation, survival, tube formation and nitric oxide (NO) production in vitro, mimicking the effect of other angiogenic growth factors. These in vitro findings indicate that there may be an angiogenic component to the pathophysiology of major tobacco related diseases such as carcinoma, atherosclerosis, and age-related macular degeneration. Indeed, nicotine stimulates pathological angiogenesis in pre-clinical models of these disorders. Subsequently, it has been demonstrated that nicotine stimulates nAChRs on the endothelium to induce angiogenic processes, that these nAChRs are largely of the α7 homomeric type, and that there are synergistic interactions between the nAChRs and angiogenic growth factor receptors at the phosphoproteomic and genomic levels. These findings are of potential clinical relevance, and provide mechanistic insights into tobacco-related disease. Furthermore, these findings may lead to novel therapies for diseases characterized by insufficient or inappropriate angiogenesis.


Propeptide levels of type III and type I procollagen in the serum and bronchoalveolar lavage fluid of patients with pulmonary sarcoidosis.
No single test is available to reliably assess the activity or prognosis of pulmonary sarcoidosis. In this study, we have evaluated two procollagen markers, aminoterminal propeptide of type III procollagen (PIIINP) and carboxyterminal propeptide of type I procollagen (PICP) in serum and bronchoalveolar lavage fluid (BALF) and compared them to other disease markers of pulmonary sarcoidosis, such as serum level of angiotensin converting enzyme (S-ACE) or serum interleukin-2 receptor (S-IL-2R). Bronchoalveolar lavage was performed in 40 sarcoidosis patients without (stages 0-I) and 20 patients with lung parenchymal involvement (stages II-III), as well as in 17 controls. Serum (S)- and BALF-PIIINP and PICP, S-ACE, S-IL-2R, BALF-albumin, BALF-lymphocytes and mast cells were determined in these patients. BALF-PIIINP was clearly and S-PIIINP slightly elevated in sarcoidosis compared to the controls. Similarly BALF-PICP, but not S-PICP, was significantly higher in sarcoidosis. BALF-PIIINP, but not BALF-PICP correlated with S-ACE and S-IL-2R levels. Patients with lung parenchymal disease had higher S-ACE and BALF-PIIINP, but neither S-IL-2R, S-PIIINP nor S- or BALF-PICP were elevated. S-PIIINP and S-IL-2R but not S-ACE were higher in symptomatic than nonsymptomatic patients. Symptomatic patients with parenchymal disease had elevated BALF-PIIINP whereas in the symptomatic nonparenchymal group S-PIIINP was elevated. In conclusion, this is the first study to evaluate carboxyterminal propeptide of type I procollagen in sarcoidosis and showed elevated levels in bronchoalveolar lavage fluid. In contrast to the levels of bronchoalveolar lavage fluid aminoterminal propeptide of type III procollagen, levels of carboxyterminal propeptide of type I procollagen did not correlate with serum level of angiotensin converting enzyme and serum interleukin-2 receptor levels, suggesting that carboxyterminal propeptide of type I procollagen may be less suitable disease marker in sarcoidosis than aminoterminal propeptide of type III procollagen. However, the role of carboxyterminal propeptide of type I procollagen as an indicator of fibrogenesis must be further studied.


Nitric oxide synthase dysfunction contributes to impaired cerebroarteriolar reactivity in experimental cerebral malaria.
Cerebrovascular dysfunction plays a key role in the pathogenesis of cerebral malaria. In experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA, cerebrovascular dysfunction characterized by vascular constriction, occlusion and damage results in impaired perfusion and reduced cerebral blood flow and oxygenation, and has been linked to low nitric oxide (NO) bioavailability. Here, we directly assessed cerebrovascular function in ECM using a novel cranial window method for intravital microscopy of the pial microcirculation and probed the role of NOS isoforms and phosphorylation patterns in the impaired vascular responses. We show that pial arteriolar responses to endothelial NOS (eNOS) and neuronal NOS (nNOS) agonists (Acetylcholine (ACh) and N-Methyl-D-Aspartate (NMDA)) were blunted in mice with ECM, and could be partially recovered by exogenous supplementation of tetrahydrobiopterin (BH4). Pial arterioles in non-ECM mice infected by Plasmodium berghei NK65 remained relatively responsive to the agonists and were not significantly affected by BH4 treatment. These findings, together with the observed blunting of NO production upon stimulation by the agonists, decrease in total NOS activity, augmentation of lipid peroxidation levels, upregulation of eNOS protein expression, and increase in eNOS and nNOS monomerization in the brain during ECM development strongly indicate a state of eNOS/nNOS uncoupling likely mediated by oxidative stress. Furthermore, the downregulation of Serine 1176 (S1176) phosphorylation of eNOS, which correlated with a decrease in cerebrovascular wall shear stress, implicates hemorheological disturbances in eNOS dysfunction in ECM. Finally, pial arterioles responded to superfusion with the NO donor, S-Nitroso-L-glutathione (GSNO), but with decreased intensity, indicating that not only NO production but also signaling is perturbed during ECM. Therefore, the pathological impairment of eNOS and nNOS functions contribute importantly to cerebrovascular dysfunction in ECM and the recovery of intrinsic functionality of NOS to increase NO bioavailability and restore vascular health represents a target for ECM treatment.


Measuring Multimorbidity: Selecting the Right Instrument for the Purpose and the Data Source.
Adults have a higher prevalence of multimorbidity-or having multiple chronic health conditions-than having a single condition in isolation. Researchers, health care providers, and health policymakers find it challenging to decide upon the most appropriate assessment tool from the many available multimorbidity measures. The objective of this study was to describe a broad range of instruments and data sources available to assess multimorbidity and offer guidance about selecting appropriate measures. Instruments were reviewed and guidance developed during a special expert workshop sponsored by the National Institutes of Health on September 25-26, 2018. Workshop participants identified 4 common purposes for multimorbidity measurement as well as the advantages and disadvantages of 5 major data sources: medical records/clinical assessments, administrative claims, public health surveys, patient reports, and electronic health records. Participants surveyed 15 instruments and 2 public health data systems and described characteristics of the measures, validity, and other features that inform tool selection. Guidance on instrument selection includes recommendations to match the purpose of multimorbidity measurement to the measurement approach and instrument, review available data sources, and consider contextual and other related constructs to enhance the overall measurement of multimorbidity. The accuracy of multimorbidity measurement can be enhanced with appropriate measurement selection, combining data sources and special considerations for fully capturing multimorbidity burden in underrepresented racial/ethnic populations, children, individuals with multiple Adverse Childhood Events and older adults experiencing functional limitations, and other geriatric syndromes. The increased availability of comprehensive electronic health record systems offers new opportunities not available through other data sources.


