Missing Teeth and Prosthodontic Replacement in an Institutionalized Dentate Population of 60 Years and Older in Qingdao, China.
The aim of this study was to investigate missing teeth and prosthodontic replacements in an institutionalized elderly population in China, and to assess dental functionality before and after the prosthodontic replacements based on a hierarchical dental functional classification (HDFC) system. A sample of 512 participants (9% aged 60-69 years; 29% aged 70-79 years; 62% aged ≥ 80 years) living in eight nursing homes in Qingdao were categorized by the HDFC with and without tooth replacements. A functional dentition in the HDFC meets all the following criteria: ≥ 10 natural teeth in each jaw; a complete anterior region; 3 or 4 posterior occluding pairs (POPs) in the premolar regions; and ≥ 1 POP bilaterally in the molar region. Participants with tooth replacements were reclassified. The score for effectiveness of replacements were as follows: 4 for ≥ 10 teeth in each jaw; 3 for a complete anterior region; 2 for 3 or 4 POPs in premolar regions; and 1 for ≥ 1 molar POP bilaterally. Twenty percent of the participants had functional dentitions, but 42% met none of the functional criteria. In the branch '≥ 10 teeth in each jaw' the mean number of teeth present was 26.3 ± 2.9, and the mean number of POPs was 6.2 ± 2.0. In the branch '< 10 teeth in each jaw,' there were 13.4 ± 5.5 teeth and 1.1 ± 1.5 POPs. Of the 384 participants with natural teeth in each jaw, 44% had no replacements and 56% had fixed dental prostheses (FDPs), partial removable dental prostheses (PRDPs), or both. FDPs usually replaced 1 or 2 teeth, and PRDPs 3 or more teeth. On the basis of natural teeth plus artificial teeth (214 participants with replacements), 46% had functional dentitions while 18% met none of the functional criteria. In the promoted participants, the mean number of teeth added by FDPs was 3.6 ± 2.5, and for PRDPs it was 11.9 ± 6.5. FDPs had a significantly higher mean promotion value per tooth added than PRDPs. Approximately half the tooth replacements effectively met all criteria for a functional dentition.


THE EVOLUTION OF COSTLY MATE PREFERENCES II. THE "HANDICAP" PRINCIPLE.
We use a general additive quantitative genetic model to study the evolution of costly female mate choice by the "handicap" principle. Two necessary conditions must be satisfied for costly preference to evolve. The conditions are (i) biased mutation pressure on viability and (ii) a direct relationship between the degree of expression of the male mating character and viability. These two conditions explain the success and failure of previous models of the "handicap" principle. Our model also applies to other sources of fitness variation like migration and host-parasite coevolution, which cause effects equivalent to biased mutation.


Compound heterozygous missense mutations p.Leu207Pro and p.Tyr544Cys in TGM1 cause a severe form of lamellar ichthyosis.
TGM1 is the most common gene responsible for lamellar ichthyosis. Previous studies have suggested that patients with lamellar ichthyosis carrying two missense mutations in TGM1 show significantly less severe phenotypes than those with at least one truncating mutation in TGM1. Here, we report a patient with severe lamellar ichthyosis who was compound heterozygous for TGM1 missense mutations, including a novel one. A 22-year-old Japanese man presented with large, dark brown, plate-like scales on the extremities and small adherent scales on the face and trunk. His other clinical findings included ectropion, hair loss, hypohidrosis, hyperthermia in summer, palmoplantar keratoderma and constriction of the fingers. Dermoscopy revealed accentuated sulci cutis with numerous large keratotic plugs in the cristae cutis. Histologically, orthohyperkeratosis and mild acanthosis were noted. Electron microscopy showed reduced cornified envelope thickness and numerous lipid droplets in the stratum corneum. Mutation analysis revealed the patient to be compound heterozygous for missense mutations, c.620T>C (p.Leu207Pro) and c.1631A>G (p.Tyr544Cys), in TGM1. Furthermore, we showed that TGM1 enzymatic activity was largely absent in his epidermis. These findings led us to diagnose him as having lamellar ichthyosis. This study has two important notions. First, even two missense mutations in TGM1 can cause severe lamellar ichthyosis. Second, this is the first report of dermoscopic findings of lamellar ichthyosis, implicating the obstruction of sweat glands by keratotic plugs in the pathogenesis of hypohidrosis in the disease. In conclusion, this study provides further insights into genotype-phenotype correlations and pathogenesis in lamellar ichthyosis.


Lateral shift of the transmitted light beam through a left-handed slab.
It is reported that when a light beam travels through a slab of left-handed medium in the air, the lateral shift of the transmitted beam can be negative as well as positive. The necessary condition for the lateral shift to be positive is given. The validity of the stationary-phase approach is demonstrated by numerical simulations for a Gaussian-shaped beam. A restriction to the slab's thickness is provided that is necessary for the beam to retain its profile in the traveling. It is shown that the lateral shift of the reflected beam is equal to that of the transmitted beam in the symmetric configuration.


Endophytic Fungus Reshapes Spikelet Microbiome to Reduce Mycotoxin Produced by Fusarium proliferatum through Altering Rice Metabolites.
Rice spikelet rot disease (RSRD) caused by Fusarium proliferatum seriously reduces rice yield and produces mycotoxins that threaten human health. The root symbiotic endophytic fungus Phomopsis liquidambaris reduces RSRD incidence and fumonisins accumulation in grain by 21.5 and 9.3%, respectively, while the mechanism of disease resistance remains largely elusive. Here, we found that B3 significantly reduced the abundance of pathogen from 79.91 to 2.84% and considerably enriched resistant microbes Pseudomonas and Proteobacteria in the spikelet microbial community. Further study revealed that B3 altered the metabolites of spikelets, especially hordenine and l-aspartic acid, which played a key role in reshaping the microbiome and supporting the growth of the functional core microbe Pseudomonas, and inhibited the pathogen growth and mycotoxin production. This study provided a feasibility of regulating the function of aboveground microbial communities by manipulating plant subsurface tissues to control disease and mycotoxin pollutants in agricultural production.


Immunofluorescence microscopy studies of the granular and keratin layers of normal human skin.
Granular and keratin layer fluorescence of normal human skin has been found to be very different, depending on whether the indirect or the direct fluorescent antibody technique is used. These layers fluoresce more brightly with the indirect than with the direct technique. These differences were interpreted as being caused by in vitro binding of antibodies such as anti-stratum corneum antibodies. The purpose of this study was to see if these differences were, in part, artifacts. on serum dilution, the appearance with the indirect technique consistently converted to that of the direct technique, but no microscopic structural differences were found between the skins subjected to the different technical procedures. Therefore, it was concluded that the indirect appearance is caused only by antibodies binding to the keratin and granular layers and is not a methodological artifact.


Human coronavirus 229E encodes a single ORF4 protein between the spike and the envelope genes.
The genome of coronaviruses contains structural and non-structural genes, including several so-called accessory genes. All group 1b coronaviruses encode a single accessory protein between the spike and envelope genes, except for human coronavirus (HCoV) 229E. The prototype virus has a split gene, encoding the putative ORF4a and ORF4b proteins. To determine whether primary HCoV-229E isolates exhibit this unusual genome organization, we analyzed the ORF4a/b region of five current clinical isolates from The Netherlands and three early isolates collected at the Common Cold Unit (CCU) in Salisbury, UK. All Dutch isolates were identical in the ORF4a/b region at amino acid level. All CCU isolates are only 98% identical to the Dutch isolates at the nucleotide level, but more closely related to the prototype HCoV-229E (>98%). Remarkably, our analyses revealed that the laboratory adapted, prototype HCoV-229E has a 2-nucleotide deletion in the ORF4a/b region, whereas all clinical isolates carry a single ORF, 660 nt in size, encoding a single protein of 219 amino acids, which is a homologue of the ORF3 proteins encoded by HCoV-NL63 and PEDV. Thus, the genome organization of the group 1b coronaviruses HCoV-NL63, PEDV and HCoV-229E is identical. It is possible that extensive culturing of the HCoV-229E laboratory strain resulted in truncation of ORF4. This may indicate that the protein is not essential in cell culture, but the highly conserved amino acid sequence of the ORF4 protein among clinical isolates suggests that the protein plays an important role in vivo.


Barriers and Facilitators to a Task-Shifted Stroke Prevention Program for Children with Sickle Cell Anemia in a Community Hospital: A Qualitative Study.
Children with sickle cell anemia (SCA) are at high risk for stroke. Protocols for stroke prevention including blood transfusions, screening for abnormal non-imaging transcranial Doppler (TCD) measurements, and hydroxyurea therapy are difficult to implement in low-resource environments like Nigeria. This study aimed to examine the contextual factors around TCD screening in a community hospital in Nigeria using qualitative interviews and focus groups. We conducted focus groups with health care providers and interviews with administrative leadership of the community hospital. Interview guides and analysis were informed by the Consolidated Framework for Implementation Research (CFIR) framework. Transcripts were coded and analyzed using an iterative deductive (CFIR)/Inductive (transcribed quotes) qualitative methodology. We conducted two focus groups and five interviews with health care workers (nurses and doctors) and hospital administrators, respectively. Themes identified key elements of the inner setting (clinic characteristics, resource availability, implementation climate, and tension for change), characteristics of individuals (normative, control, and behavioral beliefs), and the implementation process (engage, implement, and adopt), as well as factors that were influenced by external context, caregiver needs, team function, and intervention characteristics. Task shifting, which is already being used, was viewed by providers and administrators as a necessary strategy to implement TCD screening in a clinic environment that is overstressed and under-resourced, a community stressed by poverty, and a nation with an underperforming health system. Task shifting provides a viable option to improve health care by making more efficient use of already available human resources while rapidly expanding the human resource pool and building capacity that is more sustainable. NCT05434000.


Development of a sensitive ultra high performance liquid chromatography with tandem mass spectrometry method for the simultaneous quantification of nine active compounds in rat plasma and its application to a pharmacokinetic study after administration of Viscum coloratum extracts.
A simple, specific, and sensitive ultra high performance liquid chromatography with tandem mass spectrometry method was developed and validated for the simultaneous quantification of nine compounds including a new compound, rhamnazin-3-Ο-β-D-(6″-β-hydroxy-β-methyglutaryl)-β-D-glucoside-4'-Ο-β-D-glucoside, in rat plasma using baicalin as an internal standard. The plasma samples were pretreated and extracted by protein precipitation with 0.2% formic acid in acetonitrile. The analytes were separated on a Thermo Syncronis C18 column by gradient elution with a mobile phase consisting of acetonitrile and 0.1% aqueous formic acid at a flow rate of 0.25 mL/min. The detection of the analytes was performed on an electrospray ionization interface operating in positive-ion and multiple reaction monitoring acquisition modes. The calibration curves of these analytes showed good linearity (r > 0.99) within the test ranges. The lower limit of quantification ranged from 0.4 to 20.1 ng/mL for the analytes. The intra- and interday precision and accuracy were all within ±15%, and the recoveries were higher than 80.0%. The validated method was successfully applied to a pharmacokinetic study of the nine flavonoids after administration of the Viscum coloratum extracts by intravenous injection.


