Production and Characterization of Cellulose Nanocrystals from Eucalyptus Dissolving Pulp Using Endoglucanases from Myceliophthora thermophila.
Endoglucanase (EG) is a key enzyme during enzymatic preparation of cellulose nanocrystals (CNCs). Myceliophthora thermophila is a thermophilic fungus that has thermal properties and a high secretion of endoglucanases (EGs), and could serve as potential sources of EGs for the preparation of CNCs. In this work, four different GH families (GH5, GH7, GH12, and GH45) of EGs from M. thermophila were expressed and purified, and their enzymatic characteristics and feasibility of application in CNC preparation were investigated. It was shown that the MtEG5A from M. thermophila has good potential in the enzymatic preparation of CNCs using eucalyptus dissolving pulp as feedstock. It was also observed that there was a synergistic effect between the MtEG5A and other MtEGs in the preparation of CNCs, which improved the yield and properties of CNCs obtained by enzymatic hydrolysis. This study provides a reference for understanding the enzymatic characteristics of different families of EGs from M. thermophile and their potential application in nanocellulose production.


[Congenitally Corrected Transposition of the Great Arteries( TGA) in Adult].
In patients with congenitally corrected transposition of the great arteries( cc-TGA), the morphological right ventricle (RV) sustains the systemic circulation and is frequently associated with progressive tricuspid regurgitation and declining RV function. Thirty-four patients with cc-TGA and systemic RV were enrolled in this retrospective study to examine long-term outcome. Age was averaged 38.5 years. Associated cardiac anomaly included ventricular septal defect (VSD) and pulmonary stenosis in 18, VSD in 4. Twelve had no associated cardiac defect. The physiologic repair was performed in 22 patients at the mean age of 7.8 years old. Reoperation was frequent including tricuspid valve surgery in 11 and left ventricle( LV)-pulmonary artery( PA) conduit replacement in 10. Five patients needed pacemaker implantation due to heart block. Aortic insufficiency was a relatively common finding and aortic valve replacement was performed in 4. All but 2 patients were better than New York Heart Association (NYHA) class Ⅱ. One needed implantable ventricular assist device implantation and the other underwent heart transplantation. Long-term outcome for patients with cc-TGA was satisfactory. Frequent reoperations including tricuspid valve surgery and LV-PA conduit replacement were required. Further careful follow-up will be needed to detect the progression of RV dysfunction and tricuspid and aortic insufficiency.


Impacted Metallic Spring Requiring Cervical Esophagotomy: A Case Report and Review of the Literature on Foreign Body Removal.
Foreign body ingestion is a commonly encountered problem and can cause significant morbidity and mortality. When removal of a foreign body from the upper gastrointestinal tract is indicated, endoscopy is the modality of choice and has a high reported success rate. However, in less than 1% of cases, endoscopic removal of a foreign body is unsuccessful and surgical intervention is necessary. We report a unique case of a large, sharp metallic spring swallowed by an incarcerated patient which subsequently became lodged in his upper thoracic esophagus. This spring was unable to be removed endoscopically due to risk of perforation and cervical esophagotomy was needed for its successful removal, illustrating the limitations of endoscopic techniques in removal of foreign bodies and the role surgical intervention has in these rare instances.


Heterotetramers formed by an S-layer-streptavidin fusion protein and core-streptavidin as a nanoarrayed template for biochip development.
Based on the S-layer protein SbpA of Bacillus sphaericus CCM 2177, an S-layer-streptavidin fusion protein was constructed. After heterologous expression, isolation of the fusion protein, and refolding, functional heterotetramers were obtained that had retained the ability to recrystallize into the square-lattice structure on plain gold chips and on gold chips precoated with secondary cell wall polymer (SCWP), which is the natural anchoring molecule for the S-layer protein in the bacterial cell wall. Monolayers generated by recrystallization of heterotetramers on plain gold chips or on gold chips precoated with thiolated SCWP were exploited for the binding of biotinylated oligonucleotides (30-mers). Hybridization experiments with complementary fluorescently labeled oligonucleotides carrying one mismatch or no mismatch (both 15-mers) were performed and evaluated with surface-plasmon-field-enhanced fluorescence spectroscopy. For surfaces generated by the recrystallization of heterotetramers on SCWP-coated gold chips, a detection limit of 1.57 pM could be determined, whereas for surfaces obtained by direct recrystallization of heterotetramers on plain gold chips, a detection limit of 8.2 pM was found. Measuring the association and dissociation processes of oligonucleotides carrying no mismatch led to a dissociation constant of K(D)=6.3 x 10(-10) m, whereas for oligonucleotides carrying one mismatch a dissociation constant of K(D)=7.9 x 10(-9) m was determined. This finding was confirmed by measuring the whole Langmuir isotherm, which resulted in a dissociation constant of K(D)=2.6 x 10(-8) m.


Optimal testing time for suppression of competitors during interference resolution.
Interference between competing memory traces is a common cause of memory failure. Recent research has demonstrated a suppression mechanism that operates at retrieval to resolve interference. Using an adaptation of the suppression paradigm in Healey, Ngo, and Hasher [(2014). Below-baseline suppression of competitors during interference resolution by younger but not older adults. Psychological Science, 25(1), 145-151. doi: 10.1177/0956797613501169 ], we tested whether the ability to suppress competing memory traces varies with the synchrony between optimal arousal period and time of testing. We replicate the below-baseline suppression effect for young adults tested at optimal times of day, and present novel evidence that they do not show competitor suppression during non-optimal times of day. In fact, competitors are actually strengthened at non-optimal times. Our results suggest that the ability to resolve interference by suppression varies with circadian arousal.


Nuclear magnetic resonance and proton relaxation times in experimental heterotopic heart transplantation.
It should be possible to detect heart transplant rejection by nuclear magnetic resonance (NMR) imaging if it induces myocardial T1 and T2 proton relaxation time alterations or both. We studied 20 Lewis rats after a heterotopic heart transplantation. In vitro measurement of T1 and T2 was performed on a Minispec PC20 (Bruker) 3 to 9 days after transplantation. Histologic analysis allowed the quantification of rejection process based on cellular infiltration and myocardiolysis. Water content, a major determinant of relaxation time, was also studied. T1 and T2 were significantly prolonged in heterotopic vs orthotopic hearts (638 +/- 41 msec vs 606 +/- 22 msec for T1, p less than 0.01 and 58.2 +/- 8.4 msec vs 47.4 +/- 1.9 msec for T2, p less than 0.001). Water content was also increased in heterotopic hearts (76.4 +/- 2.3 vs 73.8 +/- 1.0, p less than 0.01). Most importantly, we found close correlations between T1 and especially T2 vs water content, cellular infiltration, and myocardiolysis. We conclude that rejection reaction should be noninvasively detected by NMR imaging, particularly with pulse sequences emphasizing T2.


[Fetal outcome after local prostaglandin E2 administration in a risk patient group--comparison of morbidity with a normal patient sample].
Intracervical application of prostaglandin E2 gel is considered to be effective in the induction of cervical ripening (priming). Within an 2-years period 244 perinatal risk patients primed with PGE2 were compared with matched paired controls retrospectively. These 244 controls were matched for age, gestational age, parity, birth weight and maternal body mass index and delivered spontaneously. PGE2 gel (Prepidil) was administered intracervically. Basis criteria of perinatal quality, such as neonatal umbilical cord pH and APGAR-score were significantly (p < 0.01) worse in the patients treated with PGE2 gel. In the priming group cord pH was 7.28 (+/- 0.085) and 7.30 (+/- 0.070) in the control group. APGAR 1 min. was found to be 7.56 +/- 1.86 (priming) and 8.18 +/- 1.23 (control); APGAR 5 min. 8.56 +/- 0.90 (priming) and 8.78 +/- 0.54 (control). Contraction disorders, such as hyperactivity and dyscoordination, combined with cardiotocographic pathology was found in 42% (priming) and 19% (control) resp. Severe bradycardia occurred significantly more often in the priming group, whereas no differences were found concerning fever under labor and in puerperium.


A Diastereodivergent and Enantioselective Approach to syn- and anti-Diamines: Development of 2-Azatrienes for Cu-Catalyzed Reductive Couplings with Imines That Furnish Allylic Amines.
We introduce a new reagent class, 2-azatrienes, as a platform for catalytic enantioselective synthesis of allylic amines. Herein, we demonstrate their promise by a diastereodivergent synthesis of syn- and anti-1,2-diamines through their Cu-bis(phosphine)-catalyzed reductive couplings with imines. With Ph-BPE as the supporting ligand, anti-diamines are obtained (up to 91% yield, >20:1 dr, and >99:1 er), and with the rarely utilized t-Bu-BDPP, syn-diamines are generated (up to 76% yield, 1:>20 dr, and 97:3 er).


A barley homolog of yeast ATG6 is involved in multiple abiotic stress responses and stress resistance regulation.
Autophagy is a highly conserved degradation pathway among eukaryote cells, which can recycle damaged or unwanted cell materials upon encountering stress conditions. As a key component of the Class III PI3K kinase complex, ATG6/Beclin-1 is essential for autophagosome formation. In this study, we isolated a putative HvATG6 gene in barley genome. The protein encoded by HvATG6 shares high sequence identity to ATG6 orthologs in rice and wheat, and has a typical autophagy-specific domain containing segments of repeated β-sheet-α-helix. The expression of HvATG6 protein restored the appearance of autophagosomes in yeast atg6 mutant, indicating that HvATG6 complements the deficiency of yeast ATG6 protein in autophagy. Punctate florescence signals, considered as the PAS for autophagosome initiation, were observed in the cytoplasm of cells when HvATG6-GFP fusion construct was transformed into barley protoplast. Furthermore, the expression of HvATG6 was upregulated by various abiotic stresses including dark, H2O2 treatment, nitrogen deficiency, high salinity, drought, low temperature and toxic aluminum. Knockdown of HvATG6 in barley leaves through barley strip mosaic virus (BSMV)-induced gene silencing led to accelerated yellowing under dark and H2O2 treatments. Based on the above findings, we propose that barley ATG6 plays the similar role as other plant ATG6 orthologs, and might be involved in stress-induced autophagy process.


The importance of varying the event generation process in simulation studies of statistical methods for recurrent events.
Statistical methods for the analysis of recurrent events are often evaluated in simulation studies. A factor rarely varied in such studies is the underlying event generation process. If the relative performance of statistical methods differs across generation processes, then studies based upon one process may mislead. This paper describes the simulation of recurrent events data using four models of the generation process: Poisson, mixed Poisson, autoregressive, and Weibull. For each model four commonly used statistical methods for the analysis of recurrent events (Cox's proportional hazards method, the Andersen-Gill method, negative binomial regression, the Prentice-Williams-Peterson method) were applied to 200 simulated data sets, and the mean estimates, standard errors, and confidence intervals obtained. All methods performed well for the Poisson process. Otherwise, negative binomial regression only performed well for the mixed Poisson process, as did the Andersen-Gill method with a robust estimate of the standard error. The Prentice-Williams-Peterson method performed well only for the autoregressive and Weibull processes. So the relative performance of statistical methods depended upon the model of event generation used to simulate data. In conclusion, it is important that simulation studies of statistical methods for recurrent events include simulated data sets based upon a range of models for event generation.