Recent advances in combination of microneedles and nanomedicines for lymphatic targeted drug delivery.
Numerous diseases have been reported to affect the lymphatic system. As such, several strategies have been developed to deliver chemotherapeutics to this specific network of tissues and associated organs. Nanotechnology has been exploited as one of the main approaches to improve the lymphatic uptake of drugs. Different nanoparticle approaches utilized for both active and passive targeting of the lymphatic system are discussed here. Specifically, due to the rich abundance of lymphatic capillaries in the dermis, particular attention is given to this route of administration, as intradermal administration could potentially result in higher lymphatic uptake compared to other routes of administration. Recently, progress in microneedle research has attracted particular attention as an alternative for the use of conventional hypodermic injections. The benefits of microneedles, when compared to intradermal injection, are subsequently highlighted. Importantly, microneedles exhibit particular benefit in relation to therapeutic targeting of the lymphatic system, especially when combined with nanoparticles, which are further discussed. However, despite the apparent benefits provided by this combination approach, further comprehensive preclinical and clinical studies are now necessary to realize the potential extent of this dual-delivery platform, further taking into consideration eventual usability and acceptability in the intended patient end-users. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.


[King's Parkinson's disease pain scale : Intercultural adaptation in the German language].
Pain is a frequent symptom of idiopathic Parkinson's disease and has a substantial impact on quality of life. The King's Parkinson's disease pain scale (KPPS) has become internationally established and is an English-language, standardized, reliable and valid scale for evaluation of pain in idiopathic Parkinson's disease. This article presents a validated version in German. The German translation was adapted interculturally and developed using an internationally recognized procedure in consultation with the authors of the original publication. The primary text was first translated by two bilingual neuroscientists independently of one another. Thereafter, the two versions were collated to generate a consensus version, which was accepted by the translators and preliminarily trialled with 10 patients. Hereafter, the German version was re-translated back into English by two other neurologists, again independently of one another, and a final consensus was agreed on using these versions. This English version was then compared with the original text by all of the translators, a process which entailed as many linguistic modifications to the German version as the translators considered necessary to generate a linguistically acceptable German version that was as similar as possible to the original English version. After this test text had been subsequently approved by the authors, the German text was applied to 50 patients in two hospitals, and reviewed as to its practicability and comprehensibility. This work led to the successful creation of an inter-culturally adapted and linguistically validated German version of the KPPS. The German version presented here is a useful scare for recording and quantifying pain in empirical studies, as well as in clinical practice.


Asymptomatic COVID-19 Patients Can Contaminate Their Surroundings: an Environment Sampling Study.
The contamination of patients' surroundings by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains understudied. We sampled the surroundings and the air of six negative-pressure non-intensive care unit (non-ICU) rooms in a designated isolation ward in Chengdu, China, that were occupied by 13 laboratory-confirmed coronavirus disease 2019 (COVID-19) patients who had returned from overseas travel, including 2 asymptomatic patients. A total of 44 of 112 (39.3%) surface samples were positive for SARS-CoV-2 as detected by real-time PCR, suggesting extensive contamination, although all of the air samples were negative. In particular, in a single room occupied by an asymptomatic patient, four sites were SARS-CoV-2 positive, highlighting that asymptomatic COVID-19 patients do contaminate their surroundings and impose risks for others with close contact. Placement of COVID-19 patients in rooms with negative pressure may bring a false feeling of safety, and the importance of rigorous environment cleaning should be emphasized.IMPORTANCE Although it has been well recognized that the virus SARS-CoV-2, the causative agent of COVID-19, can be acquired by exposure to fomites, surprisingly, the contamination of patients' surroundings by SARS-CoV-2 is largely unknown, as there have been few studies. We performed an environmental sampling study for 13 laboratory-confirmed COVID-19 patients and found extensive contamination of patients' surroundings. In particular, we found that asymptomatic COVID-19 patients contaminated their surroundings and therefore imposed risks for other people. Environment cleaning should be emphasized in negative-pressure rooms. The findings may be useful to guide infection control practice to protect health care workers.


Unequal competition between axons for neuronal targets.
Precise wiring of the nervous system depends not only on a matching between neurons and their synaptic targets, but also upon competition between neurons for particular targets. Neurons in adult leeches regenerate synaptic connections with their usual neuronal targets in the central nervous system, selecting only those targets with which they connect during embryogenesis. Thus during development axons of nociceptive (N) sensory cells make contacts on the cell bodies of certain neurons in adjacent ganglia but not upon those same types of cells in their own ganglion. After injury the N cell axons accurately regenerate contacts on the appropriate target cells. An abnormal feature observed after injury is that N cell axons sprout and grow to make contacts upon cell bodies within their own ganglion. This is a consequence of the normal innervation of those cells having been removed, thereby eliminating the source of competition. Similar competition during embryogenesis may guide the formation of selective connections.


Identification of a proviral structure in human breast cancer.
Involvement of a virus similar to mouse mammary tumor virus (MMTV) in human breast cancer has long been postulated but never demonstrated. We have detected by PCR a 660-bp sequence similar to the env gene of MMTV but not to the known endogenous viruses, in 38% of human breast cancers examined (Wang et al., Cancer Res., 55: 5173-5179, 1995). This sequence was expressed in 66% of the env-positive tumors as detected by reverse transcription-PCR (Wang et al., Clin. Cancer Res., 4: 2565-2568, 1998). In this article we report the amplification of a whole proviral structure from each of two human breast carcinomas that were env positive. Using nested extra-long PCR and primers from specific MMTV sequences, overlapping env-long terminal repeat (LTR), LTR-gag, gag-pol, and pol-env segments were successfully amplified. The 9.9-kb provirus is 95% homologous to MMTV but only 57% to human endogenous retrovirus K10 in 3.5 kb of the gag and pol genes. The provirus displays typical features of a replication competent virus, plus the open reading frame for the superantigen and the glucocorticoid responsive element. Fluorescence in situ hybridization with a 2.7-kb env-LTR sequence of an env-positive breast cancer cell line revealed that the sequence is inserted in several chromosomes but not in chromosomes from normal breast cells. The origin of the MMTV-like sequences is uncertain. Because they are undetectable in normal tissues, because the similarity between the two isolates is high (96%), and because they maintain open reading frames, they appear to be exogenous.


