Should non-inferiority drug trials be banned altogether?
Non-inferiority (NI) trials can be used in a situation when a new drug is expected to have a similar efficacy to its comparator but can offer other advantages over the existing drug, such as a more convenient method of administration or fewer side effects. Here, we discuss the advantages and disadvantages of NI trials from an ethical, methodological and regulatory perspective. We suggest that such trials should be designed to address simultaneously the objective of showing NI with regard to drug efficacy and the objective of establishing superiority of the additional advantages of a drug over its active comparator.


Binding of Metallated Porphyrin-Imidazophenazine Conjugate to Tetramolecular Quadruplex Formed by Poly(G): a Spectroscopic Investigation.
The binding of telomerase inhibitor ZnTMPyP(3+)-ImPzn, Zn(II) derivative of tricationic porphyrin-imidazophenazine conjugate, to tetramolecular quadruplex structure formed by poly(G) was studied in aqueous solutions at neutral pH and near physiological ionic strength using absorption and polarized fluorescent spectroscopy techniques. Three binding modes were determined from the dependences of the fluorescence intensity and polarization degree for the porphyrin and phenazine moieties of the conjugate on molar polymer-to-dye ratio (P/D). The first one is outside electrostatic binding of positively charged porphyrin fragments to anionic phosphate groups of the polymer which prevails only at very low P/D values and manifests itself by substantial fluorescence quenching. It is suggested that the formation of externally bound porphyrin dimers occurs. The other two binding modes observed at high P/D are embedding of the ZnTMPyP(3+) moiety into the groove of poly(G) quadruplex accompanied by more than 3-fold enhancement of the conjugate emission, and simultaneous intercalation of the phenazine fragment between the guanine bases accompanied by the increase of its fluorescence polarization degree up to 0.25. Thus Zn(II) conjugate seems to be promising ligand for the stabilization of G-quadruplex structures since porphyrin binding to poly(G) is strengthened by additional intercalation of phenazine moiety.


Abstention from chronic cigarette smoking normalizes blood rheology.
Smokers differ in terms of blood rheology from non-smokers. Ex-smokers differ from smokers but not from non-smokers. When investigated while abstaining from nicotine for 8 weeks, chronic cigarette smokers show a gradual normalization of blood and plasma viscosities, haematocrit, blood cell filterability, plasma fibrinogen levels as well as total white cell count. Those smokers who did not manage to abstain, reveal no such changes. The findings suggest that haemorheological alterations caused by smoking are reversible. This might play a role in the reduction of cardiovascular risk and in the elevation of tissue perfusion.


Reappraisal-but not Suppression-Tendencies Determine Negativity Bias After Laboratory and Real-World Stress Exposure.
Higher reactivity to stress exposure is associated with an increased tendency to appraise ambiguous stimuli as negative. However, it remains unknown whether tendencies to use emotion regulation strategies-such as cognitive reappraisal, which involves altering the meaning or relevance of affective stimuli-can shape individual differences regarding how stress affects perceptions of ambiguity. Here, we examined whether increased reappraisal use is one factor that can determine whether stress exposure induces increased negativity bias. In Study 1, healthy participants (n = 43) rated the valence of emotionally ambiguous (surprised) faces before and after an acute stress or control manipulation and reported reappraisal habits. Increased negativity ratings were milder for stressed individuals that reported more habitual reappraisal use. In Study 2 (n = 97), we extended this investigation to real-world perceived stress before and during the COVID-19 pandemic. We found that reappraisal tendency moderates the relationship between perceived stress and increased negativity bias. Collectively, these findings suggest that the propensity to reappraise determines negativity bias when evaluating ambiguity under stress. The online version contains supplementary material available at 10.1007/s42761-021-00059-5.


Genetic diversity and origin of Potamogeton anguillanus (Potamogetonaceae) in Lake Biwa, Japan.
We analyzed the genetic variation in Potamogeton anguillanus Koidz. and its putative parents, P. malaianus Miq. and P. perfoliatus L., at five allozyme loci of four enzymes to test the hypothesis of a hybrid origin for P. anguillanus, collected in Lake Biwa, Japan. Alleles diagnostic for either P. malaianus or P. perfoliatus were present at four loci. Of 13 single locus phenotypes (SLPs) of P. anguillanus, eight were phenotypes that were expected in F(1) hybrids between P. malaianus and P. perfoliatus. Two SLPs were different from those expected in F(1) hybrids but could have resulted from segregation of parental alleles in later generation hybrids. Each of the remaining three SLPs possessed one allele unique to P. anguillanus. Allozyme analyses thus supported the view that P. anguillanus was derived from hybridization between P. malaianus and P. perfoliatus. It seems likely that the genetic diversity of P. anguillanus found previously originated through multiple hybridizations and sexual processes in P. anguillanus. Other processes such as intragenic recombination, mutation, or hybridization with another lineage are also discussed with reference to the origin of unique alleles.


"Irregular" ventricular parasystole: the influence of sinus rhythm on a parasystolic focus.
Fifteen cases of ventricular parasystole were analyzed to determine whether the interectopic intervals were regular, as expressed by long intervals being exact multiples of the short ones, or not. The regularity of the interectopic intervals was assessed by means of the variation index: the ratio of the maximal difference between various measurements of the parasystolic cycle length and the mean parasystolic cycle length. Three out of 15 cases had a variation index less than 5, and were classified as "regular parasystole." Twelve cases were associated with a variation index greater than 7.5, and were classified as "irregular parasystole." The cases of irregular parasystole were then analyzed to determine whether the variability of the interectopic intervals was casual or dependent on action of the sinus beats. A parasystolic resetting by critically timed sinus impulses (a form of intermittent parasystole) was evident in three cases. The irregularity in the remaining nine cases was due to modulation (viz., due to electrotonic influence exerted by the sinus beats on the parasystolic focus). In every case of modulated parasystole a phase-response curve was constructed, which enabled an analysis of all the interectopic intervals on the basis of a time-dependent effect exerted by the sinus impulses on an otherwise rhythmic parasystolic focus.


Hydrolysis of myelin basic protein by IgM and IgA antibodies from the sera of patients with multiple sclerosis.
The presence of abzymes (Abzs) in human sera is a specific feature of different autoimmune pathologies. We have shown that IgGs of patients with multiple sclerosis (MS) specifically hydrolyze human myelin basic protein (hMBP). However, the presence of hMBP-hydrolyzing MS IgMs and IgAs in patients with MS has not been studied. Homogeneous IgM and IgA fractions were isolated from human sera by affinity chromatography on different adsorbents. The Ab-dependent hydrolysis of hMBP was analyzed using SDS-PAGE. We present evidence showing that MS IgMs and IgAs (but not Abs from the sera of healthy individuals) catalyze the hydrolysis of hMBP. Specific enzymatic activities of IgMs and sIgAs from sera of any single patient were usually significantly higher than those of IgGs. Specific inhibitors of acidic and thiol proteases demonstrated a weak effect on proteolytic activity of IgGs and IgMs. However, specific inhibitors of serine proteases (AEBSF, PMSF, and benzamidine) significantly inhibited proteolytic activity. IgMs and IgAs hydrolyze specifically both human and pig MBP but not many other tested proteins. Although the biological function of this proteolytic activity is not known, it is clear that MBP-hydrolyzing Abs may play an important role in MS pathogenesis. The findings display the generation by the immune systems of individual MS patients of a variety of polyclonal IgGs, IgMs, and IgAs with different proteolytic properties, which hydrolyze MBP, the major protein component of the myelin-proteolipid shell of axons and a well-known MS autoantigen.


Increased serum pigment epithelium-derived factor levels in type 1 diabetic patients with diabetic retinopathy.
Serum pigment epithelium-derived factor (PEDF) levels were significantly higher in type 1 diabetic patients with retinopathy (n=20, 10.38+/-3.87 microg/ml) compared to the patients without it (n=57, 7.68+/-2.80 microg/ml) (p=0.0013). Elevated PEDF levels may be related to the progression of diabetic retinopathy.


Identification and genetic analysis of EMS-mutagenized wheat mutants conferring lesion-mimic premature aging.
Lesion-mimic and premature aging (lmpa) mutant lmpa1 was identified from the ethyl methane sulfonate (EMS) mutant library in the bread wheat variety Keda 527 (KD527) background. To reveal the genetic basis of lmpa1 mutant, phenotypic observations and analyses of chlorophyll content and photosynthesis were carried out in lmpa1, KD527 and their F1 and F2 derivatives. Further, bulked segregation analysis (BSA) in combination with a 660 K SNP array were conducted on the F2 segregation population of lmpa1/Chinese spring (CS) to locate the lmpa1 gene. Most agronomic traits of lmpa1 were similar to those of KD527 before lesion-like spots appeared. Genetic analysis indicated that the F1 plants from the crossing of lmpa1 and KD527 exhibited the lmpa phenotype and the F2 progenies showed a segregation of normal (wild type, WT) and lmpa, with the ratios of lmpa: WT = 124:36(χ2 = 1.008 < =3.841), indicating that lmpa is a dominant mutation. The combination of BSA and the SNP array analysis of CS, lmpa1 and lmpa1/CS F2 WT pool (50 plants) and lmpa pool (50 plants) showed that polymorphic SNPs were enriched on chromosome 5A, within a region of 30-40 Mb, indicating that the wheat premature aging gene Lmpa1 was probably located on the short arm of chromosome 5A. EMS-mutagenized mutant lmpa1 deriving from elite wheat line KD527 conferred lmpa. Lmpa phenotype of lmpa1 mutant is controlled by a single dominant allele designated as Lmpa1, which affected wheat growth and development and reduced the thousand grain weight (tgw) of single plant in wheat. The gene Lmpa1 was tentatively located within the region of 30-40 Mb near to the short arm of chromosome 5A.


A High-Fat Diet Activates the BAs-FXR Axis and Triggers Cancer-Associated Fibroblast Properties in the Colon.
Dietary signals are known to modulate stemness and tumorigenicity of intestinal progenitors; however, the impact of a high-fat diet (HFD) on the intestinal stem cell (ISC) niche and its association with colorectal cancer remains unclear. Thus, we aimed to investigate how a HFD affects the ISC niche and its regulatory factors. Mice were fed a purified diet (PD) or HFD for 2 months. The expression levels of ISC-related markers, ISC-supportive signals, and Wnt2b were assessed with real-time quantitative polymerase chain reaction, in situ hybridization, and immunofluorescence staining. RNA sequencing and metabolic function were analyzed in mesenchymal stromal cells (MSCs) from PD- and HFD-fed mice. Fecal microbiota were analyzed by 16s rRNA sequencing. Bile salt hydrolase activity and bile acid (BA) levels were measured. We found that expression of CD44 and Wnt signal-related genes was higher in the colonic crypts of HFD-fed mice than in those fed a PD. Within the ISC niche, MSCs were expanded and secreted predominant levels of Wnt2b in the colon of HFD-fed mice. Of note, increased energy metabolism and cancer-associated fibroblast (CAF)-like properties were found in the colonic MSCs of HFD-fed mice. Moreover, colonic MSCs from HFD-fed mice promoted the growth of tumorigenic properties and accelerated the expression of cancer stem cell (CSC)-related markers in colon organoids. In particular, production of primary and secondary BAs was increased through the expansion of bile salt hydrolase-encoding bacteria in HFD-fed mice. Most importantly, BAs-FXR interaction stimulated Wnt2b production in colonic CAF-like MSCs. HFD-induced colonic CAF-like MSCs play an indispensable role in balancing the properties of CSCs through activation of the BAs-FXR axis.