Effects of low dietary protein and different allocations of food during rearing and restricted feeding after peak rate of lay on egg production, fertility and hatchability in female broiler breeders.
1. A 3x2x2 factorial experiment was conducted with boiler breeder females to determine the effects of body weight gain (three levels) and conventional or lower crude protein concentrations in the rations during rearing, and restricted or ad libitum feeding after the peak rate of lay on egg production, fertility, hatchability, mortality and food consumption. 2. Compared with ad libitum feeding, conventional food restriction resulted in a decrease in average daily food consumption of 0.6 during rearing, 0.2 during early lay and an increase of 0.4 after the peak rate of egg production. Mortality was decreased by more than half. 3. Restricted birds had higher total and settable egg production, fewer defective or damaged eggshells and higher fertility and hatchability than those fed ad libitum. The modified (more generous) rearing programme resulted in lower rates of egg production and higher rates of mortality compared with the conventional food restriction programme. 4. Low-protein rearing rations were associated with higher rates of food intake, higher mortalities and lower rates of egg production than the conventional protein rations. There were no differences in the fertility or hatchability of eggs between birds fed on the two concentrations of dietary crude protein. 5. Ad libitum feeding post-peak was associated with higher rates of mortality to 60 weeks of age. Post-peak feeding had little effect on the rate of lay or egg weight in conventionally restricted birds fed high protein rations or in birds fed ad libitum. Restricted feeding post-peak decreased the rate of lay and egg weight in birds on the modified restriction programme and in conventionally restricted birds fed on the low protein rations. There was no effect of post-peak feeding on fertility or hatchability of eggs. 6. The total numbers of saleable chicks per kg food consumed were 1.83, 1.72 and 0.52 for conventional, modified and ad libitum feeding during rearing; 1.56 and 1.15 for restricted and ad libitum feeding post-peak: there were no differences associated with protein concentrations of rations fed during rearing.


Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor in Caenorhabditis elegans.
During development, homeostasis, and disease, organisms must balance responses that allow adaptation to low oxygen (hypoxia) with those that protect cells from oxidative stress. The evolutionarily conserved hypoxia-inducible factors are central to these processes, as they orchestrate transcriptional responses to oxygen deprivation. Here, we employ genetic strategies in C. elegans to identify stress-responsive genes and pathways that modulate the HIF-1 hypoxia-inducible factor and facilitate oxygen homeostasis. Through a genome-wide RNAi screen, we show that RNAi-mediated mitochondrial or proteasomal dysfunction increases the expression of hypoxia-responsive reporter Pnhr-57::GFP in C. elegans. Interestingly, only a subset of these effects requires hif-1. Of particular importance, we found that skn-1 RNAi increases the expression of hypoxia-responsive reporter Pnhr-57::GFP and elevates HIF-1 protein levels. The SKN-1/NRF transcription factor has been shown to promote oxidative stress resistance. We present evidence that the crosstalk between HIF-1 and SKN-1 is mediated by EGL-9, the prolyl hydroxylase that targets HIF-1 for oxygen-dependent degradation. Treatment that induces SKN-1, such as heat or gsk-3 RNAi, increases expression of a Pegl-9::GFP reporter, and this effect requires skn-1 function and a putative SKN-1 binding site in egl-9 regulatory sequences. Collectively, these data support a model in which SKN-1 promotes egl-9 transcription, thereby inhibiting HIF-1. We propose that this interaction enables animals to adapt quickly to changes in cellular oxygenation and to better survive accompanying oxidative stress.


Improved method for determining serum protein concentrations in the far ultraviolet.
We examined the feasibility of measuring absorbance in the far ultraviolet for serum protein determination with a medium-priced, double-beam spectrophotometer. The method has been simplified by using an automatic dilutor to dilute the serum, and a flow-through cell and recorder in conjunction with the spectrophotometer. Because it is only necessary to dilute the serum and determine its absorbance, the procedure is quite rapid. As compared to the biuret reaction, interferences from hemolysis have been about halved. Interferences owing to light scattering by turbid sera have also been appreciably decreased by use of an anionic detegent (sodium dodecyl sulfate) as a serum diluent. Comparisons of the present method to the biuret and Kjeldahl methods indicate that it is relatively accurate, and is practical for routine use.


The roles of target and eye motion in the production of the visual shift in prism adaptation.
Two experiments, with a total of 48 Ss, were performed to evaluate the possible determinants of the visual shift (VS) in prism adaptation. In Experiment 1 the effects of target movement and pursuit eye movements on resultant visual adaptation were investigated. Maximal VS was produced when both of these conditions were present. Experiment 2 was conducted to determine whether hypnotic anesthesia in and around the eyes and eye muscles reduces feedback from eye-position sensations and, consequently, the magnitude of the VS. This manipulation proved to be successful and virtually eliminated the production of VS. The results of the two experiments helped to identify two factors that contribute to the production of the VS: the presence of visual target movement during prism exposure and the accompanying eye movement which produces a change in the felt position of the eyes during target tracking.


Taming the Wildness of "Trojan-Horse" Peptides by Charge-Guided Masking and Protease-Triggered Demasking for the Controlled Delivery of Antitumor Agents.
Cell-penetrating peptide (CPP), also called "Trojan Horse" peptide, has become a successful approach to deliver various payloads into cells for achieving the intracellular access. However, the "Trojan Horse" peptide is too wild, not just to "Troy", but rather widely distributed in the body. Thus, there is an urgent need to tame the wildness of "Trojan Horse" peptide for targeted delivery of antineoplastic agents to the tumor site. To achieve this goal, we exploit a masked CPP-doxorubicin conjugate platform for targeted delivery of chemotherapeutic drugs using charge-guided masking and protease-triggered demasking strategies. In this platform, the cell-penetrating function of the positively CPP (d-form nonaarginine) is abrogated by a negatively shielding peptide (masked CPP), and between them is a cleavable substrate peptide by the protease (MMP-2/9). Protease-triggered demasking would occur when the masked CPP reached the MMP-2/9-riched tumor. The CPP-doxorubicin conjugate (CPP-Dox) and the masked CPP-Dox conjugate (mCPP-Dox) were used as models for the evaluation of masking and demasking processes. It was found that exogenous MMP-2/9 could effectively trigger the reversion of CPP-cargo in this conjugate, and this trigger adhered to the Michaelis-Menten kinetics profile. This conjugate was sensitive to the trigger of endogenous MMP-2/9 and could induce enhanced cytotoxicity toward MMP-2/9-rich tumor cells. In vivo antitumor efficacy revealed that this masked conjugate had considerable antitumor activity and could inhibit the tumor growth at a higher level relative to CPP-cargo. Low toxicity in vivo showed the noticeably decreased wildness of this conjugate toward normal tissues and more controllable entry of antitumor agents into "Troy". On the basis of analyses in vitro and in vivo, this mCPP-cargo conjugate delivery system held an improved selectivity toward MMP-2/9-rich tumors and would be a promising strategy for tumor-targeted treatment.


Different cell surface oligomeric states of B7-1 and B7-2: implications for signaling.
The costimulatory ligands B7-1 and B7-2 are expressed on the surface of antigen-presenting cells and interact with the costimulatory receptors CD28 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expressed on T cells. Although B7-1 and B7-2 are homologous ligands having common receptors, they exhibit distinct biochemical features and roles in immune regulation. Several biochemical and structural studies have indicated differences in the oligomeric state of B7-1 and B7-2. However, the organization of B7 ligands on the cell surface has not been examined. By using photobleaching-based FRET (pbFRET), we demonstrate that B7-1 and B7-2 adopt different oligomeric states on the cell surface. Our study shows that B7-2 exists as a monomer on the cell surface whereas B7-1 exists predominantly as dimers on the cell surface. A series of mutations in B7-1 result in the expression of a predominantly monomeric species on the cell surface and validate the dimer interface proposed by prior crystallographic analysis. The difference in the oligomeric states of B7-1 and B7-2 provides insight into the geometric organization of the costimulatory receptor-ligand complexes in the immunological synapse and suggests constraints on signal transduction mechanisms involved in T cell activation.


Structural and metabolic changes in rhizophores of the Cerrado species Chrysolaena obovata (Less.) Dematt. as influenced by drought and re-watering.
The high fructan contents in underground organs of Cerrado species, high water solubility, and fast metabolism of these compounds highlight their role as carbon storage and as an adaptive feature in plants under drought. In this study, we showed that anatomical structure, in association with soluble compounds and metabolism of inulin-type fructans were modified in rhizophores of Crysolaena obovata submitted to water suppression and recovery after re-watering. Plants were subjected to daily watering (control), suppression of watering for 22 days (water suppression) and suppression of watering followed by re-watering after 10 days (re-watered). Plants were collected at time 0 and after 3, 7, 10, 12, 17, and 22 days of treatment. In addition to changes in fructan metabolism, high proline content was detected in drought stressed plants, contributing to osmoregulation and recovery after water status reestablishment. Under water suppression, total inulin was reduced from approx. 60 to 40%, mainly due to exohydrolase activity. Concurrently, the activity of fructosyltransferases promoted the production of short chain inulin, which could contribute to the increase in osmotic potential. After re-watering, most parameters analyzed were similar to those of control plants, indicating the resumption of regular metabolism, after water absorption. Inulin sphero-crystals accumulated in parenchymatic cells of the cortex, vascular tissues and pith were reduced under drought and accompanied anatomical changes, starting from day 10. At 22 days of drought, the cortical and vascular tissues were collapsed, and inulin sphero-crystals and inulin content were reduced. The localization of inulin sphero-crystals in vascular tissues of C. obovata, as well as the decrease of total inulin and the increase in oligo:polysaccharide ratio in water stressed plants is consistent with the role of fructans in protecting plants against drought.