The Role of IL-27 and its Receptor in the Pathogenesis of HIV/AIDS and Anti-viral Immune Response.
Cytokines have been widely demonstrated to involve in the pathogenesis of AIDS and the mechanisms of antiretroviral therapy. Interleukin 27 (IL-27) is a new member of the IL-12 cytokine family and has been shown to interfere HIV-1 virus replication with controversial findings. This study is to investigate the dynamic changes in plasma IL-27 level and cell surface IL-27 receptor expression in HIV/AIDS patients who underwent HAART. Whole blood was collected from 34 HIV-positive/AIDS patients 0, 6, and 12 months after initiation of HAART and 27 healthy subjects. Plasma IL-27, IFN-γ, and IL-4 were measured by enzyme-linked immunosorbent assay, while peripheral blood CD3+CD4+ T cells count and the gp130 expressed CD3+CD4+cell were measured by flow cytometry. The plasma IL-27 concentration, IFN-γ concentration, and percentage of positive gp130 CD4 cells were significantly decreased in previously treatment-naive HIV/AIDS patients compared to healthy controls, but gradually increased 6 and 12 months after initiation of HAART. Conversely, IL-4 levels were significantly increased in treatment-naive HIV/AIDS patients compared to healthy controls, but gradually decreased 6 and 12 months after HAART. The concentrations of plasma IL-27 were positively correlated with the percentage of gp130 positive CD4 cells (r=0.438, p=0.016). Both plasma IL-27 concentration and gp130 positive cell percentage were positively associated with peripheral blood CD3+CD4+ T cell count (P<0.05 or P<0.01), but negatively associated with plasma HIV viral load (P<0.05 or P<0.01). IL-27 signaling (IL-27 and its receptor) may be involved in the pathogenesis of HIV infection and immune reconstitution in HIV/AIDS patients who underwent HAART. IL-27 may exert effects through regulating Th1 / Th2 ratio.


Profiling multiple provider prescribing of opioids, benzodiazepines, stimulants, and anorectics.
The main objective of this study was to determine the prevalence of multiple providers for different controlled substances using the largest electronic prescription monitoring program (PMP) in the United States. A secondary objective was to explore patient and medication variables associated with prescriptions involving multiple providers. PMPs monitor the final allocation of controlled substances from pharmacist to patient. The primary purpose of this scrutiny is to diminish the utilization of multiple providers for controlled substances. This is a secondary data analysis of the California PMP, the Controlled Substance Utilization Review and Evaluation System (CURES). The prevalence of multiple provider episodes was determined using data collected during 2007. A series of binomial logistic regressions was used to predict the odds ratio (OR) of multiple prescriber episodes for each generic type of controlled substance (i.e., opioid, benzodiazepine, stimulant, or diet pill (anorectic) using demographic and prescription variables. Opioid prescriptions (12.8%) were most frequently involved in multiple provider episodes followed by benzodiazepines (4.2%), stimulants (1.4%), and anorectics (0.9%), respectively. The greatest associations with multiple provider episodes were simultaneously receiving prescriptions for different controlled substances. Opioids were involved in multiple provider prescribing more frequently than other controlled substances. The likelihood of using multiple providers to obtain one class of medications was substantially elevated as patients received additional categories of controlled substances from the same provider or from multiple practitioners. Polypharmacy represents a signal that requires additional vigilance to detect the potential presence of doctor shopping.


Sympathetic responses to cardiopulmonary vagal afferent stimulation during development.
Previous work in our laboratory has demonstrated impairment of cardiopulmonary reflex control of renal sympathetic nerve activity (RSNA) during the newborn period. The present study was designed to test the hypothesis that this delayed maturation is secondary to incomplete central integration of vagal afferent input. Term fetal (135-140 days; n = 6), newborn (3-7 days of age; n = 8), and young adult (6-8 wk old; n = 8) sheep anesthetized with alpha-chloralose underwent vagal afferent nerve stimulation. All animals had undergone prior sinoaortic denervation to eliminate influences from the arterial baroreceptors. After determination of optimal stimulation parameters, RSNA responses to gradual increases in stimulation frequency (1.0-16 Hz) were recorded and compared by one-way ANOVA. RSNA decreased progressively with increased frequency of stimulation in all three groups of animals. When comparing the three groups at any given frequency of stimulation, reflex withdrawal of RSNA tended to be more pronounced in newborn lambs (P < 0.05 for 1 and 4 Hz). Heart rate (HR) was also noted to decrease significantly with vagal afferent stimulation in each of the groups, but no significant differences in the reflex decreases in HR were noted among the three groups of animals. These results demonstrate that central integration of vagal afferent input is intact in fetal and newborn sheep. These results suggest that the delayed maturation of cardiopulmonary reflex-mediated changes in RSNA seen early in development appears to depend on intrinsic alterations in baroreceptor function rather than incomplete central integration.


Aberrantly glycosylated serum IgA1 are closely associated with pathologic phenotypes of IgA nephropathy.
IgA nephropathy (IgAN) is the most common glomerulonephritis with various histologic and clinical phenotypes. The mechanisms underlying the pathogenesis of IgAN remained unclear. But now altered O-glycosylation of serum IgA1 observed in these patients was considered to be a key contributory factor. The aim of the current study is to investigate whether aberrantly glycosylated IgA1 was associated with pathologic phenotypes of IgAN. Sera from 107 patients with IgAN recently diagnosed were collected. Fifty patients were with mild mesangial proliferative IgAN, the others were with focal proliferative and sclerosing IgAN. Sera from 22 normal blood donors were used as normal controls. Biotinylated lectins were used in enzyme-linked immunosorbent assay (ELISA) to examine different glycans on IgA1 molecules. The alpha2,6 sialic acid was detected by elderberry bark lectin (SNA), the exposure of terminal galactose (Gal) and N-acetylgalactosamine (GalNAc) were detected by arachis hypogaea [peanut agglutinin (PNA)] and vilsa villosa lectin (VVL), respectively. The serum IgA1 glycans levels corrected by serum IgA1 concentrations were compared between patients and controls. Reduced terminal alpha2,6 sialic acid (1.16 +/- 0.21 vs. 0.98 +/- 0.31) (P= 0.008) and galactosylation (0.30 +/- 0.29 vs. 0.16 +/- 0.19) (P= 0.029) increased exposure of (GalNAc) (0.00 vs. 0.03) (P= 0.024) were demonstrated in serum IgA1 from patients with IgAN as compared with those in controls. More important, the exposures of 2,6 sialic acid and Gal were significantly decreased, especially in patients with focal proliferative and sclerosing IgAN compared with that in patients with mild mesangial proliferative IgAN (0.91 +/- 0.34 vs. 1.05 +/- 0.25) (P= 0.014) (0.108 +/- 0.137 vs. 0.221 +/- 0.219) (P= 0.018). However, no significant difference was found between patients with mild mesangial proliferative IgAN and normal controls (P > 0.05). The exposure of GalNAc of serum IgA1 from patients with focal proliferative and sclerosing IgAN was significantly higher than that of controls (P= 0.017), but had no statistical difference with that of patients with mild mesangial proliferative IgAN. The desialylation and degalactosylation of IgA1 in sera of patients with IgAN were closely associated with pathologic phenotypes.