Feedback regulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 via ATM/Chk2 pathway contributes to the resistance of MCF-7 breast cancer cells to cisplatin.
The methyl methanesulfonate and ultraviolet-sensitive gene clone 81 protein is a structure-specific nuclease that plays important roles in DNA replication and repair. Knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 has been found to sensitize cancer cells to chemotherapy. However, the underlying molecular mechanism is not well understood. We found that methyl methanesulfonate and ultraviolet-sensitive gene clone 81 was upregulated and the ATM/Chk2 pathway was activated at the same time when MCF-7 cells were treated with cisplatin. By using lentivirus targeting methyl methanesulfonate and ultraviolet-sensitive gene clone 81 gene, we showed that knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 enhanced cell apoptosis and inhibited cell proliferation in MCF-7 cells under cisplatin treatment. Abrogation of ATM/Chk2 pathway inhibited cell viability in MCF-7 cells in response to cisplatin. Importantly, we revealed that ATM/Chk2 was required for the upregulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81, and knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 resulted in inactivation of ATM/Chk2 pathway in response to cisplatin. Meanwhile, knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 activated the p53/Bcl-2 pathway in response to cisplatin. These data suggest that the ATM/Chk2 may promote the repair of DNA damage caused by cisplatin by sustaining methyl methanesulfonate and ultraviolet-sensitive gene clone 81, and the double-strand breaks generated by methyl methanesulfonate and ultraviolet-sensitive gene clone 81 may activate the ATM/Chk2 pathway in turn, which provide a novel mechanism of how methyl methanesulfonate and ultraviolet-sensitive gene clone 81 modulates DNA damage response and repair.


The effect of injectable contraceptive on lipid metabolism in women.
The effect of long acting progestational contraceptive injection, norethisterone-oenanthate was studied in twenty six women. The post injection results showed a significant decrease in total lipids, free cholesterol, total cholesterol, triglycerides, phospholipids and free fatty acids.


The mechanisms of antiviral immunity induced by a vaccinia virus recombinant expressing herpes simplex virus type 1 glycoprotein D: clearance of local infection.
We have shown that immunization of mice with a vaccinia virus recombinant expressing glycoprotein D of Herpes simplex virus (HSV)-1 will induce a variety of L3T4+ T cell responses. These included a HSV-specific delayed-type hypersensitivity response, T cell help for the induction of antiviral antibodies, and the ability to eliminate a challenge dose of HSV from the pinna. This protection against a subcutaneous virus challenge was not mediated by the delayed-type hypersensitivity response because intravenous inoculation of the vaccinia virus recombinant expressing HSV-1-gD induced a state of split tolerance. Thus, mice could still clear a HSV challenge inoculum from the pinna yet were unable to mount a HSV-specific delayed-type hypersensitivity response. Evidence is presented that suggests the protective response was, at least, in part mediated by a T cell-dependent induction of virus-neutralizing antibodies. Evidence is also presented that may suggest the failure of a vaccinia virus recombinant expressing HSV-1-gD to induce HSV-specific cytotoxic T cell responses appears to minimize the protective response to only efficiently clearing low 10(4) 50% tissue culture infective dose) challenge populations of virus. These findings are discussed with relevance to the immune control of HSV infections and to the future development of anti-HSV vaccines.


Hemodynamic effect of propofol in enalapril-treated hypertensive patients during induction of general anesthesia.
Angiotensin converting enzyme inhibitor (ACE-I) treated hypertensive patients are well known to be at risk during general anesthesia, because of hypotension that can occur. We compared hemodynamic changes in these patients during induction of general anesthesia with propofol and etomidate - two intravenous anesthetics. Hypotension after propofol that we observed in ACE-I group versus normotension after etomidate (p < 0.001) in our opinion may be the result of additive effect of similar endothelium-dependent mechanism of action of propofol and ACE-I, i.e. increase in production and release of nitric oxide (NO). This very unique observation, however, needs further investigation to precisely define the mechanism of our finding.


Positional cerebral ischaemia.
Four patients are described in whom recurrent, dramatic transient clinical worsening accompanied elevation from the supine toward the sitting position, though postural hypotension was not present. In each patient occlusive cerebrovascular disease was documented angiographically. During an acute stroke syndrome, some patients' compensatory capacity may be so tenuous that postural changes may produce clinical worsening. Possible mechanisms are discussed.


The enzymes and electrolytes profiles in sera of Iranian stray dogs naturally infected with Neospora caninum
The protozoan Neospora caninum (Apicomplexa: Sarcocystidae), respectively infects canids and ruminants as the most definitive and intermediate hosts. A diagnosis of neosporosis is generally made on the basis of clinical signs together with the detection of high levels of antibodies in serum. The present study compares the serum electrolyte profile (Ca, K, Mg, Na, P) and serum enzyme level (ALP, AST, CPK) of non-infected dogs with those of stray dogs naturally infected with N. caninum. The indirect fluorescent antibody test (IFAT) revealed that 17 of the 137 analysed serum samples (12.41%) of the stray dogs were seropositive (Sp) to N. caninum. Serum levels of the electrolytes and the enzymes were evaluated in the 17 Sp and 28 seronegative (Sn, 20.44%) dogs using common enzyme kits, spectrophotometry and flame photometry techniques. The average serum level of ALP, AST, and CPK were found to be significantly higher in the Sp stray dogs. Measurements of the average serum levels of Ca, K, Mg, and P were higher in Sp than Sn stray dogs, with the average K level being significantly higher in seropositive stray dogs. It was concluded that evaluation of serum enzyme and electrolyte levels may be used to screen N. caninum infection in stray dogs.


Mild hypothermic culture conditions affect residual host cell protein composition post-Protein A chromatography.
Host cell proteins (HCPs) are endogenous impurities, and their proteolytic and binding properties can compromise the integrity, and, hence, the stability and efficacy of recombinant therapeutic proteins such as monoclonal antibodies (mAbs). Nonetheless, purification of mAbs currently presents a challenge because they often co-elute with certain HCP species during the capture step of protein A affinity chromatography. A Quality-by-Design (QbD) strategy to overcome this challenge involves identifying residual HCPs and tracing their source to the harvested cell culture fluid (HCCF) and the corresponding cell culture operating parameters. Then, problematic HCPs in HCCF may be reduced by cell engineering or culture process optimization. Here, we present experimental results linking cell culture temperature and post-protein A residual HCP profile. We had previously reported that Chinese hamster ovary cell cultures conducted at standard physiological temperature and with a shift to mild hypothermia on day 5 produced HCCF of comparable product titer and HCP concentration, but with considerably different HCP composition. In this study, we show that differences in HCP variety at harvest cascaded to downstream purification where different residual HCPs were present in the two sets of samples post-protein A purification. To detect low-abundant residual HCPs, we designed a looping liquid chromatography-mass spectrometry method with continuous expansion of a preferred, exclude, and targeted peptide list. Mild hypothermic cultures produced 20% more residual HCP species, especially cell membrane proteins, distinct from the control. Critically, we identified that half of the potentially immunogenic residual HCP species were different between the two sets of samples.


[Truncal vagotomy with pyloroplasty as a routine procedure in perforated duodenal ulcer].
Truncal vagotomy and pyloroplasty for perforated duodenal ulcer. A retrospective study of 220 patients operated upon between 1959 and 1982 for perforated duodenal ulcer by truncal vagotomy and pyloroplasty shows that this operation can be performed as safely as suture plication, even in the critically ill patient. The advantages of this procedure as the routine treatment of perforated duodenal ulcer are discussed.


Cardiovascular effects of intramuscular or inhaled terbutaline in asthmatics.
8 stable asthmatics were at random given placebo, 0.125 mg, 0.25 mg, 0.5 mg and 1 mg terbutaline intramuscularly or 2.5 mg as inhalation. Systolic time intervals, echocardiographic parameters and peak expiratory flow (PEF) were measured. Maximal circulatory and respiratory response was obtained after 0.5 mg and 0.25 mg, respectively. The circulatory effect of 2.5 mg inhaled terbutaline equalled 0.125 mg given intramuscularly, while this dosage elicited maximal bronchodilator effect. Thus, nebulized terbutaline has only a minimal circulatory effect, and even the intramuscular dosages were without dramatic circulatory side effects.


Clinical neuropathology practice guide 5-2013: markers of neuronal maturation.
This review surveys immunocytochemical and histochemical markers of neuronal lineage for application to tissue sections of fetal and neonatal brain. They determine maturation of individual nerve cells as the tissue progresses to mature architecture. From a developmental perspective, neuronal markers are all about timing. These diverse cellular labels may be classified in two ways: 1) time of onset of expression (early; intermediate; late); 2) labeling of subcellular structures or metabolic functions (nucleoproteins; synaptic vesicle proteins; enolases; cytoskeletal elements; calcium-binding; nucleic acids; mitochondria). Apart from these positive markers of maturation, other negative markers are expressed in primitive neuroepithelial cells and early stages of neuroblast maturation, but no longer are demonstrated after initial stages of maturation. These examinations are relevant for studies of normal neuroembryology at the cellular level. In fetal and perinatal neuropathology they provide control criteria for application to malformations of the brain, inborn metabolic disorders and acquired fetal insults in which neuroblastic maturation may be altered. Disorders, in which cells differentiate abnormally, as in tuberous sclerosis and hemimegalencephaly, pose another yet aspect of mixed cellular lineage. The measurement in living patients, especially neonates, of serum and CSF levels of enolases, chromogranins and S-100 proteins as biomarkers of brain damage may potentially be correlated with their corresponding tissue markers at autopsy in infants who do not survive. The neuropathological markers here described can be performed in ordinary hospital laboratories, not just research facilities, and offer another dimension of diagnostic precision in interpreting abnormally developed fetal and postnatal brains.