COVID-19: impact on colorectal surgery.
The rapid spread of the COVID-19 pandemic has created unprecedented challenges for the medical and surgical healthcare systems. With the ongoing need for urgent and emergency colorectal surgery, including surgery for colorectal cancer, several questions pertaining to operating room (OR) utilization and techniques needed to be rapidly addressed. This manuscript discusses knowledge related to the critical considerations of patient and caregiver safety relating to personal protective equipment (PPE) and the operating room environment. During the COVID-19 pandemic, additional personal protective equipment (PPE) may be required contingent upon local availability of COVID-19 testing and the incidence of known COVID-19 infection in the respective community. In addition to standard COVID-19 PPE precautions, a negative-pressure environment, including an OR, has been recommended, especially for the performance of aerosol-generating procedures (AGPs). Hospital spaces ranging from patient wards to ORs to endoscopy rooms have been successfully converted from standard positive-pressure to negative-pressure spaces. Another important consideration is the method of surgical access; specifically, minimally invasive surgery with pneumoperitoneum is an AGP and thus must be carefully considered. Current debate centres around whether it should be avoided in patients known to be infected with SARS-CoV-2 or whether it can be performed under precautions with safety measures in place to minimize exposure to aerosolized virus particles. Several important lessons learned from pressurized intraperitoneal aerosolized chemotherapy procedures are demonstrated to help improve our understanding and management. This paper evaluates the issues surrounding these challenges including the OR environment and AGPs which are germane to surgical practices around the world. Although there is no single universally agreed upon set of answers, we have presented what we think is a balanced cogent description of logical safe approaches to colorectal surgery during the COVID-19 pandemic.


Synthesis and supramolecular properties of trimethylene-bridged clips.
The novel trimethylene-bridged clips 3 and 4 have been synthesized by using repetitive stereoselective Diels-Alder reactions of the benzo- and naphthobismethylenenorbornenes 8 and 19 as dienes and norbornadiene 9 as bisdienophile, and subsequent dehydrogenation of the primary cyclobisadducts 10 and 20 by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Clips 3 and 4 serve as receptors for a variety of electron-deficient neutral and cationic aromatic substrates, comparable to the molecular tweezers 1 and 2. The thermodynamic parameters of the complex formation, K(a) and DeltaG, were determined by (1)H NMR titration experiments and, in the case of the highly stable complex TCNB 32@4, by the use of isothermal titration microcalorimetry. The finding that clip 4 forms more stable complexes than 3 can be explained by the larger van der Waals contact surfaces of the naphthalene sidewalls in 4 compared to the corresponding benzene systems in 3. In the complexes with 4 as receptor, the plane of each aromatic substrate molecule is calculated to be oriented almost parallel to the naphthalene sidewalls. However, in the complexes of tweezers 2, the substrate is usually oriented parallel to the central naphthalene spacer unit. Due to the more open topology of 4, most complexes were calculated to consist of two or more equilibrating noncovalent conformers.


The structure and dynamics of GPCR oligomers: a new focus in models of cell-signaling mechanisms and drug design.
G protein-coupled receptors (GPCRs) represent approximately half of the potential pharmaceutical targets for current drugs, and thus the way in which these receptors assemble into dimeric/oligomeric structures is of vital interest in practical as well as conceptual aspects of current drug discovery efforts. The significance of such structures is based on the recent realization that ligand-dependent signaling by GPCRs is not necessarily transduced to the G protein by receptor monomers, but possibly by GPCR dimers or even oligomers that function as dynamic macromolecular assemblies. In addition, recent evidence that GPCR hetero-oligomerization can produce signaling units with unexpected combinations of pharmacological properties suggests entirely new methods for developing successful drugs. The dynamic mechanisms of these signaling assemblies remain to be elucidated. The development of increasingly accurate dynamic molecular models of GPCR dimers is expected to produce a more complete structural context for understanding the molecular mechanisms of GPCR function, and to aid in drug discovery.


Bioactive Secondary Metabolites from Schizogyne sericea (Asteraceae) Endemic to Canary Islands.
Schizogyne sericea (Asteraceae) is a halophytic shrub endemic to the Canary Islands and traditionally employed as analgesic, astringent, anti-inflammatory, and vulnerary. A comprehensive phytochemical investigation was conducted on the flowering aerial parts by analyzing both essential oil constituents and polar compounds. The essential oil was dominated by p-cymene, with the noteworthy occurrence of β-pinene and thymol esters. From the EtOH extract, eight compounds were isolated and structurally elucidated. Essential oil, polar fractions, and isolates (2), (4), and (5) were separately in vitro assayed for antiproliferative activity on human tumor cell lines (A375, MDA-MB 231, and HCT116) by MTT assay, for antioxidant potential by DPPH, ABTS, and FRAP assays, and for antimicrobial activity by the agar disk diffusion method. Results revealed that essential oil and compounds 1 and 2 exert a strong inhibition on tumor cells, and in some cases, higher than that of cisplatin. Fractions containing thymol derivatives (1 and 2) and caffeoylquinic acid derivatives 4 and 5 displayed antioxidant activity comparable to that of Trolox, making S. sericea extract an interesting natural product with potential applications as preservative or in the treatment of diseases in which oxidative stress plays an important role.


[Physiological and psychological effects of biological feed-back training (alpha and EMG) among drug using college students].
Twenty-four volunteer college students, who were regular drug users, were randomly allocated to three training groups of equal size: alpha feedback, EMG feedback and a joked control group. Subjects, who were unaware of which feedback condition they received, were asked to practice at home during a six month follow-up period to achieve a relaxed state similar to that experienced during training. No group was successful in retaining gains made in their alpha levels during each session. The EMG group, however, significantly reduced their muscular activity during training and retained the improvement during follow-up. The alpha and joked groups did not significantly improve their EMG during training but at follow-up achieved the same levels as the EMG group. There was evidence to suggest a reduction in drug use among light and medium users that was maintained during follow-up. Significant and lasting improvements were made by each group in the duration and quality of their sleep. Anxiety levels were also reduced.


[Communication skills training for medical students: from the simple to the complex].
Communication skills training at the Medical School of Copenhagen University aims to teach students basic skills in both interviewing and giving information. The article describes a method whereby the students follow a general communication skills model for giving information. The training is conducted with simulated patients (actors). It begins with providing information about simple diagnostic or operative procedures and routine tests. These skills are also practiced in clinical courses on real patients, under supervision. Later on, the students are trained in breaking bad news, but with simulated patients only.


The Characteristics and Risk Factors of Very Asymmetric Keratoconus.
To characterize very asymmetric keratoconus (KC) in terms of clinical demographics and risk factors in the Japanese population. We retrospectively reviewed the clinical records of patients with very asymmetric KC attending a university hospital. Patients with very asymmetric KC had defined clinical KC in one eye and normal topography in the fellow eye. All patients completed a questionnaire on potential risk factors (family history of KC, atopy, asthma, allergy, heart disease, sleep apnea, Down syndrome, eye rubbing, prone sleep position, and dominant hand). These data were compared with those of patients with clinical or topographic KC in both eyes. Subgroup analysis of very asymmetric KC eyes were performed based on the KC status: mild and severe. We retrospectively investigated 66 patients with very asymmetric KC and 505 patients with KC. Patients reported eye rubbing (53%-56%), allergy (62%-63%), and atopy (28%-29%) in both groups. There was no significant difference in terms of risk factors between the two groups. Approximately half of the 66 patients with very asymmetric KC had KC eyes ipsilateral to the dominant hand. Subgroup analysis of very asymmetric KC showed that atopy and asthma were more frequent in the mild KC group than in the severe KC group. Forty-four of 60 patients (73.3%) were using corneal, rigid, gas-permeable contact lenses (corneal GPs) for the KC eye, of which 30 patients (68.2%) were also using a corneal GP for the fellow eye. The patient-reported frequency of eye rubbing, allergy, and atopy were similar between KC and very asymmetric KC. Furthermore, we found no association between hand dominance and KC laterality.


RuPHOX-Ru catalyzed asymmetric hydrogenation of α-substituted tetralones via a dynamic kinetic resolution.
The efficient RuPHOX-Ru catalyzed asymmetric hydrogenation of α-substituted tetralones via a dynamic kinetic resolution has been achieved for the synthesis of chiral tetrahydronaphthols. The mechanism study indicated that hydrogenation with H2 gas, rather than transfer hydrogenation with EtOH solvent as the hydrogen source, predominates in the reaction pathway.


Total joint arthroplasty: the final solution for knee and hip when synovitis could not be controlled.
In severely affected haemophilic patients knee and hip arthropathy is a common problem, which can leads to considerable pain and functional deficit. Surgical management, including total knee and hip arthroplasty, can be undertaken if conservative management fails. This paper reviews the functional outcome of arthroplasty in the knee and hip, the postoperative and long-term complications, and the impact of HIV. Although complications are commonly described and the surgery is technically demanding, the results of the author of this paper and the review of the literature suggest that arthroplasty of the hip and knee can be a valuable option in the management of severe haemophilic arthropathy.


CSF-1-induced and constitutive Il6 gene expression in mouse macrophages: evidence for PKC-dependent and -independent pathways.
It has been recently shown that CSF-1 enhanced the constitutive expression of the Il6 gene in resident mouse peritoneal macrophages (PM phi) but little is known about the pathways involved. In this report, we show that both constitutive and CSF-1-induced IL-6 release were enhanced and prolonged in the presence of the PKC inhibitors, staurosporine (SP) and its derivative, GF-109203X. Enhancement of constitutive IL-6 release required higher concentrations of inhibitors, while enhanced CSF-1-induced release was diminished when inhibitor concentrations exceeded defined limits. SP was also shown to activate constitutive IL-6 release by blood monocytes and elicited PM phi but had no effect on their responsiveness to CSF-1. Activation of PKC by exposure of resident PM phi to phorbol myristate acetate (PMA) also resulted in enhanced IL-6 release and PMA was shown to synergize with CSF-1. These data indicate that CSF-1 does not induce Il6 gene expression by amplifying the constitutive pathway in all mononuclear phagocyte subpopulations. It exerts its effects independently of PKC, which may activate Il6 gene expression in its own right by an alternative pathway. While CSF-1 and PKC are involved in separate pathways, the synergistic IL-6 response seen when PMA and CSF-1 interact suggests convergence of the two pathways. It is also apparent that multiple PKs, excluding PKC, may be involved in repressing constitutive and CSF-1-induced Il6 gene expression.


Pharmacokinetics of a new human monoclonal antibody against cytomegalovirus. Third communication: correspondence of the idiotype activity and virus neutralization activity of the new monoclonal antibody, regavirumab in rat serum and its pharmacokinetics in rats and monkeys.
TI-23 consists of lyophilized regavirumab (monoclonal antibody C23, MCA C23), a new human monoclonal antibody against cytomegalovirus (CMV), human serum albumin (HSA) and amino acetic acid. The pharmacokinetics of MCA C23 was studied in rats and monkeys, and virus neutralization activity was investigated after intravenous administration of TI-23 in rats. MCA C23 idiotype activity (antigenicity against idiotype antibody) was not affected by heat treatment. The rat serum obtained after injection of TI-23 showed a potent inhibition activity of plaque formation. A good correlation (r = 0.873) was observed between idiotype activity and the inhibition activity of plaque formation in the diluted serum samples. After single or repeated injection of TI-23 to cynomolgus monkeys, the MCA C23 concentration in plasma was determined by an immunological method. 1 h after single injection, 60.8 +/- 5.1 micrograms/ml of MCA C23 was detected in plasma, then the plasma level decreased with an elimination half-life of 20.5 +/- 6.2 days and the AUC value was 18.3 +/- 3.4 mg.h/ml. In the repeated administration experiment (2 mg/kg/week, 5 times), the MCA C23 plasma concentration reached a steady state (74.4 +/- 11.8 micrograms/ml) at 24 h after the fourth injection. The elimination half-life after the final injection was similar to that after the single injection.


