Metabolomics analysis reveals Oct4 overexpression drives metabolic reprogramming and enhanced glycolysis and pentose phosphate pathway in lung adenocarcinoma cells.
Poor prognosis in the underlying mechanisms involved in lung adenocarcinoma and its treatment leads to low survival rates in patients. Emerging evidence indicates that cancer is primarily a metabolic disease and metabolic reprogramming is a well-established hallmark and driving force of cancer. Oct4, acting as an oncogene, is a major regulator of cell pluripotency. It can reprogram the differentiated cells into cancer stem cells (CSCs) and plays an oncogenic role when pathologically hijacked. However, data that Oct4, the genetic reprogramming factor, could induce metabolic reprogramming have been very limited, and the direct evidence in metabolic level whether Oct4 reprograms metabolome is lacking. In the present study, integrated untargeted and targeted metabolomics analyses were utilized to investigate metabolic changes induced by Oct4 overexpression in lung adenocarcinoma cells. The results suggested that elevated expression levels of Oct4 drive metabolic reprogramming. Oct4 overexpression redirects glucose catabolism to glycolysis pathway and to the oxidative pentose phosphate pathway (PPP). This study identifies unique pathways that are candidate therapeutic targets for the treatment of lung adenocarcinoma. This study also aims to improve our understanding of the cancer-promoting activity of Oct4 and help identify novel diagnostic and therapeutic strategies for cancer treatment.


Neoadjuvant Therapy in Rectal Cancer Patients With Clinical Stage II to III Across European Countries: Variations and Outcomes.
Neoadjuvant therapy improves survival of patients with clinical stage II and III rectal cancer in clinical trials. In this study, we investigated the administration of neoadjuvant radiotherapy (neo-RT) and neoadjuvant chemoradiotherapy (neo-CRT) and its association with survival in resected patients in 2 European countries (The Netherlands and Sweden) and at 3 specialist centers. Administration of neoadjuvant treatment (all registries) and overall survival after surgery in The Netherlands and Sweden were assessed. Hazard ratios (HRs) were obtained using Cox regression adjusted for potential confounders. A total of 16,095 rectal cancer patients with clinical stage II and III were eligible for analyses. Large variations in administration of neo-RT and neo-CRT were observed. Elderly patients less often received neo-RT and neo-CRT. Patients with stage III disease received neo-CRT more frequently than neo-RT. Administration of neo-RT versus surgery without neoadjuvant treatment was significantly associated with improved survival in The Netherlands (HR, 0.62; 95% confidence interval [CI], 0.53-0.73) as well as in Sweden (HR, 0.79; 95% CI, 0.69-0.90). Administration of neo-CRT was associated with enhanced survival in The Netherlands (HR, 0.62; 95% CI, 0.50-0.78) but not in Sweden (HR, 0.97; 95% CI, 0.80-1.18). The mortality of patients treated with neo-CRT compared with neo-RT showed inconsistent results in population-based centers. Our results support an association of neo-RT with enhanced survival among stage II and III rectal cancer patients. Comparing neo-CRT with neo-RT, larger variations and inconsistent results with respect to survival were observed across centers.


The nosocomial transmission of Helicobacter cinaedi infections in immunocompromised patients.
We encountered 15 cases of Helicobacter cinaedi (H. cinaedi) infection between March and July 2008. The underlying diseases were hematological malignancies in a majority of cases, many of which received chemotherapy. All patients had a fever. The fever was followed by cellulitis in three, a skin rash in six, pain in the lower limbs in three, and diarrhea in three cases. We analyzed the bacterial 23S rRNA genes. The fifteen strains were divided according to base sequence into Groups A, B, and C, respectively. All four cases in Group A were women and all ten in Group C were men, indicating that the gender of the patient corresponded precisely to the genotypes of the separated bacilli in these two groups. These findings also suggested the strong possibility of nosocomial spread. It is highly likely that H. cinaedi infections have been overlooked due to the difficulties encountered in culturing the bacterium. The possibility of septicemia caused by H. cinaedi should be suspected especially in immunocompromised patients such as those undergoing chemotherapy, with symptoms such as fever, rash, arthritis, cellulitis, leg pain, and other systemic or local symptoms.


Microbially controlled drug delivery to the colon.
The human gastrointestinal tract consists of a highly complex ecosystem of aerobic and anaerobic microorganisms that plays a significant role in the metabolism of nutrients as well as drugs. In the colon, bacteria ferment various types of substrates that are not susceptible to digestion in the small intestine. This arouses interest in specific drugs, drug delivery systems, and prodrugs that escape small bowel digestion, arrive intact, and are absorbed or degraded in the large bowel. For the past forty years, experience has been gained with the azo prodrug of 5-amino salicylic acid, salazopyrine, which is cleaved by colonic bacteria to its parent drug. Some laxative drugs were also reported to degrade into active metabolites in the colon. Lately equally interesting and more sophisticated microbial controlled delivery systems, have been developed based on similar principles.


Role of the central and peripheral nervous system in the ovarian function.
This review attempts to give a comprehensive overview of ovarian innervation, considering the whole nervous system and its different levels that may modify the ovarian function. The connection between the ovary and the central nervous system through the autonomic pathways, including the peripheral ganglia, is highlighted. The evidence obtained over the last years highlights the role of the superior ovarian nerve (SON) in the ovarian phenomena. Besides, the effect on the ovary of conventional neurotransmitters and others such as indolamines and peptides, which have been found in this organ, are discussed. Various reproductive diseases have been studied almost exclusively from the endocrine point of view. It is evident that a better knowledge about the role of the neural factors involved in the ovarian physiology may facilitate the understanding of some of these. A review of the concepts and an update of some experimental designs is made that permits clarifying several aspects of the relationship between the neural system and the ovary. At present, there is no doubt that the innervation of the ovary is involved in several physiological aspects of this gland function. However, the relationship of some levels of the nervous system and the ovary offer a wide avenue for future research.


Expedient Construction of the Hexacycle of Franchetine.
Franchetine, a unique 7,17-seco type of norditerpenoid alkaloid, possesses a highly congested polycyclic architecture coupled with nine stereogenic centers. Here we present an efficient synthetic approach for the intact hexacyclic framework of franchetine from the known tricyle 16 in 20 steps. The synthesis features a diastereoselective 6-exo-tet radical cyclization for construction of ring A and a unique oxidative Wagner-Meerwein-type rearrangement to realize the functionalized [3.2.1] bridging ring CD.


[Evaluation of an ELISA kit made in our laboratory for intratypic discrimination of poliovirus type 1 strains isolated from acute flask paralysis].
In this study, we aimed to develop and evaluate an enzyme based immunological method (ELISA) for the intratypic differentiation (whether if Sabin like-SL, or non Sabin like/wild type-NSL) of poliovirus type 1 isolates, in the frame of Polio Eradication Programme (PEP) in Turkey. Five poliovirus type 1 strains which were formerly isolated and identified in our laboratory from fecal samples of acute flask paralysis (AFP) patients, and standard reference strains of vaccine type 1 and prototype wild (Mahoney) polioviruses have been tested into plate wells that bounded with 5 different monoclonal antibodies (mAbs B18, S2-36, M18, B82, M49). The wells which gave high absorbance than cutoff value estimated by comparing negative control wells, were accepted as positive. As a result, the standard poliovirus strains were differentiated correctly, whereas 2 patient isolates were identified as SL and 3 were NSL. In conclusion, our home-made ELISA method found to be successful for intratypic differentiation of poliovirus type 1 isolates, however more detailed studies are necessary in order to increase the susceptibility and specificity of this test.


[Efficacy of hierarchical medical mode path management on the continuous treatment for chronic wound patients].
Objective: To explore the efficacy of hierarchical medical mode path management on the continuous treatment for chronic wound patients. Methods: From June 2017 to September 2018, the clinical data of 101 patients with chronic wounds who were just discharged from Department of Wound Repair of the Affiliated Hospital of Jiangnan University (hereafter referred to as the author's affiliation) and still needed continuous treatment, meeting the inclusion criteria, were analyzed with the method of retrospective cohort study. Based on the management method of continuous treatment after discharge, the patients were divided into path management group (52 patients, 27 males and 25 females, aged (44±6) years, 57 wounds) and conventional management group (49 patients, 26 males and 23 females, aged (45±6) years, 53 wounds). The patients in path management group were carried out with full-path management under hierarchical medical mode, and the patients in conventional management group were carried out with conventional continuous treatment management. The discharge time from the author's affiliation was the time before continuous treatment management (hereafter referred to as before management), and 12 weeks post discharge was the time after continuous treatment management (hereafter referred to as after management). The depression and anxiety of patients in two groups were assessed by Hamilton Depression Scale 24 item version (HAMD-24) and Self-rating Anxiety Scale (SAS), and the positive ratios of depression and anxiety were calculated. The effective rates of wound treatment, times of debridement and dressing change, and treatment cost during the continuous treatment management period were counted. Data were statistically analyzed with two independent sample t test, chi-square test, Fisher's exact probability test, and Wilcoxon rank-sum test. Results: (1) Before management, the HAMD-24 and SAS scores of patients in two groups were similar. After management, the HAMD-24 and SAS scores of patients in path management group were significantly lower than those of conventional management group (t=4.341, 3.840, P<0.01). Before and after management, the positive rates of depression and anxiety of patients in two groups were similar. (2) After management, the effective rate of wound treatment of patients in path management group was 98.25% (56/57), which was significantly higher than 86.79% (46/53) of conventional management group (χ(2)=5.341, P<0.05). (3) During the management, the times of debridement and dressing change in patients of path management group was 20±4, which was significantly less than 27±7 of conventional management group (t=5.833, P<0.01). (4) During the management, the treatment cost of patients in path management group was (2 479±213) yuan, which was significantly less than (5 215±326) yuan of conventional management group (t=50.185, P<0.01). Conclusions: In the continuous treatment of chronic wound patients, the full-path management under hierarchical medical mode can improve the effective rate of wound treatment, reduce the times of debridement and dressing change and treatment cost, and improve their psychological state.