Femoral vascular access for endovascular resuscitation.
Endovascular resuscitation is an emerging area in the resuscitation of both severe traumatic hemorrhage and nontraumatic cardiac arrest. Vascular access is the critical first procedural step that must be accomplished to initiate endovascular resuscitation. The endovascular interventions presently available and emerging are routinely or potentially performed via the femoral vessels. This may require either femoral arterial access alone or access to both the femoral artery and vein. The time-critical nature of resuscitation necessitates that medical specialists performing endovascular resuscitation be well-trained in vascular access techniques. Keen knowledge of femoral vascular anatomy and skill with vascular access techniques are required to meet the needs of critically ill patients for whom endovascular resuscitation can prove lifesaving. This review article addresses the critical importance of femoral vascular access in endovascular resuscitation, focusing on the pertinent femoral vascular anatomy and technical aspects of ultrasound-guided percutaneous vascular access and femoral vessel cutdown that may prove helpful for successful endovascular resuscitation.


Parameterized MDPs and Reinforcement Learning Problems-A Maximum Entropy Principle-Based Framework.
We present a framework to address a class of sequential decision-making problems. Our framework features learning the optimal control policy with robustness to noisy data, determining the unknown state and action parameters, and performing sensitivity analysis with respect to problem parameters. We consider two broad categories of sequential decision-making problems modeled as infinite horizon Markov decision processes (MDPs) with (and without) an absorbing state. The central idea underlying our framework is to quantify exploration in terms of the Shannon entropy of the trajectories under the MDP and determine the stochastic policy that maximizes it while guaranteeing a low value of the expected cost along a trajectory. This resulting policy enhances the quality of exploration early on in the learning process, and consequently allows faster convergence rates and robust solutions even in the presence of noisy data as demonstrated in our comparisons to popular algorithms, such as Q -learning, Double Q -learning, and entropy regularized Soft Q -learning. The framework extends to the class of parameterized MDP and RL problems, where states and actions are parameter dependent, and the objective is to determine the optimal parameters along with the corresponding optimal policy. Here, the associated cost function can possibly be nonconvex with multiple poor local minima. Simulation results applied to a 5G small cell network problem demonstrate the successful determination of communication routes and the small cell locations. We also obtain sensitivity measures to problem parameters and robustness to noisy environment data.


Imaging and modulating antisense microdistribution in solid human xenograft tumor models.
The tumor microenvironment is complex and heterogeneous, populated by tortuous irregular vasculature, hypoxic cells, and necrotic regions. These factors can all contribute to the biodistribution difficulties encountered by most cancer therapeutic agents. Antisense oligodeoxynucleotides (ASO) are a class of therapeutics where limited information is available about their distribution within a solid tumor environment. To assess ASO distribution, a fluorescein-labeled phosphorothionated ASO based on the G3139 mismatch control was injected systemically (i.v.) into tumor-bearing severe combined immunodeficient mice. Hoechst 33342 was injected i.v. to visualize active vasculature. Unstained sections were imaged through tiled fluorescence stereomicroscopy and then quantitated using novel algorithms. Tumor sections from four human tumor models were examined (CaSki, DU-145, C666-1, and C15) for hypoxia, apoptosis/necrosis, and morphology. For all four tumors, ASO accumulated within regions of hypoxia, necrosis, and apoptosis. Scatter plots of ASO versus active vasculature generated for each individual tumor revealed a consistent pattern of distribution of the ASO within each model. In C666-1 xenografts, the slopes of these scatter plots were significantly reduced from 0.41 to 0.16 when pretreated with the antivascular agent ZD6126 48 h before ASO injection. This was accompanied by the formation of large disseminated necrotic regions in the tumor, along with a 13.1 mmHg reduction in interstitial fluid pressure. These data suggest the possibility that these algorithms might offer a generalizable and objective methodology to describe the distribution of molecular therapeutic agents within a tumor microenvironment and to quantitatively assess distribution changes in response to combination therapies.


Charge transport and trapping in bulk-heterojunction solar cells.
Charge carrier transport and trapping was investigated in organic solar cell structures consisting of poly-3-hexylthiophene blended with the fullerene derivative [6,6]-phenyl-C61-butyric acid methyl ester in 6:5 weight ratio. The analysed devices having solar efficiency of 3.7 per cent were produced in the inverted layer sequence. The fill factor of the IV characteristics was as high as 68 per cent. It was demonstrated that despite of such relatively high fill factor carrier trapping is effectively involved in the charge transport phenomena. The density of the trapping states was evaluated to be up to 10(20) division by 7 x 10(21) cm(-3) and their activation energy was about 0.18 eV. At such high densities these states may probably act as transport states, limiting carrier mobility. The results were analyzed by taking into account carrier thermal generation from traps as well their mobility variation according to the Gaussian disorder model. The mobility parameters obtained by both methods demonstrated good coincidence.


Skin microcirculatory effect of exogenous calcitonin gene-related peptide (CGRP) evaluated by laser Doppler flowmetry coupled with iontophoresis in healthy subjects.
The aim of our study was to evaluate the feasibility of laser Doppler flowmetry (LDF) coupled with iontophoresis in exploring the skin vasodilator activity of exogenous calcitonin gene-related peptide (CGRP) in healthy subjects and to investigate the mechanisms involved in the skin vasodilator activity of this peptide. Forearm skin blood perfusion was measured in conventional perfusion unit (PU; 1 PU=10 mV), using a LDF apparatus (Periflux PF4001, Perimed, Sweden), before and following exogenous CGRP dissolved in distilled water (0.02%) or pure saline iontophoresis. Different iontophoresis protocols were used in a preliminary dose finding study in six subjects. Two pulses (0.1 mA for 30 s each) of anodal CGRP or saline iontophoresis were used in the definitive study in 20 subjects. Power spectral density (PSD) of skin blood flowmotion frequency intervals (FI), related to endothelial (0.009-0.02 Hz), sympathetic (0.02-0.06 Hz), myogenic (0.06-0.2 Hz), respiratory (0.2-0.6 Hz) and heart (0.6-1.6 Hz) activities, was also measured in PU(2)/Hz, by means of spectral analysis of the skin LDF signal registered before and following iontophoresis of CGRP or saline in the definitive study. A significantly higher per cent increase in skin perfusion compared to baseline was observed following CGRP than saline iontophoresis (548+/-369% vs. 326+/-192%, p<0.05), with higher hyperaemic response to pure saline than CGRP iontophoresis in only five subjects. A significant increase (p<0.05) in PSD mean value of the five FI considered, was also observed following CGRP iontophoresis, while saline iontophoresis elicited a significant increase (p<0.05) only in PSD of the FI related to endothelial, respiratory and heart activity. These findings demonstrated that LDF coupled with iontophoresis is a feasible method in evaluating the vasodilator effect of exogenous CGRP in human skin and suggest that this peptide directly or indirectly induces a smooth muscle vascular cells and sympathetic fibres stimulation.


Amplitude death in a pair of one-dimensional complex Ginzburg-Landau systems coupled by diffusive connections.
This paper shows that, in a pair of one-dimensional complex Ginzburg-Landau (CGL) systems, diffusive connections can induce amplitude death. Stability analysis of a spatially uniform steady state in coupled CGL systems reveals that amplitude death never occurs in a pair of identical CGL systems coupled by no-delay connection, but can occur in the case of delay connection. Moreover, amplitude death never occurs in coupled identical CGL systems with zero nominal frequency. Based on these analytical results, we propose a procedure for designing the connection delay time and the coupling strength to induce spatial-robust stabilization, that is, a stabilization of the steady state for any system size and any boundary condition. Numerical simulations are performed to confirm the analytical results.


Robustness to Training Disturbances in SpikeProp Learning.
Stability is a key issue during spiking neural network training using SpikeProp. The inherent nonlinearity of Spiking Neuron means that the learning manifold changes abruptly; therefore, we need to carefully choose the learning steps at every instance. Other sources of instability are the external disturbances that come along with training sample as well as the internal disturbances that arise due to modeling imperfection. The unstable learning scenario can be indirectly observed in the form of surges, which are sudden increases in the learning cost and are a common occurrence during SpikeProp training. Research in the past has shown that proper learning step size is crucial to minimize surges during training process. To determine proper learning step in order to avoid steep learning manifolds, we perform weight convergence analysis of SpikeProp learning in the presence of disturbance signals. The weight convergence analysis is further extended to robust stability analysis linked with overall system error. This ensures boundedness of the total learning error with minimal assumption of bounded disturbance signals. These analyses result in the learning rate normalization scheme, which are the key results of this paper. The performance of learning using this scheme has been compared with the prevailing methods for different benchmark data sets and the results show that this method has stable learning reflected by minimal surges during learning, higher success in training instances, and faster learning as well.


Fluorescence techniques for diagnosing intestinal microsporidiosis in stool, enteric fluid, and biopsy specimens from acquired immunodeficiency syndrome patients with chronic diarrhea.
To evaluate three fluorescent chitin stains for detecting microsporidia spores in specimens from acquired immunodeficiency syndrome (AIDS) patients with chronic diarrhea. We compared the Fungifluor, Calcofluor White, and Fungiqual A fluorochrome stains for identifying Enterocytozoon bieneusi and Septata intestinalis spores in stool, intestinal fluid, biopsy imprints, and paraffin biopsy sections. The modified chromotrope trichrome stain was used as the standard light microscopic technique for stool and fluid specimens. Stained and unstained paraffin sections and fluid preparations were also evaluated. Multiple specimens from 50 consecutive symptomatic AIDS patients and archival material from known microsporidia-positive AIDS patients were analyzed. Spores of E bieneusi and S intestinalis fluoresce brightly with all three fluorochrome stains in all of the types of diagnostic specimens. Fluorescing debris and the much larger fungal forms were readily distinguished. Spores were equally well detected in unfixed and formalin-fixed stool specimens, but were not as well detected after sodium acetate-acetic acid, polyvinyl acetate, and ethanol fixation. Bouin's tissue fixative gave a higher background staining than formalin. Spores were readily detected in archival paraffin sections and stool preparations, even when the specimens had been stained previously. Repeat fluorochrome staining was possible. The methods also could detect extraintestinal parasites in paraffin sections. The three fluorescent chitin stains are sensitive and rapid methods for detecting microsporidia spores in stool, intestinal fluid, biopsy imprint, and tissue specimens, even from archived material.