[Septal ablation in the treatment of hypertrophic myocardiopathy].
Hypertrophic cardiomyopathy is a relative frequent disease and probably the most common genetic transmitted cardiovascular disease. Fortunately, the more aggressive varieties of the disease represent the less common manifestation of it. Outflow left ventricular obstruction is present in about 25 to 30% of the cases. Recently, septal ablation by means of the selective alcohol injection in left anterior descendent septal branches was introduced as a therapeutic alternative in cases associated with left ventricular outflow obstruction. Results with this technique have been encouraging with a success rate over 90%, and a low rate incidence of complications and mortality. These results are similar to those of surgical myectomy. We review indications, technique, and results obtained with this procedure.


Relationship of ADHD symptoms and global illness severity in adults treated with lisdexamfetamine dimesylate.
The relationship between attention-deficit/hyperactivity disorder (ADHD) symptoms and global clinical assessment of functionality is complex. This post-hoc analysis explores this relationship and suggests implications for patient assessment in clinical practice. Adults with ADHD on a stable lisdexamfetamine dimesylate (LDX) dose for ≥ 6 months were enrolled in a double-blind, placebo-controlled, randomized withdrawal study. Participants entered a 3-week open-label phase continuing their prior LDX dose and were then randomized to placebo or the same LDX dose for a 6-week, double-blind, randomized withdrawal phase. ADHD symptom distribution was measured by the ADHD Rating Scale IV (ADHD-RS-IV) with Adult Prompts total score reflecting DSM-IV-TR ADHD symptom criteria and severity by Clinical Global Impressions-Severity (CGI-S) ratings at study entry and at end of study. Of 123 participants enrolled in the open-label phase, 116 were included in the randomized withdrawal phase (placebo, n = 60; LDX, n = 56). As reported in a prior publication, mean (standard deviation) ADHD-RS-IV total score change from baseline (week 3) to end of study (randomized-withdrawal phase) was 16.8 (11.80) for placebo and 1.6 (8.63) for LDX. At end of study, for placebo and LDX, 5.0% and 32.1% of participants, respectively, had a CGI-S = 1, 11.7% and 35.7% had a CGI-S = 2, 11.7% and 17.9% had a CGI-S = 3, 33.3% and 7.1% had a CGI-S = 4, 35.0% and 7.1% had a CGI-S = 5, and 3.3% and 0% had a CGI-S = 6; no participants had a CGI-S = 7 (P < 0.0001). The CGI-S ratings increased (worsened) as ADHD symptom scores worsened. Post-hoc regression analysis between ADHD-RS-IV scores and CGI-S demonstrated shared variance of 47% at week 3 and 69% for both placebo and LDX at end of study. Although ADHD symptom scores demonstrate a linear relationship with global illness severity, the variance suggests that other factors not captured by symptom scales are also important in assessing patient outcomes in clinical practice. ( ClinicalTrials.gov NCT00877487.).


Colony-stimulating factors in the modulation of sepsis.
Colony-stimulating factors, a complex family of cytokines often referred to as hematopoietic growth factors, are a family of glycoprotein hormones that regulate production and differentiation of hematopoietic cells. The study of colony-stimulating factors was originally confined to stimulation and formation of clonal colonies in in vitro culture systems. The study of hematopoietic growth factors has since evolved into an expanding number of clinical applications in the treatment of patients with hematopoietic and immunologic diseases. Increased occurrence rates of infection have been demonstrated to be associated with both severity and duration of neutropenia. Sepsis has also been associated with phagocytic functional abnormalities. Both neutropenia and neutrophil dysfunction have been shown, in part, to be corrected by granulocyte colony-stimulating factor or granulocyte-monocyte colony-stimulating factor. In clinical trials to date, neither of these growth factors has shown significant toxicity. This article discusses the possible use of these and other growth factors in the treatment of sepsis.


Stepwise Formation of Photoconductive Nanotubes through a New Top-Down Method.
In contrast to the widely used bottom-up strategy for preparing various complex nanostructures, the top-down strategy is rarely applied to generate complex nanostructures. This study reports the use of a unique combination of bottom-up and top-down processes for the time-resolved stepwise fabrication of novel photoconductive nanotubes from elaborately designed asymmetric perylene diimide molecules.


Catalytic asymmetric methallylation of ketones with an (H8-BINOLate)Ti-based catalyst.
The first catalytic asymmetric methallylation of ketones is reported. The catalyst, which is generated from titanium tetraisopropoxide, H8-BINOL, 2-propanol, and tetramethallylstannane, reacts with ketones in acetonitrile to afford tertiary homoallylic alcohols in fair to excellent yields (55-99%) and fair to high enantioselectivities (46-90%). Ozonolysis of the resulting products provides access to chiral beta-hydroxy ketones, which are not readily prepared from direct asymmetric aldol reaction of acetone with ketones.


Reversible Pressure-Controlled Depolymerization of a Copper(II)-Containing Coordination Polymer.
A unique pressure-induced Cu-N bond breaking/bond forming reaction is reported. The variation of pressure on a single crystal of a one-dimensional copper- (II)-containing coordination polymer (Cu2 L2 (1-methylpiperazine)2 ]n , where H2 L is 1,1'-(1,3-phenylene)-bis(4,4-dimethylpentane-1,3-dione)), was monitored using single crystal X-ray diffraction with the aid of a diamond anvil cell. At a very low elevated pressure (≈0.05 GPa) a remarkable reversible phase change was observed. The phase change results in the depolymerization of the material through the cleavage and formation of axial Cu-N bonds as well as "ring flips" of individual axially coordinated 1-methylpiperazine ligands. Overall, the pressure-induced phase change is associated with a surprising (and non-intuitive) shift in structure-from a 1-dimensional coordination polymer to a discrete dinuclear complex.


The role of genetics and ethnicity in epilepsy management.
Recent exciting developments in epilepsy genetics have led to significant insights into the mechanisms underlying seizure disorders. Success in epilepsy genetics research to date has resulted from identification of genes responsible for rare monogenic disorders, the majority encoding either voltage- or ligand-gated ion channels. For some conditions, such as benign familial neonatal seizures, an understanding of the underlying genetics is helpful in predicting prognosis. However, for other disorders, such as autosomal dominant nocturnal frontal lobe epilepsy, phenotypic severity is determined by factors other than the major dominant nicotinic subunit mutation found in some families. Further complexity arises when single-gene mutations give rise to heterogeneous phenotypes, as typically occur with generalized epilepsy with febrile seizures plus. Another area of increasing genetic endeavour, pharmacogenetics will allow tailoring of antiepileptic medication for each patient. Pharmacogenetics explores genetic polymorphisms in genes coding for drug-metabolizing enzymes, receptors and transporters. Polymorphisms have been identified that result in marked ethnic and interindividual differences in response to treatment. With further understanding of the impact of these differences, pharmacogenetic screening is likely to guide the management of epilepsy in the future.


Effects of Exercise on Cardiorespiratory Fitness and Biochemical Progression in Men With Localized Prostate Cancer Under Active Surveillance: The ERASE Randomized Clinical Trial.
Men with prostate cancer who are undergoing active surveillance are at an increased risk of cardiovascular death and disease progression. Exercise has been shown to improve cardiorespiratory fitness, physical functioning, body composition, fatigue, and quality of life during and after treatment; however, to date only 1 exercise study has been conducted in this clinical setting. To examine the effects of exercise on cardiorespiratory fitness and biochemical progression in men with prostate cancer who were undergoing active surveillance. The Exercise During Active Surveillance for Prostate Cancer (ERASE) trial was a single-center, 2-group, phase 2 randomized clinical trial conducted at the University of Alberta, Edmonton, Canada. Eligible patients were recruited from July 24, 2018, to February 5, 2020. Participants were adult men who were diagnosed with localized very low risk to favorable intermediate risk prostate cancer and undergoing active surveillance. They were randomized to either the high-intensity interval training (HIIT) group or usual care group. All statistical analyses were based on the intention-to-treat principle. The HIIT group was asked to complete 12 weeks of thrice-weekly, supervised aerobic sessions on a treadmill at 85% to 95% of peak oxygen consumption (V̇o2). The usual care group maintained their normal exercise levels. The primary outcome was peak V̇o2, which was assessed as the highest value of oxygen uptake during a graded exercise test using a modified Bruce protocol. Secondary and exploratory outcomes were indicators of biochemical progression of prostate cancer, including prostate-specific antigen (PSA) level and PSA kinetics, and growth of prostate cancer cell line LNCaP. A total of 52 male patients, with a mean (SD) age of 63.4 (7.1) years, were randomized to either the HIIT (n = 26) or usual care (n = 26) groups. Overall, 46 of 52 participants (88%) completed the postintervention peak V̇o2 assessment, and 49 of 52 participants (94%) provided blood samples. Adherence to HIIT was 96%. The primary outcome of peak V̇o2 increased by 0.9 mL/kg/min in the HIIT group and decreased by 0.5 mL/kg/min in the usual care group (adjusted between-group mean difference (1.6 mL/kg/min; 95% CI, 0.3-2.9; P = .01). Compared with the usual care group, the HIIT group experienced decreased PSA level (-1.1 μg/L; 95% CI, -2.1 to 0.0; P = .04), PSA velocity (-1.3 μg /L/y; 95% CI, -2.5 to -0.1; P = .04), and LNCaP cell growth (-0.13 optical density unit; 95% CI, -0.25 to -0.02; P = .02). No statistically significant differences were found in PSA doubling time or testosterone. The ERASE trial demonstrated that HIIT increased cardiorespiratory fitness levels and decreased PSA levels, PSA velocity, and prostate cancer cell growth in men with localized prostate cancer who were under active surveillance. Larger trials are warranted to determine whether such improvement translates to better longer-term clinical outcomes in this setting. ClinicalTrials.gov Identifier: NCT03203460.