Geochemical fractionation of thallium in contaminated soils near a large-scale Hg-Tl mineralised area.
Enriched levels of thallium (Tl) in the environment are not only derived from anthropogenic sources but also have potential natural origins owing to Tl-rich sulphide mineralization. However, little is known regarding the geochemical fractionations of Tl in contaminated soils from geogenic sources. This study aims to reveal the Tl geochemical fractionations in different types of soils from a large-scale independent Tl mine in southwestern China, via a modified Institute for Reference Materials and Measurement (IRMM) sequential extraction (four-step) scheme. The results revealed that a large percentage of Tl was related to the labile portions (including reducible, weak-acid-exchangeable, and oxidizable fraction) of the soils (68.8-367 mg kg-1). Further analyses by Scanning Transmission Electron Microscopy-Energy Dispersive X-ray Spectrometer (STEM-EDS) found that Tl mainly existed in the Fe-containing minerals (such as jarosite and hematite) with fine particles (∼1 μm). These results highlight that, apart from the anthropogenically induced Tl pollution, the naturally occurring Tl contamination in soils may also pose significant risks to human health and ecological safety. Owing to the relatively high mobility and bioavailability of Tl in the labile fractions, it is important to understand geochemical fractionations of this element for alleviating Tl pollution and effective management of naturally occurring Tl contaminated soils.


Efficacy and safety of copanlisib in patients with relapsed or refractory marginal zone lymphoma.
Marginal zone lymphoma (MZL) is challenging to treat, with many patients relapsing following initial treatment. We report the long-term efficacy and safety of copanlisib, a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in the subset of 23 patients with relapsed/refractory MZL treated in the phase 2 CHRONOS-1 study (#NCT01660451, Part B; www.clinicaltrials.gov). Patients had a median of 3 prior lines of therapy, including rituximab and alkylating agents, and received IV copanlisib 60 mg on days 1, 8, and 15 of 28-day cycles for a median of 23 weeks. The objective response rate was 78.3% (18/23; 3 complete responses and 15 partial responses). The median duration of response was 17.4 months (median follow-up, 9.4 months), and median time to response was 2.1 months. Median progression-free survival was 24.1 months (median follow-up, 10.3 months), and median overall survival was not reached (median follow-up, 28.4 months). The most common all-grade treatment-emergent adverse events (TEAEs) included fatigue (52.2%, 12/23), diarrhea, and transient, infusion-related hyperglycemia (each 47.8%, 11/23). Nineteen patients (82.6%) had grade 3/4 TEAEs, most commonly transient, infusion-related hyperglycemia and hypertension (each 39.1%, 9/23). TEAEs led to dose reduction or dose interruptions /delays in 9 patients (39.1%) and 18 patients (78.3%), respectively. Patients with activated PI3K/B-cell antigen receptor signaling had improved response rates. Overall, copanlisib demonstrated strong efficacy, with a short time to objective response, improved objective response rate with longer treatment duration, durable responses, and manageable safety, in line with previous reports. These data provide rationale for long-term treatment with copanlisib in patients with relapsed/refractory MZL.


Direct involvement of the Y-box binding protein YB-1 in genotoxic stress-induced activation of the human multidrug resistance 1 gene.
The human multidrug resistance 1 (MDR1) gene encoding P-glycoprotein is often overexpressed in various human tumors after chemotherapy. During treatment with various chemotherapeutic agents, the MDR1 gene is activated at the transcriptional level and/or amplified, resulting in overexpression. Our previous studies demonstrated that an inverted CCAAT box (Y-box) might be a critical cis-regulatory element regulating UV or drug-induced MDR1 gene expression. We have now established various cell lines from human head and neck cancer KB cells which were stably transfected with the chloramphenicol acetyltransferase (CAT) reporter gene driven by various MDR1 promoter deletion constructs. Transient transfection of antisense YB-1 expression constructs resulted in a decrease of both YB-1 protein levels and DNA binding activity to the inverted CCAAT box, as determined by Western blot and gel mobility shift assays. The limited expression and binding activity due to expression of antisense YB-1 constructs were also observed when cells were treated with UV. CAT activity of constructs containing the Y-box was enhanced after treatment with UV irradiation as well as genotoxic agents such as cisplatin and etoposide. Moreover, this activation was reduced by 50-80% by transfection of antisense YB-1 expression constructs. In contrast, transfection of antisense YB-1 expression constructs had no effect on CAT activity driven by MDR1 promoter constructs not containing the Y-box. These data indicate that YB-1 is directly involved in MDR1 gene activation in response to genotoxic stress.


American ginseng suppresses Western diet-promoted tumorigenesis in model of inflammation-associated colon cancer: role of EGFR.
Western diets increase colon cancer risk. Epidemiological evidence and experimental studies suggest that ginseng can inhibit colon cancer development. In this study we asked if ginseng could inhibit Western diet (20% fat) promoted colonic tumorigenesis and if compound K, a microbial metabolite of ginseng could suppress colon cancer xenograft growth. Mice were initiated with azoxymethane (AOM) and, two weeks later fed a Western diet (WD, 20% fat) alone, or WD supplemented with 250-ppm ginseng. After 1 wk, mice received 2.5% dextran sulfate sodium (DSS) for 5 days and were sacrificed 12 wks after AOM. Tumors were harvested and cell proliferation measured by Ki67 staining and apoptosis by TUNEL assay. Levels of EGF-related signaling molecules and apoptosis regulators were determined by Western blotting. Anti-tumor effects of intraperitoneal compound K were examined using a tumor xenograft model and compound K absorption measured following oral ginseng gavage by UPLC-mass spectrometry. Effects of dietary ginseng on microbial diversity were measured by analysis of bacterial 16S rRNA. Ginseng significantly inhibited colonic inflammation and tumorigenesis and concomitantly reduced proliferation and increased apoptosis. The EGFR cascade was up-regulated in colonic tumors and ginseng significantly reduced EGFR and ErbB2 activation and Cox-2 expression. Dietary ginseng altered colonic microbial diversity, and bacterial suppression with metronidazole reduced serum compound K following ginseng gavage. Furthermore, compound K significantly inhibited tumor xenograft growth. Ginseng inhibited colonic inflammation and tumorigenesis promoted by Western diet. We speculate that the ginseng metabolite compound K contributes to the chemopreventive effects of this agent in colonic tumorigenesis.