Displacement, Deprivation and Development: The Impact of Relocation on Income and Livelihood of Tribes in Similipal Tiger and Biosphere Reserve, India.
A large volume of literature describes adverse consequences of conservation-induced displacement on indigenous communities depended on natural resources of wildlife habitat. Resettlement policies in protected areas the world over are mainly designed and implemented without consideration of social and economic costs of exclusion. This study examined income and poverty profile of tribal residents in Similipal Tiger and Biosphere Reserve in India, relative to the households relocated out of the reserve. The income from different sources and livelihood diversification of displaced reserve dwellers reflected changes resulting from the loss of access to natural and household assets. The results contradicted common perception about impoverishment outcome of relocation. It showed an increase in the per capita income for poorer segments with an overall 8% increase in absolute household income and corresponding improvement in the poverty ratio (head count ratio) and FGT index (0.241) for the relocated community. Contrary to other studies, the finding did not observe social alignment or marginalization; however, on-farm livelihood diversification reduced with increased dependence on off-farm sources. Expulsion of people from forest reserves to support conservation is inadequate in restricting habitat use of locals unless suitable alternative livelihood options are available for forest dependent was proven from the study.


Wood-inspired elastic and conductive cellulose aerogel with anisotropic tubular and multilayered structure for wearable pressure sensors and supercapacitors.
Cellulose nanofiber (CNF) aerogels hold considerable potential in wearable devices as pressure sensors and flexible electrochemical energy storage. However, the undirectional assembly of CNFs results in poor mechanical performance, which limits their application in structural engineering. In this study, we propose an anisotropic aerogel with both elastic and conductive properties inspired by the micro-nanostructure of natural wood. One-dimensional TEMPO cellulose nanofibers (TOCNF) were utilized as structural building blocks, while two-dimensional reduced graphene oxide (rGO) served as the electron transfer platform, owing to their high mechanical strength. The directionally aligned tubular structure composed of multilayered sheets was formed through rapid unidirectional freezing and subsequent steam heating reduction. These structures efficiently transferred stress throughout the porous skeleton, resulting in TOCNF-rGO aerogels with high compressibility and excellent fatigue resistance (2000 cycles at 60 % strain). The aerogel also exhibited high sensitivity, wide detection range, relatively fast response, and excellent compression cycle stability, making it suitable for accurately detecting various human biological and motion signals. Additionally, TOCNF-rGO can be assembled into a flexible all-solid-state symmetric supercapacitor that delivers excellent electrochemical performance. It is expected that this biomass-derived aerogel will be a versatile material for flexible electronic devices for energy conversion and storage.


Cancer after exposure to metronidazole.
We assessed the risk of occurrence of cancer associated with exposure to metronidazole in the 771 female residents of Rochester, Minnesota, who were treated with metronidazole for vaginal trichomoniasis during the period 1960 through 1969 and were followed up for a total of 12,628 person-years. Standardized morbidity and mortality ratios were determined by using an expected number calculated by applying age-specific incidence rates from Rochester studies and Cancer Surveillance, Epidemiology, and End-Results Reporting (SEER) data to the person-years of follow-up. The overall standardized morbidity ratios for cancer at all sites were 1.4 (Rochester, 1978 through 1983), 1.5 (SEER data for Iowa, 1978 through 1981), and 1.2 (SEER data for Connecticut, 1978 through 1981). By site of the cancers, the standardized morbidity ratios greater than unity were those for malignant lesions of the lung, breast, thyroid, bladder, brain, kidney, nasopharynx, and oral cavity, as well as for multiple myeloma and malignant melanoma; however, the only significantly elevated standardized morbidity ratio was that for bronchogenic carcinoma. After adjustment for smoking status, the standardized morbidity ratio for bronchogenic cancer was 2.5 (95% confidence interval of 1.3 to 4.4). The standardized mortality ratio for cancer at all sites was 1.4 (95% confidence interval of 0.9 to 2.2). The analysis of these data suggests no significant increase in cancer-related morbidity or mortality for women exposed to metronidazole for treatment of vaginal trichomoniasis.


[Clinical insignificance of prostate cancer: are there morphological findings?].
Overdiagnosis and overtreatment of microfocal nonpalpable and early-stage prostatic adenocarcinoma are currently a topic of strong discussion. We tried to find morphological findings of such insignificant carcinomas of the prostate. More than 1,000 consecutive core needle biopsy specimens of prostate carcinoma taken during 1 year (2007) were graded according to the modified Gleason scoring system. The results were correlated to serum prostate-specific antigen (PSA) and tumor extent in the cores. Cases with PSA <10 ng/ml and tumor extent <20% frequently (up to 55%) had Gleason scores of 6 or 7a. Cases with PSA >10 ng/ml or tumor extent >20% had higher Gleason scores (>7a). Cancers with tumor infiltration of <1 mm in one of up to 12 cores and PSA <10 ng/ml mainly had low Gleason scores (6 and 7a), but only 5% of the carcinomas in the studied specimens corresponded to such a parameter. Only 25% of such patients had a pT2a tumor after radical prostatectomy. With a very restricted parameter of a microfocal adenocarcinoma of the prostate with a Gleason score <7a, tumor infiltration of <or=1 mm in only one core needle biopsy, and PSA of <or=10 ng/ml, clinical insignificance may be possible, and in agreement with the patient, active surveillance is feasible. However, such cases are rare.


A metabolomic study on the biological effects of metal pollutions in oysters Crassostrea sikamea.
Metal pollution has become a great threat to organisms in the estuaries in South China. In the present study, the oysters Crassostrea sikamea were collected from one clean (Jiuzhen) and five metal polluted sites (Baijiao, Fugong, Gongqian, Jinshan and Songyu). The tissue metal concentrations in oysters indicated that the five metal sites were polluted by several metals, including Cr, Ni, Co, Cu, Zn, Ag, Cd and Pb with different patterns. Especially, Cu and Zn were the major contaminants in Baijiao, Fugong and Jinshan sites. The metabolic responses in oysters C. sikamea indicated that the metal pollutions in BJ, FG, JS and SY sites induced disturbances in osmotic regulation and energy metabolism via different metabolic pathways. However, the metal pollution in GQ site mainly influenced the osmotic regulation in the oysters C. sikamea. This study demonstrates that NMR-based metabolomics is useful to characterize metabolic responses induced by metal pollution.


Complete structure of the human transferrin gene. Comparison with analogous chicken gene and human pseudogene.
The complete structure of the human transferrin gene is presented. This gene has a total size of about 33.5 kb and is organized in 17 exons separated by 16 introns. The chicken ovotransferrin gene has a size of 10.5 kb and is also organized in 17 exons and 16 introns. The analysis of the structure of the two genes confirm, at the gene level, that transferrins originated by a gene duplication phenomenon. Finally, the existence of a new member of the transferrin family, a human transferrin non-processed pseudogene is demonstrated.


Molecular function of microtubule-associated protein 2 for filial imprinting in domestic chicks (Gallus gallus domesticus).
RNA interference (RNAi)-mediated gene-silencing can be a tool for elucidating the role of genes in the neural basis of behavioral plasticity. Previously, we reported that exogenous DNA could be successfully delivered into newly-hatched chick brains via electroporation. Here, we used this in vivo gene-transfer technique and showed that transfected microRNA vectors preferentially silence exogenous DNA expression in neuronal cells. Using this system, the up-regulation of microtubule-associated protein 2 (MAP2) accompanying filial imprinting was suppressed in vivo, which impaired the filial imprinting in chicks. In addition, the phosphorylation of MAP2 was found to increase in parallel with filial imprinting, and lithium chloride, an inhibitor of glycogen synthase kinase 3 (GSK3), was found to impair filial imprinting. Our results suggest that the regulation of MAP2 expression and its phosphorylation are required for filial imprinting and may modify microtubule stability, thereby leading to cytoskeletal reorganization during imprinting. This in vivo RNAi-mediated gene-silencing system will facilitate the analysis of gene function in the living chick brain and provides further clues regarding the molecular mechanisms underpinning avian learning.


A thoracostomy tube for field and emergency department use.
A small, easily insertable tube in combination with a one-way flutter valve serves as a quick but effective small chest tube for use in trauma both in the prehospital stage and the emergency department. The dart was effective in resolving pneumothorax in dogs and humans. Paramedics can be trained easily to use it.


Clinical spectrum of the upper gastrointestinal effects of nonsteroidal anti-inflammatory drugs. Natural history, symptomatology, and significance.
Nonsteroidal anti-inflammatory drugs (NSAIDs) relieve rheumatic pain and are in extensive use. Symptomatic complications of NSAIDs requiring the discontinuation of their use occur in 2 to 10 percent of patients with rheumatic diseases in sharp contrast to the common asymptomatic problems of gastroduodenal erosions, ulcerations, and bleeding, with resulting anemia in more than 40 percent of these patients. Opinions concerning the clinical significance of these complications are not uniform. The natural history of the effects of NSAIDs on the gastroduodenal mucosa reveals a sequence of initial subepithelial hemorrhage over a 24-hour period followed by gastroduodenal erosions and ulcerations in the next two weeks. From one week to three months, gastroduodenal erosions and ulcerations disappear in about half of the patients as an adaptation to continuing NSAID ingestion occurs. Hemorrhage may occur at any time in most patients and in a small minority (1 percent) it is massive. Non-aspirin NSAIDs (NANSAIDs) exhibit significantly fewer complications than do aspirin. These complications, however, demand considerable clinical attention and are ordered in a constant hierarchy, suggesting variable risks of complications among agents. NSAIDs are a blessing for those who have chronic pain, but that blessing does not prevent significant asymptomatic complications in the same patients. Prophylaxis for high-risk groups, such as women over the age of 65 years, should be subjected to study.