[Gonadotroph Pituitary Adenoma Causing Severe Headache Following Repeated Use of GnRH Agonist for Prostate Cancer].
Gonadotropin-releasing hormone (GnRH) agonists play an important role in androgen deprivation therapy (ADT) employed for locally advanced prostate cancer. A 76-year-old man presented with elevated levels of prostate-specific antigen (PSA, 8.33 ng/ml). Subsequently he was diagnosed with cT3bN0M0 prostate cancer, Gleason score 4+5. Before he was referred to our clinic, he had been administered bicalutamide (80 mg/day) daily by the referring physician, followed by subcutaneous injection of goserelin (3. 6 mg) 15 days later. The second dose of another GnRH agonist (leuprolide, 22.5 mg) was administered at his first visit to our clinic, 11 days after goserelin injection, at the discretion of the attending physician (26th day after bicalutamide administration). Bicalutamide administration was concomitantly maintained throughout the period. The patient presented with severe headache the next morning, and imaging studies detected a prominent pituitary adenoma. A trans-sphenoidal surgery was conducted for symptomatic relief. Histopathological analysis revealed a gonadotroph (follicle-stimulating hormone-secreting) pituitary adenoma. Although speculative, repeated injection of GnRH agonist was concluded to be the most likely cause of acute symptomatic gonadotroph pituitary adenoma. The irregular use of medication can cause undesirable and unanticipated adverse events. Awareness is the key to the prevention of such conditions.


Moldavica acid A, a new salicylic acid derivative from Dracocephalum moldavica.
In this paper, we present the discovery of a novel salicylic acid derivative, moldavica acid A (1), and a new natural dibenzo[b,f]oxepin, moldavica acid B (2), together with four known phenylpropionic acids (3-6) and protocatechuic acid (7) that were isolated from Dracocephalum moldavica L. Their structures were elucidated by comprehensive spectroscopic methods, including infrared and nuclear magnetic resonance. Compound 1 is the first example of salicylic acid linking a carboxylated α-pyrone via an ethyl bridge. Beyond expanding the knowledge of the chemical diversity of D. moldavica, both compounds 1 and 2 were shown to upregulate the expression of Kruppel-like factor 2, which could serve as a prospective therapeutic target for the treatment of atherosclerosis.


Relative affinity of quazepam for type-1 benzodiazepine receptors in brain.
Quazepam and its major metabolite, 2-oxoquazepam, were the first benzodiazepine (BZ) compounds shown to be capable of differentiating between central nervous system (CNS) subtypes of BZ receptors. Initial studies suggested that quazepam preferentially binds to the BZ1-receptor population with high affinity at relatively low doses. Subsequent binding experiments, performed in both human and rodent brain, confirmed this hypothesis for both the parent compound and its principal metabolite. Autoradiographic studies revealed a differential distribution of BZ1 and BZ2 receptors within regions of the brain associated with behavior, sensory input, control of movement, and coordination. BZ1 receptors are concentrated in specific, well-localized regions of the brain. BZ2 receptors are more widespread and diffusely localized throughout most brain regions. These observations suggest that a selective BZ1 agent such as quazepam might have a different pharmacologic profile than other nonselective benzodiazepines. Restricting the number of sites where BZ drugs act has been proposed as a strategy for producing a more circumscribed therapeutic effect; the BZ1 selectivity of quazepam embodies this concept.


Proteolytic activity of the nematophagous fungus Arthrobotrys sinensis on Angiostrongylus vasorum larvae.
The predatory nematophagous fungus Arthrobotrys sinensis (SF53) produces three proteases with nematicidal activity when grown on solid media culture. However, the proteolytic profile produced by this fungus, when grown in liquid culture medium remains unknown. Thus, the objective of this work was to evaluate the production of proteases from nematophagous fungus Arthrobotrys sinensis in liquid medium and its nematicidal activity on first stage larvae of A. vasorum. Proteases were obtained in its crude form, using Whatman no.1 filter paper, followed by centrifugation for 5 min at 10 × g and 4°C. A zymogram was performed with co-polymerized casein in an acrylamide gel as substrate. An in vitro assay to evaluate the nematicidal action of the proteases of A. sinensis (SF53) produced in liquid medium on A. vasorum L1 was conducted. By the analysis of the zymogram, it was observed a single halo at the beginning of digestion of the gel, suggesting that the three proteases of SF53 are produced in an enzymatic complex of large molecular weight. Regarding nematicidal activity, within 24 hours, the proteases produced in liquid medium of A. sinensis (SF53) showed a percentage reduction of 64% on the number of L1 of A. vasorum. In the present work, it is suggested that the three proteases of SF53 are produced in an enzymatic complex and was also demonstrated that these enzymes were effective in destroying A. vasorum L1.


The mechanism of aldosterone response to furosemide test in patients with Shy-Drager syndrome.
We examined the renin-angiotensin-aldosterone system in seven patients with Shy-Drager syndrome by studying their response to the stimulation of 1 mg/kg furosemide injection followed by sitting for 1 hour. Six of the seven patients showed a low response of plasma renin activity to the stimulation. However, in five of the low responders, the plasma aldosterone levels after stimulation were observed to be similar to those of the control subjects; in addition, an increment in the plasma cortisol level appeared although no such increment was observed in normal subjects. Next, we studied the aldosterone response to angiotensin II. The five patients who showed a low plasma renin activity response and a normal aldosterone response to furosemide administration also showed low plasma aldosterone response to angiotensin II. Furthermore, in the patients who demonstrated a low plasma renin activity response and a normal aldosterone response to furosemide administration, the pretreatment with 2 mg dexamethasone for 2 days caused a marked inhibition of aldosterone response to the stimulation. These findings suggested that in most patients with Shy-Drager syndrome, the plasma aldosterone response to the stimulation of furosemide injection followed by sitting for 1 hour might be controlled by ACTH but not by plasma renin activity.


Familial aggregation of haematological neoplasms: a controlled study.
Advances in molecular biology techniques suggest that many haematological neoplasms originate from a transformation process at the level of the haemopoietic pluripotential stem cell. While familial aggregation has been reported for many haematological neoplasms, most studies were uncontrolled and examined the presence of the same haematological neoplasm as the index case. We assessed the familial aggregation of all haematological neoplasms in 4061 family members of 189 patients with various haematological neoplasms and two control groups: 955 relatives of 36 patients with non-malignant haematological disorders and 508 relatives of 33 patients with type II diabetes mellitus. Data collection included self-administered questionnaires. The odds ratio for haematological neoplasms among relatives of the index cases adjusted for age, sex, ethnicity, number of relatives in the family, and degree of familial linkage in the study group versus the two control groups was 3.62 (95% confidence interval, 1.44-9.07; P < 0.01). The vast majority of the haematological neoplasms among family members did not belong to the same histopathological category as the index cases. The data support the hypothesis of a genetic predisposition to haematological neoplasms. The fact that the aggregation is not disease specific is consistent with a defect in the pluripotent haemopoietic stem cell.


Composite sequence proteomic analysis of protein biomarkers of Campylobacter coli, C. lari and C. concisus for bacterial identification.
Protein biomarkers observed in the matrix-assisted laser desorption/ionization time-of-flight mass spectra (MALDI-TOF-MS) of cell lysates of three strains of Campylobacter coli, two strains of C. lari and one strain of C. concisus have been identified by 'bottom-up' proteomic techniques. The significant findings are as follows. First, the protein biomarkers identified were: PhnA-related protein, 4-oxalocrotonate tautomerase (DmpI)-related protein, NifU-like protein, cytochrome c, DNA-binding protein HU, 10 kDa chaperonin, thioredoxin, as well as several conserved hypothetical and ribosomal proteins. Second, variations in the biomarker ion m/z in MALDI-TOF-MS spectra across species and strains are the result of variations in the amino acid sequence of the protein due to non-synonymous mutations of the biomarker gene. Third, the most common post-translational modifications (PTMs) were the removal of the N-terminal methionine and N-terminal signal peptides. However, in the case of the NifU protein (an iron-sulfur cluster transport protein), post-translational cleavage occurred from the C-terminus. Fourth, only the genomes of the C. coli strain RM2228 and C. lari strain RM2100 have been sequenced; thus, proteomic identification of the proteins of the other strains in this study relied upon sequence homology to the genomic sequence of these strains as well as the genomes of sequences of other Campylobacter strains. In some cases, the determination of the full amino acid sequence of a protein biomarker from a genomically non-sequenced strain was accomplished by combining non-overlapping partial sequences from proteomic identifications of genomically-sequenced strains that were of the same species (or of a different species) to that of the non-sequenced strain. The accuracy of this composite sequence was confirmed by both MS and MS/MS. It was necessary, in some cases, to perform de novo sequencing on 'gaps' in the composite sequence that were not homologous to any genomically-sequenced strain. In order to validate the composite sequence approach, composite sequences were further confirmed by subsequent DNA sequencing of the biomarker gene. Thus, using the composite sequence approach, it was possible to determine the full amino acid sequence of an unknown protein from a genomically non-sequenced bacterial strain without the necessity of either sequencing the biomarker gene or performing full de novo MS/MS sequencing. The sequence obtained could then be used as a strain-specific biomarker for analysis by 'top-down' proteomics techniques.


Components of the AIN-93 diets as improvements in the AIN-76A diet.
The AIN-93 rodent diets were formulated to substitute for the previous version (AIN-76A) and to improve the performance of animals that consume them. They are called AIN-93G, formulated for growth, and AIN-93M, for maintenance. Major changes included substituting cornstarch for sucrose and soybean oil for corn oil and increasing the amount in order to supply both essential fatty acids (linoleic and linolenic). L-Cystine was substituted for DL-methionine to supplement the casein component. The mineral mix was reformulated to lower the amounts of phosphorus, manganese and chromium, to increase the amount of selenium, and to add molybdenum, silicon, fluoride, nickel, boron, lithium and vanadium. The amounts of vitamins E, K-1 and B-12 were increased over those in the AIN-76A vitamin mix. The AIN-93G diet contains 200 g of casein and 70 g of soybean oil/kg diet. The maintenance diet (AIN-93M) contains 140 g of casein and 40 g of soybean oil/kg diet. The 1993 diets have a better balance of essential nutrients than the 1976 diet and are better choices for studies with laboratory rodents.