Complexation of uranium by cells and S-layer sheets of Bacillus sphaericus JG-A12.
Bacillus sphaericus JG-A12 is a natural isolate recovered from a uranium mining waste pile near the town of Johanngeorgenstadt in Saxony, Germany. The cells of this strain are enveloped by a highly ordered crystalline proteinaceous surface layer (S-layer) possessing an ability to bind uranium and other heavy metals. Purified and recrystallized S-layer proteins were shown to be phosphorylated by phosphoprotein-specific staining, inductive coupled plasma mass spectrometry analysis, and a colorimetric method. We used extended X-ray absorption fine-structure (EXAFS) spectroscopy to determine the structural parameters of the uranium complexes formed by purified and recrystallized S-layer sheets of B. sphaericus JG-A12. In addition, we investigated the complexation of uranium by the vegetative bacterial cells. The EXAFS analysis demonstrated that in all samples studied, the U(VI) is coordinated to carboxyl groups in a bidentate fashion with an average distance between the U atom and the C atom of 2.88 +/- 0.02 A and to phosphate groups in a monodentate fashion with an average distance between the U atom and the P atom of 3.62 +/- 0.02 A. Transmission electron microscopy showed that the uranium accumulated by the cells of this strain is located in dense deposits at the cell surface.


What is and what is not cell senescence.
Cell senescence is a process that occurs due to telomere erosion or can be induced by various stresses. Senescent cells cease to divide but remain alive, metabolically active and able to secrete many molecules. They also show many hallmarks of senescence, such as enlarged size, increased granularity, increased activity of SA-β-galactosidase, increased level of cyclin-dependent kinase inhibitors, p16 and p21, and DNA damage foci. Originally, cell senescence was attributed to proliferating normal cells, in contrast to cancer cells, which were considered as those endowed with indefinite growth ability. Recently, it has become evident that anticancer treatment induces senescence in cancer cells. Moreover, certain hallmarks of senescence were detected in non-proliferating post-mitotic cells. There are many signalling pathways involved in cell senescence, but the most prevalent is the DNA damage response pathway. In this review we have summarized our long lasting input in the global study of the mechanisms of senescence of normal and cancer cells and discussed the diversity of the concept of cell senescence.


Priority options of anti-vascular endothelial growth factor agents in wet age-related macular degeneration under the National Health Insurance Program.
Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, for which intravitreal injection of anti-vascular endothelial growth factor (VEGF) is the primary treatment option. The purpose of the current study was to investigate the prioritization of anti-VEGF agents for wet AMD under the National Health Insurance (NHI) Program, and their clinical outcomes. Patients who were diagnosed with active choroidal neovascularization caused by AMD, and who met the criteria for reimbursement for anti-VEGF therapy by the NHI program in Taiwan between August 1, 2014 and May 31, 2015, were included in the study. Factors potentially influencing the choice of treatment agent were analyzed, and clinical outcomes were compared between the two different agents and their protocols. A total of 166 treatment applications in 166 eyes from 159 patients were enrolled in the study. Age, laterality, presence of retinal pigment epithelial detachment, history of hypertension, coronary artery disease, and cerebral vascular accidents were significantly associated with the selection of the anti-VEGF agent. Treatment patterns and clinical outcomes were similar between the patients treated with ranibizumab and those treated with aflibercept. Significantly fewer injections were given during the follow-up period in those treated with aflibercept. Under the restrictive insurance program in Taiwan, more patients and ophthalmologists chose to treat wet AMD using aflibercept. However, in clinical practice, no significant differences in efficacy or clinical outcomes were found between the patients treated with ranibizumab and those treated with aflibercept.


Change of barometric pressure influences low back pain in patients with vacuum phenomenon within lumbar intervertebral disc.
The present study investigates whether changes in barometric pressure influence low back pain in patients with vacuum phenomenon within lumbar intervertebral discs. Twenty-four patients with low back pain were examined: 12 with vacuum phenomenon within the intervertebral discs (VP [+] group) and 12 without the vacuum phenomenon (VP [-] group). All patients consented to an evaluation of low back pain in a hyperbaric oxygen chamber. In the VP (+) group, low back pain became more severe in one patient when atmospheric pressure was elevated, and in eight patients when atmospheric pressure was decreased. In the VP (-) group, two patients experienced more severe low back pain when atmospheric pressure was decreased. Our study demonstrated that low back pain might be aggravated by atmosphere depression in patients with lumbar disease associated with the vacuum phenomenon.


Evaluation of serum-associated embryotoxicity/mutagenicity in females with reproductive dysfunctions using preimplantation mouse embryos in vitro.
Reproductive failures may be caused by chromosomal anomalies, complex interactions of maternal/fetal genotype and environmental factors. Some of them have also been attributed to undefined maternal serum factor(s). We have developed an assay to evaluate maternal-serum associated embryotoxicity/mutagenicity using the preimplantation mouse embryo. It is based on in vitro culture of 8-cell mouse embryos for 48 h in the presence of 10% sera from females with reproductive dysfunction along with suitable controls. The human sera were obtained from three groups of females: (i) with normal reproductive histories (negative controls), (ii) undergoing cancer chemotherapy (positive controls), and (iii) with a history of failing to achieve or maintain pregnancy (test group). The preimplantation mouse embryos were cultured in the three types of human sera and female rat serum (as an internal control for each experiment) and evaluated for toxicity (embryo survival) and mutagenicity (as measured by SCE). Embryos cultured in serum from women with normal reproductive histories and female rats had survival rates of 70.8 +/- 4.3 and 78.9 +/- 0.9%, respectively. The SCE frequencies for these two sera types were similar: 15.7 +/- 0.2 SCEs/cell (rat) and 16.3 +/- 0.3 SCEs/cell (human). Mouse embryos cultured in medium supplemented with serum from females undergoing chemotherapy had significantly (P less than 0.01) reduced survival (33.7 +/- 5.2%) and significantly (P less than 0.01) increased SCEs/cell (26.5 +/- 0.6). The effect of sera from women with histories of reproductive failures on preimplantation mouse embryos was variable and individual specific. Approximately 40% of the test group female sera yielded survival and SCEs/cell comparable to the sera from patients undergoing chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)


Spontaneous perinatal epidural haemorrhage in a newborn.
A full-term neonate, born by caesarean section, presents with focal seizures. EEG and cranial ultrasound are normal. MRI of the cerebrum shows an epidural haematoma. Perinatal intracranial haemorrhage in the full-term newborn is an important cause of morbidity and mortality. Most perinatal intracranial haemorrhages are located either subdural or intracerebral, rarely epidural. Epidural haemorrhage is usually a complication of assisted delivery, however it may also occur without forcipal or vacuum extraction, as demonstrated in this case. An epidural haemorrhage should be suspected on clinical findings, even in the absence of an assisted delivery. As cranial ultrasound sonography often misses epidural haemorrhage due to parietal location of the haemorrhage, the diagnosis needs either cerebral CT or MRI.


[Correlation analysis between fatigue and job stressors of nurses].
To explore the correlation between the degree of fatigue and job stressors in nurses. A survey was conducted by using a questionnaire of, Fatigue Scale -14 (FS-14) and Nurse Job Stressors Scale in 306 nurses. The total score of fatigue was 7.17 +/- 3.41, the score of physical fatigue was 4.84 +/- 2.19, and the score of mental fatigue was 2.33 +/- 1.67 in nurses. The total score of fatigue, the score of physical fatigue and mental fatigue were positively correlated with five aspects of job stressors (P < 0.01). The total score of fatigue and the score of physical fatigue were positively correlated with age and the length of service. In logistic regression analysis, in comparison with ICU, the OR for total job stressors is 1.068, the OR for medicine department, surgical department, operation room, gynecology and pediatrics departments were 0.095, 0.187, 0.187, 0.029 and 0.005 respectively. Job stress is the major factor inducing fatigue in nurses, the managers of hospital should pay more attention to improve the capacity of nurses to cope with stress; and to care about their work and life to reduce the degree of fatigue.


CDase is a pan-ceramidase in Drosophila.
Ceramidases catalyze the conversion of ceramide to sphingosine. They are acylaminohydrolases that catalyze the deacylation of the amide-linked saturated fatty acid from ceramide to generate sphingosine. They also catalyze the reverse reaction of ceramide biosynthesis using sphingosine and fatty acid. In mammals, different proteins catalyze these reactions while individually exhibiting optimal activity over a narrow pH range and have been accordingly called acid, neutral, and alkaline ceramidases. Several genes encode for variants of alkaline ceramidase in mammals. Brainwashing (Bwa) is the only putative alkaline ceramidase homologue present in Drosophila. In this study we have demonstrated that BWA does not exhibit ceramidase activity and that bwa null mutants display no loss of ceramidase activity. Instead, the neutral ceramidase gene CDase encodes the protein that is responsible for all measurable ceramidase activity in Drosophila. Our studies show strong genetic interaction of Bwa with CDase and the Drosophila ceramide kinase gene (DCERK). We show that, although BWA is unlikely to be a ceramidase, it is a regulator of sphingolipid flux in Drosophila. Bwa exhibits strong genetic interaction with other genes coding for ceramide-metabolizing enzymes. This interaction might partly explain its original identification as a ceramidase.


Is There a Relationship Between the Functional Movement Screen, Star Excursion Balance Test, and Balance Error Scoring System?
To evaluate associations between the Functional Movement Screen (FMS), Star Excursion Balance Test (SEBT), and Balance Error Scoring System (BESS) scores. Correlational. College athletic training facilities. Fifty-two intercollegiate athletes (men = 36 and women = 16) representing 8 sports and cleared for unrestricted sport participation. Participants completed the FMS, SEBT, and BESS, in random order, during 1 testing session. Testing order was randomized to control for fatigue and learning effects. Composite and item scores for the FMS, SEBT, and BESS. A fair, negative correlation was found between FMS asymmetry and SEBT composite (r = -0.31, P = 0.03) scores. Fair, positive correlations were reported for FMS rotary stability task and SEBT anterior (r = 0.37-0.41, P ≤ 0.007) and posteromedial (r = 0.31, P = 0.03) reaches. Fair, negative correlations were reported for FMS deep squat and BESS single-leg firm (r = -0.33, P = 0.02), double-leg foam (r = -0.34, P = 0.02) and tandem foam (r = -0.40, P = 0.003), FMS inline lunge and BESS single-leg firm (r = -0.39, P = 0.004), FMS trunk stability pushup and tandem foam (r = -0.31, P = 0.025), and FMS composite and BESS single-leg firm (r = -0.37, P = 0.007). Little-to-no correlations were reported for remaining comparisons. Results indicate that each instrument provides distinct information about function, with only small areas of overlap. Associations between the FMS asymmetry score and SEBT composite score may indicate a relationship between movement asymmetry and postural stability. Associations between the FMS deep squat and BESS foam tasks may be related to underlying neuromuscular control factors.