The effect of anti-inflammatory agents on the clinical expression of bovine ephemeral fever.
The effect of two anti-inflammatory drugs on the development and persistence of clinical signs in cattle experimentally infected with bovine ephemeral fever (BEF) virus was investigated by their administration, either before or after the commencement of fever. A total of 16 cattle was given phenylbutazone sodium (PBZ). The drug prevented fever and other clinical signs in six cattle when given daily during the incubation period, and at 8-h intervals for 5 days when clinical disease might be expected. When treatment with PBZ was deferred until 2-4 h after the commencement of fever, the rectal temperature returned to normal within 4 h in four of six cattle and the development of other clinical signs was suppressed. Clinical signs of ephemeral fever occurred in four untreated cattle infected at the same time. Viraemia, the development of neutralizing antibodies (at 8-11 days), resistance to subsequent challenge with BEF virus, neutrophilia, lymphopenia and a rise in plasma fibrinogen occurred in all BEF-infected animals whether treated or untreated, despite different clinical appearances. The mean peak of plasma fibrinogen in the untreated cattle was 6.9 g l-1; 3.2 g l-1 when treated 2-4 h after fever developed and 3.8 g l-1 when treated from 18-h post-infection. BEF virus was isolated from leucocytes of each of the cattle, but the frequency of isolation was lower in the treated group. The results indicate that treatment with PBZ blocked the host response which produces the clinical signs and did not have an anti-viral effect. In a similar experiment, a long-acting anti-inflammatory drug, flunixin meglumine, failed to prevent BEF or to modify the clinical signs once they had developed, except for the rectal temperature which returned to normal within 2-4 h of the administration of the drug. The efficacy of this drug was not improved by increasing the dosage to two or three times the recommended level.


Fatty Acid Profiling and Chemometric Analyses for Zanthoxylum Pericarps from Different Geographic Origin and Genotype.
Zanthoxylum plants, important aromatic plants, have attracted considerable attention in the food, pharmacological, and industrial fields because of their potential health benefits, and they are easily accessible because of the wild distribution in most parts of China. The chemical components vary with inter and intraspecific variations, ontogenic variations, and climate and soil conditions in compositions and contents. To classify the relationships between different Zanthoxylum species and to determine the key factors that influence geographical variations in the main components of the plant, the fatty acid composition and content of 72 pericarp samples from 12 cultivation regions were measured and evaluated. Four fatty acids, palmitic acid (21.33-125.03 mg/g), oleic acid (10.66-181.37 mg/g), linoleic acid (21.98-305.32 mg/g), and linolenic acid (0.06-218.84 mg/g), were the most common fatty acid components in the Zanthoxylum pericarps. Fatty acid profiling of Zanthoxylum pericarps was significantly affected by Zanthoxylum species and geographical variations. Stearic acid and oleic acid in pericarps were typical fatty acids that distinguished Zanthoxylum species based on the result of DA. Palmitic acid, palmitoleic acid, trans-13-oleic acid, and linoleic acid were important differential indicators in distinguishing given Zanthoxylum pericarps based on the result of OPLS-DA. In different Zanthoxylum species, the geographical influence on fatty acid variations was diverse. This study provides information on how to classify the Zanthoxylum species based on pericarp fatty acid compositions and determines the key fatty acids used to classify the Zanthoxylum species.


Gallium scanning for the detection of abdominal abscesses.
The use of gallium scanning for the diagnosis of abdominal abscesses was studied in 59 cases in which the diagnosis was verified by laparotomy or autopsy. In 23 of the cases the patients were subsequently found to have abdominal abscesses and 11 patients had abdominal malignancies. Excluding the latter group, the scan was specific for abscess in 86 per cent of the cases and sensitive for abscess in 67 per cent. Recent abdominal incisions, concurrent intestinal, hepatic, biliary and pancreatic inflammatory conditions, without abscess, seldom caused gallium accumulation. False-negative scans (18 per cent) occurred more frequently than false-positive scans (8 per cent) and were seen in patients with large (often palpable) masses of short evolution and with secondarily infected lesions such as hematomas and pseudocysts. The gallium scan was of little help in the search for abdominal lesions in patients with obscure febrile illnesses without abdominal symptoms or signs.


[The possibility of the preservation of foreign DNA in the organs of mice after the intraperitoneal administration of plasmids to adult animals].
We studied the possibility of introduction of heterogeneous genetic information in adult animals through intraperitoneal injection of plasmid DNA precipitated by calcium phosphate. Accumulation of heterogeneous DNA in the liver was shown by Southern hybridization and polymerase chain reaction. Unlike the published data, we obtained a more prolonged (up to 11 days) preservation of heterogeneous DNA in the animals.


Gas chromatographic-mass fragmentographic determination of propiverine and its metabolites in plasma and urine.
1-Methyl-4-piperidyl diphenylpropoxyacetate hydrochloride has been developed clinically for the therapy of urinary bladder dysfunction. A gas chromatographic-mass fragmentographic method was developed for the determination of this drug and its seven metabolites in plasma and urine. The sample was first treated with a Sep-Pak C18 cartridge, the methanol eluate was evaporated to dryness, and the resulting residue was redissolved in distilled water. This solution was then extracted with chloroform and adjusted to pH 9.0 with 0.1 M sodium borate solution. The acidified aqueous layers were extracted with ethyl acetate. The chloroform layer, which contained non-polar metabolites, was concentrated to dryness, then subjected to trifluoroacetylation, decomposition and methylation. The extract from the plasma sample was trimethylsilylated. The dried residue of the ethyl acetate layer, which contained polar metabolites, was subjected to methylation, trifluoroacetylation and decomposition. Aliquots of each reactant solution were injected into the gas chromatograph-mass spectrometer and analysed by the selected-ion monitoring method using an internal standard. Detection was limited to 1-2 ng/ml of plasma and urine for each metabolite. A precise and sensitive assay for the determination of 1-methyl-4-piperidyl diphenylpropoxyacetate hydrochloride and its metabolites in plasma and urine was thus established, and it should prove useful in basic and clinical pharmacological studies.


Exploring the redox potential induced by low-intensity focused ultrasound on tumor masses.
Cancer is still a major health problem worldwide despite huge efforts being spent on its biomedical research. Beyond the mainstream therapeutic interventions (i.e., surgery, chemotherapy, immunotherapy and radiotherapy), further significant progresses in anticancer therapy could rely on the development of novel treatment paradigms. To this end, one emerging approach consists in the use of non-thermal low-intensity focused ultrasound (LIFU) for conditioning cancer molecules and/or cancer-targeted compounds, thereby leading to cancer cell death with least side-effects. Cellular redox homeostasis manifested as the generation of reactive oxygen species (ROS) during energy metabolism as well as the antioxidant capacity is interwoven to the composition, size and anatomical location of the tumor masses. The higher content of "oxide free radicals" in cancers makes them vulnerable to disruption of redox homeostasis than in the healthy cells and therefore, one of the best options for preferentially eradicating them is increasing their oxidative stress, excessively. A little is known about the modulation of cellular redox homeostasis by LIFU, and so it will be of great interest and utility to understand the effects of LIFU on the energy metabolism of cancer cells. This review is intended to improve our knowledge on the effect of LIFU on cancer cells with particular reference to its redox metabolism for ultrasound-based therapies. Thereby, it could pave the way for exploring novel methodologies and designing combined anti-cancer therapies, especially, for faster and safer eradication of drug resistant and metastasizing solid tumors.


Biallelic deletion 13q14.3 in patients with chronic lymphocytic leukemia: cytogenetic, FISH and clinical studies.
Monoallelic deletion of 13q14.3 (13q14x1) is the most common abnormality in chronic lymphocytic leukemia (CLL). As a sole alteration, it predicts a favorable outcome. Biallelic 13q14.3 (13q14x2) deletion or concomitant 13q14x1/13q14x2 has been scarcely evaluated in the literature. We present the clinical, cytogenetic and fluorescence in situ hybridization (FISH) analysis of six CLL patients with normal karyotypes and 13q14x2 and their comparison to cases with 13q14x1 as a single abnormality. A total of 103 CLL patients were studied. Cytogenetic and FISH analysis were performed on stimulated peripheral blood lymphocytes. Specific fluorescence DNA probes for CLL were used. Six out of 103 (5.8%) patients showed normal karyotypes and 13q14x2. It was observed as a single alteration in one patient and combined with 13q14x1 in five cases. Biallelic clones were larger than monoallelic ones in 3/5 patients (60%). The comparison of clinical and hematological data between 13q14x1 and 13q14x2 groups showed progression of the disease in all 13q14x2 patients respect to 12/32 (37.5%) cases with 13q14x1 (P = 0.008), significant differences in the distribution by Rai stage (P = 0.042) and a tendency of a higher lactate dehydrogenase level in 13q14x2 patients (P = 0.054). Treatment free survival for 13q14x2 group was 28.5 months, shorter than those observed in patients with 13q14x1 alone (49 months). Our data would suggest that 13q14x2 could represent a more aggressive FISH anomaly than 13q14x1 alone, probably as a consequence of clonal evolution and/or due to the complete inactivation of this critical region by mean of more complex mechanisms.


Initiation of RNA synthesis in vitro by vesicular stomatitis virus. Role of ATP.
The ATP requirement during RNA transcription by the RNA-dependent RNA polymerase associated with purified vesicular stomatitis virus was studied during chain initiation and chain elongation steps. Initiation of transcription in vitro has an apparent Km for ATP of approximately 500 micron, whereas the apparent Km for ATP during chain elongation is almost identical with those for the other three ribonucleoside triphosphates, i.e. 20 to 30 micron. Further analysis of the transcription process demonstrated that the beta-gamma imido analogue of ATP cannot be used for the initiation step. However, it can be incorporated into RNA during chain elongation. These results indicate that a hydrolyzable form of the beta-gamma phosphodiester bond in ATP is required for the initiation process and also support the hypothesis for a single promoter site for the initiation of transcription on the genome of vesicular stomatitis virus.


Beware, commercial chondroitinases vary in activity and substrate specificity.
Chondroitin sulfate (CS)and dermatan sulfate (DS) are negatively charged polysaccharides found abundantly in animal tissue and have been extensively described to play key roles in health and disease. The most common method to analyze their structure is by digestion into disaccharides with bacterial chondroitinases, followed by chromatography and/or mass spectrometry. While studying the structure of oncofetal CS, we noted a large variation in the activity and specificity of commercially available chondroitinases. Here studied the kinetics of the enzymes and used high-performance liquid chromatography-mass spectrometry to determine the di- and oligosaccharide products resulting from the digestion of commercially available bovine CS A, shark CS C and porcine DS, focusing on chondroitinases ABC, AC and B from different vendors. Application of a standardized assay setup demonstrated large variations in the enzyme-specific activity compared to the values provided by vendors, large variation in enzyme specific activity of similar enzymes from different vendors and differences in the extent of cleavage of the substrates and the generated products. The high variability of different chondroitinases highlights the importance of testing enzyme activity and monitoring product formation in assessing the content and composition of chondroitin and DSs in cells and tissues.