Evaluation of toxicity of gadolinium-based contrast agents on neuronal cells.
Gadolinium-based contrast agents (GBCAs) are widely used in magnetic resonance imaging (MRI). Recently, increased signal intensity has been reported in specific brain areas after repeated administrations of GBCAs. To investigate the toxic effects of GBCAs on neuronal cells by using SH-SY5Y neuroblastoma cell cultures. For toxicity assays, SH-SY5Y cells were incubated with different doses (0-1000 µM) of several macrocyclic (gadoterate meglumine and gadobutrol) and linear GBCAs (gadoversetamide, gadopentetate dimeglumine, gadodiamide, and gadoxetate disodium) for 48 h. Cell viability and proliferation capacity were evaluated by using MTS assay, LDH assay, and colony-forming assay. In addition, Western blotting of Bcl-2 and Bax proteins and nuclear Hoechst 33258 staining were performed to evaluate apoptotic cell death. The results were expressed as mean ± SEM. The data were analyzed using Student's t-test. A P value < 0.05 was accepted as statistically significant. Both macrocyclic and linear GBCAs significantly and dose-dependently reduced cell viability in neuronal cells compared to control. Cell viability was measured between 89.5% ± 4% and 61% ± 0.7% in GBCA-treated groups. In addition, neurotoxicity was more prominent in linear GBCA-treated cultures (P < 0.0005). Bax protein levels were increased in GBCA-treated cells particularly with linear agents whereas Bcl-2 expression was decreased concomitantly. The results of the present study indicated that exposure to specific GBCAs, even at low micro-molar concentrations, may have detrimental effects on neuronal survival. Further investigations are required to clarify the molecular mechanism underlying GBCA-induced cell death.


Insulin sensitization with a peroxisome proliferator-activated receptor γ agonist prevents adrenocortical lipid infiltration and secretory changes induced by a high-sucrose diet.
It has been hypothesized that deviations in glucocorticoid secretion and/or action may contribute to somatic and biochemical changes observed in patients with and animal models of insulin resistance (IR). In this study, we analyzed changes in rat adrenocortical function and morphology associated with the development of IR, generated in male adult rats by the addition of 30% sucrose to the drinking water. Caloric intake, body and adipose tissue weights, and biochemical parameters associated with IR were determined. Expression levels of Star, Cyp11A1, Mc2r, Pparγ (Pparg), and Cd36 were evaluated by real-time PCR, histochemical analysis of the adrenal cortex was performed using Masson's trichrome and Sudan III staining, and corticosterone levels were measured by RIA. After 7 weeks of sucrose administration, higher serum glucose, insulin, and triglyceride levels and an altered glycemic response to an i.p. insulin test were detected. Adrenal glands showed a neutral lipid infiltration. An increase in Star, Cyp11A1, Mc2r, Pparg and Cd36 and a decrease in Mc2r levels were also found. Furthermore, sucrose-treated animals exhibited higher basal corticosterone levels and a blunted response to ACTH injection. Noteworthy, the adrenocortical (functional and histological) abnormalities were prevented in sucrose-treated rats by the simultaneous administration of an insulin-sensitizing PPARγ agonist. In conclusion, sucrose-induced IR affects adrenocortical morphology and function possibly via the generation of adipokines or lipid metabolites within the adrenal gland. These abnormalities are prevented by the administration of a PPARγ agonist by mechanisms involving both extra- and intra-adrenal effects.


Bacithrocins A, B and C, novel thrombin inhibitors.
Novel thrombin inhibitors, bacithrocins A, B and C, have been isolated from the culture broth of Bacillus laterosporus Laubach NR 2988. The structures of these inhibitors have been determined to be N-acyl-L-phenylalanyl-DL-arginal by the 2D-NMR experiments on their oxidation products and by amino acid analysis. Bacithrocin A inhibits thrombin, factor Xa and trypsin with IC50s of 48, 13 and 0.65 microM, respectively, which are similar to those of bacithrocins B and C. Bacithrocins prolong the clotting time induced by thrombin and factor Xa.


Sire and liveweight affect feed intake and methane emissions of sheep confined in respiration chambers.
Daily methane production and feed intake were measured on 160 adult ewes, which were the progeny of 20 sires and 3 sire types (Merino, dual-purpose and terminal) from a genetically diverse flock. All animals were housed in individual pens and fed a 50/50 mix of chaffed lucerne and oaten hays at 20 g/kg liveweight (LW), with feed refusals measured for at least 10 days before the first of three 22-h measurements in respiration chambers (RC). Feed was withdrawn at 1600 h on the day before each RC test to encourage the ewes to eat the entire ration provided for them in the RC. After the first 1-day RC test, the sheep were returned to their pens for a day, then given a second 1-day RC test, followed by another day in their pens, then a third RC test. After all animals had been tested, they were ranked according to methane emissions adjusted for feed intake in the RC and on the previous day, enabling 10 low and 10 high methane animals to be chosen for repeat measurement. No variation between sires nor consistent effects of LW on feed eaten (%FE, expressed as per cent of feed offered) was evident in the 10 days before the first RC measurement. However, significant differences between sires (equivalent to an estimated heritability of 41%) were identified for %FE during the 2(nd) and 3(rd) days of RC testing (2 and 4 days after the initial RC test). The analysis of all data showed that methane emissions in the RC were related to feed intake on the day of testing and the two previous days (all P<0.0005). Before correcting for feed intake on previous days, there was some variation between sires in methane yield, equivalent to an estimated heritability of 9%. Correction for feed intake on the 2 previous days halved the residual variation, allowing other effects to be detected, including effects of LW, twins reared as singles, test batch, RC and test-day effects, but estimated sire variation fell to zero. In order to avoid potential biases, statistical models of methane emissions in the RC need to consider potential confounding factors, such as those identified as significant in this study.


Lessons Learned From Frontline Nurses: Considerations for Nurses in Professional Development During the COVID-19 Pandemic.
The COVID-19 pandemic has compounded the stress level of nurses and the nursing shortage. In addition, the disruption of bedside clinical experiences has raised concerns about the preparedness of nurses entering practice. A mixed methods study was conducted to learn about the perceptions of frontline nurses during the COVID-19 pandemic. Findings revealed implications for nurses in professional development as they are challenged to reimagine new nurse orientation and meet the needs of graduates transitioning to practice.


On the mechanism of the calcium paradox: the release of hydrolytic enzymes.
Sequential perfusion of the heart with Ca2+-free and Ca2+ containing solutions leads to defects in myocytal surface membranes through which excess Ca2+ enters and cytosolic constituents leave the cells. During Ca2+-free perfusion the glycocalyx of the cells is damaged. Lipoprotein lipase, bound to mucopolysaccharides on the outside of cells, is released during Ca2+-free perfusion. This enzyme, involved in lipoprotein triglyceride uptake into the cells, is an alpha-lipase, which also hydrolyzes phospholipids. In addition to this phospholipase A1 activity some phospholipase A2 activity, due to another enzyme, is partially lost during Ca2+-free perfusion. The partial loss of this enzyme might be a reflection of the known increase of motional freedom of membrane phospholipids in the absence of Ca2+. The reintroduction of Ca2+ might rearrange phospholipids and activate residual phospholipase A2 so that pores arise that allow the passage of excess amounts of Ca2+. There is no reason to believe that the membranes of the organelles beyond the plasmalemma contribute to the early phenomena of the calcium paradox, as no soluble enzymes, contained within these organelles, are initially released from the heart. However, the calcium overload may stimulate Ca2+-dependent (phospho)lipases and proteases to contribute to the irreversible loss of structure and function.


Altered L-arginine/nitric oxide synthase/nitric oxide pathway in the vascular adventitia of rats with sepsis.
1. In recent studies, the vascular adventitia has been established as an important source of inducible nitric oxide synthase (iNOS) and subsequent nitric oxide (NO) production, even more powerful than the media in response to certain inflammatory factors, such as lipopolysaccharide (LPS). The adventitia has an independent L-arginine (L-Arg)/NOS/NO pathway and is involved in the regulation of vascular function. In the present study, we explored the changes in and the pathophysiological significance of the L-Arg/NOS/NO pathway in the adventitia of rats with sepsis. 2. Sepsis was induced by caecal ligation and puncture in order to observe changes in L-Arg transport, NOS gene expression and activity and NO generation in the vascular adventitia to determine the mechanism of activation of the L-Arg/NOS/NO pathway. 3. Severe sepsis resulted in severe disturbance of haemodynamic features, with decreased mean arterial blood pressure, brachycardia and inhibited cardiac function (decreased left ventricular +/-dP/dt(max)). Left ventricular end-diastolic pressure was elevated threefold (P < 0.01) under anaesthesia. Rats with sepsis showed severe glucopenia and lacticaemia. Plasma levels of the inflammatory factors macrophage chemoattractant protein-1 and interleukin-8 were increased five- and 29-fold, respectively (P < 0.01). 4. In the adventitia of the thoracic and abdominal aortas, the L-Arg/NO pathway was similarly characterized: the uptake of [(3)H]-L-Arg was Na(+) independent, with the peak occurring at approximately 40 min incubation. Total NOS activity was largely calcium independent (> 90%). The V(max) of L-Arg transport in the sepsis group was increased by 83.5% (P < 0.01), but the K(m) value was not significantly different compared with controls. 5. The mRNA levels of cationic amino acid transporter (CAT)-1 and CAT-2B in the sepsis group were increased by 86 and 62%, respectively (both P < 0.01). Inducible NOS activity was increased 2.8-fold compared with controls (P < 0.01) and iNOS mRNA levels were elevated approximately sixfold (P < 0.01). The NO levels in the plasma and incubation media (incubation for 40 min) in the sepsis group were increased by 144 and 273%, respectively (both P < 0.01). 6. The Arg/NOS/NO pathway was activated in the vascular adventitia of rats with sepsis shock. The L-Arg/NOS/NO pathway in the aortic adventitia may play an important role in the pathogenesis of sepsis and septic shock.


Functional expression of organic cation/carnitine transporter 2 (OCTN2/SLC22A5) in human brain capillary endothelial cell line hCMEC/D3, a human blood-brain barrier model.
The aim of this study was to examine whether organic cation/carnitine transporter 2 (OCTN2/SLC22A5) plays a role in the human blood-brain barrier (BBB) by evaluating its functional activity in human brain endothelial cells (hCMEC/D3), which are considered to be a model of the BBB. The uptake of [(3)H]L-carnitine by hCMEC/D3 cells was time-, extracellular sodium- and concentration-dependent, with a Km value of 15.7 µM. These results are consistent with the properties of OCTN2-mediated L-carnitine transport. hCMEC/D3 cells showed relatively high expression of OCTN2 mRNA, and this expression was effectively decreased at 24-72 h after lipofection of cells with OCTN2 siRNA under optimized conditions. [(3)H]L-Carnitine uptake was dramatically suppressed by silencing of the OCTN2 gene. The inhibitory effect of OCTN2 gene silencing was similar to that of an excess amount of unlabeled L-carnitine. These results indicate that OCTN2 is involved in L-carnitine transport at the human BBB.