Incidence, risk factors and outcomes of early post-operative stroke in a university-based, tertiary care hospital: A 7-year retrospective case-control study.
Most post-operative stroke cases occur within 24 hours. This retrospective case-control study aimed to investigate the incidence, risk factors, and outcomes of early post-operative stroke that occurred within 24 hours after surgery in a university-based tertiary care hospital. Medical records were collected and reviewed between 2015 and 2021. Early post-operative stroke cases were compared with age-matched controls in a 1:3 ratio, and data regarding patient characteristics, intra-operative events, and post-operative outcomes were analyzed. Multiple logistic regression was performed to identify the risk factors for post-operative stroke. The incidence of early (≤24 hours) post-operative stroke was 0.015% (43 out of 284,105 cases). The multivariable analysis revealed that American Society of Anesthesiologists (ASA) physical status ≥3 (adjusted odds ratio [OR]: 3.12; 95% confidence interval [CI]: 1.22-7.99, P = .017), operation time >120 minutes (adjusted OR: 10.69; 95% CI: 3.95-28.94, P < .001), and intra-operative hypotension and inotrope/vasopressor use (adjusted OR: 2.80; 95% CI: 1.08-7.24, P = .034) were risk factors for early post-operative stroke. Compared to the controls, stroke patients had higher rates of planned and unplanned intensive care unit (ICU) admission, length of stay, ventilator use, and death. Despite its low incidence (0.015%), stroke is associated with poor clinical outcomes and increased mortality. Stratification of potential risks and establishment of risk optimization may help reduce stroke incidence.


Semiconducting Transition Metal Dichalcogenide Heteronanotubes with Controlled Outer-Wall Structures.
Transition metal dichalcogenide (TMDC) nanotubes exhibit unique physical properties due to their nanotube structures. The development of techniques for synthesizing TMDC nanotubes with controlled structures is very important for their science and applications. However, structural control efforts have been made only for the homostructures of TMDC nanotubes and not for their heterostructures that provide an important platform for their two-dimensional counterparts. In this study, we synthesized heterostructures of TMDC nanotubes, MoS2/WS2 heteronanotubes, and demonstrated a technique for controlling features of their structures, such as diameters, layer numbers, and crystallinity. The diameter of the heteronanotubes could be tuned with inner nanotube templates and was reduced by using small-diameter WS2 nanotubes. The layer number and crystallinity of the MoS2 outer wall could be controlled by controlling their precursors and synthesis temperatures, resulting in the formation of high-crystallinity TMDC heteronanotubes with specific chirality. This study can expand the research of van der Waals heterostructures.


Bridging Multiple Dementias.
Tau phosphorylation has come into the limelight again, this time as a critical player in the earliest stages of dementia pathology. Mislocalization of phosphorylated tau to dendritic spines and the resultant degeneration of synapses are observed across multiple neurodegenerative diseases, even in the absence of tau aggregation. Moreover, other molecules phosphorylated by the same kinases, such as MARCKS, might contribute to ultra-early phase pathology by promoting synapse dysfunction.


Novel immunoregulatory B cell pathways revealed by lpr-+ mixed chimeras.
lpr, a murine mutation of the Fas apoptosis receptor, causes lymphadenopathy and autoantibody production, with lymphadenopathy primarily due to a population of CD4-CD8-B220+ T cells. Previous in vivo experiments, in which lpr and normal bone marrow cells were coinfused into lpr hosts, have demonstrated that only T cells of lpr origin accumulated abnormally and only B cells of lpr origin produced autoantibodies. Moreover, in these chimeras, B cells of normal origin were unable to respond to conventional, T cell-dependent exogenous Ag. To address the role of lpr B cells in regulation of lpr autoimmunity, we have prepared lpr-+ mixed chimeras and selectively eliminated lpr B cells using allele-specific, mAb treatment, thus allowing normal B cells to develop in an environment with lpr T cells. From these data, we arrived at four major conclusions: 1) Compared with control-treated chimeric mice, lpr B cell-depleted mice had greatly reduced total lymph node cell counts; 2) the T cells were derived equally from normal and lpr donors, and the percentage of lpr-derived CD4-CD8- T cells was greatly reduced; 3) despite the presence of the remaining lpr T cells, no autoantibodies were produced by the normal derived B cells; and 4) lpr T cells without lpr B cells were unable to prevent a normal B cell response to conventional Ag. These data demonstrate that B cells can play a critical and expansive regulatory role, not only for T cells, but for other B cells as well.


Adaptive balanced detection spectral domain optical coherence tomography.
Balanced detection optical coherence tomography (BD-OCT) enables near-shot noise-limited imaging by suppressing wavelength-dependent relative intensity noise (RIN) originating from the light source. In spectral-domain BD-OCT (SD-BD-OCT), the level of RIN suppression relies on the co-registration accuracy of the spectra simultaneously captured by two independent spectrometers. However, existing matching methods require careful pre-calibration using a RIN-dominated dataset or subjective post-processing using a signal-dominated dataset. We developed an adaptive subpixel matching approach, referred to as adaptive balance, that can be applied to any SD-BD-OCT dataset regardless of RIN or signal level without the need for pre-calibration. We showed that adaptive balance performed comparable to or better than reported methods by imaging phantoms with varying spectrometer camera gain, exposure time, and supercontinuum laser repetition rate. We further demonstrated the benefits of adaptive balance in human retinal imaging.


Extraction frequencies at a university orthodontic clinic in the 21st century: Demographic and diagnostic factors affecting the likelihood of extraction.
The aims of this study were to report contemporary orthodontic extraction frequencies at a university center and to investigate what patient-related factors might influence the likelihood of extraction. The records of 2184 consecutive patients treated at the University of North Carolina from 2000 to 2011 were analyzed. Year-by-year rates for overall orthodontic extractions and for extraction of 4 first premolars were calculated. Logistic regression, adjusting for all recorded patient risk factors for extraction, was used to examine both the changes in extraction frequencies over time and the influence of individual patient factors on the odds of extraction. Small linear decreases in orthodontic extraction frequency overall (OR, 0.91; 95% CI, 0.88-0.95) and in extraction of 4 first premolars (OR, 0.95; 95% CI, 0.90-0.99) were seen. The overall extraction rate was 37.4% in 2000, and it fell just below 25% from 2006 onward. Four first premolar extraction rates ranged from 8.9% to 16.5%. Extractions were significantly more likely as crowding and overjet increased (OR, 1.2; 95% CI, 1.14-1.25; OR, 1.1; 95% CI. 1.07-1.19), as overbite decreased (OR, 0.8; 95% CI, 0.77-0.89), with Class II dental or skeletal relationships (OR, 1.5; 95% CI, 1.12- 2.05; OR, 1.4; 95% CI, 1.04-1.85), and for nonwhite patients (OR, 3.0; 95% CI, 2.2-4.06 for other races; OR, 4.1; 95% CI, 3.03-5.66 for African Americans). Extractions were just as likely to be associated with Class II dental and skeletal problems and with open-bite problems as with crowding alone.


A hematoxylin and eosin-like stain for glycol methacrylate embedded tissue sections.
A staining procedure is described for use with glycol methacrylate embedded tissue sections which does not stain the plastic embedment or remove the sections from the glass slides. The basic dye is celestine blue B. It is prepared by treating 1 g of the dye with 0.5 ml concentrated sulfuric acid. It is then dissolved with the following solution. Add 14 ml glycerine to 100 ml 2.5% ferric ammonium sulfate and warm the solution to 50 C. Finally adjust the pH to 0.8 to 0.9 The acid staining solution consists of 0.075% ponceau de xylidine and 0.025% acid fuchsin in 10% acetic acid. Slides containing the dried plastic sections are immersed in the celestine blue solution for five minutes and in the ponceau-fuchsin solution for ten minutes with an intervening water rinse. After a final wash, the sections are air dried and coverslipped. This staining procedure colors the tissues nearly the same as hematoxylin and eosin procedures.


The significance of involvement of a free serosal surface for recurrence and survival following resection of clinicopathological stage B and C rectal cancer.
To determine whether the presence of tumour at a free serosal surface was independently associated with pelvic recurrence or survival in patients who had a resection for clinicopathological stage B or stage C rectal cancer and who had not received adjuvant therapy. Data were drawn from a comprehensive, prospective hospital registry of all resections for rectal cancer from January 1971 to December 1998 with follow up to December 2003. Statistical analysis employed the chi(2) test or Fisher's exact probability, Kaplan-Meier estimation and proportional hazards regression, with a significance level of < or =0.05 and 95% confidence intervals (CI). In 665 patients with stages B or C tumour, 35 (5.3%; CI 3.7-7.2%) had tumour at a free serosal surface. These comprised 6/332 (1.8%; CI 0.8-3.7%) patients with stage B tumour and 29/333 (8.7%; CI 6.1-12.2%) with stage C tumour. After adjustment for other relevant variables, involvement of a free serosal surface was significantly associated with pelvic recurrence [hazard ratio (HR) 2.7; CI 1.3-5.5] and diminished survival (HR 1.6; CI 1.1-2.4) but not with systemic (only) recurrence. This study has confirmed that direct tumour spread to a free serosal surface independently predicts pelvic recurrence and diminished survival after resection of clinicopathological stage B and C rectal cancer. This feature should always be sought by the pathologist and reported when present, and noted by the surgeon and oncologist. Serosal involvement should be evaluated further for its utility in selecting patients for adjuvant therapy.


Activation in vitro of rat liver polyribosomes.
The increase in the incorporation of amino acids into protein in vitro by preparations obtained from protein-fed rats as compared with preparations obtained from carbohydrate-fed rats has been described previously. After molecular sieving through Sephadex G-25 of cell-free preparations, the difference in incorporating activity between the two types of rats was diminished in systems containing ATP, phosphoenolpyruvate, pyruvate kinase, GTP, and a mixture of amino acids. When, after molecular sieving, a mitochondrial (15,000 g) supernatant was incubated for 4 min at 35 degrees C the polysomal pattern of the preparations was unchanged. In the presence of ATP, phosphoenolpyruvate, and pyruvate kinase the polysomal incorporating activity was low and the polysomal pattern was only slightly changed. Addition of GTP increased the activity markedly, and a more pronounced activity was observed when a mixture of amino acids was added as well. As the amino acid incorporation ability increased, monosomes were formed from the polyribosomes. The activity of the polyribosomes was severalfold higher than that of non-Sephadex-treated preparations, indicating an activation of polysomal aggregates which under the usually applied conditions of incubation and prior to molecular sieving show little or insignificant activity. It was possible to activate polyribosomes from carbohydrate-fed and protein-fed rats to almost the same extent.