The TB structural genomics consortium crystallization facility: towards automation from protein to electron density.
The crystallization facility of the TB (Tuberculosis) structural genomics consortium, one of nine NIH sponsored p50 structural genomic centres, provides TB consortium members with automated crystallization, data collection and basic molecular replacement (MR) structure solution up to bias minimized electron density maps. Crystallization setup of up to ten proteins per day follows the CRYSTOOL combinatorial screen protocol using a modular and affordable robotic design with an open architecture. Components include screen preparation, plate setup, automated image acquisition and analysis, and optimisation design. A new 96 well crystallization plate has been designed for optimal robotic handling while maintaining ease of manual crystal harvesting. Robotic crystal mounting, screening, and data collection are conducted in-house and at the Advanced Light Source (ALS) in Berkeley. A simple automated protocol based on MR and homology based structure prediction automatically solves modestly difficult problems. Multiple search models are evaluated in parallel MR and the best multi-segment rigid body refined MR solution is subjected to simulated annealing torsion angle molecular dynamics using CNS, bringing even marginal MR solutions within the convergence radius of the subsequent highly effective bias removal and map reconstruction protocol, Shake&wARP, used to generate electron density for initial rebuilding. Real space correlation plots allow rapid assessment of local structure quality. Modular design of robotics and automated scripts using publicly available programs for structure solution allow for efficient high throughput crystallography - at a reasonable cost.


Interplay of different contextual motivations and their implications for exercise motivation.
The aim of this study was to analyze the interaction between different contextual motivations and exercise motivation. The sample consisted of 449 exercisers aged between 16 and 53 years. Questionnaires were used to measure the satisfaction of basic psychological needs, self-determined motivation and the autotelic experience during exercise. The level of self-determined motivation regarding health, leisure and interpersonal relationships was also measured. The results of the structural equation modeling demonstrated that basic psychological needs and self-determined motivations about health and leisure positively predicted the self-determined motivation to exercise. Moreover, the self-determined motivation to exercise positively predicted the autotelic experience. The model was invariant across age, although some gender differences were found. Specifically, the self-determined motivation towards health in men did not significantly predict the self-determined motivation to exercise. These results represent to evaluate the role that other contextual motivations play in exercise motivation. Key pointsSelf-determined motivations about health and leisure positively predicted exercise motivation.Motivation in interpersonal relationships did not relate to exercise motivation.Relationships were invariant across age, although some gender differences were found. Self-determined motivation towards health in men did not significantly predict self-determined motivation to exercise, whereas leisure motivation played a major role in explaining this variable.


Comparative Analyses of Single-Cell Transcriptomic Profiles between In Vitro Totipotent Blastomere-like Cells and In Vivo Early Mouse Embryonic Cells.
The developmental potential within pluripotent cells in the canonical model is restricted to embryonic tissues, whereas totipotent cells can differentiate into both embryonic and extraembryonic tissues. Currently, the ability to culture in vitro totipotent cells possessing molecular and functional features like those of an early embryo in vivo has been a challenge. Recently, it was reported that treatment with a single spliceosome inhibitor, pladienolide B (plaB), can successfully reprogram mouse pluripotent stem cells into totipotent blastomere-like cells (TBLCs) in vitro. The TBLCs exhibited totipotency transcriptionally and acquired expanded developmental potential with the ability to yield various embryonic and extraembryonic tissues that may be employed as novel mouse developmental cell models. However, it is disputed whether TBLCs are 'true' totipotent stem cells equivalent to in vivo two-cell stage embryos. To address this question, single-cell RNA sequencing was applied to TBLCs and cells from early mouse embryonic developmental stages and the data were integrated using canonical correlation analyses. Differential expression analyses were performed between TBLCs and multi-embryonic cell stages to identify differentially expressed genes. Remarkably, a subpopulation within the TBLCs population expressed a high level of the totipotent-related genes Zscan4s and displayed transcriptomic features similar to mouse two-cell stage embryonic cells. This study underscores the subtle differences between in vitro derived TBLCs and in vivo mouse early developmental cell stages at the single-cell transcriptomic level. Our study has identified a new experimental model for stem cell biology, namely 'cluster 3', as a subpopulation of TBLCs that can be molecularly defined as near totipotent cells.


Neuroendocrine responses following graded traumatic brain injury in male adults.
In an effort to characterize thyroid, gonadal and adrenal function following neurotrauma, the present study determined serum concentrations of thyroid-stimulating hormone (TSH), total triiodothyronine (T3), thyroxine (T4), testosterone and cortisol over a 7 day period in 31 patients with traumatic brain injury. The study group consisted of eight patients with mild closed head injury (Glasgow Coma Scale--GCS 13-15), 10 patients with extensive penetrating head injury (GCS 4-6) and 13 patients with blast injuries but without direct head trauma. The latter group was included in the study because the development of indirect brain trauma has previously been implicated in blast injuries. Patients with multiple injuries were not included. Following mild injury (GCS 13-15), TSH was increased up until day 3 after injury. T3 levels were elevated on days 1, 5 and 7 after injury while T4 remained unchanged throughout. While testosterone was decreased over only the first 2 days post-trauma, cortisol was increased over these first 2 days after injury. In contrast, following severe penetrating injury (GCS 4-6), there were significant declines in TSH, T3 and testosterone over the 7 day observation period post-trauma. Serum cortisol also declined in these patients between 1-3 days after injury, before increasing again on days 5 and 7 after injury. Following indirect neurotrauma, TSH was slightly decreased immediately after trauma but increased to above normal levels on days 5 and 7 post-trauma. Similarly, T3 initially declined after injury, but then increased to above normal levels between 5 and 7 days after injury. T4 and testosterone remained unchanged over the entire post-traumatic period. Serum cortisol was significantly increased after indirect neurotrauma but only up to day 2 post-trauma. In summary, patients with both direct and indirect traumatic brain injury demonstrated endocrine alterations after trauma, the dynamics of which may be a reflection of the severity of brain damage.


Evaluation of Knee Joint after Open Reduction and Internal Fixation Surgery of Posterior Cruciate Ligament in Patients with Avulsion Fracture.
The posterior cruciate ligament is one of the important tissues and structures sustaining the knee joint, and its rupture or detachment may lead to joint instability or destruction. The present study aimed at investigating the Open Reduction and Internal Fixation surgery of posterior cruciate ligament and comparing it to the normal knee of the same side. In this study, 25 patients with avulsion fracture at the PCL joint were treated with open surgery and screw fixation. The patients were followed up by Lysholm knee score for at least 12 months after surgery. All patients were male with an average age of 25 years over the years 2010-2018. The common mechanism of injury in these patients was motorcycle-car accident. In the study with Lysholm knee score, 21 patients (80%) obtained the good score of 60-90 while 20% of patients were placed in the fair group (30-59). The average score was 86. The obtained score of knee function questionnaire in this study had no significant difference from other similar studies, and most patients achieved a good and acceptable score after the surgery. There was no knee instability and functional impairment in the patients compared to the normal knee. Considering the clinical results after the fixation of the PCL avulsion fracture causing a significant improvement in patients, the surgery could be considered as an acceptable and effective method for treating such impairment and fracture.


Toward integration of systems biology formalism: the gene regulatory networks case.
We consider the problem of integrating different systems biology formalisms, namely, the process calculi based formalism, the modeling approach based on systems of differential equations, and the one relying on automata-like descriptions (and model checking). Specifically, we define automatic procedures for translating stochastic pi-calculus descriptions of gene regulatory networks to S-systems differential equations. Tools for extracting and reasoning on (approximate) solutions of S-systems have been recently developed in the literature, and can be exploited to establish a link with automata-based systems biology and model checking techniques.


Thermo- and light responsive micellation of azobenzene containing block copolymers.
In this communication, the synthesis and characterization of thermo- and light responsive block copolymers is reported. PEO-b-PNIPAM polymers with azobenzene moieties were prepared and analyzed by turbidimetry, fluorescence, NMR and DLS measurements. A temperature controlled reversible formation as well as a light induced disruption and reformation of micellar structures in water was found.


ATG2 regulation of phagophore expansion at mitochondria-associated ER membranes.
The mechanism by which ATG2 (ATG2A and ATG2B in mammals) regulates autophagosome biogenesis remains largely unknown. In our recent study, we showed that ATG2A translocates to the mitochondria-associated ER membranes (MAM) to promote phagophore growth during nutrient starvation. Mechanistically, the mitochondrial translocase TOMM40 binds to a C-terminal domain of ATG2A, termed the MAM localization domain (MLD), and mediates its MAM translocation in a manner dependent on the TOMM receptor TOMM70. Moreover, ATG2A associates with ATG9A through its N-terminal domain and this interaction is required for phagophore expansion and efficient autophagic flux. These observations suggest that ATG2 operates a mechanism for phagophore expansion at the MAM through the TOMM40-TOMM70 complex and ATG9 during autophagy.


Complications associated with the use of silicone oil in vitreoretinal surgery: A systemic review and meta-analysis.
Silicone oil (SO) still represents the main choice for long-term intraocular tamponade in complicated vitreoretinal surgery. This review compared the complications associated with the use of SO and other vitreous substitutes after pars plana vitrectomy in patients with different underlying diseases. Meta-analysis was conducted in accordance with PRISMA guidelines. We retrieved randomized clinical trials (RCTs), retrospective case-control and cohort studies evaluating the risk of using SO, published between 1994 and 2020, conducting a computer-based search of the following databases: PubMed, Web of Science, Scopus and Embase. Primary outcome was the rate of complications such as intraocular hypertension, retinal re-detachment, unexpected vision loss or hypotony. Secondary outcome was to compare the rate of adverse events of different SO viscosities, especially emulsification. Forty-three articles were included. There were significant differences in intraocular hypertension (p = 0.0002, OR = 1.66; 95% CI = 1.27-2.18) and the rate of retinal re-detachment (p < 0.0009, OR = 0.65; 95% CI = 0.50-0.64) between SO and other agents, including placebo. However, there were no differences in other complication rates. Silicone oil (SO)-emulsification rate was non-significantly higher in low than high SO viscosity, and results from other complications were comparable in both groups. The high quality of most of the studies included in this study is noteworthy, which provides some certainty to the conclusions. Among them is the high variability of the SO residence time. The fact that ocular hypertension and not hypotension is related to SO use. A clear relationship is not found for the so-called unexplained vision loss, which affects a significant percentage of eyes. Re-detachment cases are less if SO is used and that surprisingly there does not seem to be a relationship in the percentage of emulsification between the low- and high-viscosity silicones. All these data warrant more standardized prospective studies.