[Ultrastructural identification of Ehrlichia sp in an experimentally infected dog in Venezuela].
This study is the first report made in Venezuela concerning the ultrastructural characteristics of Ehrlichia sp in mononuclear blood cells from an experimentally infected dog. The animal developed clinical manifestations characteristic of the infection, and typical intracitoplasmic inclusion bodies were clearly seen in blood smears stained with modified Giemsa examined by light microscopy. Microorganisms were visualized by transmission electron microscopy. The cytoplasmic inclusions, consisted of membrane-lined vacuole-containing elementary bodies. The organisms were extremely pleomorphic. Elementary bodies were surrounded by two distinct membranes and each was constituted by electro-dense granules. These findings corresponded to the described electron microscopy morphology which characterizes the Ehrlichia genus.


Diving into the complexity of the spirochetal endoflagellum.
Spirochaetes, a phylum that includes medically important pathogens such as the causative agents of Lyme disease, syphilis, and leptospirosis, are in many ways highly unique bacteria. Their cell morphology, subcellular organization, and metabolism reveal atypical features. Spirochetal motility is also singular, dependent on the presence of periplasmic flagella or endoflagella, inserted subterminally at cell poles and not penetrating the outer membrane and elongating outside the cell as in enterobacteria. In this review we present a comprehensive comparative genomics analysis of endoflagellar systems in spirochetes, highlighting recent findings on the flagellar basal body and filament. Continued progress in understanding the function and architecture of spirochetal flagella is uncovering paradigm-shifting mechanisms of bacterial motility.


How Should Technology-Dependent Patients' Care Be Managed Collaboratively to Avoid Turfing?
Technology-dependent patients require interventions (eg, tracheostomies, gastrostomy tubes, or total parenteral nutrition) to survive. Such patients are commonly "turfed" between general services or from subspecialty to general services within the hospital. This case commentary proposes several explanations for why technology-dependent patients are particularly susceptible to turfing, including clinicians' lack of familiarity with managing patients' technology, bias and ableism, and quality-of-life quandaries. It also addresses ways to combat turfing of technology-dependent patients and proposes educational strategies for managing common problems in the care of technology-dependent patients.


Glycoprotein gE of herpes simplex virus type 1: effects of anti-gE on virion infectivity and on virus-induced fc-binding receptors.
An Fc-binding glycoprotein, designated gE, was detected previously in cells infected with herpes simplex virus type 1 (HSV-1) and in virion preparations isolated from infected cells. For the studies reported here, we purified gE from HSV-1 strain HFEM(syn) by affinity chromatography and preparative electrophoresis and then immunized a rabbit to produce an antiserum to glycoprotein gE. We found that this antiserum selectively precipitated gE and its precursors from detergent-solubilized extracts of HSV-1 strain HFEM(syn)-infected HEp-2 cells, from extracts of other cell lines infected with the same virus, and from extracts of HEp-2 cells infected with several other HSV-1 strains. The antiserum did not precipitate any proteins from uninfected cells. The several forms of gE detected by immunoprecipitation accumulated in variable quantities in different cells infected with the different virus strains and also varied slightly with respect to electrophoretic mobility, suggesting some differences in the gE's from different HSV-1 strains and some effects of the host cell on the nature and extent of post-translational processing. One of the electrophoretic forms of gE previously detected in purified preparations of virions could be precipitated by anti-gE from extracts of purified HSV-1 strain HFEM(syn) virions. Moreover, anti-gE neutralized HSV-1 infectivity, but only in the presence of complement. Finally, F(ab')2 fragments of the anti-gE immunoglobulin partially inhibited the binding of 125I-labeled immunoglobulin G to the Fc receptors on HSV-1-infected cells.


Purification and properties of formate dehydrogenase from Pseudomonas aeruginosa. Characterization of haem and iron-sulphur centres by magnetic-circular-dichroism and electron-paramagnetic-resonance spectroscopy.
The purification of formate dehydrogenase (FDH) from Pseudomonas aeruginosa after anaerobic growth on nitrate-containing medium was carried out. The separation of the FDH enzyme from nitrate reductase (NiR), which are found together in a particle fraction and constitute the short respiratory chain of this bacterium, has been followed by optical, magnetic c.d. (m.c.d.) and e.p.r. spectroscopy. These techniques have allowed the haem, iron-sulphur clusters and molybdenum components to be detected and, in part, their nature to be determined. Attempts to extract FDH anaerobically in the absence of sodium dithionite led to loss of activity. Addition of sodium dithionite maintained the activity of the enzyme, even after subsequent exposure to air, in an assay involving formate reduction with Nitro Blue Tetrazolium as reductant. Three preparations of FDH have been examined spectroscopically. The preparations vary in the amount of contaminating nitrate reductase, the amount of cytochrome c present and the concentration of oxidized [3Fe-4S] cluster. Optical spectra and low-temperature m.c.d. spectroscopy show the loss of a cytochrome-containing protohaem IX co-ordinated by methionine and histidine as NiR is separated from the preparation. In its purest state FDH contains one molecule of cytochrome co-ordinated by two histidine ligands in the oxidized state. This cytochrome has an e.p.r. spectrum with gz = 3.77, the band having the unusual ramp shape characteristic of highly anisotropic low-spin ferric haem. It also shows a charge-transfer band of high intensity in the m.c.d. spectrum at 1545 nm. It has recently been shown [Gadsby & Thomson (1986) FEBS Lett. 197, 253-257] that these spectroscopic properties are diagnostic of a bishistidine co-ordinated haem with steric constraint of the axial ligands. The e.p.r. and m.c.d. spectra of the reduced state of FDH reveal the presence of an iron-sulphur cluster of the [4Fe-4S]+ type. The g-values are 2.044, 1.943 and 1.903. An iron-sulphur cluster of the class [3Fe-4S], detected by e.p.r. spectroscopy in the oxidized state and by low-temperature m.c.d. spectroscopy in the reduced state, is purified away with the NiR. Finally, an e.p.r. signal at g = 2.0 with a narrow bandwidth which persists to 80 K is observed in the purest preparation of FDH. This may arise from an organic radical species.