Renal dysplasia in children with posterior urethral valves: a primary or secondary malformation?
Routine prenatal ultrasound examination of the urogenital tract is of importance in patients with posterior urethral valves (PUV), because the renal function and long-term prognosis of these patients depend on early diagnosis and subsequent therapy. Opinion is divided as to whether the often-observed association of PUV with renal dysplasia represents a primary malformation or a secondary pathology caused by recurrent infections. These aspects should have an influence on therapeutic consequences and optimal timing of therapy in order to preserve long-term renal function. The histology of kidney specimens from 13 children with PUV who underwent nephrectomy was reviewed to attempt to differentiate between primary dysplastic malformations and secondary pathologies. Clinical data were analyzed and compared with the histologic findings. The average age at nephrectomy was 29 months (range 3-158 months). Approximately 80% of the specimens showed primary dysplastic malformations (mesenchymal or fetal cartilage tissue or dysplastic glomeruli and tubuli) in the presence of well-developed renal parenchyma. All specimens showed secondary pathologies such as renal-cortical atrophy, interstitial fibrosis, and interstitial-nephritis atrophy. The histologic evidence of well-differentiated renal parenchyma in concurrence with dysplastic parenchyma makes infravesical obstruction as the only cause of renal alterations in patients with PUV questionable. This coincides with the fact that organogenesis of the kidney is terminated at the 12th gestational week and secondary renal damage is irreversible at the 20th gestational week, but prenatal urinary diversion of the upper urinary tract is feasible in the 20th gestational week at the earliest. These facts must be taken into account when considering intrauterine urinary diversion.


How do emergency medicine applicants evaluate residency programs in the post-COVID-19 era?
Pandemic disruptions to interviews and away rotations led applicants to rely on alternative sources of information about residency programs. We sought to compare program characteristics important to emergency medicine (EM)-bound applicants from before and after the pandemic. We also investigated the sources of information pandemic impacted applicants used during residency recruitment. This was a multi-institutional, cross-sectional survey of applicants to EM residency programs. We asked applicants about important factors in choosing a program and compared their response to results from 2019 National Residency Match Program. We also asked about alternative information sources used during this time of restricted access to programs of interest. We surveyed 414 applicants from 40 medical schools and attained a response rate of 38.4%. Compared to 2019 applicants, our respondents identified morale of residents and quality of faculty as important factors in choosing a residency. Our subjects cited websites of the program and hospital affiliate, current residents, faculty/mentor advice, Reddit, and Doximity as sources of program information. Compared to 2019, our EM-bound applicants who, because of the pandemic, were unable to visit programs of interest valued resident morale and faculty quality as factors in choosing a residency program. Without in-person visits, our subjects also had to use both virtual resources (e.g., websites) and traditional sources (e.g., mentor advice) to investigate a program's culture, reputation, and diversity and inclusion. Residency programs should monitor their online presence now that this has become an alternative source of information for applicants during curtailment of in-person visits.


Racemic Monomer-Based One-Handed Helical Polymer Recognizes Enantiomers through Auto-Evolution of Its Helical Handedness Excess.
A racemic monomer-based optically inactive polyacetylene folds into a one-handed helix assisted by a nonracemic alcohol, which can separate various enantiomers as a chiral stationary phase in chromatography. The chiral-resolving power is virtually identical to that of the enantiopure monomer-based one-handed helical polyacetylene. Because of its unique static memory of the induced helicity, the original racemic polyacetylene expresses an auto-evolution of its helical handedness over time, and at the same time, chirality of the nonracemic alcohol is discriminated accompanied by successive enhancement of its optical purity enantioselectively adsorbed on the helical polyacetylene owing to the chiral filter effect as directly monitored by NMR, which contributes to further enhancing the helix-sense-excess of the helical polyacetylene.


Height of the cerebellar vermis and gestational age at birth.
The objective of this study was to construct reference ranges of the neonatal cerebellar vermis height with respect to the gestational age at birth. This observational study assessed 434 neonates born at 25-42 weeks' gestation. The neonates were singleton and appropriate in size for gestational age, and did not exhibit any abnormalities or neonatal disease. Gestational age was based on the date of the last menstrual period and confirmed by ultrasound examination performed within the 12(th) week of pregnancy. Sonographic measurements of the height of the cerebellar vermis in the mid-sagittal plane were performed within 24 h of birth by the same neonatal sonographer. Reference ranges (5(th), 50(th) and 95(th) centiles) were estimated by a mean and SD model based on least-squares polynomial regression. Neonatal sonographic measurements were obtained in all cases. Mean (SD) maternal age was 30.2 (4.3) years. Mean cerebellar vermis height adjusted for gestational age did not differ between males and females, the mean adjusted difference being 0.012 (95% CI, - 0.009 to 0.033) cm. Mean cerebellar vermis height (cm) against gestational age (weeks) was suitably modeled by a linear-cubic polynomial as - 1.784 + 0.137 x GA - 0.000019 x GA(3) (SD = - 0.147 + 0.008 x GA), where GA = gestational age. Reference ranges for the height of the cerebellar vermis at birth with respect to gestational age at birth have been constructed in appropriate-for-gestational-age neonates.


Enlarged choroid plexus related to iron rim lesions and deep gray matter atrophy in relapsing-remitting multiple sclerosis.
Choroid plexus (CP) is considered to be linked to inflammation of multiple sclerosis (MS), but its connection with markers of inflammation in vivo in MS is unclear, the markers such as lesions load and brain atrophy, particularly the white matter lesions (WMLs) edge surrounded by an iron rim, termed as iron rim lesions (IRLs). To investigate the association between CP volume and brain lesions load, especially IRLs load and atrophy in MS, and its relationship with clinical characteristics. 3.0 T brain MRI images were acquired from 99 relapsing-remitting MS (RRMS) and 60 healthy controls (HCs) to obtain the volumes of CP, whole brain and lesions. Volumes were expressed as a ratio of intracranial volume. Expanded Disability Status Scale (EDSS), Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT) were used to assess the severity of disability and cognitive function. Student's t-test and Multivariable regression analyses were performed to evaluate the difference of CP volumes between RRMS and HC and the association between CP volume and lesions load, brain volumes and clinical scale scores in RRMS. CP volume was 30% larger in patients with RRMS than HCs (p < 0.001) and was 20% larger in patients with IRLs than those without IRLs (p = 0.007). Moreover, the larger CP volume was related to greater WMLs volume in the whole RRMS (r = 0.46, p < 0.001). Further analysis in patients with IRLs showed a positive correlation between CP volume and WMLs volume (r = 0.45, p = 0.003), and IRLs volume (r = 0.51, p < 0.001). Meanwhile, enlarged CP was related to lower volumes in the whole brain (r = -0.30, p = 0.006), deep gray matter (r = -0.51, p < 0.001) and most regional deep gray matter nuclei (except amygdala), but no correlation with cortical lesions or cortex volume (both p > 0.05). In addition, CP volume was significantly higher in patients with cognitive impairment than those with cognitive preservation by MoCA scores (p = 0.011); the larger CP volume was associated with higher EDSS scores (r = 0.25, p = 0.014) and lower SDMT Z scores in RRMS (r = -0.26, p = 0.014). The enlargement of CP in RRMS had close correlations with inflammatory lesions, especially IRLs and deep gray matter atrophy, but not the cortex. Meanwhile, the larger CP volume was associated with higher disability and lower cognitive scores. CP volume may be a surrogate imaging marker for MS disease activity.


MiR-22-3p regulates the proliferation and invasion of Wilms' tumor cells by targeting AKT3.
In this study, the regulatory mechanism of miR-22-3p/AKT3 in the development of Wilms' tumor (WT) was investigated. Twenty-seven pairs of surgical tumor specimens and adjacent normal tissues were obtained from Jining No. 1 People's Hospital. The expression level of miR-22-3p in WT tissues and cell lines was measured by quantitative RT-PCR. MTT and transwell assays were performed to analyze cell proliferation and invasion in WT. The relationship between miR-22-3p and AKT3 was verified by a Dual-Luciferase assay. The protein expression of AKT3 was evaluated by Western blotting analysis. MiR-22-3p was downregulated and AKT3 was upregulated in WT. Functionally, overexpression of miR-22-3p inhibited cell proliferation and invasion in WT. Moreover, miR-22-3p directly targets AKT3. The knockdown of AKT3 suppressed cell proliferation and invasion in WT. In addition, upregulation of AKT3 restored the tumor suppressive effect of miR-22-3p in WT. MiR-22-3p inhibits the proliferation and invasion of WT cells by downregulating AKT3, indicating that miR-22-3p may be developed as a new biomarker for the diagnosis of WT.


A polarographic study of the photodegradation of nitrendipine.
Nitrendipine produces a well-defined polarographic peak due to the four-electron reduction of the nitro group. This peak is used for tracking the photodecomposition of nitrendipine in both UV light and daylight conditions. The results show that nitrendipine remains unaltered in the short time scale of a normal analytical procedure and no special care with visible light exposure is necessary. However nitrendipine is strongly altered with UV irradiation showing a first-order degradation kinetics. A degradation rate constant of 0.0665 min-1 with a t1/2 of 10.423 min has been obtained. The UV degradation product was isolated and identified as the nitro pyridine analogue of nitrendipine.


Sodium Glucose Cotransporter-2 Inhibitor Treatment and the Risk of Diabetic Ketoacidosis in Denmark: A Retrospective Cohort Study of Five Years of Use.
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been associated with increased risk of diabetic ketoacidosis (DKA) in both people with type 1 and type 2 diabetes mellitus. Few studies using data from high-quality registries exist that attempt to determine the real- world impact of the increasing use of this drug. The aim of this study was to investigate the incidence and risk of DKA in connection with SGLT2i treatment in Denmark between 2013-2017. A nationwide retrospective cohort of people with type 2 diabetes mellitus using SGLT2i or glucagon-like peptide-1 receptor agonists (GLP1-RA) was established and analysed using both Cox-proportional hazard regression and Kaplan-Meier survival analysis. The 37,058 individuals included in the cohort, were made up of SGLT2i (10,923), GLP1- RA (18,849), SGLT2i+insulin (2,069), and GLP1-RA+insulin (10,178) users. The incidence rate (IR) of DKA was 0.84 (95% CI 0.49-1.44) and 0.53 (95% CI 0.36-0.77) for the SGLT2i and GLP1-RA groups, respectively. There was no statistically significant increase in the risk for DKA with SGLT2i use (HR 1.02, 95% CI, 0.44-2.36). However, for the SGLT2i+insulin and GLP1- RA+insulin groups, IRs were 3.47 (95% CI 1.92-6.27) and 0.97 (95% CI 0.68-1.37) respectively, and the risk was statistically significantly higher (HR 5.42, 95% CI 2.16-13.56). We observed no significant increase in the risk of DKA for SGLT2i users compared to GLP1-RA. However, a significantly higher IR of DKA was observed with concomitant insulin use, and the risk of DKA was considerably higher for the SGLT2 group using insulin.