Infiltration of resin into white spot caries-like lesions of enamel: an in vitro study.
The aim of this study was to determine the extent to which caries lesions can be infiltrated successfully with polymerisable resins. This could provide dentists with an additional means of managing white spot lesions in high caries risk patients rather than relying on improved plaque control and fluoride application. Artificial caries lesions were produced in extracted premolar teeth using an acidified gel. The lesions were infiltrated using two of the resins currently available to the dental profession. The effects of acid etching the surface, and of drying the lesion by two methods, were investigated. The degree of resin penetration was evaluated by scanning electron microscopy. The results showed that following a short etch (5s with 36% phosphoric acid), prior dehydration of the lesion with ethanol and the application of multiple layers of bonding resin, lesions could be infiltrated almost completely with organic resin. This approach could offer an alternative approach for the management of uncavitated lesions.


Effect of inulin on rheological, textural, and structural properties of brown wheat flour dough and in vitro digestibility of developed Arabic bread.
The brown wheat flour (BWF)-based Arabic bread was fortified with chicory-derived inulin. The objective of this work was to assess the influence of the inulin concentration (1.25 to 5%) on the rheological, textural properties, and fermentation efficacy of enriched BWF dough. Farinographic measurement established that only 3.75% BWF can be substituted by inulin in a dough formulation, which resulted in lowering the water absorption capacity. The peak gelatinization temperature, Tp detected at 74.4 °C by rheometric measurement, which increased linearly with increasing the inulin concentration. The elastic modulus (G'), however, differed significantly among doughs with the addition of inulin. The dough hardness and compressibility increased as a function of inulin concentration. TPA measurement indicated that the Arabic bread fortified with 3.75% inulin was the best in texture. The addition of inulin improved the volume of CO2 generation in the yeasted dough. The distribution of starch particles on the top layer of bread surface was visualized through SEM. In-vitro digestion and steady-flow measurement of the BWF/inulin bread digesta exhibited a slow digestion and an increment in the apparent viscosity against the control bread, which further confirmed potential health benefits of the developed Arabic bread. PRACTICAL APPLICATION: Arabic bread is a staple food in many Asian countries, and an incorporation of soluble fiber, like inulin, definitely improves its health benefits. This work optimized a formulation based on BWF and inulin with technical feasibility. Rheological and textural studies demonstrated that blend bread could be made by replacing 3.75% BWF by inulin with significantly lower water content. Inulin has replaced the sugar in the yeasted dough, and carried out the bread fermentation adequately.


Unveiling the Genetic History of the Maniq, a Primary Hunter-Gatherer Society.
The Maniq of southern Thailand is one of the last remaining practicing hunter-gatherer communities in the world. However, our knowledge on their genetic origins and demographic history is still largely limited. We present here the genotype data covering ∼2.3 million single nucleotide polymorphisms of 11 unrelated Maniq individuals. Our analyses reveal the Maniq to be closely related to the Semang populations of Malaysia (Malay Negritos), who altogether carry an Andamanese-related ancestry linked to the ancient Hòabìnhian hunter-gatherers of Mainland Southeast Asia (MSEA). Moreover, the Maniq possess ∼35% East Asian-related ancestry, likely brought about by recent admixture with surrounding agriculturist communities in the region. In addition, the Maniq exhibit one of the highest levels of genetic differentiation found among living human populations, indicative of their small population size and historical practice of endogamy. Similar to other hunter-gatherer populations of MSEA, we also find the Maniq to possess low levels of Neanderthal ancestry and undetectable levels of Denisovan ancestry. Altogether, we reveal the Maniq to be a Semang group that experienced intense genetic drift and exhibits signs of ancient Hòabìnhian ancestry.


Efficient homogeneous catalysis in the reduction of CO2 to CO.
The well-defined copper(I) boryl complex [(IPr)Cu(Bpin)] [where IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, and pin = pinacolate: 2,3-dimethyl-2,3-butanediolate] deoxygenates CO2 rapidly and quantitatively, affording CO and the borate complex [(IPr)Cu(OBpin)]. The boryl may be regenerated by treatment with the diboron compound pinB-Bpin, giving the stable byproduct pinB-O-Bpin. The use of a copper(I) alkoxide precatalyst and stoichiometric diboron reagent results in catalytic reduction of CO2, with high turnover numbers (1000 per Cu) and frequencies (100 per Cu in 1 h) depending on supporting ligand and reaction conditions.


The achievement of normal homocysteinemia in regular extracorporeal dialysis patients.
High total homocysteinemia (tHcy) is a vascular risk factor in regular dialysis treatment (RDT) patients. A near normal tHcy has previously been achieved (from 33 +/- 11 to 13 +/- 5 micromol/L) in 23 patients on hemodiafiltration (HDF) by adjusting intravenous (i.v.) supplements of folinic acid, vitamin B12 and B6, gradually during a 2-yr follow-up. Thereafter, the same therapeutic schedule was used for all patients undergoing RDT in our unit to confirm its efficacy on a larger scale. Patients (n=63, F 34, age 66 +/- 14 yrs, dialytic age 60 +/- 53 months) underwent high UF post-dilutional on-line HDF for at least 6 months. They received i.v. folinic acid 3 mg, vitamin B12 50 microg and vitamin B6 450 mg/wkly. After 4 months, pre- and post-dialytic serum Hcy (n.v. 11 +/- 2 micromol/L), as well as pre-dialytic serum folate (sFA, n.v. 3-17 ng/mL) and vitamin B12 (sB12, n.v. 226-966 pg/mL) were determined. The mean pre-dialytic tHcy fell to within the normal range (from 31 +/- 10 to 12.5 +/- 5 umol/L), it was slightly above the normal limits (19 +/- 2 umol/L) in only 11 patients (17%), whereas the post-dialytic value was normal in all patients (7 +/- 2.5 umol/L). The average values of sFA (25 +/- 10 ng/mL) and sB12 (1500 +/- 320 pg/mL) were approximately twice the normal limits. Therefore, HDF appears to remove tHcy efficiently and tHcy is generally normalized by adjusting the dose of vitamin B12, vitamin B6 and folinic acid supplements.


[Artificial tube feeding of elderly suffering from advanced dementia].
There is a notable discord between physicians' opinions and reported practice regarding percutaneous endoscopic gastrostomy (PEG) nutrition in nursing homes for demented residents. The aim of this study was to describe the decision and the outcomes of PEG placement in elderly nursing home residents, suffering from advance dementia and dysphagia. The retrospective study evaluated frequency, complications of dysphagia and survival in 90 patients of Geriatric Center (61 women, 29 men) who underwent PEG. Average age was 85.7 +/- 0.8 years. Dysphagia diagnosed at 58, refusal of food of 36 patients. Following data was examined: age, time of dysphagia, anthropometric and laboratory tests. Post PEG complications were found in 62.2% of patients and lung aspiration was 38.7% among them. Mortality within 30 days was 14.4% and 1 year survival was 54.4%. Early mortality rate increased with advanced age (over 85 years old), lower serum albumin (< 3.0 gr/dl), hemoglobin (<1 1.0 gr/dl) and cholesterol (< 160 mg/dl), underweight (BMI < 20.0 kg/m2) and time of dysphagia less than 2 months. Artificial tube feeding (PEG) of elderly nursing home residents, suffering from advanced dementia, may be clinically beneficial for most patients with dysphagia or meal rejection aside to gradual constriction of the indications for PEG, seeing aforesaid predictor factors.


Design of Branch Definition Algorithm for Top-k Inverse Queries for Image Processing.
Images are the main way for human beings to obtain and exchange information, and they play a crucial role in the process of human understanding and exploration of the world. Top-k inverse queries are widely used in real life. Currently, the most efficient algorithm for computing top-k inverse sets is the inverse top-k algorithm. Our algorithm is significantly limited when dealing with top-k inverse queries. To address these limitations, an intuitive branch-and-bound algorithm is proposed to efficiently handle top-k inverse queries, and novel optimization methods are discussed to mention its high performance. Experimental evaluation shows that the algorithm is far more efficient than the inverse top-k algorithm.


trans-Bis[1-methyl-3-(p-nitrophenyl)triazenido 1-oxide-kappa2N3,O]dipyridinenickel(II).
In the centrosymmetric title complex, [Ni(C(7)H(7)N(4)O(3))(2)(C(5)H(5)N)(2)], the coordination geometry about the Ni(2+) ion is octahedral, with two deprotonated 1-methyl-3-(p-nitrophenyl)triazenide 1-oxide ions, viz. [O(2)NC(6)H(4)NNN(O)CH(3)](-), acting as bidentate ligands (four-electron donors). Two neutral pyridine (py) molecules complete the coordination sphere in positions trans to each other. The triazenide 1-oxide ligand is almost planar, the largest interplanar angle of 8.80 (12) degrees being between the phenyl ring of the p-nitrophenyl group and the plane defined by the N(3)O moiety. The Ni-N(triazenide), Ni-O and Ni-N(py) distances are 2.0794 (16), 2.0427 (13) and 2.1652 (18) A, respectively.


A promotion ladder for teachers at Harvard Medical School: experience and challenges.
The authors describe the development, implementation, and institutionalization at Harvard Medical School of a promotion ladder that recognizes the teaching and scholarly contributions of full-time clinical faculty. They also discuss the challenges that arose during this process, for example, how to make the new track creditable and attractive to both the appointed faculty and the faculty at large. The criteria developed for promotion focus on a candidate's skills and accomplishments in teaching, scholarship, clinical work, and departmental service. The authors present the elements of these criteria for the three professional levels of the ladder and outline the appointment process, including the steps for consideration of a given promotion. The development of this teacher-clinician ladder has had a positive influence on faculty who are committed to teaching by allowing recognition of their contributions in a track held to be the equal of the other full-time tracks in a medical faculty traditionally committed to research and patient care. Data are given for the 70 faculty who were promoted over the five years from 1989 to 1994. The true success of this promotion ladder will be measured only over time through its impact on the educational enterprise within the medical school and its hospitals, and its capacity to both successfully advance the careers of qualified medical educators and further the development of the field of medical education.