The facilitating role of mobile dental van programs in promoting professional dental education.
The main goal of the University of Texas Health Science Center (UTHSCSA) dental van programs is to provide training in delivering care to diverse segments of the population. The UTHSCSA is the Academic Health Center for all of South Texas, a region with 25% of the State's population and 60% Hispanic. About 60% of the region's counties are federally designated dental health personnel shortage areas. Interdepartmental efforts with the participation of dental hygiene, community dentistry, oral diagnosis, periodontics and general practice carried out two programs during the 1994-95 academic year. At the Saint Philip of Jesus Clinic, a charity clinic, and at the Willows Development Center for Severely and Profoundly Mentally Retarded, the dental van was used to provide preventive and restorative care. A questionnaire to measure the value of the programs indicated that students perceived them as important educational activities which increased their confidence in treating persons in the community, especially persons with disabilities. Program output was quantitatively assessed. An average of 8 preventive procedures, 7 fillings, 2 sealants and 1 extraction or referral were provided each working day. Eighty patients were seen at the Saint Philip Clinic (2.5 visits per patient) and 130 patients were seen at the Willows Development Center. Overall, 80 students and 6 faculty participated in providing screening, treatment and referral services. Dental van programs promote access to dental care and increase the visibility of dental schools within the university and community. Current tendencies to halt new program initiatives and phase out existing programs due to shifting financial priorities should be carefully considered in view of the 1995 Institute of Medicine (IOM) report on the future of dental education.


Economic modelling of diagnostic and treatment pathways in National Institute for Health and Care Excellence clinical guidelines: the Modelling Algorithm Pathways in Guidelines (MAPGuide) project.
National Institute for Health and Care Excellence (NICE) clinical guidelines (CGs) make recommendations across large, complex care pathways for broad groups of patients. They rely on cost-effectiveness evidence from the literature and from new analyses for selected high-priority topics. An alternative approach would be to build a model of the full care pathway and to use this as a platform to evaluate the cost-effectiveness of multiple topics across the guideline recommendations. In this project we aimed to test the feasibility of building full guideline models for NICE guidelines and to assess if, and how, such models can be used as a basis for cost-effectiveness analysis (CEA). A 'best evidence' approach was used to inform the model parameters. Data were drawn from the guideline documentation, advice from clinical experts and rapid literature reviews on selected topics. Where possible we relied on good-quality, recent UK systematic reviews and meta-analyses. Two published NICE guidelines were used as case studies: prostate cancer and atrial fibrillation (AF). Discrete event simulation (DES) was used to model the recommended care pathways and to estimate consequent costs and outcomes. For each guideline, researchers not involved in model development collated a shortlist of topics suggested for updating. The modelling teams then attempted to evaluate options related to these topics. Cost-effectiveness results were compared with opinions about the importance of the topics elicited in a survey of stakeholders. The modelling teams developed simulations of the guideline pathways and disease processes. Development took longer and required more analytical time than anticipated. Estimates of cost-effectiveness were produced for six of the nine prostate cancer topics considered, and for five of eight AF topics. The other topics were not evaluated owing to lack of data or time constraints. The modelled results suggested 'economic priorities' for an update that differed from priorities expressed in the stakeholder survey. We did not conduct systematic reviews to inform the model parameters, and so the results might not reflect all current evidence. Data limitations and time constraints restricted the number of analyses that we could conduct. We were also unable to obtain feedback from guideline stakeholders about the usefulness of the models within project time scales. Discrete event simulation can be used to model full guideline pathways for CEA, although this requires a substantial investment of clinical and analytic time and expertise. For some topics lack of data may limit the potential for modelling. There are also uncertainties over the accessibility and adaptability of full guideline models. However, full guideline modelling offers the potential to strengthen and extend the analytical basis of NICE's CGs. Further work is needed to extend the analysis of our case study models to estimate population-level budget and health impacts. The practical usefulness of our models to guideline developers and users should also be investigated, as should the feasibility and usefulness of whole guideline modelling alongside development of a new CG. This project was funded by the Medical Research Council and the National Institute for Health Research through the Methodology Research Programme [grant number G0901504] and will be published in full in Health Technology Assessment; Vol. 17, No. 58. See the NIHR Journals Library website for further project information.


Bivariate line-fitting methods for allometry.
Fitting a line to a bivariate dataset can be a deceptively complex problem, and there has been much debate on this issue in the literature. In this review, we describe for the practitioner the essential features of line-fitting methods for estimating the relationship between two variables: what methods are commonly used, which method should be used when, and how to make inferences from these lines to answer common research questions. A particularly important point for line-fitting in allometry is that usually, two sources of error are present (which we call measurement and equation error), and these have quite different implications for choice of line-fitting method. As a consequence, the approach in this review and the methods presented have subtle but important differences from previous reviews in the biology literature. Linear regression, major axis and standardised major axis are alternative methods that can be appropriate when there is no measurement error. When there is measurement error, this often needs to be estimated and used to adjust the variance terms in formulae for line-fitting. We also review line-fitting methods for phylogenetic analyses. Methods of inference are described for the line-fitting techniques discussed in this paper. The types of inference considered here are testing if the slope or elevation equals a given value, constructing confidence intervals for the slope or elevation, comparing several slopes or elevations, and testing for shift along the axis amongst several groups. In some cases several methods have been proposed in the literature. These are discussed and compared. In other cases there is little or no previous guidance available in the literature. Simulations were conducted to check whether the methods of inference proposed have the intended coverage probability or Type I error. We identified the methods of inference that perform well and recommend the techniques that should be adopted in future work.