Effects of β-glucans from Coriolus versicolor on macrophage phagocytosis are related to the Akt and CK2/Ikaros.
Coriolus versicolor has been known to be an immune stimulator effects. For further understanding of the phagocytic activity and the intracellular mechanisms of β-glucan from C. versicolor (CVG), we examined the phagocytic activity, phosphorylation of Akt and CK2, nucleus translocation of p65 and Ikaros activity in β-glucan-treated macrophages using RT-PCR, western blotting, and IP assay. The role of Ikaros in regulating phagocytic effects of CVG was also determined using Ikaros dominant negative isoform cells. This study suggests that CK2/Ikaros are positive regulators and novel signaling pathway involved in phagocytosis and contributes to elucidating the mechanism underlying phagocytic activity induced by β-glucan.


Asymmetry in hemifield macular thickness as an early indicator of glaucomatous change.
To investigate whether asymmetry in hemifield macular thickness can serve as an early indicator of glaucomatous structural damage using spectral domain optical coherence tomography. Five zones in the macular thickness map were defined. Each zone included reciprocal areas in the superior and inferior hemifield. Differences in average retinal thickness (DRT) between corresponding regional pairs were measured in each of the five zones in 50 healthy eyes. An abnormality was defined as the DRT value lying outside the 95% confidence intervals. An eye was considered to yield an "abnormal macular hemifield test" (MHT) if abnormality was evident in any zone. The sensitivity and specificity for glaucoma detection of MHT and average circumpapillary retinal nerve fiber layer (cRNFL) classification were determined. A total of 114 healthy, 103 glaucoma-suspect, and 74 glaucomatous eyes were included. Overall, 5.8%, 36.9%, 88.4%, and 77.4% of the eyes of the healthy, glaucoma-suspect (GS), early glaucoma (EG), and advanced glaucoma (AG) groups yielded abnormal MHT results, respectively. In EG eyes, the sensitivity of an abnormal MHT result was significantly greater than that of abnormal average cRNFL classification (P=0.008). In the GS and AG groups, the sensitivity did not significantly differ between an abnormal MHT result and an average cRNFL classification (P=0.880, 0.180). Compared with sectoral cRNFL thickness measurements, MHT showed a similar level of diagnostic performance. Specificity was not different between an abnormal MHT result and an average cRNFL classification (P=0.687). Evaluation of asymmetry in hemifield macular thickness may serve as an assessment tool in the early diagnosis of glaucoma.


A microprocessor system for the digital synthesis of pulsed and continuous discharges of electric fish (or animal vocalizations).
Traditionally, the sensitivity of electric fish to electric stimuli has been investigated using a variety of electronically generated signal functions, for example sine, square, and sawtooth waves (both continuous and pulsed). None of these resemble the species- or sex-specific electric organ discharges (EODs) of fish. Therefore, EODs recorded on magnetic tape were used in open-loop playback experiments. However, as shown in the present paper, the waveforms of EODs reproduced from magnetic tape are distorted, and cannot be manipulated with speed and accuracy as to frequency or pulse repetition rate by feedback from the experiment. Good EOD imitations are generated by our microprocessor-based system for the digital synthesis of EODs which is controlled by a small 'personal computer'. Digitized EOD samples edited by computer are output by the fast digital-to-analogue converter of the microprocessor system. This system was devised for the synthesis of pulse-type (discontinuous) and wave type (continuous) EODs with continuous, on-line frequency and amplitude control. The rate of digital synthesis is 500 kHz in pulse-type EODs, and 250-500 kHz in wave type EODs at 0.06-0.24 Hz frequency resolution, depending on the repetition frequency of the synthesized wave EOD. The present paper describes the steps in EOD synthesis, and indicates some applications which benefit from the playback of high-fidelity imitations of natural EODs at amplitudes and frequencies selected by the experimenter, or automatically controlled by feedback from the experiment in closed-loop applications.


Open Popliteus Tendon Reconstruction Using a Hamstring Tendon Autograft.
The popliteus tendon plays a critical role in restraining the tibia against external rotation. It is often injured in the setting of posterolateral corner injuries. However, it is rarely injured in isolation from other structures of the posterolateral corner. This Technical Note describes an open anatomic reconstruction of the popliteus tendon. Although several techniques exist, this technique has been biomechanically validated and shown to have good outcomes. An early rehabilitation protocol focused on protected range of motion, edema control, quadriceps strengthening, and pain control is essential for maximizing patient outcomes.


RCT of a promising vocational/employment program for high-risk juvenile offenders.
Juvenile offenders with substance use problems are at high risk for deleterious long-term outcomes. This study evaluated the capacity of a promising vocational and employment training program in the building sector (i.e., Community Restitution Apprenticeship-Focused Training, CRAFT) to mitigate such outcomes through enhanced employment and education. Participants were 97 high-risk juvenile offenders (mean age=15.8 years) randomized to CRAFT versus education as usual (EAU) intervention conditions. Multi-method procedures measured employment, education, substance use, mental health, and criminal outcomes through a 30-month post-baseline follow-up. CRAFT was significantly more effective than EAU at increasing rates of youth employment and GED attendance. Intervention effects were not observed, however, for months employed, hours worked, or hourly wage. Measures of youth substance use, mental health symptoms, and criminal activity showed no favorable or iatrogenic effects. The potential of CRAFT was modestly supported, and suggestions were made for future research.


Relative roles of the fla/che P(A), P(D-3), and P(sigD) promoters in regulating motility and sigD expression in Bacillus subtilis.
Three promoters have been identified as having potentially important regulatory roles in governing expression of the fla/che operon and of sigD, a gene that lies near the 3' end of the operon. Two of these promoters, fla/che P(A) and P(D-3), lie upstream of the >26-kb fla/che operon. The third promoter, P(sigD), lies within the operon, immediately upstream of sigD. fla/che P(A), transcribed by E sigma(A), lies >/=24 kb upstream of sigD and appears to be largely responsible for sigD expression. P(D-3), transcribed by E sigma(D), has been proposed to participate in an autoregulatory positive feedback loop. P(sigD), a minor sigma(A)-dependent promoter, has been implicated as essential for normal expression of the fla/che operon. We tested the proposed functions of these promoters in experiments that utilized strains that bear chromosomal deletions of fla/che P(A), P(D-3), or P(sigD). Our analysis of these strains indicates that fla/che P(A) is absolutely essential for motility, that P(D-3) does not function in positive feedback regulation of sigD expression, and that P(sigD) is not essential for normal fla/che expression. Further, our results suggest that an additional promoter(s) contributes to sigD expression.


Quality of Life of Prostate Cancer Survivors Participating in a Remotely Delivered Web-Based Behavioral Intervention Pilot Randomized Trial.
Following a prostate cancer (PC) diagnosis, treatment-related symptoms may result in diminished quality of life (QoL). Improved diet and increased exercise may improve QoL in men with PC. We conducted a 4-arm pilot randomized trial to assess feasibility and acceptability of a 3-month web-based diet and exercise intervention, among men (>18 years of age) with PC (reported elsewhere). The purpose of this study is to describe the change in QoL measured by surveys (eg, QLQ-C30, PROMIS Fatigue) at enrollment and following the intervention. Men were randomized 1:1:1:1 to increasing levels of web-based behavioral support: Level 1: website; Level 2: Level 1 plus personalized diet and exercise prescription; Level 3: Levels 1-2 plus Fitbit and text messages; Level 4: Levels 1-3 plus 2 30-minute coaching calls. T-tests were used to compare pre-post change in mean QoL scores between each Level and Level 1. Two hundred and two men consented and were randomized (n = 49, 51, 50, 52 for Levels 1-4, respectively). Men were predominantly white (93%), with a median age of 70 years (Intra-quartile Range [IQR]: 65,75) and 3 years (IQR: 1,9) post primary treatment for mostly localized disease (74% with T1-2). There were no meaningful changes in QoL, but there were notable trends. Level 3 participants had small improvements in QLQ-C30 Global Health (5.46; 95% CI: -0.02, 10.95) compared to Level 1. In contrast, Level 2 participants trended toward decreasing Global QoL (-2.31, 95% CI: -8.05, 3.42), which may reflect declines in function (eg, Cognitive: -6.94, 95% CI: -13.76, -0.13) and higher symptom burden (eg, Diarrhea: 4.63, 95% CI: -1.48, 10.74). This short, web-based intervention did not appear to have an impact on PC survivors' QoL. Most men were several years past treatment for localized disease; the potential for this approach to reduce symptoms and improve QoL in men who have worse health may still be warranted.


Mechanisms of lipopolysaccharide-induced changes in effects of contractile agonists on pregnant rat myometrium.
The study was undertaken to investigate the mechanisms underlying enhanced uterine contractility induced by lipopolysaccharide (LPS) in pregnant rats. Wistar rats were administered intrauterine either LPS (50 microg) or normal saline solution (0.05 mL) on day 17 of gestation. On day 19, the animals were killed and uterus was isolated for isometric recording, (45)Ca(++) influx measurement, and determination of plasma membrane Na(+)-K(+)-ATPase. Uterine strips, taken from LPS-treated rats, displayed a marked increase in amplitude of spontaneous rhythmic contractions compared with controls. Enhancement in the sensitivity of uterine strips to agonists such as oxytocin, 5-hydroxytryptamine (5-HT), and BAY K8644 was also observed in rats treated with LPS. Cyclo-oxygenase-2 inhibitor, nimesulide (10 micromol/L) had no significant effect on the LPS-induced increase in spontaneous rhythmic contractions. On the other hand, nimesulide attenuated the increased sensitivity of uterine strips to oxytocin induced by LPS. Nimesulide significantly inhibited 5-HT-induced uterine contractions in both control and LPS-treated rats. However, the enhanced sensitivity of uterine strips to 5-HT was evident even in the presence of nimesulide in rats treated with LPS. Nifedipine-sensitive (45)Ca(++)-influx into uterine strips both in the basal state as well as those stimulated by high K(+) (80 mmol/L) and 5-HT (1 micromol/L) was greater in LPS-treated group compared with the controls. LPS treatment caused a marked inhibition in the Na(+)-K(+)-ATPase activity of the uterine plasma membrane compared with controls. LPS had no effect on plasma 17beta-estradiol levels. LPS appears to increase uterine contractility of pregnant rats both through the release of endogenous prostaglandins and increased influx of Ca(++) through L-type Ca(++) channels. Inhibition of sodium pump by LPS may be an additional mechanism in augmentation of uterine excitability.