Steroids excreted in urine by neonates with 21-hydroxylase deficiency. 4. Characterization, using GC-MS and GC-MS/MS, of 11oxo-pregnanes and 11oxo-pregnenes.
In 21-hydroxylase deficiency, urinary metabolites of 21-deoxycortisol, mainly derived from its 11oxo form 21-deoxycortisone, are indicators of intra-adrenal overproduction of 17-hydroxyprogesterone. In affected neonates these metabolites are numerous and most have not been previously described. This work forms the concluding part of a comprehensive study of urinary steroids, aiming to enhance the diagnosis of this disorder and to further elucidate steroid metabolism in neonates. Cortisol metabolites found in untreated patients, similarly almost exclusively present in their 11oxo form in neonates, have been included for completeness. Steroids were analyzed, after extraction and enzymatic conjugate hydrolysis, as methyloxime-trimethylsilyl ether derivatives on gas-chromatographs coupled to quadrupole and ion-trap mass-spectrometers. GC-MS and GC-MS/MS spectra were used together to determine the structure of hitherto undescribed 11oxo-pregnane(enes). Few GC-MS features were associated with the presence of the non-derivatizeable 11oxo group in pregnane(ene)s. GC-MS/MS contributed only to the characterization of structures outside the C-ring, as described in the preceding parts of this study. Parallels were found between the metabolism of 21-deoxycortisone and cortisone. The major metabolic pathway was that of classical 3α,5β-reduction with a prominent further hydroxylation, predominantly at C6. Oxidation of the 6-hydroxyl was also common. We conclude that further oxygenated metabolites of 21-deoxycortisone have potential as more reliable markers of 21-hydroxylase deficiency in the early neonatal period, because their levels are higher during that period of life than for the classical marker 11oxo-pregnanetriol.


Association between smoking history and optical coherence tomography angiography findings in diabetic patients without diabetic retinopathy.
To investigate any associations between cigarette smoking and retinal microvascular changes in diabetic patients without visible retinopathy. Retrospective, cross-sectional study. 1099 eyes from 1099 diabetic patients with no clinical evidence of diabetic retinopathy (DR) were included in this study. Diabetic patients underwent optical coherence tomography angiography (OCTA) scanning at Zuckerberg San Francisco General Hospital and Trauma Center between April 2018 and September 2019. Patient demographic and clinical information was collected. Standard bivariate statistics and multivariate linear regression were performed. OCTA parameters included metrics related to the foveal avascular zone (FAZ; area, perimeter, circularity), perfusion density (PD; full, center, inner), and vessel length density (VLD; full, center, inner). The study population included 750 non-smokers and 349 smokers. FAZ perimeter was the only OCTA parameter that was significantly different between the two groups on uncontrolled analysis (P = 0.033). Multivariate regression analyses revealed significant associations between lower VLD full (β = -0.31, P = 0.048), lower VLD inner (β = -0.35, P = 0.046) and a history of smoking. No significant associations between cigarette smoking and either FAZ or PD were detected. Our results suggest that smoking is likely associated with deleterious changes in the retinal microvasculature of patients with a history of diabetes and no visible DR. Based on these findings, diabetic patients with a history of smoking may benefit from higher prioritization in terms of ophthalmic screening.


[The role of octahedral montone in colonic barrier protection in severe acute pancreatitis rat model.].
To investigate the protective mechanism of octahedral montone in rats with acute pancreatitis. Seventy-two SD rats were randomly divided into a sham-operation (SO) group, a severe acute pancreatitis (SAP) group and a treatment with octahedral montone group. Retrograde pancreatic ductal injection of 5% cholate sodium in rats was used to establish SAP models. Sham operation was done with intraperitoneal injection of normal saline. In the treated group octahedral montone was given through enema half hour before inducing SAP model. Then, we evaluate the pancreatic injury and detect the level of TNF-alpha, diamine oxidase (DAO) and endotoxin. Western blot and RT-PCR were used to determine the expressions of the tight junction protein occludin in the endothelial cells of intestinal mucosa at the time of hour 3, 6, 12 after operation. (1) The pathological scores of pancreatitis were significantly higher in the SAP group than those in the treatment group and SO group (P < 0.05). (2) Compared with the SO group, the level of TNF-alpha in the SAP group and the treatment group was much higher (P < 0.05), but the level in the treatment group was lower than that in the SAP group (P < 0.05). (3) The serum concentration of DAO and endotoxin was significantly increased in the SAP group, and the concentration in treatment group was higher than that in the SO group (P < 0.01), but lower than that in the SAP group (P < 0.01). The occludin protein and mRNA expression in the SAP group was the lowest and the expression in the treatment group was higher than that in the SAP group (P < 0.01), but lower than that in the SO group (P < 0.01). Octahedral montone can improve the colonic barrier function, reduce the endotoxemia, and ameliorate the inflammation during acute pancreatitis.


Low incidence of gross leukemia virus-induced lymphomas in spontaneously hypertensive rats with thymic dysfunction.
We compared the incidence of lymphomas induced by Gross leukemia virus (GLV) between spontaneously hypertensive rats (SHR) with a congenital T-cell depression related to thymic dysfunction and normal Wistar rats, the original strain of SHR. Of 20 SHR given neonatal injections of GLV, only 3 (15%) died with thymic lymphomas about 100 days after the virus infection. In contrast, 27 of 28 Wistar rats (96%) developed lymphomas of mostly thymic origin. The 3 lymphomas derived from the SHR bore only a Thy 1.1 antigen, whereas most of the lymphomas derived from Wistar rats carried not only a Thy 1.1 antigen but also a guinea pig red blood cell rosette receptor and a T (W3/13) antigen. Grafts of 1-week-old male Wistar thymus into the neonatal female SHR promoted a differentiation of thymocytes and markedly increased the incidence of the lymphomas which were positive for a guinea pig red blood cell rosette receptor and a T-antigen; grafts of 1-week-old SHR thymus, however, failed to do this. These results suggest that the low incidence of GLV-induced lymphomas in SHR may correlate closely with the absence or decreased numbers of the rosette-forming thymocytes which are presumably the target cells for GLV.


Perspective from a hotbed of managed care.
An environmental assessment of the current healthcare market in the United States shows four stages of evolution: (1) the unstructured stage, (2) the loose framework, (3) consolidation, and (4) managed competition. Recognition of these stages should help in the development of strategies for the future. After determining the existing stage of the health-care market in a particular geographic area, clinical endocrinologists can compose a vision statement, develop goals and objectives, and formulate strategies to achieve the established goals. For example, one strategy is to join a managed-care plan. Some practical business advice about assuming risk (responsibility) for various health-care services is provided, and the concept of disease-specific capitation is discussed. Health-care reform is likely to proceed regardless of what the federal government does. In the managed-care environment, the most successful physician participants will be those who are thoroughly informed.


Identification and Functional Characterization of Metabolites for Skeletal Muscle Mass in Early Postmenopausal Chinese Women.
Low skeletal muscle mass (SMM) is a crucial component of the sarcopenia phenotypes. In the present study, we aim to identify the specific metabolites associated with SMM variation and their functional mechanisms of decreased SMM in early postmenopausal women. We performed an untargeted metabolomics analysis in 430 early postmenopausal women to identify specific metabolite associated with skeletal muscle mass indexes (SMIes). Then, the potential causal effect of specific metabolite on SMM variation was accessed by one-sample Mendelian randomization (MR) analysis. Finally, in vitro experiments and transcriptomics bioinformatics analysis were conducted to explore the impact and potential functional mechanisms of specific metabolite on SMM variation. We detected 65 metabolites significantly associated with at least one SMI (variable importance in projection > 1.5 by partial least squares regression and p < .05 in multiple linear regression analysis). Remarkably, stearic acid (SA) was negatively associated with all SMIes, and subsequent MR analyses showed that increased serum SA level had a causal effect on decreased SMM (p < .05). Further in vitro experiments showed that SA could repress myoblast's differentiation at mRNA, protein, and phenotype levels. By combining transcriptome bioinformatics analysis, our study supports that SA may inhibit myoblast differentiation and myotube development by regulating the migration, adhesion, and fusion of myoblasts. This metabolomics study revealed specific metabolic profiles associated with decreased SMM in postmenopausal women, first highlighted the importance of SA in regulating SMM variation, and illustrated its potential mechanism on decreased SMM.


Survey on acrylamide in roasted coffee and barley and in potato crisps sold in Italy by a LC-MS/MS method.
A survey on the occurrence of acrylamide (AA) in roasted coffee, barley, and potato crisps was carried out using an intra-lab validated liquid chromatography (LC)-MS (mass spectrometry)/MS method. Over the years 2015-2016, 66 samples of coffee, 22 of roasted barley, and 22 of potato crisps were collected from retail outlets in Italy. AA was detected in almost all samples. In roasted coffee, the level exceeded 450 µg kg-1, the limit recommended by the European Commission (EC), in 36.4% of the samples. In roasted barley, mean contamination was slightly lower than in coffee and no sample exceeded the EC limit of 2000 µg kg-1. The AA contamination in potato crisps was remarkable. A percentage of 36.4 (n = 8) showed a value higher than the EC limit of 1000 µg kg-1. Considering the average consumption of coffee and potato crisps by Italian people, AA exposure is significant and should be decreased.


Effect of surface-bulk partitioning on the heterogeneous oxidation of aqueous saccharide aerosols.
The OH-initiated heterogeneous oxidation of mixed saccharide aqueous aerosols is investigated using an atmospheric-pressure flow tube coupled to off-line analysis of the particle composition. For equimolar monosaccharide/disaccharide aqueous aerosol mixtures, the decay of the disaccharide is found to be significantly slower than that of the monosaccharide. Molecular dynamics simulations of the mixed aqueous solutions reveal the formation of a ∼10 Å disaccharide exclusion layer below the water surface. A simple chemical model is developed to discuss the possible effect of the disaccharide surface partitioning on the heterogeneous kinetics. The observed decays are consistent with a poor spatial overlap of the OH radical at the interface with the disaccharide in the particle bulk. The effect of partitioning on the heterogeneous oxidation of atmospheric organic aerosols is discussed.


Algebraic characteristics and satisfiability threshold of random Boolean equations.
The satisfiability of a class of random Boolean equations named massive algebraic system septated to linear and nonlinear subproblems is studied in this paper. On one hand, the correlation between the magnetization of generators and the clustering of solutions of the linear subproblem is investigated by analyzing the Gaussian elimination process. On the other hand, the characteristics of maximal elements of solutions of the nonlinear subproblem are studied by introducing the partial order among solutions. Based on the algebraic characteristics of these two subproblems, the upper and lower bounds of satisfiability threshold of massive algebraic system are obtained by unit-clause propagation and leaf-removal process, and coincide as the ratio of nonlinear equations q>0.739 in which analytical values of the satisfiability threshold can be derived. Furthermore, a complete algorithm with heuristic decimation is proposed to observe the approximation of the satisfiability threshold, which performs more efficiently than the classical ones.