Nanolayered siRNA delivery platforms for local silencing of CTGF reduce cutaneous scar contraction in third-degree burns.
Wound healing is an incredibly complex biological process that often results in thickened collagen-enriched healed tissue called scar. Cutaneous scars lack many functional structures of the skin such as hair follicles, sweat glands, and papillae. The absence of these structures contributes to a number of the long-term morbidities of wound healing, including loss of function for tissues, increased risk of re-injury, and aesthetic complications. Scar formation is a pervasive factor in our daily lives; however, in the case of serious traumatic injury, scars can create long-lasting complications due to contraction and poor tissue remodeling. Within this report we target the expression of connective tissue growth factor (CTGF), a key mediator of TGFβ pro-fibrotic response in cutaneous wound healing, with controlled local delivery of RNA interference. Through this work we describe both a thorough in vitro analysis of nanolayer coated sutures for the controlled delivery of siRNA and its application to improve scar outcomes in a third-degree burn induced scar model in rats. We demonstrate that the knockdown of CTGF significantly altered the local expression of αSMA, TIMP1, and Col1a1, which are known to play roles in scar formation. The knockdown of CTGF within the healing burn wounds resulted in improved tissue remodeling, reduced scar contraction, and the regeneration of papillary structures within the healing tissue. This work adds support to a number of previous reports that indicate CTGF as a potential therapeutic target for fibrosis. Additionally, we believe that the controlled local delivery of siRNA from ultrathin polymer coatings described within this work is a promising approach in RNA interference that could be applied in developing improved cancer therapies, regenerative medicine, and fundamental scientific research.


Aortoscopy: a guidance system for endoluminal aortic surgery.
The aim of this project was to evaluate the feasibility of aortoscopy for guidance of endoluminal aortic procedures and to determine whether aortoscopy has advantages over fluoroscopy in a pig model. To establish feasibility aortoscopic guidance was used for making endoluminal aortic measurements, cannulating small arteries for arteriograpy, and placing intraaortic stents and grafts in 11 pigs. To compare aortoscopy and fluoroscopy measurements were made and stents were placed by a surgeon using only aortoscopic guidance in 10 pigs and by an interventional radiologist using only fluoroscopic guidance in 10 pigs. Postmortem dissections were performed to determine measurement and device placement accuracy. In the feasibility study aortoscopic measurements differed from postmortem measurements by a mean distance (+/- SD) of 1.2 +/- 0.2 mm. Stents and grafts were placed a mean of 2.3 +/- 1.9 mm distal to the most inferior renal artery with no stent covering an orifice. All attempts at cannulating spinal arteries greater than 2 mm in diameter were successful. In the comparison of aortoscopic and fluoroscopic guidance, fluoroscopic measurements differed from postmortem measurements by 2.6 +/- 2.4 mm (p = 0.223). Stents placed with aortoscopic guidance were 1.1 +/- 1.3 mm distal to the most inferior renal artery, whereas stents placed with fluoroscopic guidance were 3.4 +/- 2.5 mm distal to the most inferior renal artery (p = 0.019). These results demonstrate that aortoscopy is a useful guidance system for endoluminal aortic procedures and may have advantages over fluoroscopy alone.


Grading Pancreatic Neuroendocrine Tumors Via Endoscopic Ultrasound-guided Fine Needle Aspiration: A Multi-institutional Study.
To identify factors associated with concordance between World Health Organization (WHO) grade on cytological analysis (c-grade) and histopathological analysis (h-grade) of surgical specimen in patients with PanNETs and examine trends in utilization and accuracy of EUS-FNA in preoperatively predicting grade. WHO grading system is prognostic in pancreatic neuroendo-crine tumors (PanNETs). The concordance between c-grade and h-grade is reported to be between 50% and 92%. A multicenter retrospective study was performed on patients undergoing resection for PanNETs at four high-volume centers between 2010 and 2019. Patients with functional or syndrome-associated tumors, and those receiving neoadjuvant therapy were excluded. Factors associated with concordance between c-grade and h-grade and trends of utilization of EUS-FNA were assessed. Of 869 patients included, 517 (59.5%) underwent EUS-FNA; 452 (87.4%) were diagnostic of PanNETs and WHO-grade was reported for 270 (59.7%) patients. The concordance between c-grade and h-grade was 80.4% with moderate concordance ( Kc = 0.52, 95% CI: 0.41-0.63). Significantly higher rates of concordance were observed in patients with smaller tumors (<2 vs. ≥2cm, 81.1% vs. 60.4%, P = 0.005). Highest concordance (98.1%) was observed in patients with small tumors undergoing assessment between 2015-2019 with a near-perfect concordance ( Kc = 0.88, 95% CI: 0.61-1.00). An increase in the utilization of EUS-FNA (56.1% to 64.1%) was observed over the last 2 decades ( P = 0.017) and WHO-grade was more frequently reported (44.2% vs. 77.6%, P < 0.001). However, concordance between c-grade and h-grade did not change significantly (P = 0.118). Recently, a trend towards increasing utilization and improved diagnostic accuracy of EUS-FNA has been observed in PanNETs. Concordance between c-grade and h-grade is associated with tumor size with near-perfect agreement when assessing PanNETs <2cm in size.


Analysis of quantitative proteomic data generated via multidimensional protein identification technology.
We describe the analysis of quantitative proteomic samples via multidimensional protein identification technology (MudPIT). Ratio amounts of the soluble portion of the S. cerevisiae proteome from cultures of S. cerevisiae strain S288C grown in either 14N minimal media or 15N-enriched minimal media were mixed and digested into a complex peptide mixture. A 1 x 14N/1 x 15N complex peptide mixture was analyzed by single-dimensional reversed-phase chromatography and electrospray ionization quadrapole time-of-flight mass spectrometry in order to demonstrate the replacement of 14N by 15N under the growth conditions used. After conformation of the incorporation of 15N into the labeled sample, three separate samples consisting of a 1 x 14N/1 x 15N complex peptide mixture, a 5 x 14N/1 x 15N complex peptide mixture, and a 10 x 14N/1 x 15N complex peptide mixture were analyzed via MudPIT. We demonstrate the dynamic range of the system by analyzing a 1:1, 5:1, and 10:1 data set using the soluble portion from S. cerevisiae grown in either 14N or 15N-enriched minimal media. The method described provides an accurate way to undertake a large-scale quantitative proteomic study.


Breast tumors: composition of microcalcifications.
The authors investigated the crystallographic patterns of calcifications in breast tissue from 31 patients, including eight calcified benign lesions, 17 calcified carcinomas, and six noncalcified control samples. Scanning electron microscopy, energy-dispersive x-ray analysis, and x-ray diffraction with the Guinier camera were employed and yielded information on the shape and composition of breast calcifications. Polyhedral crystals (with energy-dispersive x-ray analysis response to calcium) contained calcite, aragonite, or calcium oxalate, depending on the case. Calcium oxalate crystals were found only in malignant breast tissues. Spherical crystals (with energy-dispersive x-ray analysis response to calcium and phosphorus) contained apatite. Spherical crystals predominated in malignant processes, but all shapes and compositions were present in both benign and malignant processes. The relationship of the calcification to its surrounding tissue may account for differences in structure, but results are inconclusive and require further study.


Separation of Different Blogs from Skin Disease Data using Artificial Intelligence.
A combination of environmental conditions may cause skin illness everywhere on the earth, and it is one of the most dangerous diseases that can develop as a result. A major goal in the selection of characteristics is to produce predictions about skin disease instances in connection with influencing variables, which is one of the most important tasks. As a consequence of the widespread usage of sensors, the amount of data collected in the health industry is disproportionately large when compared to data collected in other sectors. In the past, researchers have used a variety of machine learning algorithms to determine the relationship between illnesses and other disorders. Forecasting is a procedure that involves many steps, the most important of which are the preprocessing of any scenario and the selection of forecasting features. A major disadvantage of doing business in the health industry is a lack of data availability, which is particularly problematic when data is provided in an unstructured format. Filling in missing numbers and converting between various types of data take somewhat more than 70% of the total time. When dealing with missing data in machine learning applications, the mean, average, and median, as well as the stand mechanism, may all be employed to solve the problem. Previous research has shown that the characteristics chosen for a model's overall performance may have an influence on the overall performance of the model's overall performance. One of the primary goals of this study is to develop an intelligent algorithm for identifying relevant traits in models while simultaneously eliminating nonsignificant attributes that have an impact on model performance. To present a full view of the data, artificial intelligence techniques such as SVM, decision tree, and logistic regression models were used in conjunction with three separate feature combination methodologies, each of which was developed independently. As a consequence of this, their accuracy, F-measure, and precision are all raised by a factor of ten, respectively. We then have a list of the most important features, together with the weights that have been allocated to each of them.


Inhibition of 5-HT3 receptor-mediated ion current by divalent metal cations in NCB-20 neuroblastoma cells.
1. The effect of micromolar concentrations of divalent metal cations on ion current activated by 5-hydroxytryptamine (5-HT) was investigated in NCB-20 neuroblastoma cells by the use of the whole-cell, patch-clamp technique. 2. Ion current activated by 5-HT in these cells was mimicked by 5-HT3 receptor agonists, blocked by nanomolar concentrations of selective 5-HT3 receptor antagonists and reversed polarity at approximately 0 mV. These properties indicate that this current is carried primarily if not exclusively by the nonspecific cation channel activated by the 5-HT3 receptor. 3. The Group IIb metal cations Cd2+ and Zn2+ and the Group Ib cation Cu2+ inhibited 5-HT-activated current with inhibition increasing in a concentration-dependent manner over micromolar concentrations of the ions. The order of potency of the ions for inhibiting 5-HT-activated current was Zn2+ (IC50 = 20 microM) greater than or equal to Cu2+ (IC50 = 25 microM) greater than Cd2+ (IC50 = 75 microM) at -50 mV. The other divalent metal cations tested (Ba2+, Co2+, Mg2+, Mn2+, and Ni2+) produced little or no inhibition of 5-HT-activated current at concentrations up to 200 microM. 4. Inhibition of 5-HT-activated current by Cd2+ and Zn2+ was dependent on membrane potential with the Kd increasing e-fold per 72 and 52 mV, respectively. Inhibition by Cu2+ was much less voltage dependent with the Kd increasing e-fold per 233 mV. 5. Inhibition by all three cations decreased with increasing concentration of agonist over a range of 5-HT concentrations from 1 to 10 microM.(ABSTRACT TRUNCATED AT 250 WORDS)


Multilamellar liposomes entrapping aminosilane-modified maghemite nanoparticles: "magnetonions".
4.6 nm-sized aminosilane-modified maghemite (γ-Fe(2)O(3)) nanoparticles (aMNPs) were synthesized and encapsulated into onion-type multilamellar vesicles of soybean phosphatidylcholine (90%mol) and monoolein (10%mol). The magnetic multilamellar vesicles were obtained by shearing lipids with an aqueous dispersion of the preformed aMNPs (ferrofluid). The influence of ferrofluid concentration on the stability of the constitutive lamellar phase and the resulting dispersed onions was analyzed by small-angle X-ray diffraction (SAXD) and cryo-TEM imaging, respectively. When [Fe(III)] <60 mM, stable, magnetic onions were produced with aMNPs inserted inside onion water compartments as isolated or aggregated particles. Encapsulation efficiencies were measured by EPR spectroscopy and magnetic measurements: much higher values (up to 75%) than unilamellar liposomes were found. The deduced aMNP-to-onion ratio increased with ferrofluid concentration before reaching a maximal value of ca. 45 as confirmed by cryo-TEM imaging. When [Fe(III)] >60 mM, uni- or oligolamellar vesicles in addition to onions formed, probably because of a two-phase separation between an aMNP-rich phase and an aMNP-containing lamellar phase as revealed by SAXD.