Empirical determination of thresholds for case identification: validation of the Personality Diagnostic Questionnaire-Revised.
The Personality Diagnostic Questionnaire-Revised (PDQ-R) was sent to first-degree relatives of major psychotic patients for identification of DSM-III-R personality disorders (PDs). Responses to the PDQ-R were interpreted both literally and empirically, and compared with the Structured Interview for DSM-III PDs (SIDP) as the standard. For literal interpretation, symptoms reported were counted directly for case identification using fixed DSM-III-R thresholds. The empirical approach adjusted the threshold for case identification to maximize concordance with the SIDP. Comparison of the two methods showed that using empirically determined thresholds in some scales gives better concordance with the SIDP. For the dependent and histrionic PD scales, the improvements were statistically significant. The area under the receiver operating characteristic (ROC) curve was computed for each PDQ-R scale to summarize its discriminatory capability across all thresholds. Areas under the ROC curve indicated that the schizoid, schizotypal, borderline, dependent, passive-aggressive, and histrionic PD scales in the PDQ-R have better discriminatory qualities than other PDQ-R scales.


A controlled trial of two bicarbonate-containing dialysis fluids for CAPD--final report.
The combination of a low pH and a high concentration of lactate which is present in most dialysis fluids is found to be cytotoxic in vitro. For these reasons it would seem logical to use a bicarbonate-containing solution and thus automatically provide a solution with a neutral pH. A parallel, randomized, open-label, prospective 2-month trial with an optional 4 month extension was undertaken to compare two novel bicarbonate-based solutions; one containing 38 mmol/l of bicarbonate (B), and one containing a mixture of 25 mmol/l bicarbonate and 15 mmol/l of lactate (B/L), with a control solution (C) containing 40 mmol/l lactate. Three groups of 19 (C), 20 (B), and 20 (B/L) patients were recruited and data from approximately 55 patient months were accumulated in each group. The data show that both bicarbonate-based solutions maintain acid-base levels within the normal range, that there were no changes in any of the other blood biochemistry parameters measured in the peritoneal equilibration test or with regard to adequacy of dialysis, and that furthermore, both solutions were well tolerated. This study showed that either the bicarbonate or bicarbonate/lactate solutions could be utilized efficaciously in patients undergoing CAPD.


Augmenting neurogenesis rescues memory impairments in Alzheimer's disease by restoring the memory-storing neurons.
Hippocampal neurogenesis is impaired in Alzheimer's disease (AD) patients and familial Alzheimer's disease (FAD) mouse models. However, it is unknown whether new neurons play a causative role in memory deficits. Here, we show that immature neurons were actively recruited into the engram following a hippocampus-dependent task. However, their recruitment is severely deficient in FAD. Recruited immature neurons exhibited compromised spine density and altered transcript profile. Targeted augmentation of neurogenesis in FAD mice restored the number of new neurons in the engram, the dendritic spine density, and the transcription signature of both immature and mature neurons, ultimately leading to the rescue of memory. Chemogenetic inactivation of immature neurons following enhanced neurogenesis in AD, reversed mouse performance, and diminished memory. Notably, AD-linked App, ApoE, and Adam10 were of the top differentially expressed genes in the engram. Collectively, these observations suggest that defective neurogenesis contributes to memory failure in AD.


PET/Computed Tomography in Treatment Response Assessment in Cancer: An Overview with Emphasis on the Evolving Role in Response Evaluation to Immunotherapy and Radiation Therapy.
The effectiveness of cancer treatment must be assessed early in the course of the therapy so that regimens can be tailored in an individualized manner. Whole-body metabolic burden, metabolic tumor volume and total lesion glycolysis are the newer quantitative PET metrics that reflect the overall disease burden and take into account the stage of the disease, the heterogeneous intra-tumoral metabolism and uptake of PET tracer. Immunotherapy response evaluation in solid tumors is challenging, and combined use of anatomical and molecular imaging could evolve as the optimal way for assessing treatment response to immunotherapy. PET based parameters may be better predictors of response, necrosis and recurrence of disease after radiation therapy vis-à-vis the conventional cross-sectional imaging.


The cell biology of neural stem and progenitor cells and its significance for their proliferation versus differentiation during mammalian brain development.
The switch of neural stem and progenitor cells from proliferation to differentiation during development is a crucial determinant of brain size. This switch is intimately linked to the architecture of the two principal classes of neural stem and progenitor cells, the apical (neuroepithelial, radial glial) and basal (intermediate) progenitors, which in turn is crucial for their symmetric versus asymmetric divisions. Focusing on the developing rodent neocortex, we discuss here recent advances in understanding the cell biology of apical and basal progenitors, place key regulatory molecules into subcellular context, and highlight their roles in the control of proliferation versus differentiation.


Arterial pulse wave propagation velocity in healthy dogs by pulse wave Doppler ultrasound.
The aim of this study was to prospectively evaluate the carotid-femoral pulse wave velocity (PWV) values in healthy dogs using pulse wave Doppler ultrasound. A secondary aim was to determine the feasibility of this method and to report the intra- and interobserver reproducibilities of the PWV in conscious dogs. The data were studied in 30 healthy, adult, male (n = 15) and female (n = 15) dogs. The time interval marked between the R wave peak of the electrocardiogram and the intersection of the blood flow wave upstroke of the Doppler spectrum with the baseline of zero frequency was determined for the carotid (T1) and for the femoral (T2) arteries. The distance covered by the pulse wave (L) was determined. The PWV was then calculated using the following formula: L/T2 - T1. The mean values of PWV calculated from the total sample (n = 30) evaluated were 13.41 ± 2.20 m/s. No significant statistical difference was observed for the PWV measurements between males (14.82 ± 3.18 m/s) and females (12.64 ± 2.45 m/s). The analysis revealed no intra nor interobserver differences. A reasonable reproducibility of the PWV measurements was showed by intraclass correlation coefficients (ICC), and the coefficients of variation (CV). These data demonstrate that noninvasive vascular Doppler analysis is a feasible and reproducible method to determine the carotid-femoral PWV in dogs.


Potency and specificity of the pharmacological action of a new, antiasthmatic, topically administered soft steroid, etiprednol dicloacetate (BNP-166).
In the present study, the pharmacological effects of etiprednol dicloacetate (BNP-166; ethyl-17alpha-dichloroacetoxy-11beta-hydroxyandrosta-1,4-diene-3-one-17beta-carboxylate), a new soft steroid, intended to use for the treatment of asthma, were investigated in an animal model of allergen sensitized and challenged Brown Norway rats using local treatment. The examinations involved the determination of the effect of the compound on the extent of allergen induced broncho-alveolar fluid and lung tissue eosinophilia, goblet cell hyperplasia and mucus production, perivascular edema formation, and airways hyperresponsiveness. The activity of etiprednol dicloacetate was compared with that of budesonide. Using in vitro methods, the soft character of etiprednol dicloacetate was investigated together with its capability to dissociate transrepressing and transactivating properties. We found that combining all the examined parameters etiprednol dicloacetate was at least equipotent with budesonide in the animal model, but in several investigated variables it surpassed the activity of budesonide. The effect of etiprednol dicloacetate in vitro was shown to be the function of the quantity of the serum, present in the assay, it was also strongly affected by the incubation time and decreased significantly when it was preincubated with human plasma. These features are characteristics of a soft drug that is quickly inactivated in the systemic circulation. In addition, it was revealed that while the transrepressing potential of etiprednol dicloacetate remained high, its transactivating activity was greatly reduced. These data indicate that the strong local effect of the compound will very likely be accompanied with a significantly reduced systemic activity predicting favorable selectivity in the pharmacological action of etiprednol dicloacetate.


MicroRNAs as targets for engineering of CHO cell factories.
MicroRNAs (miRNAs) are strongly implicated in the global regulation of gene expression, and, in this regard, they consequently affect metabolic pathways on every regulatory level in different species. This characteristic makes miRNAs a promising target for cell engineering, and they could have multiple applications in medicine and biotechnology. However, a more profound, mechanistic understanding of miRNA action is needed for their potential to be translated into the development of industrially relevant cell factories with novel features. Here, we highlight the potential of miRNAs for the engineering of Chinese hamster ovary (CHO) cells, these being the most prevalent cell factory system for biopharmaceutical production. A key advantage of miRNAs, in contrast to most cell-engineering approaches that rely on overexpression of regulatory proteins, is that they do not compete for the translational machinery that is required to express the recombinant product. However, we also summarize the limitations and challenges that will have to be overcome to exploit fully miRNA technology.


Formation and persistence of procoagulant and fibrinolytic activities in circulation after strenuous physical exercise.
Seven healthy male volunteers were subjected to exercise of short (STR; 1.7 km), middle (MTR; 4.8 km) and long (LTR; 10.5 km) term runs at a speed close to maximal capacity. Blood samples were drawn before, immediately after exercise and at intervals over the next 10 h. FVIIIR:Ag (von Willebrand factor) rose 2.2-3.2 fold and persisted at higher levels than baseline during the observation time. A spontaneous drop in FVII (p less than 0.03) was found immediately after STR (13.5 +/- 2.5%) and LTR (18.3 +/- 2.4%), whereas only a minor decrease (7.5 +/- 6.5%) occurred in MTR. The procoagulant activity of monocytes isolated from whole blood exposed to LPS showed a striking enhancement in STR and MTR. An immediate enhancement in fibrinolytic activity was found in all groups (p less than 0.03) assessed by increased plasma levels of t-PA and shortened whole blood clot lysis time (WBCLT). The transient shortening of WBCLT was succeeded by a tendency to prolongation of the lysis time. A 45-year old male differed markedly from the others by demonstrating an extreme and consistent prolongation of WBCLT. Thus, it has been speculated that strenuous exercise possibly makes a subject more susceptible to a thrombotic event.


Survival status and predictors of mortality from severe community-acquired pneumonia among under-five children admitted at Debre Tabor comprehensive specialized hospital: a prospective cohort study.
Globally, Pneumonia continues to be the leading cause of mortality among under-five children. Ethiopia ranks fourth out of 15 countries worldwide in terms of the highest death rate of under-five children due to severe community-acquired pneumonia (SCAP). However, to date, there is no recent study that shows survival status and predictors of mortality from SCAP. Therefore, this study aimed to determine survival status and predictors of mortality from this dangerous disease among under-five children. A facility-based prospective cohort study was conducted from 1 November 2021 to 31 October 2022 at Debre Tabor comprehensive specialized hospital. All under-five children with SCAP admitted during the study period were included. Participants were selected using a systematic sampling technique. The collected data were coded, edited, and entered into epi-data version 4.2 and then exported to STATA version 17 for further analysis. The Kaplan Meier failure estimate with log-rank test was employed to determine the survival estimates. A cox-proportional hazard regression model was fitted to identify significant variables. The overall incidence density rate of mortality was 5.7 /1000 children with a median hospital stay of 8.2 days. Heart disease (AHR: 4.37; 95%CI: 1.68-11.32), previous admission of SCAP (AHR: 3.87; 95% CI: 1.31-11.43), WFL < -3Z score (AHR: 3.57; 95% CI: 1.02-12.42), impaired consciousness level at admission 3.41(1.14-10.19), and pleural effusion (AHR: 3.42; 95%CI: 1.18-9.93) were significant predictors of mortality. In this study, the survival probability of children with SCAP was low. Children with heart disease, previous admission of SCAP, WFL < -3Z score, impaired consciousness level at admission, and pleural effusion had low survival. Therefore, much emphasis is needed on children with SCAP, particularly those with identified predictors.