Treatment of Cardiac Fibrosis with Extracellular Vesicles: What Is Missing for Clinical Translation?
Heart failure is the leading cause of morbidity and mortality and currently affects more than 60 million people worldwide. A key feature in the pathogenesis of almost all forms of heart failure is cardiac fibrosis, which is characterized by excessive accumulation of extracellular matrix components in the heart. Although cardiac fibrosis is beneficial in the short term after acute myocardial injury to preserve the structural and functional integrity of the heart, persistent cardiac fibrosis contributes to pathological cardiac remodeling, leading to mechanical and electrical dysfunction of the heart. Despite its high prevalence, standard therapies specifically targeting cardiac fibrosis are not yet available. Cell-based approaches have been extensively studied as potential treatments for cardiac fibrosis, but several challenges have been identified during clinical translation. The observation that extracellular vesicles (EVs) derived from stem and progenitor cells exhibit some of the therapeutic effects of the parent cells has paved the way to overcome limitations associated with cell therapy. However, to make EV-based products a reality, standardized methods for EV production, isolation, characterization, and storage must be established, along with concrete evidence of their safety and efficacy in clinical trials. This article discusses EVs as novel therapeutics for cardiac fibrosis from a translational perspective.


Acquired resistance to PRMT5 inhibition induces concomitant collateral sensitivity to paclitaxel.
Epigenetic regulators play key roles in cancer and are increasingly being targeted for treatment. However, for many, little is known about mechanisms of resistance to the inhibition of these regulators. We have generated a model of resistance to inhibitors of protein arginine methyltransferase 5 (PRMT5). This study was conducted in KrasG12D;Tp53-null lung adenocarcinoma (LUAD) cell lines. Resistance to PRMT5 inhibitors (PRMT5i) arose rapidly, and barcoding experiments showed that this resulted from a drug-induced transcriptional state switch, not selection of a preexisting population. This resistant state is both stable and conserved across variants arising from distinct LUAD lines. Moreover, it brought with it vulnerabilities to other chemotherapeutics, especially the taxane paclitaxel. This paclitaxel sensitivity depended on the presence of stathmin 2 (STMN2), a microtubule regulator that is specifically expressed in the resistant state. Remarkably, STMN2 was also essential for resistance to PRMT5 inhibition. Thus, a single gene is required for both acquisition of resistance to PRMT5i and collateral sensitivity to paclitaxel in our LUAD cells. Accordingly, the combination of PRMT5i and paclitaxel yielded potent and synergistic killing of the murine LUAD cells. Importantly, the synergy between PRMT5i and paclitaxel also extended to human cancer cell lines. Finally, analysis of The Cancer Genome Atlas patient data showed that high STMN2 levels correlate with complete regression of tumors in response to taxane treatment. Collectively, this study reveals a recurring mechanism of PRMT5i resistance in LUAD and identifies collateral sensitivities that have potential clinical relevance.


5,5'-substituted indirubin-3'-oxime derivatives as potent cyclin-dependent kinase inhibitors with anticancer activity.
To enhance the ability of indirubin derivatives to inhibit CDK2/cyclin E, a target of anticancer agents, we designed and synthesized a new series of indirubin-3'-oxime derivatives with combined substitutions at the 5 and 5' positions. A molecular docking study predicted the binding of derivatives with OH or halogen substitutions at the 5' position to the ATP binding site of CDK2, revealing the critical interactions that may explain the improved CDK2 inhibitory activity of these derivatives. Among the synthesized derivatives, the 5-nitro-5'-hydroxy analogue 3a and the 5-nitro-5'-fluoro analogue 5a displayed potent inhibitory activity against CDK2, with IC(50) values of 1.9 and 1.7 nM, respectively. These derivatives also showed antiproliferative activity against several human cancer cell lines, with IC(50) values of 0.2-3.3 microM. A representative analogue, 3a, showed greater than 500-fold selectivity for CDK relative to selected kinase panel and potent in vivo anticancer activity.


Analytical gradient polyacrylamide gel-crossed line immunoelectrophores. A technique for locating species specific Mycobacterium tuberculosis H37RV antigens in polyacrylamide gel columns.
Analytical gradient polyacrylamide gel electrophoresis of antigens from Mycobacterium tuberculosis H37RV was combined with crossed line immunoelectrophoresis to locate the position of antigens in polyacrylamide gel columns that appeared to be specific for M. tuberculosis H37RV. Specificity was established by comparing H37RV with M. kansaii CE in the electrophoretic procedure and the relative mobility (Rm) values are being used in an effort to recover and enrich specific antigens from preparative gel columns. Such fractions should be more suitable in efforts to recover purified monospecific components from M. tuberculosis H37RV.


The SWISS-2DPAGE database of two-dimensional polyacrylamide gel electrophoresis.
SWISS-2DPAGE is a database of proteins identified on two-dimensional polyacrylamide gel electrophoresis (2-D PAGE), created and maintained at the University Hospital of Geneva in collaboration with the Department of Medical Biochemistry of Geneva University. The proteins have been identified on various 2-D PAGE reference maps by microsequencing, immunoblotting, gel comparison and amino acid composition.


One-Year Results of Using a Treat-and-Extend Regimen without a Loading Phase with Anti-VEGF Agents in Patients with Treatment-Naive Diabetic Macular Edema.
To evaluate real-life outcomes in treatment-naive patients with diabetic macular edema (DME) treated with anti-vascular endothelial growth factor (VEGF) agents using a treat-and-extend regimen without a fixed loading phase. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) measured using optical coherence tomography at baseline and after 1 year of treatment, intervals and number of injections were analyzed. Subgroup analysis was performed to compare anatomical and functional outcomes between patients receiving ranibizumab or aflibercept. Seventy-five eyes of 61 patients met the inclusion criteria and had follow-up for 1 year. Baseline BCVA and CRT were 68.1 ± 13.2 letters and 424 ± 135 µm, retrospectively. After 1 year, there was a significant mean gain in BCVA of +5.8 ± 7.4 letters (paired t test: p < 0.0001) and a significant decrease in mean CRT of -117 ± 134 µm (paired t test: p < 0.0001). The mean number of anti-VEGF injections was 10.0 ± 1.6 (range 6-12). The mean maximum interval between injections was 8.5 ± 2.9 weeks (range 4-14) and the mean interval 6.0 ± 1.2 weeks (range 4.1-8.9). 96% of eyes could be extended after a mean of 5.3 injections and 17% of patients could be extended before reaching a formal loading dose of 3 injections. Subgroup analysis did not reveal any differences in outcomes between patients treated with ranibizumab or aflibercept. Subretinal fluid at baseline was associated with better BCVA gain after 1 year (stepwise forward regression analysis, p = 0.003). Our results suggest that not all patients with DME require a fixed loading phase when initiating anti-VEGF treatment. Finding anatomical predictors to identify this subgroup of patients would help to reduce treatment burden and optimize clinical outcomes.


Determination of (4-(1,3-dioxo-1,3-dihydro-2H-isoindol- 2-yl)-N'-[(4-ethoxyphenyl) methylidene] benzohydrazide, a novel anti-inflammatory agent, in biological fluids by UPLC-MS/MS: Assay development, validation and in vitro metabolic stability study.
A thalidomide analog, (4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N'-[(4-ethoxyphenyl) methylidene] benzohydrazide), has been identified as a promising broad-spectrum anti-inflammatory agent in previous study. In this study, a sensitive and selective UPLC-MS/MS assay was developed and validated for its determination in rat plasma samples. The chromatographic separation was performed on an Aquity BEH C18 column using mobile phase comprising of acetonitrile and 10 mm ammonium acetate in the ratio of 85: 15, at flow rate of 0.3 mL/min. The detection and quantification were performed in positive multiple reaction monitoring mode by parent to daughter ion transition of 414.06 ˃ 148.05 for analyte and 411.18 ˃ 191.07 for internal standard (risperidone), respectively using electrospray ionization source. The sample extraction process consisted of liquid-liquid extraction method using diethyl ether as the extracting solvent. The assay was validated by following FDA guidelines and all parameters were found to be within acceptable limits. The linearity was between 10.1 and 2500 ng/mL and the lower limit of quantification was 10.1 ng/mL. The reported results indicate that the assay could meet the requirement for analysis of this compound in amounts expected to the present in actual samples. Further, in vitro metabolic stability study was performed in rat liver microsomes by using the validated assay.


Early Onset Diabetes - Genetic And Hormonal Analysis In Pakistani Population.
Mitochondrial DNA mutation and hormonal imbalance is involved in the pathogenesis of early onset diabetes but data is lacking in Pakistani population. The study was planned to delineate the clinical presentation of early onset diabetes with possible hormonal and genetic etiological factors and aascertain the possible etiological role of insulin and glucagon in these patients either on oral hypoglycaemic or subcutaneous insulin therapy. Retrospective, analytical case control study with conventional sampling technique carried at Centre for Research in Experimental and Applied Medicine (CREAM) affiliated with the department of Biochemistry and Molecular Biology, Army Medical College Rawalpindi from Dec 2006 to July 2011. Study included the patients (20-35 years of age) with early onset diabetes on oral hypoglycemic (n=240), insulin therapy (n=280), and compared with non-diabetic healthy controls (n=150). A fragment surrounding tRNALeu (UUR) gene was amplified by AmpliTaq from mtDNA which was extracted from peripheral blood leucocytes. Then it was subjected to restriction endonucleases, ApaI for A3242G mutation and HaeIII for G3316A mutation detection. Plasma glucose, glycosylated Hb, osmolality, insulin and glucagon levels along with ABGs analysis was also done. Non diabetic controls comprised of 51% males and 49% females, diabetics on oral hypoglycemic 60% males and 40 % females and on insulin therapy 54% males and 46% females. Insulin dependent diabetics had statistically significant hyperglucagonemia, acidemia and bicarbonate deficit. MtDNA A3242G and G3316A mutations were not detected. relative hyperglucagonemia and acidemia in Insulin dependent diabetics was a potent threat leading to DKA. The absence of two mtDNA mutations in ND1 gene rules out the possibility of involvement of these mutations in early onset diabetes in Pakistani population.


Induced fit or conformational selection for RNA/U1A folding.
The hairpin II of U1 snRNA can bind U1A protein with high affinity and specificity. NMR spectra suggest that the loop region of apo-RNA is largely unstructured and undergoes a transition from unstructured to well-folded upon U1Abinding. However, the mechanism that RNA folding coupled protein binding is poorly understood. To get an insight into the mechanism, we have performed explicit-solvent molecular dynamics (MD) to study the folding kinetics of bound RNA and apo-RNA. Room-temperature MD simulations suggest that the conformation of bound RNA has significant adjustment and becomes more stable upon U1A binding. Kinetic analysis of high-temperature MD simulations shows that bound RNA and apo-RNA unfold via a two-state process, respectively. Both kinetics and free energy landscape analyses indicate that bound RNA folds in the order of RNA contracting, U1A binding, and tertiary folding. The predicted Phi-values suggest that A8, C10, A11, and G16 are key bases for bound RNA folding. Mutant Arg52Gln analysis shows that electrostatic interaction and hydrogen bonds between RNA and U1A (Arg52Gln) decrease. These results are in qualitative agreement with experiments. Furthermore, this method could be used in other studies about biomolecule folding upon receptor binding.