Effects of roughage concentration in dry-rolled corn-based diets containing wet distillers grains with solubles on performance and carcass characteristics of finishing beef steers.
Distillers grains and distillers solubles are by-products of grain fermentation used to produce ethanol and contain greater concentrations of NDF and ADF, compared with other grains and concentrates they replace in feedlot diets. Typical finishing diets in the United States contain 8.3% and 9.0% roughage. Therefore, it is plausible that the dietary concentration of roughage can be altered when distillers grains are included in feedlot diets. The effects of roughage concentration in dry-rolled, corn-based diets containing wet distillers grains with solubles (WDGS) were evaluated in steers (n = 128; initial BW = 339 kg), using Calan gates. Each diet was based on dry-rolled corn and contained 25% WDGS with coarsely ground alfalfa hay (AH), replacing corn at 2% (AH-2), 6% (AH-6), 10% (AH-10), and 14% (AH-14) of DM. Feed offered was recorded daily, orts were measured weekly, and BW was measured on d 0, 1, 35, 70, 105, 140, 174, and 175. After commercial harvest and chilling, carcasses were evaluated on-line with a beef carcass grading camera to assess marbling and yield grade traits. The data were analyzed using the Mixed Procedure of SAS, in which contrast statements were used to separate linear and quadratic effects of AH inclusion. Decreasing concentrations of AH in the finishing diet resulted in a tendency for a quadratic response (P = 0.07) in final BW, where BW increased from 2 to 6% AH inclusion but then decreased from 6 to 14% inclusion. Similarly, ADG from d 0 to end responded quadratically (P < 0.01), in which ADG increased from 2 to 6% yet subsequently decreased from 6 to 14% AH inclusion. Dry matter intake from d 0 to end increased linearly (P = 0.02) as AH inclusion increased in the diet, whereas G:F increased from 2 to 6% AH inclusion and then decreased linearly (P < 0.01) from 6 to 14% AH inclusion. Concentration of AH in the finishing diet did not affect HCW, marbling score, or the proportion of cattle grading USDA choice (P ≥ 0.18). However, dressing percent and LM area did respond in a quadratic manner (P < 0.02), in which they decreased from 2 to 10% AH inclusion and increased from 10 to 14% AH in the diet. Yield grade and adjusted 12th rib fat responded quadratically (P < 0.01), in which both increased from 2 to 6% AH inclusion and decreased from 6 to 14% inclusion. Analysis of responses of G:F and ADG on AH predict the apex at 3% and 7% for G:F and ADG, respectively, when fed in diets containing 25% WDGS.


[Effect of unsaponifiable extracts of avocado and soybean (Piasclédine) on the collagenolytic action of cultures of human rheumatoid synoviocytes and rabbit articular chondrocytes treated with interleukin-1].
In this work, the authors have studied the effect of advocate/soya-bean extracts (Piasclédine) on the collagenolytic activity of cultured rabbit articular chondrocytes and human rheumatoid synovial cells. Incubation of these cells for 48 h with 10 micrograms/ml of Piasclédine show that this drug slightly increases collagenase production. As expected, incubation of these cells with interleukin-1 (100 pg/ml) induces an important release of collagenase. Piasclédine partially reverses the effect of interleukin-1 on synovial cells and totally abolishes its action on chondrocytes. Moreover, incubation of the two cell types for 5 days with Piasclédine prior to a 48 h-exposure to interleukin-1 prevents partially the effect of interleukin-1. These data suggest a potential role for Piasclédine to limit the deleterious effects of interleukin-1 in osteoarticular diseases by reducing the capacity of this cytokine to stimulate collagenase production by synoviocytes and chondrocytes.


Individual responses in spring arrival date to ecological conditions during winter and migration in a migratory bird.
1. We studied lifetime arrival patterns in the barn swallow (Hirundo rustica L.) in relation to variation in ecological conditions, as reflected by the normalized difference vegetation index (NDVI) in the Sub-Saharan winter quarters and at stopover sites in North Africa. 2. Migratory birds have recently advanced their arrival dates, but the relative role of microevolution and phenotypic plasticity as mechanisms of response to changing environmental conditions remains unknown. To distinguish between these two possibilities, we investigated the change in the arrival date using cross-sectional and longitudinal analyses. 3. We predicted that the effect (i.e. slopes) of environmental conditions in stopover or winter areas on arrival date should be similar using cross-sectional and longitudinal analyses in case phenotypic plasticity is the underlying mechanism, or they should differ in case microevolution is the mechanism. 4. As expected according to a previous cross-sectional study, we found an advance in the arrival date when ecological conditions improve in stopover areas and a delay in the arrival date when ecological conditions improve in the winter quarters. 5. Change in the arrival time at the breeding grounds due to ecological conditions found en route and, in the winter areas, was mainly due to phenotypic plasticity as shown by similarities in the slopes found in these relationships using cross-sectional and longitudinal analyses. 6. We also investigated sex and age of barns swallows as sources of variation in the arrival time with respect to conditions experienced in winter and stopover areas. We found that earlier arrival at the breeding grounds due to prevailing ecological conditions found en route in North Africa was similar for males and females of all age-classes. In contrast, individuals tended to delay departure when ecological conditions improved in the winter quarters, but this delay differed among age classes, with old individuals delaying departure more than middle-aged and yearling birds. 7. The migratory response of individuals to changing climatic conditions experienced during different parts of their life provides evidence for individuals responding differently to prevailing conditions in the winter quarters depending on their age, but not to conditions experienced en route during spring migration.


On the influence of sample set structure on decision rule quality for the case of a linear discriminant function.
The influence of sample set structure on decision rule quality for the case of a linear discriminant function is considered. Specifically, the case of missing data in the sample set and the case when the multivariate random variable is to be registered with the help of a single-channel device are investigated. Some rather unusual phenomena are discussed, such as when some new samples are added to the sample set, and as a result the quality of parameter estimations used in a decision rule become better, but at the same time the quality of the decision rule itself becomes worse. The investigation is performed for the classical model of a twocategory classifier when the categories are described by the multivariate normal densities having common covariance matrices. Some results of statistical simulation experiments are included.


Buprenorphine versus methadone in pregnant opioid-dependent women: a prospective multicenter study.
In order to investigate the effects of exposure to buprenorphine compared with methadone during pregnancy, a prospective multicenter study was conducted in collaboration with maternity hospitals, maintenance therapy centers, and general practitioners involved in addiction care. Ninety pregnant women exposed to buprenorphine and 45 to metadone were selected for the study. During pregnancy, some women were exposed to illicit agents: cannabis (42% in the buprenorphine group vs. 58% in the methadone-treated group), heroin (17% vs. 44%), or cocaine (3% vs. 11%). Pregnancies ended in 85 vs. 40 live births, one vs. two stillbirths, two vs. one spontaneous abortion, two vs. one voluntary termination, and one vs. one medical termination in the buprenorphine and the methadone groups, respectively. Newborns had a birth weight of 2,892 ± 506 g (buprenorphine) vs. 2,731 ± 634 g (methadone) and a body length of 47.6 ± 2.5 cm vs. 47.1 ± 3 cm. 18.8% vs. 10% of newborns were delivered before 37 weeks of amenorrhea. Neonatal withdrawal syndrome occurred more frequently in the methadone group (62.5% vs. 41.2, p = 0.03). After adjustment for heroin exposure in late pregnancy, rates of neonatal withdrawal were no longer different between the methadone and buprenorphine groups. Twenty-one babies (84%) in the methadone group and 20 (57%) in the buprenorphine group (p = 0.03) required opiate treatment. We did not observe more frequent malformations or cases of withdrawal syndrome in the buprenorphine group than in the methadone-treated group. Buprenorphine appears to be as safe as the currently approved substitute methadone considered to date as the reference treatment for pregnant opioid-dependent women.