[Application of contribute degree in forensic mental trauma assessments].
It is very difficult to identify the relationships between tangle events and accompanied mental disorders. There are often different descriptions of the same controversial conclusion. This thesis introduce the conception of contribute degree and discusses the causality of tangle events and accompanied mental disorders in forensic mental trauma assessments.


Impact Assessment of Urethral Meatus Morphology and Penile Biometry in Transurethral Prostate and Bladder Surgery.
Objective. To analyze the penile and urethral meatus biometry and its correlation with meatoplasty during endoscopic resections. We also propose a new classification for urethral meatus morphology. Materials and Methods. We prospectively studied 105 patients who underwent prostate and bladder transurethral resections. We performed standardized measurement of penile and urethral meatus biometry followed by penile photo in the front position. The need to perform meatoplasty or dilatation during resectoscope introduction was registered. Data were analyzed comparing the correlation between two groups: without intervention (Group A) and with intervention (Group B). Results. We observed in Group A and Group B, respectively, the average length of urethral meatus of 1.07 cm versus 0.75 cm (p < 0.001) and average width of urethral meatus of 0.59 cm versus 0.38 cm (p < 0.001). Considering the morphology of the urethral meatus, we propose a new classification, in the following groups: (a) typical; (b) slit; (c) point-like; (d) horseshoe; and (e) megameatus. The point-like meatus was the one that most needed intervention, followed by the slit and the typical meatus (p < 0.001). Conclusions. Point-like and slit-shaped urethral meatus, as well as reduced length and width of the urethral meatus, are the determining factors.


The psychological adjustment of young immigrants in Norway.
In order to examine the adjustment of young immigrants to their new cultural environment, questionnaires were administered to young Third World immigrants living in Norway. Responses (N = 568) obtained from these children aged 10 through 17 years old, indicated that even though they evaluated their health and present life as satisfactory, a good deal of low self-image, depressive tendencies and psychological and somatic symptoms were present among them. Approximately between 11 and 14% of the children were found to have from high to extreme levels of symptomatology. Anti-social behaviors were on the other hand almost entirely absent among the sample, a situation believed to be an artifact of the measuring instrument used. While no differences were observed between boys and girls with respect to how they evaluated their health and present life, girls were found to report more disorders than boys. Boys on the other hand reported engaging in more anti-social behaviours than girls. Using Norwegians of similar age as a reference group, these children were found to be worse off than their native peers. The children's psychological disorders were found to be related to their mode of acculturation, and that integration may be the most adaptive mode of acculturation.


[Pulmonary artery hypertension in HIV seropositive drug addicts. Apropos of 10 cases].
Pulmonary hypertension (PH) is a classic complication associated with intravenous drug addiction. Various pathogenic mechanisms may be involved but HIV infection now appears to be the main etiologic factor. We report herein 10 case of PH occurred in HIV+ intravenous drug abusers. Each patient had several pathogenic factors: HIV infection, pills crushed and intravenously injected (6 cases), heavy and repeated consumption of amphetamines and cocaine (6 cases), cirrhosis with portal hypertension (2 cases), anticardiolipid antibodies (2 cases). The clinical findings were similar to those reported for PH in HIV seronegative patients; however, in 5 cases, opiates could have alleviated dyspnea, which became perceptible only at the time of drug withdrawal. Because drug addicts usually exhibit a weak support for medical prescriptions, long term therapy needing regular follow-up such as anticoagulation appears to be hazardous and even dangerous. The prognosis remains poor, since the progression of PH led to the death of one third patients within the year following the diagnosis.


A novel mutation in lamin a/c causing familial dilated cardiomyopathy associated with sudden cardiac death.
Dilated cardiomyopathy (DCM), a cardiac heterogeneous pathology characterized by left ventricular or biventricular dilatation, is a leading cause of heart failure and heart transplantation. The genetic origin of DCM remains unknown in most cases, but >50 genes have been associated with DCM. We sought to identify the genetic implication and perform a genetic analysis in a Spanish family affected by DCM and sudden cardiac death. Clinical assessment and genetic screening were performed in the index case as well as family members. Of all relatives clinically assessed, nine patients showed clinical symptoms related to the pathology. Genetic screening identified 20 family members who carried a novel mutation in LMNA (c.871 G>A, p.E291K). Family segregation analysis indicated that all clinically affected patients carried this novel mutation. Clinical assessment of genetic carriers showed that electrical dysfunction was present previous to mechanical and structural abnormalities. Our results report a novel pathogenic mutation associated with DCM, supporting the benefits of comprehensive genetic studies of families affected by this pathology.


Inhibition of RNA-dependent DNA polymerase of avian myeloblastosis virus by pyran copolymer.
PYRAN COPOLYMER, A KNOWN IMMUNOSTIMULATOR, WAS FOUND TO BE A POTENT INHIBITOR OF PURIFIED DNA POLYMERASE (DEOXYNUCLEOSIDETRIPHOSPHATE: DNA deoxynucleotidyltransferase; EC 22.214.171.124) isolated from avian myeloblastosis virus. Unlike other inhibitors, pyran showed unique features of inhibition. It interacts with the polymerase at a region other than the template site. The inhibitory effect was overcome only by excess enzyme and not affected by excess template. The degree of inhibition was not template specific for the templates tested: 70S RNA from avian myeloblastosis virus, synthetic hybrid poly(rA).oligo(dT)(10), synthetic copolymer poly(dA-dT), and activated calf-thymus DNA. The observed rate of inhibition by pyran was shown to vary with the different polymerases tested. Inhibition was shown with all oncornaviral polymerases and, to a lesser extent, with mammalian polymerases. However, two of the three bacterial polymerases, by contrast, showed a marked activation.


Multiple antigenic epitopes expressed on gag proteins, p26 and p15, of a human immunodeficiency virus (HIV) type 2 as defined with a library of monoclonal antibodies.
Thirty-two hybridoma clones producing monoclonal antibody (MAb) against HIV-2[GH-1] were established from mice immunized with NP-40-disrupted purified whole virus of a Ghanaian isolate of human immunodeficiency virus type 2 (HIV-2), strain HIV-2[GH-1]. Of these 32 MAbs, 20 reacted with p26 and the other MAbs recognized p15 of the HIV-2[GH-1] isolate. From the results of serological characterization by these MAbs, p26 and p15 were identified as capsid proteins and matrix protein, respectively, of HIV-2[GH-1] gag products. In addition to two gag proteins, a 55-kD protein corresponding to the primary translational product of gag gene and 39-kD protein corresponding to an intermediate product of cleavage of p55 were recognized by these MAbs in the lysate of HIV-2[GH-1]-infected cells. Moreover, these MAbs were used to analyze the number of antigenic epitopes on p26 and p15 of HIV-2[GH-1] isolate. The results of cross-reactivity with different HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates and competitive binding assay suggest that there are at least four and five antigenic epitopes in p26 and p15, respectively, of the HIV-2[GH-1] isolate. The biological activity of MAbs was studied by performing syncytium inhibition assay and infection inhibition assays. However, our MAbs could not inhibit syncytium formation and infection by cell-free virus.


Lipid peroxidation in rat brain is increased by simulated weightlessness and decreased by a soy-protein diet.
This study tested whether or not simulated weightlessness by tail-suspension increases the levels of lipid peroxidation products in rat brain. The brain tissues of rats on a soybean diet were also assayed for lipid peroxidation products to evaluate the possible role of soy-protein as a dietary anti-oxidant. Male Sprague-Dawley rats were used. Group 1 rats were fed standard Purina rat chow ad libidum and served as controls. Group 2 rats were fed a soybean diet containing 37% soy-protein and were not tail-suspended. Group 3 rats were fed standard Purina rat chow ad libidum and were tail-suspended to induce simulated weightlessness. After 2 wk, all of the rats were killed. Each whole brain was segmented into frontal cortex, cerebellum, and brain stem. After a specific weight of each segment was excised, the residual tissues were combined and used as a whole brain sample. The samples were analyzed for lipid peroxidation products by a chromogenic assay that reacts with malondialdehyde (MDA) and 4-hydroxyalkenals (4-HNE). The mean concentrations of lipid peroxidation products (MDA plus 4-HNE) in whole brain, frontal cortex, cerebellum, and brain stem of the control rats ranged from 16 to 18 micromol/g; the corresponding means ranged from 10 to 13 micromol/g in rats fed the soybean diet, and from 22 to 26 micromol/g in the tail-suspended rats. Thus, the mean levels of lipid peroxidation products in brain tissues were decreased in the rats fed the soy diet and were increased in the rats that were tail-suspended to simulate weightlessness, when compared to those of rats fed a regular diet.


Eosinophilic Fasciitis following Checkpoint Inhibitor Therapy with Pembrolizumab.
With the increasing number of indications for checkpoint inhibitor therapy in cancer patients, rheumatology specialists are often involved in the diagnosis and management of immune-related adverse events (irAEs). The most common rheumatic irAEs are arthritis, sicca syndrome, polymyalgia rheumatica, and myositis. Eosinophilic fasciitis, an already rare rheumatic disease, is a very unusual rheumatic irAE. Eosinophilic fasciitis, whether idiopathic or checkpoint inhibitor-associated, has very particular clinical symptoms and findings, such as the orange peel skin appearance and the Groove sign, which the physicians need to be aware of and recognise timely in order to diminish morbidity.


Regulation of puberty.
Pubertal development is the last phase of a continuum of changing gonadotrophin releasing hormone (GnRH) activities. Whether or not puberty tends to start at a younger age, as has been recently described in a population of black Americans, remains under debate. Such early onset has not been confirmed in different European countries. Ideas about the underlying mechanisms responsible for the reawakening of GnRH release at the onset of puberty have changed significantly during the last decades. At this moment, the common opinion is that neuronal outgrowth of both GnRH and other regulatory neurons results in changing interactions and activities. Sex steroids, as well as various central neurotransmitters, play a role in modulating GnRH release. Active release after birth is followed by the restraint of childhood. A re-onset of GnRH excitatory activities heralds the onset of puberty. This chapter gives an overview of the many factors involved.


[Psychotherapy-drugs combined. Mixed psychotherapeutic-chemotherapeutic treatment. Countertransference aspects].
This is a clinical case report on young female patient aged 30 whom the author has followed with a mixed treatment of psychotherapy and chemotherapy for one and a half year. This patient has a "borderline" symptomatology. The approach through counter-transfer is preponderant. The importance and use of this analysis are emphasized, first to allow a dynamic research of adequate therapeutic attitudes, then to furnish basic knowledge for understanding the type of material and anxiety brought up by this patient. A more comprehensive reflexion is made concerning the situations leading to the use of a first, then second psychotherapeutic drug, in parallel to the psychotherapeutic approach, and to the problems resulting in the therapeutic relationship throughout the transfer and counter-transfer.