Nucleic acid probes in the study of latent viral disease.
Despite the apparent complexities of vocabulary and techniques involved in nucleic acid hybridization, these methods should become important new weapons in the pathologist's armoury. The particular strengths lie in the analysis of genes whose protein products defy detection either because they are absent (due, for example, to cellular controls as found in viral latency), to a point mutation, or to gene deletion (as is often the case with cellular oncogenes). However, the mere application of this technology will not solve all diagnostic problems. One must be aware, particularly in applying in situ hybridization to a new system, of the artefactual binding of the probes, and suitable control and duplicate experiments should be performed. In addition, it is vital to verify the identity of the probes and the specificity of the reaction by filter hybridization. The latter procedure may seem unwieldy, but is, in fact, no more complex than the recommended procedures for immunohistochemistry, as discussed by Matthews (this symposium). Sadly, for both hybridization and immunological detection, operator inexperience has often prevented such checks of specificity and as a result many spurious results populate the scientific literature, for example a recent controversy over the detection of Human T cell Lymphotrophic Virus Type 1 in multiple sclerosis patients. With careful application, however, these techniques will permit the detection of viral molecules under conditions where traditional electron microscopy/histology have failed, and may reveal possible viral aetiologies for a range of hitherto non-viral diseases.


Multisector longitudinal administrative databases: an indispensable tool for evidence-based policy for maltreated children and their families.
This article describes the need for and the practicality and utility of longitudinal, multisector, and multilevel administrative data to address key issues in child maltreatment prevention and intervention. The goal is not to alert the reader to a new technology, but rather to clarify its potential and overview the process of creating such a database. Changes in technology, including data storage, computational speed, transfer systems, and software advances have made the creation of truly advanced multisector databases vastly easier than was the case even 10 years ago. We argue that this meshes well with the emerging recognition that practice and policy should be evidence based. We are entering a time when child welfare policy can now be informed by a much more complete understanding of who we serve, how they are served over time, what other social service systems they encounter, and what outcomes they commonly experience.


Genotoxicity of a variety of mycotoxins in the hepatocyte primary culture/DNA repair test using rat and mouse hepatocytes.
Twenty-eight mycotoxins were studied in the hepatocyte primary culture/DNA repair test using rat and mouse hepatocytes. DNA repair synthesis was elicited by several compounds of unknown carcinogenicity, 5,6- dimethoxysterigmatocystin , versicolorins A and B, averufin , xanthomegnin , luteosporin , and chrysazin , as well as by the carcinogenic myocotoxins , aflatoxin B1, sterigmatocystin, luteoskyrin , ochratoxin A, azaserine, mitomycin C, and actinomycin D. The positive results with compounds of unknown carcinogenicity suggest that they are possibly genotoxic carcinogens. The carcinogenic mycotoxins, penicillic acid, patulin, griseofulvin, and rugulosin , which did not elicit repair synthesis may be nongenotoxic carcinogens.


Glomerular and tubular adaptive responses to acute nephron loss in the rat. Effect of prostaglandin synthesis inhibition.
These studies, using in vivo micropuncture techniques in the Munich-Wistar rat, document the magnitude of changes in glomerular and tubular function and structure 24 h after approximately 75% nephron loss (Nx) and compared these results with those obtained in sham-operated rats. The contribution of either nephron hypertrophy or renal prostaglandin to these adjustments in nephron function was also explored. After acute Nx, single nephron GFR (SNGFR) was increased, on average by approximately 30%, due primarily to glomerular hyperperfusion and hypertension. The approximately 45% reduction in preglomerular and the constancy in postglomerular vascular resistances was entirely responsible for these adaptations. Although increases in fluid reabsorption in proximal convoluted tubules correlated closely with increase in SNGFR, the fractional fluid reabsorption between late proximal and early distal tubular segments was depressed. Nephron hypertrophy could not be substantiated based on either measurements of protein content in renal tissue homogenates or morphometric analysis of proximal convoluted tubules. However, acute Nx was associated with increased urinary excretory rates per functional nephron for 6-keto-PGF1 alpha and TXB2. Prostaglandin synthesis inhibition did not affect function in control nephrons, but this maneuver was associated with normalization of glomerular and tubular function in remnant nephrons. The results suggest that enhanced synthesis of cyclooxygenase-dependent products is one of the earliest responses to Nx, and even before hypertrophy the pathophysiologic effects of prostaglandin may be important contributors to the adaptations in remnant nephron function.


Mandibular alveolar bone mass, structure and thickness in relation to skeletal bone density in dentate women.
The aim of this series of studies was to investigate the relationship between skeletal bone mineral density (BMD) and mandibular alveolar bone mass (MABM), structure, and thickness, as well as to evaluate the possible effect of local functional factors on MABM and alveolar thickness. A further aim was to elucidate whether longitudinal changes in mandibular radiographic characteristics and the bucco-lingual dimension of the alveolar process were related to alterations of BMD. BMD was measured in 160 dentate women using dual X-ray absorptiometry of the forearm. On periapical radiographs MABM was estimated using densitometry and the grey-level value. The alveolar bone structure was evaluated with a visual index and by examining the bone texture on periapical radiographs. The thickness of the masseter was assessed with ultrasound imaging to estimate the masticatory functional factor, and the bucco-lingual alveolar thickness was measured on casts. MABM and alveolar structure were significantly correlated to BMD. The best correlation was found between BMD and trabecular pattern evaluated with the visual index (r = 0.62, p < 0.001). The alveolar thickness was correlated to BMD, and to masseter thickness. MABM was influenced of age, the alveolar thickness, the number of occluding teeth, and the masseter muscle thickness but these factors had no effect on the trabecular structure. After five years, all measurements except the ultrasound imaging of the masseter muscle were repeated in 136 women. The mean BMD, MABM, and alveolar thickness decreased significantly during this period, whereas no significant change was found in the bone structure. In posterior region, the alterations in alveolar bone thickness, radiographic grey-level value, and bone texture were significantly correlated to the changes in BMD. In the anterior region, the alterations in alveolar thickness were not correlated with the changes in BMD. Furthermore, no correlation was found between alterations in MABM, estimated by densitometry, and changes in BMD. In conclusion, a significant relationship exists between BMD and mandibular alveolar bone mass, structure, and thickness. The local functional factors mainly influence MABM and the alveolar thickness in the molar region, whereas BMD influences the trabecular structure. Dense trabeculation is a strong indicator of high BMD, whereas sparse trabeculation predicts low bone mass. In peri- and postmenopausal women the alveolar shape in the premolar region can be used to predict BMD level. In the lower premolar region, the longitudinal alterations in BMD are related to longitudinal changes in grey-level value, bone texture and alveolar thickness. The decrease in bucco-lingual alveolar thickness may be due to periosteal resorption related to skeletal bone loss.


The Effects of Physical Exercises on Ocular Physiology: A Review.
Sport has been known to be one of the most important factors in preventing cardiovascular disorders; some studies suggest its role in preventing neurodegenerative diseases. This review discusses the results of various studies regarding the effects of physical exercises on intraocular pressure (IOP), myopia, certain physical parameters of the eye, ocular blood flow, and retinal electrical function. Although dynamic exercises are known to reduce IOP from 1.2 to 5.9 mm Hg only for a short period of time, uncertainty persists about whether isometric exercises or activities such as yoga can increase IOP up to 16.7 mm Hg. There has been an established connection between the time being spent outdoor and reduction in the odds of myopia-2% less odds for every hour spent outdoor. Physical activity and the level of physical fitness have an impact on the changes of b-wave electroretinogram and P100. Physical exercises increase perfusion pressure up to 190% baseline and also increase choroidal blood flow up to 140%, thus providing more blood to retina. Sport-induced change on visual field is a subject of controversy. Majority of patients show a better ocular physiological function due to sports and sports are thus considered essential for preventing common ocular diseases. Further research should focus more on long-term effects of sport-induced changes in ocular physiology and newly discovered techniques may be utilized for such purposes.


[The Constantinople Imperial Bacteriology Institute].
The Constantinople Imperial Bacteriology Institute (CIBI) allowed the development of a common medical effort between France and Turkey at a time when the main European powers were competing to have an influence on the Ottoman Empire. In 1887, Turkey sent Zoreos Pacha, a medical doctor, to Paris to learn anti-rabies immunization techniques, and he started a rabies control institute after his coming back. In 1893, a cholera epidemic in Constantinople was vanquished by A. Chantemesse, sent by Pasteur, and France was allowed to start another microbiologic Institute. The first director of this Constantinople Imperial Bacteriology Institute was Maurice Nicolle. A brillant man, but suffering from a lack of diplomacy; he encountered numerous difficulties and regularly threatened to turn in his resignation. His successor, Paul Remlinger, arrived in 1900. His main research topic was rabies, and he became later a world-class expert on the subject. His position was taken over in 1911 by Paul-Louis Simond, unjustly forgotten nowadays despite his major discovery in 1898 showing that the plague was transmitted by ratfleas. The next director was a veterinary doctor, P. Forgeot, but his tenure was cut short by World War I, and he was the last French director of the CIBI. Since that time, Turkey has felt some gratitude towards France for its medical efforts. It organized in 1957 in Istambul a very congenial celebration for the 70th anniversary of the Rabies Control Institute, which numerous Pasteur Institute alumni attended. There is a clear contrast between the CIBI, the target of many intrigues and hostile maneuvers, and the North African Pasteur Institutes, which were making crucial discoveries during the same period. This contrast was mostly due to the absolute power of the Sultan, who would arbitrarily oppose some directors decisions, whereas the French government allowed the balanced growth of the Pasteur Institutes in territories under his control.