Correction to: Optimized THP-1 differentiation is required for the detection of responses to weak stimuli.
After the publication of our article [1] we were made aware that in Fig. 2D the images for PMA 2.5 ng/ml and PMA 25 ng/ml are identical.


New Perspective in Atrial Fibrillation.
Despite a large number of publications on this subject, the pathophysiological mechanisms involved in atrial fibrillation (AF) onset and recurrence are uncertain [...].


Comparable outcome after single-antigen-mismatched versus matched unrelated donor haematopoietic cell transplantation.
Allogeneic haematopoietic stem cell transplantation (HSCT) is a proven treatment for patients with haematological malignancies. In this retrospective analysis, the impact of donor matching on outcome of unrelated HSCT was analysed in patients transplanted at the University of Leipzig. From 2000 to 2009, 206 patients were transplanted from unrelated donors, of which 51 were mismatched (39 in 1 and 12 in ≥ 2 HLA-antigens), using peripheral blood or bone marrow grafts after total body irradiation and cyclophosphamide or busulfan and cyclophosphamide preparative regimens in combination with ATG. For graft-versus-host disease (GvHD) prophylaxis cyclosporine and MTX were administered. After a median follow-up of 49 months, outcome at 5 years in recipients of HLA-identical grafts was comparable to that of patients transplanted from HLA-incompatible donors with an overall survival (OS) of 52 % (95 % CI 43-61) versus 48 % (95 % CI 34-63), respectively (p = 0.48). Results were also comparable for event-free survival at 5 years [47 % (95 % CI 38-56) vs. 39 % (95 % CI 25-54); p = 0.44], relapse incidence (RI) [29 % (95 % CI 20-38) vs. 41 (95 % CI 25-57); p = 0.22] and non-relapse mortality [24 % (95 % CI 16-33) vs. 20 % (95 % CI 8-33); p = 0.84] in the matched versus mismatched groups. Incidence of acute and chronic GvHD was similar in both groups. Advanced disease (p = 0.02) and low-resolution typing (p = 0.04) are risk factors for OS and RI in univariate and multivariate analysis. Donors with one antigen mismatch are an acceptable option for patients with malignant disease for whom no fully matched donor is available.


Natural occurrence of aflatoxins, deoxynivalenol, fumonisins and zearalenone in maize from Entre Ríos Province, Argentina.
In Entre Ríos, Argentina, corn is one of the most important cereal grains produced, being an important income for the regional economy. The aim of this work was to assess aflatoxins, zearalenone, deoxynivalenol (DON) and fumonisins (FB) in corn harvest in 2003 and 2004 in the most contaminated departments found in previous studies in selected sampling places. At the harvest time, when the trucks arrived to store plants, samples of corn were taken from seven different positions of the trucks and from five in the trailer. Composite samples were randomised reduced to 10 kg. The samples were analysed by immunological tests, by thin layer chromatography (TLC), high performance liquid chromatography (HPLC) and/or gas liquid chromatography-electron capture detector (GLC-ECD). In 2003 average contamination was 3.19 u.g/kg for aflatoxins, 118.5 μg/kg for deoxynivalenol, 230.8 μg/kg for zearalenone and 10200 μg/kg of total fumonisins (HPLC and ELISA quantification showed a linear correlation (r(2) =0.9618), but RIDASCREEN®FAST values were 1.7 higher than HPLC values); in 2004 deoxynivalenol and zearalenone were not detected and an average of 2.0 μg/kg for aflatoxins and 4700 μg/kg for total fumonisins was found.This province, with the earliest harvested corn in the country each summer, tends to display different contaminations from the rest of the provinces, probably due to climate characteristics, particularly hotter weather.


Endothelin receptor-mediated vasodilatation: effects of organ culture.
Culture of intact arteries is a frequently employed experimental model for investigating the mechanisms governing the regulation of vascular endothelin receptors. Endothelin type A (ET(A)) and type B (ET(B)) receptors on vascular smooth muscle cells are up-regulated in organ culture and the enhanced vasoconstriction mimics the changes that occur in cardiovascular disease. The effect of organ culture on endothelial dilatory endothelin ET(B) receptors is not known. We hypothesize that organ culture decreases the endothelin receptor-mediated dilatation and that this is one possible mechanism by which the effects of the endothelin in blood vessels are altered during culture. Porcine coronary arteries were studied before and after 24 h of culture, using in vitro pharmacology and immunofluorescence. Sarafotoxin 6c and endothelin-1 were used to examine the endothelin ET(A) and ET(B) receptor effects, and the antagonists, Nomega-nitro-l-arginine (l-NOARG) for nitric oxide (NO), indomethacin for prostaglandins and charybdotoxin in combination with apamin for endothelium-derived hyperpolarizing factor (EDHF), were used to study the endothelium-derived dilatory mediators. Organ culture induced up-regulation of the sarafotoxin 6c (ET(B) receptor agonist) and endothelin-1 (ET(A) receptor agonist) elicited vasoconstriction. The sarafotoxin 6c contraction was stronger after endothelium denudation, suggesting endothelium-dependent dilatation. The endothelin-1 contraction was not affected by endothelium denudation. The increase in sarafotoxin 6c contraction after removal of the endothelium was more pronounced before than after organ culture, suggesting down-regulated endothelial endothelin ET(B) receptors. Also, the immunofluorescence staining intensities for endothelial endothelin ET(B) receptors were higher before than after organ culture. Pre-incubation with inhibitors for dilatory mediators suggested that both NO and EDHF play a vasodilatory role, while prostaglandins are not involved. In conclusion, endothelial endothelin ET(B) receptors induce NO and EDHF mediated vasodilatation in porcine coronary arteries. In organ culture, endothelial endothelin ET(B) receptors are down-regulated, mimicking the changes that occur in cardiovascular disease. Down-regulation of endothelial endothelin ET(B) receptors may in part explain the increased endothelin ET(B) receptor-mediated vasoconstriction frequently studied in organ culture.


Systematic review and meta-analysis of long-term oncological outcomes of lateral lymph node dissection for metastatic nodes after neoadjuvant chemoradiotherapy in rectal cancer.
Standard Western management of rectal cancers with pre-treatment metastatic lateral lymph nodes (LLNs) is neoadjuvant (chemo)radiotherapy (nCRT) followed by total mesorectal excision (TME). In recent years, there is growing interest in performing an additional lateral lymph node dissection (LLND). The aim of this systematic review and meta-analysis was to investigate long-term oncological outcomes of nCRT followed by TME with or without LLND in patients with pre-treatment metastatic LLNs. PubMed, Ovid MEDLINE, Embase, Cochrane Library and Clinicaltrials.gov were searched to identify comparative studies reporting long-term oncological outcomes in pre-treatment metastatic LLNs of nCRT followed by TME and LLND (LLND+) vs. nCRT followed by TME only (LLND-). Newcastle-Ottawa risk-of-bias scale was used. Outcomes of interest included local recurrence (LR), disease-free survival (DFS), and overall survival (OS). Summary meta-analysis of aggregate outcomes was performed. Seven studies, including 946 patients, were analysed. One (1/7) study was of good-quality after risk-of-bias analysis. Five-year LR rates after LLND+ were reduced (range 3-15%) compared to LLND- (11-27%; RR = 0.40, 95%CI [0.25-0.62], p < 0.0001). Five-year DFS was not significantly different after LLND+ (range 61-78% vs. 46-79% for LLND-; RR = 0.72, 95%CI [0.51-1.02], p = 0.143), and neither was five-year OS (range 69-91% vs. 72-80%; RR = 0.72, 95%CI [0.45-1.14], p = 0.163). In rectal cancers with pre-treatment metastatic LLNs, nCRT followed by an additional LLND during TME reduces local recurrence risk, but does not impact disease-free or overall survival. Due to the low quality of current data, large prospective studies will be required to further determine the value of LLND.


Performance of Deep Learning-Based Algorithm for Detection of Pediatric Intussusception on Abdominal Ultrasound Images.
Diagnosing pediatric intussusception from ultrasound images can be a difficult task in many primary care hospitals that lack experienced radiologists. To address this challenge, this study developed an artificial intelligence- (AI-) based system for automatic detection of "concentric circles" signs on ultrasound images, thereby improving the efficiency and accuracy of pediatric intussusception diagnosis. A total of 440 cases (373 pediatric intussusception and 67 normal cases) were retrospectively collected from Children's Hospital affiliated to Zhejiang University School of Medicine from January 2020 to December 2020. An improved Faster RCNN deep learning framework was used to detect "concentric circle" signs. Finally, independent validation set was used to evaluate the performance of the developed AI tool. The data of pediatric intussusception were divided into a training set and validation set according to the ratio of 8 : 2, with training set (298 pediatric intussusception) and validation set (75 pediatric intussusception and 67 normal cases). In the "concentric circle" detection model, the detection rate, recall, specificity, and F1 score assessed by the validation set were 92.8%, 95.0%, 92.2%, and 86.4%, respectively. Pediatric intussusception was classified by "concentric circle" signs, and the accuracy, recall, specificity, and F1 score were 93.0%, 92.0%, 94.1%, and 93.2% on the validation set, respectively. The model established in this paper can realize the automatic detection of "concentric circle" signs in the ultrasound images of abdominal intussusception in children; the AI tool can improve the diagnosis speed of pediatric intussusception. It is necessary to further develop an artificial intelligence system for real-time detection of "concentric circles" in ultrasound images for the judgment of children with intussusception.


Procongopain from Trypanosoma congolense is processed at basic pH: an unusual feature among cathepsin L-like cysteine proteases.
Congopain, the major cysteine protease from Trypanosoma congolense, is synthesized as an inactive zymogen, and further converted into its active form after removal of the proregion, most probably via an autocatalytic mechanism. Processing of recombinant procongopain occurs via an apparent one-step or a multistep mechanism depending on the ionic strength. The auto-activation is pH-dependent, with an optimum at pH 4.0, and no activation observed at pH 6.0. After addition of dextran sulfate (10 microg/ml), an approx. 20-fold increase of processing (expressed as enzymatic activity) is observed. Furthermore, in the presence of dextran sulfate, procongopain can be processed at pH 8.0, an unusual feature among papain-like enzymes. Detection of procongopain and trypanosomal enzymatic activity in the plasma of T. congolense-infected cattle, together with the capacity of procongopain to be activated at weakly basic pH, suggest that procongopain may be extracellularly processed in the presence of blood vessel glycosaminoglycans, supporting the hypothesis that congopain acts as a pathogenic factor in host-parasite relationships.