Synbiotic effect of various prebiotics on in vitro activities of probiotic lactobacilli.
In the present study, five Lactobacillus strains were evaluated for their viability in presence of different prebiotics viz. inulin, oligofructose, lactulose, raftilose, and honey. The viability of lactobacilli was observed before and after 5 weeks of refrigerated storage. The doubling time varied from 5.2 hrs to 9.6 hrs. The lowest doubling time was for Lactobacillus plantarum M5 followed by L. plantarum Ch1 with inulin. Viability of lactobacilli was greatest with inulin. The growth and viability in presence of prebiotics were found to be strain-specific. Hence, it could be concluded that the addition of prebiotics have a significant effect on probiotics, and hence, a combination of suitable Lactobacillus strain(s) with a specific prebiotic could be a viable probiotic-based functional food approach in administering the beneficial bacteria in-vivo.


Epidemiology of human immunodeficiency virus infection in blood donations in Europe and Italy.
The safety of blood with regards to transmission of infectious diseases is guaranteed by European laws that regulate both the selection of donors through pre-donation questionnaires and serological screening. However, variability in the epidemiology of human immunodeficiency virus (HIV) infection in different countries and some differences in the selection of donors can influence the efficacy (with regards to the safety of blood) of these processes. In this study we compared the prevalence of HIV in blood donations in the three macro-areas of Europe and in various western European countries, analysed the criteria of selection and rewarding of donors in western European countries, and studied the trend in the prevalence of HIV in Italy from to 1995 and 2006. European data were derived from the European Centre for the Surveillance of HIV; Italian data were obtained from the Transfusion-Transmitted Infections Surveillance System and National and Regional Register of blood and plasma. The information on eligibility criteria and rewarding offered to donors was derived from international sources. The prevalence of HIV in blood donations was highest in eastern Europe, followed by central Europe and western Europe. Among the western European countries, Spain, Italy and Israel had the highest prevalences; the prevalence was noted to be higher in countries which did not offer any rewarding to the donor. In Italy the prevalence of HIV was 3.8 cases per 100,000 donations in 2006 and increased between 1995 and 2006, both among donations from repeat donors and first time donors. The data highlight the need to continue improving the selection of donors and the coverage of the surveillance systems for HIV infection in transfusion services.


[International migration and development: the new paradigms].
"In the present context of economic crisis which prevails in most receiving countries, two paradigms dominate the approach of international migration issues: ¿control', as a means to contain them, and ¿development', as a means to suppress the need to migrate.... The author [stresses] the need for research aimed at a better understanding of why consequences of international migration and refugee movements can be positive in certain cases, and negative in others, and more generally [emphasizes] the need for research on the relationships between international migration and development." (SUMMARY IN ENG AND SPA)


Dohn v. Lovell, 3 June 1988.
The Court held that language in the Georgia Voluntary Sterilization Act requiring "a full and reasonable medical explanation" to be given to a person wishing to be sterilized "as to the meaning and consequences" of the operation necessarily requires that the explanation be given as to the method to be employed. It rejected the argument of physicians in a medical malpractice suit that they needed to give an explanation only of the intended results of sterilization and that they could not be sued for medical malpractice unless they had been negligent in performing the actual sterilization.


Transfer RNA-derived small RNAs in the cancer transcriptome.
The cellular lifetime includes stages such as differentiation, proliferation, division, senescence and apoptosis. These stages are driven by a strictly ordered process of transcription dynamics. Molecular disruption to RNA polymerase assembly, chromatin remodelling and transcription factor binding through to RNA editing, splicing, post-transcriptional regulation and ribosome scanning can result in significant costs arising from genome instability. Cancer development is one example of when such disruption takes place. RNA silencing is a term used to describe the effects of post-transcriptional gene silencing mediated by a diverse set of small RNA molecules. Small RNAs are crucial for regulating gene expression and microguarding genome integrity. RNA silencing studies predominantly focus on small RNAs such as microRNAs, short-interfering RNAs and piwi-interacting RNAs. We describe an emerging renewal of interest in a 'larger' small RNA, the transfer RNA (tRNA). Precisely generated tRNA-derived small RNAs, named tRNA halves (tiRNAs) and tRNA fragments (tRFs), have been reported to be abundant with dysregulation associated with cancer. Transfection of tiRNAs inhibits protein translation by displacing eukaryotic initiation factors from messenger RNA (mRNA) and inaugurating stress granule formation. Knockdown of an overexpressed tRF inhibits cancer cell proliferation. Recovery of lacking tRFs prevents cancer metastasis. The dual oncogenic and tumour-suppressive role is typical of functional small RNAs. We review recent reports on tiRNA and tRF discovery and biogenesis, identification and analysis from next-generation sequencing data and a mechanistic animal study to demonstrate their physiological role in cancer biology. We propose tRNA-derived small RNA-mediated RNA silencing is an innate defence mechanism to prevent oncogenic translation. We expect that cancer cells are percipient to their ablated control of transcription and attempt to prevent loss of genome control through RNA silencing.


Clinical outcomes of early closure versus conservative strategy after diagnosis with atrial septal defect: a nationwide population-based cohort study.
The long-term clinical benefits of atrial septal defect (ASD) closure remain controversial. We aimed to compare long-term clinical outcomes between patients who underwent early surgical closure after ASD diagnosis and those who did not. Using the Korean National Health Insurance Service database, we identified patients with isolated ASDs diagnosed between 1 January 2003 and 31 December 2006. The ASD patients who underwent closure surgery within 6 months after diagnosis were allocated to the early-closure group and the rest were allocated to the conservative-strategy group. The primary outcome was all-cause mortality. Secondary outcomes were atrial flutter/fibrillation (AFF) and ischaemic stroke. Among patients without a history of AFF or stroke, 1644 patients in the early-closure group were propensity score matched to 1644 patients in the conservative-strategy group and their median follow-up durations were 12.9 and 12.8 years, respectively. The early closure was associated with a significantly lower risk of mortality (hazard ratio, 0.55 [95% confidence interval, 0.43-0.70]). In an age-stratified analysis, significant mortality reductions in the early-closure group were found in patients aged 40 years or older. The risk of AFF was significantly higher in the early-closure group, which might be mainly ascribed to postoperative transient AFF, while there was no difference in ischaemic stroke between the 2 groups. Our data suggest that timely ASD closure without delay is necessary for ASD patients without previous history of clinical events, especially in patients aged 40 years or older.


Perventricular Muscular Ventricular Septal Defect (VSD) Closure under Epicardial Echocardiography Guidance: A Case Report.
Ventricular septal defects (VSDs) are among the most common congenital cardiac lesions. Large defects at apicomuscular regions, especially in young patients, are far from accessible to surgeons for conventional surgery. Moreover, the transcatheter closure of VSDs in these patients is difficult and carries a high risk of complications because of the large sheath size relative to the patient's size. The periventricular approach simplifies VSD closure and, thus, eliminates the potential complications of cardiac catheterization and fluoroscopy as it is performed under echocardiographic guidance. A 3-year-old girl with a body weight of 11 kg (failure to thrive) was referred to us. She had multiple adjacent apicomuscular VSDs, the largest one being about 19 mm in diameter, and subsystemic pulmonary artery pressure (PAP). The patient underwent periventricular apicomuscular VSD closure with a Lifetech muscular VSD occluder (size 22 mm) under epicardial echocardiography guidance without cardiopulmonary bypass. Post procedure, the PAP was decreased to mild level. The residual shunt was mild across the adjacent small defects. She was discharged after 7 days without complications. At 2 years' follow-up, the patient was hemodynamically stable and had a normal PAP (PAP = about 16 mmHg) by transthoracic echocardiographic assessment.


Coupled assays for monitoring protein refolding in Saccharomyces cerevisiae.
Proteostasis, defined as the combined processes of protein folding/biogenesis, refolding/repair, and degradation, is a delicate cellular balance that must be maintained to avoid deleterious consequences (1). External or internal factors that disrupt this balance can lead to protein aggregation, toxicity and cell death. In humans this is a major contributing factor to the symptoms associated with neurodegenerative disorders such as Huntington's, Parkinson's, and Alzheimer's diseases (10). It is therefore essential that the proteins involved in maintenance of proteostasis be identified in order to develop treatments for these debilitating diseases. This article describes techniques for monitoring in vivo protein folding at near-real time resolution using the model protein firefly luciferase fused to green fluorescent protein (FFL-GFP). FFL-GFP is a unique model chimeric protein as the FFL moiety is extremely sensitive to stress-induced misfolding and aggregation, which inactivates the enzyme (12). Luciferase activity is monitored using an enzymatic assay, and the GFP moiety provides a method of visualizing soluble or aggregated FFL using automated microscopy. These coupled methods incorporate two parallel and technically independent approaches to analyze both refolding and functional reactivation of an enzyme after stress. Activity recovery can be directly correlated with kinetics of disaggregation and re-solubilization to better understand how protein quality control factors such as protein chaperones collaborate to perform these functions. In addition, gene deletions or mutations can be used to test contributions of specific proteins or protein subunits to this process. In this article we examine the contributions of the protein disaggregase Hsp104 (13), known to partner with the Hsp40/70/nucleotide exchange factor (NEF) refolding system (5), to protein refolding to validate this approach.