Influence of Enzymatically Hydrophobized Hemp Protein on Morphology and Mechanical Properties of Bio-Based Polyurethane and Epoxy Foams.
Biomass fillers offer the possibility to modify the mechanical properties of foams, increasing their cost-effectiveness and reducing their carbon footprint. In this study, bio-based PU (soft, open cells for the automotive sector) and epoxy (EP, hard, closed cells for construction applications) composite foams were prepared by adding pristine and laccase-mediated lauryl gallate-hydrophobized hemp protein particles as filler (HP and HHP, respectively). The fillers were able to modify the density, the mechanical properties and the morphology of the PU and EP foams. The addition of HP filler increases the density of PU foams up to 100% and significantly increases the σ values by 40% and Emod values. On the other hand, the inclusion of the HHP as filler in PU foams mostly results in reduced density, by almost 30%, and reduced σ values in comparison with reference and HP-filled foams. Independently from filler concentration and type, the biomass increased the Emod values for all foams relative to the reference. In the case of the EP foams, the tests were only conducted for the foams filled with HHP due to the poor compatibility of HP with the EP matrix. HHP decreased the density, compressive strength and Emod values of the composites. For both foams, the fillers increased the size of the cells, while reducing the amount of open cells of PU foams and the amount of closed cells for EP foams. Finally, both types of foams filled with HHP reduced the moisture uptake by 80 and 45%, respectively, indicating the successful hydrophobization of the composites.


New insights into the mechanism of gelation of alginate and pectin: charge annihilation and reversal mechanism.
Studies have been undertaken on the binding of Mn2+ ions to two alginate samples of different mannuronate:guluronate ratios (M:G), a sample of low-ester amidated pectin and poly(acrylic acid) (PAA). The binding of Ca2+ ions has also been included for the latter for comparison. The binding curves showed an initial steep rise at low additions of Mn2+ or Ca2+ indicating that all of the ions were bound to the polymer chains with none remaining in solution. At higher additions, the binding curves showed a plateau region and the maximum amount bound, theta, was found to be 0.2, 0.2, 0.25, and 0.33 mol M(2+)/mol COO- for high M:G alginate, low M:G alginate, pectin, and PAA, respectively. The binding curves for Mn2+ and Ca2+ with PAA were superimposable. In all cases, theta was less than the stoichiometric equivalent and also less than predicted by Manning counterion condensation theory. The linear charge density, xi, for the polymers is 1.49, 1.55, 1.62, and 2.85, and it was found that at maximum binding the effective linear charge density, xi(effective), decreased to a value close to 1 in each case and not 0.5 as predicted from Manning's two-variable theory. The mobility of the PAA chains has been followed by electron spin resonance spectroscopy using nitroxide spin labels covalently attached to the polymer, and the gelation of the pectin and alginate samples has been monitored using small deformation oscillatory experiments. For PAA at maximum binding, it was noted that there was a loss of chain mobility and precipitation. For pectin and alginate, gelation occurred and the stoichiometric ratio for maximum binding corresponded to the stoichiometric ratio for the maximum in G'. Precipitation and gelation are attributed to the formation of polymer-metal complexes involving one or two carboxylate groups resulting in charge reversal or charge annihilation.


Validating the Turkish version of the Weinstein noise sensitivity scale: effects of age, sex, and education level
Subjective noise sensitivity (SNS) is not only one of the most important predictors of perceived noise annoyance for the subjects exposed to the noise, but also strongly related with some psychological conditions and poor health perception of the subjects. Weinstein's Noise Sensitivity Scale (WNSS) is widely used for measuring of SNS. In this study we adapted WNSS to Turkish (Tr-WNSS) and evaluated its psychometric properties and effect of age, sex and education level on SNS. The study included 105 males and 105 female subjects between 18 and 55 years of age. Our data demonstrated that Tr-WNSS was a reliable, valid, and invariant scale for the Turkish population, and not affected by sex, age and education level.


Alpha1,6-fucosyltransferase-deficient mice exhibit multiple behavioral abnormalities associated with a schizophrenia-like phenotype: importance of the balance between the dopamine and serotonin systems.
Previously, we reported that α1,6-fucosyltransferase (Fut8)-deficient (Fut8(-/-)) mice exhibit emphysema-like changes in the lung and severe growth retardation due to dysregulation of TGF-β1 and EGF receptors and to abnormal integrin activation, respectively. To study the role of α1,6-fucosylation in brain tissue where Fut8 is highly expressed, we examined Fut8(-/-) mice using a combination of neurological and behavioral tests. Fut8(-/-) mice exhibited multiple behavioral abnormalities consistent with a schizophrenia-like phenotype. Fut8(-/-) mice displayed increased locomotion compared with wild-type (Fut8(+/+)) and heterozygous (Fut8(+/-)) mice. In particular, Fut8(-/-) mice showed strenuous hopping behavior in a novel environment. Working memory performance was impaired in Fut8(-/-) mice as evidenced by the Y-maze tests. Furthermore, Fut8(-/-) mice showed prepulse inhibition (PPI) deficiency. Intriguingly, although there was no significant difference between Fut8(+/+) and Fut8(+/-) mice in the PPI test under normal conditions, Fut8(+/-) mice showed impaired PPI after exposure to a restraint stress. This result suggests that reduced expression of Fut8 is a plausible cause of schizophrenia and related disorders. The levels of serotonin metabolites were significantly decreased in both the striatum and nucleus accumbens of the Fut8(-/-) mice. Likewise, treatment with haloperidol, which is an antipsychotic drug that antagonizes dopaminergic and serotonergic receptors, significantly reduced hopping behaviors. The present study is the first to clearly demonstrate that α1,6-fucosylation plays an important role in the brain, and that it might be related to schizophrenia-like behaviors. Thus, the results of the present study provide new insights into the underlying mechanisms responsible for schizophrenia and related disorders.