Recent trends in stem cell therapy for premature ovarian insufficiency and its therapeutic potential: a review.
Stem cell therapy is attracting attention in the field of regenerative medicine and is advancing rapidly. Many recent studies have applied stem cell therapy to treat reproductive system diseases; however, data are not yet available as to whether this therapy shows enhanced therapeutic effects. This paper analyzes recent preclinical studies on stem cell therapy for ovarian dysfunction in several types of animal models. Several clinical trials and pending projects are also discussed. This review will provide a background for developing stem cell therapies to enhance ovarian function.


Asymptomatic Chlamydia trachomatis infections in teenage males.
This study examined the prevalence of Chlamydia trachomatis infections of the urethra in asymptomatic teenage males in a juvenile detention setting. Gonorrhea cultures, chlamydia smears using the direct immunofluorescent antibody (DFA) technique, and 15-20 ml of a first-catch urine (FCU) sample were obtained. Of the 227 adolescent males screened, 205 had experienced sexual intercourse. Twenty-seven (13.2%) of the sexually active adolescents had positive DFA smears for C. trachomatis. Three (1.5%) had positive Neisseria gonorrhoeae cultures. A urine leukocyte count of greater than 10 per high-power field gave a 91% specificity but only a 26% sensitivity for a positive DFA. The high prevalence of chlamydia in this population and the relative low cost of the DFA screen for chlamydia make this a useful procedure for discovering unsuspected disease, particularly in a high-risk population. The FCU screen for leukocytes was of limited value in identifying asymptomatic infection.


Inhibition of HIF-1α/EP4 axis by hyaluronate-trimethyl chitosan-SPION nanoparticles markedly suppresses the growth and development of cancer cells.
Increased expression of Hypoxia-inducible factor-1α (HIF-1α) in the tumor microenvironment, mainly due to tumor growth, plays a major role in the growth of cancer. Tumor cells induce the expression of cyclooxygenase 2 (COX2) and its product, prostaglandin E2 (PGE2), through overexpression of HIF-1α. It has been shown that ligation of PGE2 with its receptor, EP4, robustly promotes cancer progression. HIF-1α/COX2/PGE2/EP4 signaling pathways appear to play an important role in tumor growth. Therefore, we decided to block the expansion of cancer cells by blocking the initiator (HIF-1α) and end (EP4) of this pathway. In this study, we used hyaluronate (HA), and trimethyl chitosan (TMC) recoated superparamagnetic iron oxide nanoparticles (SPIONs) loaded with HIF-1α-silencing siRNA and the EP4 antagonist (E7046) to treat cancer cells and assessed the effect of combination therapy on cancer progression. The results showed that optimum physicochemical characteristics of NPs (size 126.9 nm, zeta potential 27 mV, PDI < 0.2) and linkage of HA with CD44 molecules overexpressed on cancer cells could deliver siRNAs to cancer cells and significantly suppress the HIF-1α in them. Combination therapy of cancer cells by using HIF-1α siRNA-loaded SPION-TMC-HA NPs and E7046 also prevent proliferation, migration, invasion, angiogenesis, and colony formation of the cancer cells, remarkably.


Increased expression of low-affinity NGF receptor in rat retinal Müller cells after ischemia and reperfusion.
Low affinity nerve growth factor receptor (p75LNGFR) it is thought to play an important role in recovering damaged nerve. To investigate the possible role of p75LNGFR in transient retinal ischemia, we investigated p75LNGFR gene expression and localization. Using rats under anesthetized conditions, we incised the bulbar conjunctive around the limbus, and then clamped the eyes. A sham operation was performed on the contralateral eyes. Ocular ischemia was maintained for 90 minutes. The p75LNGFR gene expression in ischemic rat retinas was examined by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) at 0, 3, 6, and 72 hours after reperfusion, and the localization of p75LNGFR protein in rat retinas was examined by light and electron microscopic immunohistochemistry. The expression of p75LNGFR gene in ischemic rat retinas increased, as compared with that of the contralateral eyes after 6 hours and 3 days of reperfusion. The p75LNGFR protein increased in the outer plexiform layer and in the outer limiting membrane by immunohistochemical technique. Electron microscopic immunohistochemistry demonstrated that the staining is present in the Müller glial cells. The fact that p75LNGFR gene expression increased in Müller cells after reperfusion suggested that p75LNGFR expression may play a curative role in ischemic injury.


Silent brain infarctions and cognition decline: systematic review and meta-analysis.
Silent brain infarction (SBI) may be associated with cognitive decline in the general population. We systematically reviewed prior literature on: (1) SBI and cognition cross-sectionally; (2) baseline SBI and future cognitive decline and risk for cognitive disorders including dementia, and (3) incident SBI and the emergence of cognitive decline or cognitive disorders. The MEDLINE and EMBASE databases were searched for relevant studies. Data were independently extracted by two reviewers. Quality was assessed using the Newcastle Ottawa Scale. Data were pooled using a random effects model when more than two comparable estimates were found. Thirty relevant studies were identified: 17 had a cross-sectional design, 10 evaluated the association of baseline SBI with future cognitive decline, and 5 evaluated the association of incident SBI with cognitive decline. Most cross-sectional studies reported lower cognitive performance in persons with SBI. The pooled risk for incident dementia in persons with SBI was 1.48 (95% CI 1.12-1.97), but there was significant heterogeneity (p = 0.009); removing one outlier eliminated the heterogeneity (p = 0.53), giving a lower but still significant estimate (hazard ratio 1.27, 95% CI 1.06-1.51). The pooled risk for incident MCI was not increased in persons with SBI (hazard ratio 0.83, 95% CI 0.40 to 1.72), but there was significant heterogeneity (p < 0.001). The appearance of new SBI was associated with steeper rate of cognitive decline and the appearance of dementia. SBI are associated with worse cognition and increased risk for dementia. More standardization of cognitive assessment methods would facilitate future cross-study comparisons.


Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients.
Combination therapy for longer periods but at low dose might be an effective and tolerable manner to treat patients with relapsed multiple myeloma (MM). We used bortezomib, dexamethasone and low-dose oral cyclophosphamide as an induction regimen, followed by 1 year of maintenance consisting of bortezomib and cyclophosphamide. Relapsed MM patients were treated with six cycles of bortezomib twice weekly, cyclophosphamide 50 mg daily and dexamethasone. Maintenance therapy was given for 1 year. Primary endpoints were toxicity during re-induction and maintenance therapy. Secondary endpoints were response to treatment and progression-free (PFS) and overall survival (OS). This study included 59 patients. Myelosuppression and neuropathy were the most common side effects. Median follow-up was 27·1 (0·46-54·4) months with an overall response of 71%, and a very good partial response or more of 33%. During maintenance, improved responsiveness was observed in 19% of the patients. The median PFS was 18·4 months (range 0·13-43·5) and the median OS was 28·1 months (range 0·13-54·4). In conclusion, our study demonstrates that treatment with bortezomib, dexamethasone and low-dose cyclophosphamide is an effective and manageable regimen. Adding 1 year of maintenance was feasible, with limited side effects and an increased response rate.


Effect of Si and Fe doping on calcium phosphate glass fibre reinforced polycaprolactone bone analogous composites.
Reinforcing biodegradable polymers with phosphate-based glass fibres (PGF) is of interest for bone repair and regeneration. In addition to increasing the mechanical properties, PGF can also release bioinorganics, as they are water soluble, a property that may be controllably translated into a fully degradable composite. Herein, the effect of Si and Fe on the solubility of calcium-containing phosphate-based glasses (PG) in the system (50P(2)O(5)-40CaO-(10-x)SiO(2)-xFe(2)O(3), where x=0, 5 and 10 mol.%) were investigated. On replacing SiO(2) with Fe(2)O(3), there was an increase in the glass transition temperature and density of the PG, suggesting greater crosslinking of the phosphate chains. This significantly reduced the dissolution rates of degradation and ion release. Two PG formulations, 50P(2)O(5)-40CaO-10Fe(2)O(3) (Fe10) and 50P(2)O(5)-40CaO-5Fe(2)O(3)-5SiO(2) (Fe5Si5), were melt drawn into fibres and randomly incorporated into polycaprolactone (PCL). Initially, the flexural strength and modulus significantly increased with PGF incorporation. In deionized water, PCL-Fe(5)Si(5) displayed a significantly greater weight loss and ion release compared with PCL-Fe10. In simulated body fluid, brushite was formed only on the surface of PCL-Fe(5)Si(5). Dynamic mechanical analysis in phosphate buffered saline (PBS) at 37°C revealed that the PCL-Fe10 storage modulus (E') was unchanged up to day 7, whereas the onset of PCL-Fe(5)Si(5)E' decrease occurred at day 4. At longer-term ageing in PBS, PCL-Fe(5)Si(5) flexural strength and modulus decreased significantly. MC3T3-E1 preosteoblasts seeded onto PCL-PGF grew up to day 7 in culture. PGF can be used to control the properties of biodegradable composites for potential application as bone fracture fixation devices.


Modeling climate effects on hip fracture rate by the multivariate GARCH model in Montreal region, Canada.
Changes in extreme meteorological variables and the demographic shift towards an older population have made it important to investigate the association of climate variables and hip fracture by advanced methods in order to determine the climate variables that most affect hip fracture incidence. The nonlinear autoregressive moving average with exogenous variable-generalized autoregressive conditional heteroscedasticity (ARMAX-GARCH) and multivariate GARCH (MGARCH) time series approaches were applied to investigate the nonlinear association between hip fracture rate in female and male patients aged 40-74 and 75+ years and climate variables in the period of 1993-2004, in Montreal, Canada. The models describe 50-56% of daily variation in hip fracture rate and identify snow depth, air temperature, day length and air pressure as the influencing variables on the time-varying mean and variance of the hip fracture rate. The conditional covariance between climate variables and hip fracture rate is increasing exponentially, showing that the effect of climate variables on hip fracture rate is most acute when rates are high and climate conditions are at their worst. In Montreal, climate variables, particularly snow depth and air temperature, appear to be important predictors of hip fracture incidence. The association of climate variables and hip fracture does not seem to change linearly with time, but increases exponentially under harsh climate conditions. The results of this study can be used to provide an adaptive climate-related public health program and ti guide allocation of services for avoiding hip fracture risk.