A lysine ring in HIV capsid pores coordinates IP6 to drive mature capsid assembly.
The HIV capsid self-assembles a protective conical shell that simultaneously prevents host sensing whilst permitting the import of nucleotides to drive DNA synthesis. This is accomplished through the construction of dynamic, highly charged pores at the centre of each capsid multimer. The clustering of charges required for dNTP import is strongly destabilising and it is proposed that HIV uses the metabolite IP6 to coordinate the pore during assembly. Here we have investigated the role of inositol phosphates in coordinating a ring of positively charged lysine residues (K25) that forms at the base of the capsid pore. We show that whilst IP5, which can functionally replace IP6, engages an arginine ring (R18) at the top of the pore, the lysine ring simultaneously binds a second IP5 molecule. Dose dependent removal of K25 from the pore severely inhibits HIV infection and concomitantly prevents DNA synthesis. Cryo-tomography reveals that K25A virions have a severe assembly defect that inhibits the formation of mature capsid cones. Monitoring both the kinetics and morphology of capsids assembled in vitro reveals that while mutation K25A can still form tubes, the ability of IP6 to drive assembly of capsid cones has been lost. Finally, in single molecule TIRF microscopy experiments, capsid lattices in permeabilised K25 mutant virions are rapidly lost and cannot be stabilised by IP6. These results suggest that the coordination of IP6 by a second charged ring in mature hexamers drives the assembly of conical capsids capable of reverse transcription and infection.


Physical activity correlates across the lifespan in people with epilepsy: a systematic review.
Understanding barriers and facilitators of physical activity (PA) participation in people with epilepsy is an essential first step to enable development of targeted and effective interventions. This systematic review examined that PA correlates in people with epilepsy across the lifespan. Major electronic databases were searched from inception until 1 April 2019. Keywords included "physical activity" or "exercise" and "epilepsy". Out of 31 correlates from 10 studies (n = 495, 5-72 years) no consistent (i.e., reported in four or more studies) correlates were identified. In children and adolescents, membership of a sports club was a facilitator for being physically active (confirmed in one study: 1/1), while lower maternal educational level was a barrier (1/1). In adults, the most reported barrier was the presence of depression (3/3), followed by trait anxiety (2/3), state anxiety (1/1), side effects of medication (1/1), and perceived stigma (1/1). No studies focusing on middle-aged and old age people with epilepsy were available. The current review found that quantitative research about PA barriers and facilitators in people with epilepsy is still in its infancy, but PA participation is associated with a range of biological, social, and psychological factors which should be considered in rehabilitation programs.Implications for rehabilitationMany people living with epilepsy do not engage in physical activity on a regular basis.Children with epilepsy who are member of a sports club are more physically active.Depression, anxiety, and perceived stigma are important barriers for being active in adults with epilepsy.Side-effects of antiepilepstic drugs are a barrier for being active in adults with epilepsy.


Lysobacter panaciterrae sp. nov., isolated from soil of a ginseng field.
A Gram-negative, aerobic, rod-shaped, non-spore-forming bacterial strain, designated Gsoil 068(T), was isolated from soil of a ginseng field in Pocheon Province (South Korea), and was characterized to determine its taxonomic position by using a polyphasic approach. Comparative 16S rRNA gene sequence analysis showed that strain Gsoil 068(T) belonged to the family Xanthomonadaceae, class Gammaproteobacteria, and was related most closely to Lysobacter brunescens ATCC 29482(T) and Lysobacter gummosus ATCC 29489(T) (96.1 % sequence similarity). The G+C content of the genomic DNA of strain Gsoil 068(T) was 67.0 mol%. The detection of a quinone system with ubiquinone Q-8 as the predominant component and a fatty acid profile with iso-C(15 : 0), iso-C(17 : 1)omega9c, iso-C(17 : 0) and iso-C(11 : 0) 3-OH as the major components supported the affiliation of strain Gsoil 068(T) to the genus Lysobacter. On the basis of its phenotypic properties and phylogenetic distinctiveness, strain Gsoil 068(T) is considered to represent a novel species of the genus Lysobacter, for which the name Lysobacter panaciterrae sp. nov. is proposed. The type strain is Gsoil 068(T) (=KCTC 12601(T) =DSM 17927(T)).


Silicone migration from silicone-injected breasts: magnetic resonance images.
Injection of liquid silicone into the breast was performed illicitly in the 1950s to 1960s and was subsequently prohibited. Many complications arise from silicone injection, and liquid silicone migration is a complication that has not been widely reported. The authors present magnetic resonance images of a patient with liquid silicone migration from the breast to the upper chest and lower neck. Breast ultrasonographic and mammographic findings are also presented for correlation.


Endovascular management of unruptured intracranial aneurysms: does outcome justify treatment?
The appropriate management of unruptured intracranial aneurysms depends on a complete understanding of their natural history and on the risks and efficacy of treatment options. There is little current data on the risks of endovascular therapy for these aneurysms. The aim of this study was to assess outcome of endovascular treatment of unruptured intracranial aneurysms. A retrospective analysis was performed on all unruptured aneurysms treated by Guglielmi detachable (GD) coils at this institution from 1994 to 2000. Seventy three unruptured aneurysms were treated in 62 patients. There were 52 female and 10 male patients, with a median age of 55.7 years. Clinical background was: subarachnoid haemorrhage due to rupture of an additional aneurysm (40), headache (4), third nerve palsy (four), familial (four), and incidental (10). There were 14 technical failures with no clinical sequelae. Four procedural complications occurred (5.5%, 95% confidence interval (95% CI) 0.3% to 10.9%). One patient had temporary clinical sequelae (1.4%, 95% CI 0% to 2.7%); 79% of treated aneurysms had stable occlusions at follow up, 10.5% showed improved occlusion grade, 10.5% showed some recurrence, and three patients have required retreatment. Follow up modified Glasgow outcome scores were grade 1, 71%; grade 2, 18%; grade 3, 3%; grade 4, 3%. There were no deaths or haemorrhages during the follow up period. Two patients died as a result of complications from subarachnoid haemorrhage. The endovascular treatment of patients with unruptured aneurysms is safe with few clinical or procedural complications. Poor outcomes were only seen in those patients who presented with subarachnoid haemorrhage due to rupture of an aneurysm at another site.


Visible light-induced photocatalytic activity of Bi2O3 prepared via microwave-assisted method.
Bi2O3 was successfully synthesized via microwave-assisted reaction of Bi2O3 precursor in aqueous solution using a microwave system. Their morphologies, structures and photocatalytic performances in the degradation of methylene blue (MB) were characterized by scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction spectroscopy, photoluminescence spectroscopy and UV-vis absorption spectroscopy, respectively. The results show that Bi2O3 synthesized at pH value of 7 exhibits an optimal photocatalytic performance with the MB degradation rate of 76% at 240 min under visible light irradiation due to its higher visible light absorption and comparatively low electron-hole pair recombination.


An epidemiological survey of dog bites presenting to the emergency department of a children's hospital.
German shepherds are the most popular registered breed of dog in South Australia, but are also the most hazardous to children, biting more often and more severely. A study of the victims of dog bites presenting to the Emergency Department of the Adelaide Children's Hospital over an 18 month period revealed that, although many breeds were involved, only German shepherds were implicated more frequently than their prevalence in the community. Attacks occurred most often in a domestic setting involving a friendly dog that was known to the victim. Boys were more often bitten than girls and children aged 1-6 years most commonly involved. Injuries to the face and scalp were frequent and the usual ones to require admission for suture under general anaesthetic. Some scarring was a common sequel and resulting fear of dogs remained with some children. Most attacks were reported to be unprovoked and a previous biting history on the part of the dog was uncommon. Parents who are contemplating obtaining a dog for a family pet should be made aware of these facts and advised regarding the biting hazards and possible prevention. The German shepherd situation especially should be brought to their attention.


[Patients' competences. What do patients need to know and be able to do?].
Patients today are rarely patient. More and more they want to be--and should be--responsible partners to their doctors and participants in healthcare policy. However, even though recent health reforms offered some incentives in this direction, the basic requirements are still lacking. One area that is woefully neglected is the furthering of the patients' competences. These are described as fourfold: competence in dealing with one's own disease and its symptoms; relational competence in the interaction between patient and doctor; social competence in cooperation with fellow patients, e. g., in self-help groups; and democratic competence to participate in formulating healthcare policy. The question is asked in which organizations and training measures these competences have already been developed. The text concludes with the call for a patient academy network operating nationwide.


[Clinical end-points and surrogate markers of pulmonary arterial hypertension in the light of evidence-based treatment].
Pulmonary arterial hypertension (PAH) is a rare, fatal and progressive disease. There is an acceleration in the advent of new therapies in parallel to the development of the knowledge about etiogenesis and pathogenesis of PAH. Therefore, to optimize the goals of PAH-specific treatment and to determine the time to shift from monotherapy to combination therapy, simple, objective and reproducible end-points, which may predict the disease severity, progression rate and life expectancy are needed. The adventure of end points in PAH has started with six minute walk distance and functional capacity, and continues with new parameters (biochemical marker, time to clinical worsening, echocardiography and magnetic resonance imaging etc.), which can better reflect the clinical outcome.