Using behavioural design and theories of change to integrate communication solutions into health systems in India: evolution, evidence and learnings from practice.
Between 2011 and 2019, an integrated communication programme to address reproductive, maternal, neonatal and child health was implemented in the Indian state of Bihar. Along with mass media, community events and listening groups, four mobile health services were co-designed with the government of Bihar. These were Mobile Academy-a training course for frontline health workers (FLHWs) supporting them as the last mile of the health system; Mobile Kunji-a job aid to support FLHWs' interactions with families; Kilkari-a maternal messaging service delivering information directly to families' mobile phones, encouraging families to seek public health services through their FLHWs; and GupShup Potli-mobile audio stimulus used by FLHWs in community events. While Mobile Kunji and GupShup Potli scaled to other states (two and one, respectively), neither was adopted nationally. The Government of India adopted Kilkari and Mobile Academy and scaled to 12 additional states by 2019. In this article, we describe the programme's overarching person-centred theory of change, reflect on how the mHealth services supported integration with the health system and discuss implications for the role of health communication solutions in supporting families to navigate healthcare systems. Evaluations of Kunji, Academy and GupShup Potli were conducted in Bihar between 2013 and 2017. Between 2018-2020, an independent evaluation was conducted involving a randomised controlled trial for Kilkari in Madhya Pradesh; qualitative research on Kilkari and Academy and secondary analyses of call record data. While the findings from these evaluations are described elsewhere, this article collates key findings for all the services and offers implications for the role digital and non-digital communication solutions can play in supporting joined-up healthcare and improving health outcomes.


Predictors of placebo group decline in the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-Cog) in 24 week clinical trials of Alzheimer's disease.
One limitation of several recent 24 week Alzheimer's disease (AD) clinical trials was the lack of cognitive decline detected by the AD Assessment Scale-cognitive subscale (ADAS-cog) in the placebo groups, possibly obscuring true medication effects. Data from 733 individuals in the placebo arms of six AD clinical trials performed 1996-1997 were pooled to examine the relationship of clinical, demographic, and genetic characteristics with the 24 week change in ADAS-cog. Baseline cognitive and functional status and the screening-to-baseline change in ADAS-cog were the strongest independent predictors of the 24 week change in ADAS-cog. The ADAS-cog did not detect progression in patients with mild dementia (screening Mini-Mental State Exam, MMSE, >or=20). The change in ADAS-cog from screening to baseline was inversely correlated with the 24 week change score; it was more difficult to detect cognitive decline at 24 weeks if individuals markedly worsened from screening to baseline. The effects of baseline MMSE and screening-to-baseline change in ADAS-cog generalized to the placebo group (N=106) of another AD study performed in 2004-2005. Overcoming lack of placebo decline in AD clinical trials will require scales more sensitive to cognitive decline in mild AD and strategies to reduce within-person variability in outcome measures.


Sonography of the coccyx in newborns and infants.
The ultrasonic appearance of the coccyx was studied in 61 newborn infants and young children without known congenital abnormalities. The coccyx was easily seen in all children as a hypoechoic structure with a variable number of vertebral body ossification centers. Knowledge of the normal appearance of the coccyx can prevent confusion with pathologic conditions such as abscesses or tumors and can be helpful in the detection of congenital coccygeal abnormalities.


Strong Blue Emissive Supramolecular Self-Assembly System Based on Naphthalimide Derivatives and Its Ability of Detection and Removal of 2,4,6-Trinitrophenol.
Two simple and novel gelators (G-P with pyridine and G-B with benzene) with different C-4 substitution groups on naphthalimide derivatives have been designed and characterized. Two gelators could form organogels in some solvents or mixed solvents. The self-assembly processes of G-P in a mixed solvent of acetonitrile/H2O (1/1, v/v) and G-B in acetonitrile were studied by means of electron microscopy and spectroscopy. The organogel of G-P in the mixed solvent of acetonitrile/H2O (1/1, v/v) formed an intertwined fiber network, and its emission spectrum had an obvious blue shift compared with that of solution. By contrast, the organogel of G-B in acetonitrile formed a straight fiber, and its emission had an obvious red shift compared with that of solution. G-P and G-B were employed in detecting nitroaromatic compounds because of their electron-rich property. G-P is more sensitive and selective toward 2,4,6-trinitrophenol (TNP) compared with G-B. The sensing mechanisms were investigated by 1H NMR spectroscopic experiments and theoretical calculations. From these experimental results, it is proposed that electron transfer occurs from the electron-rich G-P molecule to the electron-deficient TNP because of the possibility of complex formation between G-P and TNP. The G-P molecule could detect TNP in water, organic solvent media, as well as using test strips. It is worth mentioning that the organogel G-P can not only detect TNP but also remove TNP from the solution into the organogel system.


Elevated Levels of Monocyte Chemotactic Protein-1 in the Follicular Fluid Reveals Different Populations among Women with Severe Endometriosis.
To determine if a modification of the cytokine profile occurs in the follicular fluid (FF) of women with endometriosis undergoing in vitro fertilization (IVF), we performed a prospective observational study from January 2018 to February 2019. In total, 87 women undergoing IVF were included: 43 for severe endometriosis-related infertility and 40 controls with other causes of infertility. The cytokine profile of the FF was determined by multiplex fluorescent-bead-based technology allowing the measurement of 59 cytokines. Monocyte Chemoattractant Protein 1 (MCP-1) was the only variable retained in the multivariate analysis. We identified two subgroups of patients in the endometriosis group: MCP-1-low group (n = 23), which had FF MCP-1 levels comparable to the control group, and MCP-1-high (n = 20), which had significantly higher FF levels. Only patients in the MCP-1-high group had a significantly altered cytokine profile in the FF, and had a significantly higher serum estradiol level (p = 0.002) and a significantly lower number of oocytes recovered (p = 0.01) compared to the MCP-1-low and the control group. Our study has shown an alteration of the oocyte microenvironment in women with endometriosis associated with high follicular fluid levels of MCP-1, allowing the identification of a subgroup of endometriosis patients with a potentially worse prognosis.


[Basal cell epitheliomas of the face. General treatment principles (author's transl)].
The author describes the advantages and disadvantages of the three possible types of treatment for basal cell epitheliomas: --Dermatological which combines all the physical methods for destroying the tumor. --Surgical involving wide excision and wound repair. --Radiotherapeutic by the application of radium curietherapy or iridium wires.


Measurements of glomerular filtration in the intensive care unit are only a rough guide to renal function.
An estimate of glomerular filtration rate (GFR) is important in intensive care units (ICUs) to individualize drug dosages, and for the early detection of acute renal failure (ARF). Creatinine clearance or calculations based on plasma creatinine are the most widely used indicators of GFR, but may be very inaccurate in critically ill patients. We have assessed the accuracy of predictions of GFR by creatinine clearance and plasma creatinine in critically ill patients with variable creatinine kinetics. This is a retrospective record review set in a 24-bed multidisciplinary ICU. Eighteen patient records (9 normal renal function, 9 with ARF-250 patient days) were evaluated. Creatinine clearance measured daily over an 8-hour period, plasma creatinine, creatinine production and 8-hourly urine output were recorded for each day of ICU stay. The discrepancy between measured creatinine clearance and creatinine clearance predicted by the Cockcraft-Gault equation was determined. The coefficient of variation (CV) for each of the contributing variables and the final inherent error for the estimation of GFR were determined. The difference between measured and predicted creatinine clearance was large (predicted GFR may be from 60 ml/min above to 70 ml/min below measured creatinine clearance). The mean CV for creatinine production was 28% and for 8-hourly urine output it was 34%. The estimation of GFR from creatinine clearance can be made at +/- 52% of the calculated value, whereas the estimation of GFR by Cockcraft-Gault is accurate at +/- 37% of the calculated value. Unstable creatinine kinetics from variable urine output and creatinine production in critically ill patients make accurate estimation of GFR impossible. While prediction methods have fewer inherent sources of error, plasma creatinine may be influenced by factors other than renal function. The use of prediction equations is as inaccurate as measured clearance in unstable ICU patients.


Lithium discontinuers. II. Therapeutic outcome.
Eleven patients from a lithium-treated cohort of 64 patients with major affective disorder (DSM-III) were investigated after a mean of 6.7 years on lithium prophylaxis and reinvestigated 7 years later, at which point they had discontinued lithium for a mean of 2.3 years. Therapeutic outcome was compared in the 11 discontinuers and 20 continuers on lithium from the same cohort, matched for sex, age, and mental status on admission to the study. Ratings of psychopathology (CPRS) at the end of the 7-year follow-up period showed that the only significant difference between the patient categories was a higher frequency of reported autonomic disturbances and worry over trifles in the discontinuers. Daily doses of neuroleptic drugs were significantly higher in discontinuers than in controls by the end of the study. Alternative concomitant treatment outside conventional medicine was sought by 45% of the discontinuers, whereas no lithium-treated control reported the need for such additional therapeutic measures.


IL-10 is highly expressed in the cryptorchid cryptepididymal epithelium: a probable mechanism preventing immune responses against autoantigenic spermatozoa in the epididymal tubule.
The expression of several immunoregulatory adhesion proteins and cytokines was studied in the normal epididymis, cryptorchid cryptepididymis, the epididymis of oestrogen-treated mice and the epididymis of non-obese diabetic (NOD) mice at the protein level to see which of these immunoregulatory proteins may be involved in lymphocyte regulation in the normal or pathological epididymis and if cytokine balance in this organ is on the cellular or humoral side. The aim of the study was to characterize the immunological microenvironment of the epididymis to explain the survival of the autoantigenic spermatozoa in this site. In the 6-week-old BALB/c or NOD mouse epididymis there were some CD18 and CD44 expressing cells in the interstitial tissue. There were no differences between these strains in the expression of the studied antigens, except that some CD4 positive cells were present in the interstitial tissue of BALB/c mice. In the cryptorchid cryptepididymis CD4, CD8, CD18, CD44, CD54 and CD106 expressing cells were occasionally present in the connective tissue surrounding the epididymal tubule. In the epididymis of the oestrogen-treated mice these antigens were not expressed. In the cryptorchid cryptepididymis the epithelial cells expressed IL-10 highly and the myoid peritubular cells IL-6. The present results suggest that the epididymal epithelial IL-10 suppressing TH0, TH1 and TH2 immune responses may be involved in the protection of autoantigenic spermatozoa from immune destruction.


Isolation of nine human plasma proteinase inhibitors by sequential affinity chromatography.
Purification of nine plasma proteinase inhibitors and one zymogen from a single batch of human plasma, using affinity chromatography has been accomplished. Those isolated were plasminogen (lysine-Sepharose), alpha-2-antiplasmin (plasminogen-Sepharose), high and low molecular weight kininogens (CM-papain-Sepharose), alpha-2-macroglobulin (Zn++ chelate-Sepharose), alpha-1-proteinase inhibitor, alpha-1-antichymotrypsin, Cl-inhibitor, inter-alpha-trypsin inhibitor (Blue-Sepharose) and antithrombin III (heparin-Sepharose). Alpha-2-macroglobulin and alpha-1-proteinase inhibitor required gel filtration as additional purification steps. Each protein was recovered in both high yield and purity.