Immunogenicity and protective efficacy induced by an mRNA vaccine encoding gD antigen against pseudorabies virus infection.
Messenger RNA-based vaccines represent new tools with prophylactic and therapeutic potential characterized by high flexibility of application for infectious diseases. Pseudorabies virus (PRV) is one of the major viruses affecting the pig industry. PRV has serious effects in piglets, sows, and growing-fattening pigs and can lead to huge economic losses. In this study, an envelope glycoprotein D (gD) gene-based specific mRNA vaccine was generated, and a mouse model was used to investigate the protective efficacy of the vaccine. The gD mRNA vaccine and the recombinant plasmid pVAX-gD were transfected into BHK21 cells, and the antigenicity of the expressed proteins was detected by Western blot analysis. Groups of mice were vaccinated with the gD mRNA vaccine, pVAX-gD, and PBS. T cell immune responses were measured by flow cytometry or ELISA and serum neutralization tests every two weeks. The challenge with the PRV-XJ strain was performed eight weeks after the primary immunization, and the response was monitored for 15 days. The levels of specific and neutralizing antibodies in the gD mRNA vaccine group were significantly increased in 8 weeks compared to those in the control group, and cytokine levels, including that of IFN-γ/IL-2, were considerably higher than those in the control animal. Additionally, the proportion of CD4+/CD8+ cells in peripheral lymphocytes was remarkably increased. Our data demonstrate that mRNA is a promising and effective tool for the development of vaccines. The PRV-gD-based mRNA vaccine can elicit an efficient neutralizing antibody response and induce effective protection in mice in defense against PRV infection.


[The effect of fatigue on the biopotential of muscle fiber cells].
Muscular fatigue is a biological situation which is very difficult to quantify. The Authors studied through a computer analysis the power spectrum of electromyogram, recorded from abductor digiti minimi muscle during maximal and minimal contraction effort before and after fatigue and after muscle prolonged relaxation in 8 normal subjects. No significant spectrum differences were found between maximal and minimal effort in each trial, and between the spectra obtained before fatigue and after muscle prolonged relaxation. On the contrary significant differences were found between the spectra obtained after fatigue and the other conditions. The power spectrum analysis appears, also, to be a reliable neurophysiological parameter for the study of biological aspects of muscular fatigue.


An investigation into the sensitivities of translocating bacteria to a prophylactic antibiotic regimen.
It is well established that bacterial translocation is associated with a significant increase in septic morbidity. The purpose of this study was to determine the antibiotic sensitivities of translocating bacteria on the basis that this information may influence antibiotic prophylaxis in surgical patients. Routine microbiological techniques were used to assess the antibiotic sensitivities of those bacteria cultured from a mesenteric lymph node harvested at laparotomy in a large series of patients. Culture of the mesenteric lymph nodes yielded growth in 51 out of a total of 447 patients studied (11.4%). The isolates from 40 patients, a total of 60 organisms, were available for sensitivity testing. The most common species grown was Escherichia coli (48% of isolates). Thirty-three patients (83%) grew organisms sensitive to the antibiotic prophylaxis used, but there was no significant difference in the incidence of postoperative septic complications between these patients and those in whom resistant bacteria were grown (39% versus 29%, P = 0.64 Fisher's Exact test mid P). The majority of translocating bacteria are sensitive to the prophylactic antibiotics commonly used in patients undergoing laparotomy. However, the occurrence of postoperative septic morbidity is independent of this variable.


High-throughput sequencing of natively paired antibody chains provides evidence for original antigenic sin shaping the antibody response to influenza vaccination.
We developed a DNA barcoding method to enable high-throughput sequencing of the cognate heavy- and light-chain pairs of the antibodies expressed by individual B cells. We used this approach to elucidate the plasmablast antibody response to influenza vaccination. We show that >75% of the rationally selected plasmablast antibodies bind and neutralize influenza, and that antibodies from clonal families, defined by sharing both heavy-chain VJ and light-chain VJ sequence usage, do so most effectively. Vaccine-induced heavy-chain VJ regions contained on average >20 nucleotide mutations as compared to their predicted germline gene sequences, and some vaccine-induced antibodies exhibited higher binding affinities for hemagglutinins derived from prior years' seasonal influenza as compared to their affinities for the immunization strains. Our results show that influenza vaccination induces the recall of memory B cells that express antibodies that previously underwent affinity maturation against prior years' seasonal influenza, suggesting that 'original antigenic sin' shapes the antibody response to influenza vaccination.


Balloon Valvuloplasty via the Pulmonary Artery Trunk for Treating Neonates With Severe Pulmonary Valve Disease.
Percutaneous balloon pulmonary valvuloplasty has proven to be a standard of care for neonates with severe pulmonary valve disease. However, the peripheral vessel injury, tricuspid chordae tendineae rupture, and cardiac tamponade could occur. Recently, we performed balloon valvuloplasty through pulmonary artery trunk. To date, the obtained outcome was promising. Between January 2018 and December 2018, three neonates with critical pulmonary stenosis and two with membranous pulmonary atresia with intact ventricular septum were enrolled in our center. Balloon valvuloplasty through pulmonary artery trunk was performed in all patients. A 2-cm parasternal incision was made in the left third intercostal space. A guidewire was used to advance or perforate the pulmonary valve from the pulmonary artery trunk into the right ventricle, followed by balloon dilation of the valve. The procedure was successful in all patients. The oxygen saturation increased immediately after the balloon dilation, while the right ventricular systolic pressure and the gradient across the pulmonary valve decreased. No severe complications occurred. Balloon valvuloplasty through the pulmonary artery trunk is a safe and feasible alternative procedure. Thus, it could serve as a supplementary choice for treating severe pulmonary valve disease.


A STUDY ON THE HAEMODYNAMIC INTERACTIONS BETWEEN ACTIVATED CHARCOAL AND PROPRANOLOL/ATENOLOL IN NORMAL HUMAN SUBJECTS.
A random, observer blind, crossover design of study was undertaken in twelve normal male volunteers. Both propranolol (40 mg) and atenolol (50 mg) in single dose oral administration had significantly reduced the heart rate, systolic blood pressure and the value for double product under resting and postexercise conditions compared to the corresponding pretreatment values. Orally administered activated charcoal (15 g) had abolished the haemodynamic effects of propranolol but failed to do so against atenolol under both resting and postexercise periods. The results suggest the possibility of successful antidotal intervention with activated charcoal in the case of propranolol overdosage only.


Intraoperative radiation therapy for early stage breast cancer.
We report our experiences with Intraoperative radiation therapy (IORT) among breast cancer (BC) patients in our region. All patients who received radical IORT from April 2014 on to March 2020 were included in the study. Patient selection criteria included: Age equal or older than 45 years old; All cases of invasive carcinomas (in cases of lobular carcinomas only with MRI and confirmation); Patients who were 45-50 years old with a tumor size of 0-2 cm, 50-55 years old with a tumor size of < 2.5 cm, and those who were ≥ 55 years old with a tumor size of < 3 cm; Invasive tumors only with a negative margin; Negative nodal status (exception in patients with micrometastasis); A positive estrogen receptor status. Primary endpoints included death and recurrence which were assessed using the Kaplan-Meier method. Overall, 252 patients entered the study. Mean (SD) age of patients was 56.43 ± 7.79 years. In total, 32.9% of patients had a family history of BC. Mean (SD) tumor size was 1.56 ± 0.55 cm. Mean (IQR) follow-up of patients was 36.3 ± 18.7 months. Overall, 8 patients (3.1%) experienced recurrence in follow-up visits (disease-free-survival of 96.1%), among which four (1.5%) were local recurrence, two (0.8%) were regional recurrence and two patients (0.8%) had metastasis. Median (IQR) time to recurrence was 46 (22, 53.7) months among the eight patient who had recurrence. Overall, one patient died due to metastasis in our series. Eleven patients (4.3%) with DCIS in our study received IORT. All these patients had free margins in histopathology examination and none experienced recurrence. Inhere we reported our experience with the use of IORT in a region where facilities for IORT are limited using our modified criteria for patient selection.


Posterior non-ischemic left ventricular aneurysm. Report of 2 surgical cases.
Posterior non-ischemic left ventricular aneurysms are unusual aneurysms of different etiology that develop adjacent to the mitral valve annulus causing mitral regurgitation and progressive heart failure. Surgical correction is mandatory and involves repair of the aneurysm along with repair or replacement of the mitral valve. Two cases of posterior non-ischemic left ventricular aneurysms are reported. Both patients were females (19 and 9 years old) and they presented with symptoms of progressive heart failure. Definite diagnosis was made with transesophageal echocardiography (TEE) and confirmed with left ventriculography. Both patients were successfully treated by surgery. The first patient underwent repair of the aneurysm from inside the left ventricle and mitral valve replacement. The second patient had resection of the aneurysm through an extracardiac route. Both patients are in NYHA class 1, 5 and 4 years respectively after their operation with no evidence of mitral valve dysfunction. Posterior non-ischemic left ventricular aneurysms can securely be diagnosed by TEE and angiocardiography. Surgical treatment is mandatory in order to forestall potential life threatening cardiovascular events and should be tailored to the operative findings.


A descriptive study of breastfeeding practices and policies in Missouri hospitals.
All Missouri hospitals that offer maternity services were assessed to measure their compliance with WHO/UNICEF Baby Friendly Hospital Initiative (BFHI). Representatives from seventy six hospitals responded to a telephone survey relating to hospital breastfeeding practices and policies as defined by BFHI's Ten Steps to Successful Breastfeeding. No hospital fully supported the Ten Steps. Compliance with the WHO/UNICEF criteria varied greatly. The least support was for Step I, only 28% of hospitals had a written breastfeeding policy that was communicated to all staff. The greatest support was for Step 3, 93% of hospitals had staff who informed all pregnant women of breastfeeding benefits. In order to increase breastfeeding rates and duration, administrators of hospitals that offer maternity services must increase their efforts to consistently implement the Ten Steps, to become more baby friendly, and to more fully establish a breastfeeding culture within their institutions.


Method for Recording Broadband High Resolution Emission Spectra of Laboratory Lightning Arcs.
Lightning is one of the most common and destructive forces in nature and has long been studied using spectroscopic techniques, first with traditional camera film methods and then digital camera technology, from which several important characteristics have been derived. However, such work has always been limited due to the inherently random and non-repeatable nature of natural lightning events in the field. Recent developments in lightning test facilities now allow the reproducible generation of lightning arcs within controlled laboratory environments, providing a test bed for the development of new sensors and diagnostic techniques to understand lightning mechanisms better. One such technique is a spectroscopic system using digital camera technology capable of identifying the chemical elements with which the lightning arc interacts, with these data then being used to derive further characteristics. In this paper, the spectroscopic system is used to obtain the emission spectrum from a 100 kA peak, 100 µs duration lightning arc generated across a pair of hemispherical tungsten electrodes separated by a small air gap. To maintain a spectral resolution of less than 1 nm, several individual spectra were recorded across discrete wavelength ranges, averaged, stitched, and corrected to produce a final composite spectrum in the 450 nm (blue light) to 890 nm (near infrared light) range. Characteristic peaks within the data were then compared to an established publicly available database to identify the chemical element interactions. This method is readily applicable to a variety of other light emitting events, such as fast electrical discharges, partial discharges, and sparking in electrical equipment, apparatus, and systems.


Managing wound pain in patients with vacuum-assisted closure devices.
The etiology and management of wound pain for patients with vacuum-assisted closure devices can be complex. Patients, such as the patient with necrotizing fasciitis described in this case study, may experience all three types of pain described in the Chronic Wound Pain Experience Model--acute noncyclic, acute cyclic, and chronic. Strategies that include local wound management to reduce all three types of pain and holistic psychological care to reduce the ache and anguish that may accompany dressing change procedures may help provide comfort and reduce pain and suffering.


Evaluation of a novel approach in the prevention of white spot lesions around orthodontic brackets.
The purpose of this study was to evaluate and compare the relative efficacy of a resin fissure sealant, nano-filled self-adhesive protective coating, resin infiltrant, glass ionomer cement (GIC), and GIC containing casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) in preventing the formation of subsurface lesions of enamel (SLE) adjacent to orthodontic brackets by acting as an enamel surface sealant (ESS). Eighty-five enamel specimens with molar tubes bonded at their centre were randomly divided into five groups, each treated with a different material at the bracket's periphery. Specimens were stored in an acetate demineralization solution at pH 4.5 for 7 days at 37 °C then imaged using quantitative light-induced fluorescence (QLF) to determine the difference in fluorescence (∆F) between sound- and acid-exposed enamel. Lesion cross-sections were then examined using backscattered scanning electron microscopy (SEM) to measure lesion depth. The use of GIC alone or incorporating CPP-ACP significantly reduced ∆F compared with other materials. Backscattered SEM images showed no measurable demineralization for enamel treated with either GIC material in contrast with other groups, which showed statistically significant demineralization levels. The fluoride-releasing effects and CPP-ACP benefits of the GIC materials show promise as an effective ESS in inhibiting enamel demineralization adjacent to orthodontic brackets.


Selective, covalent modification of beta-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors.
Microtubules are linear polymers of alpha- and beta-tubulin heterodimers and are the major constituents of mitotic spindles, which are essential for the separation of chromosomes during mitosis. Here we describe a synthetic compound, 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067), which covalently and selectively modifies the beta1, beta2, and beta4 isotypes of beta-tubulin at a conserved cysteine residue, thereby disrupting microtubule polymerization. Cells exposed to T138067 become altered in shape, indicating a collapse of the cytoskeleton, and show an increase in chromosomal ploidy. Subsequently, these cells undergo apoptosis. Furthermore, T138067 exhibits cytotoxicity against tumor cell lines that exhibit substantial resistance to vinblastine, paclitaxel, doxorubicin, and actinomycin D. T138067 is also equally efficacious in inhibiting the growth of sensitive and multidrug-resistant human tumor xenografts in athymic nude mice. These observations suggest that T138067 may be clinically useful for the treatment of multidrug-resistant tumors.


Genetics of isolated hypogonadotropic hypogonadism: role of GnRH receptor and other genes.
Hypothalamic gonadotropin releasing hormone (GnRH) is a key player in normal puberty and sexual development and function. Genetic causes of isolated hypogonadotropic hypogonadism (IHH) have been identified during the recent years affecting the synthesis, secretion, or action of GnRH. Developmental defects of GnRH neurons and the olfactory bulb are associated with hyposmia, rarely associated with the clinical phenotypes of synkinesia, cleft palate, ear anomalies, or choanal atresia, and may be due to mutations of KAL1, FGFR1/FGF8, PROKR2/PROK2, or CHD7. Impaired GnRH secretion in normosmic patients with IHH may be caused by deficient hypothalamic GPR54/KISS1, TACR3/TAC3, and leptinR/leptin signalling or mutations within the GNRH1 gene itself. Normosmic IHH is predominantly caused by inactivating mutations in the pituitary GnRH receptor inducing GnRH resistance, while mutations of the β-subunits of LH or FSH are very rare. Inheritance of GnRH deficiency may be oligogenic, explaining variable phenotypes. Future research should identify additional genes involved in the complex network of normal and disturbed puberty and reproduction.


The pharmacokinetics of orally absorbed cefuroxime compared with amoxycillin/clavulanic acid.
The pharmacokinetics of a new orally absorbed pro-drug of cefuroxime were compared with those of co-administered amoxycillin and clavulanic acid in six healthy male volunteers. Doses of 600 mg of acetoxyethyl cefuroxime and 500 mg amoxycillin plus 250 mg clavulanic acid were each administered for ten doses 8 hourly. Tissue penetration after the first dose of the antibiotic was estimated by a cantharides blister method. The faecal flora of the volunteers was studied throughout the study. The pharmacokinetics of cefuroxime and amoxycillin were very similar, peak levels of about 6.4 mg/l being found between 2 and 2.5 h after administration. The peak serum level of clavulanic acid was 4.3 mg/l at 1.25 h after administration. The serum half-lives were about 1.1 h for all three agents. No drug accumulation occurred over the four days of the study. The 0-8 h urinary recovery of cefuroxime was 30%. All three agents penetrated the blister fluid rapidly, the main peak levels being 64% of the peak serum level for cefuroxime, 72% for amoxycillin and 55% for clavulanic acid. The incidence of side effects was similar for each regimen. Three volunteers having diarrhoea after cefuroxime showed significant alterations in their bowel flora.


Effect of Na+/H+ exchange inhibitors on agonist-induced contraction of rat aorta.
A number of vasoconstrictor agonists activate the Na+/H+ antiport system in vascular smooth muscle, leading to alkalinization of the cytosol and influx of Na+. It is believed that agonist-induced Na+/H+ exchange may play an important role in contraction. We have evaluated this hypothesis by determining the effect of inhibition of Na+/H+ exchange on phenylephrine (PE)-induced contraction of rat aorta. Preincubation of rat aorta with the Na+/H+ exchange inhibitor amiloride (0.5 mM) inhibited subsequent PE-induced contraction. However, the more potent and specific Na+/H+ exchange inhibitor hexamethylene amiloride (10 microM) did not inhibit PE-induced contraction. Inhibition of Na+/H+ exchange by removal of extracellular Na+ and substitution with N-methyl-D-glucamine only moderately reduced PE-induced contraction. Hexamethylene amiloride (10 microM) and methyl-isobutyl amiloride (30 microM), another potent and specific inhibitor of Na+/H+ exchange, caused a slow, sustained and reversible contraction of rat aorta which was 114.7 and 86.6%, respectively, of maximal PE-induced contraction. Hexamethylene amiloride-induced contraction was dose-dependent, dependent on extracellular calcium and inhibited by nifedipine. We conclude that the vasorelaxant effects of amiloride are unrelated to inhibition of Na+/H+ exchange, and may be mediated by inhibition of kinases involved in contraction. These results demonstrate that inhibition of Na+/H+ exchange has no major effect on agonist-induced contraction of rat aorta, and suggest that vasoconstrictor activation of Na+/H+ exchange does not play a major role in agonist-induced contraction of rat aorta.


Micronucleus frequencies in exfoliated urothelial cells among individuals residing near a waste water drain and using underground water resources.
A study was conducted to score for any genetic damage in residents of a village of the Amritsar district. The village is located near an open drain that receives industrial effluents and municipal wastes. Earlier analyses of samples from the drain and from underground water resources of the village showed the presence of heavy metals and bacteria, respectively. As the contaminants have a potential to leach into the ground water and as the residents of the village depend only on the underground water for their anthropogenic activities, it was thought pertinent to look for genetic damage in some of the residents. Urothelial cells of 50 male residents and 25 normal healthy males (not living near any drain) were analyzed for the presence of micronuclei using standard micronucleus (MN) test protocol. The mean percent frequency of micronucleated cells in the resident group was statistically significant (t-test) as compared to the value in the control group. The MN frequency also increased with increasing age of the residents and their stay in the village. A higher frequency was further observed in the subgroup using only ground water as compared to that also using tap water (but only for drinking purposes). These results indicate exposure from genotoxicants to the residents, most probably from using underground water in the light of absence of exposure to other sources.


Citalopram-associated SIADH.
To report a case of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with use of citalopram in an elderly male patient and to review the English-language literature for any previous reports of SIADH or hyponatremia caused by citalopram. An 87-year-old Filipino man was admitted to the hospital reporting malaise, confusion, dizziness, and falls approximately 3 weeks following an increase in his citalopram dosage from 10 to 20 mg/d. On physical examination, the patient was euvolemic and had no evidence of malignancy, cardiac, renal, or hepatic disease. Pertinent laboratory test results revealed hyponatremia, serum hypoosmolality, urine hyperosmolality, and elevated urine sodium concentration, leading to a diagnosis of SIADH. Citalopram was discontinued and fluid restrictions were instituted. The patient was discharged after his serum sodium increased from 122 to 128 mEq/L and he reported increased strength and decreased confusion. Five days after discharge, the patient denied experiencing any new falls, weakness, confusion, or lethargy. His serum sodium measured that day was 131 mEq/L; 2 months later, it was 135 mEq/L. We report the seventh case of citalopram-induced hyponatremia published in the English language and the second in a man. Review of the cases demonstrated that the onset of citalopram-induced hyponatremia or SIADH ranged from 6 to 20 days. Potential risk factors for SIADH due to citalopram included advanced age, female gender, concomitant use of medications known to cause SIADH or hyponatremia, and, possibly, higher citalopram doses. Elderly patients receiving citalopram should be monitored for signs and symptoms of SIADH, especially in the first few weeks of therapy, in the presence of risk factors, and during dose escalation.


The spinning rotation of ash and tulip tree samaras.
Ash and tulip tree samaras rotate on their long axes as they fall, as well as spin around like maple samaras. They descend faster than would maple samaras of the same size and weight and much faster than would zanonia samaras, but they are very stable, which may explain their evolutionary success.