Toward a US Army Pacific (USARPAC) rapid deployment medical component in support of Human Assistance/Disaster Relief (HA/DR) operations: challenges with "Going in Light".
This article reports the exploratory development and study efforts regarding the viability of a novel "going-in light" or "Going Light" medical component in support of US Army Pacific (USARPAC) Humanitarian Assistance/Disaster Relief (HA/DR) missions, namely, a BLU-MED® incremental modular equipment package along with a Rapid Deployment Medical Team (RDMT). The study was conducted to uncover a way for the U.S. Army to: (1) better medically support the greater U.S. military Pacific Command, (2) prepare the Army for Pacific HA/DR contingencies, and (3) imprint a swift presence and positive contribution to Pacific HA/DR operations. The findings were derived from an intensive quasi-Military Decision Making Planning (MDMP) process, specifically, the Oracle Delphi. This process was used to: (1) review a needs assessment on the profile of disasters in general and the Pacific in particular and (2) critically examine the viability and issues surrounding a Pacific HA/DR medical response of going in light and incrementally. The Pacific area of operations contains 9 of 15 countries most at risk for disasters in the most disaster-prone region of the world. So, it is not a matter of whether a major, potentially large-scale lethal disaster will occur but rather when. Solid empirical research has shown that by every outcome measured Joint Forces (Army, Navy, Air Force, and Marines) medical HA/DR operations have been inordinately successful and cost-effective when they employed U.S. Army medical assets inland near disasters' kinetic impact and combined sister services' logistical support and expertise. In this regard, USARPAC has the potential to go in light and successfully fill a vital HA/DR medical response gap with the RDMT and a BLU-MED®. However, initially going in fast and light and expanding and contracting as the situation dictates comes with subsequent challenges as briefly described herein that must be addressed. The challenges to going in light are not insurmountable "show stoppers." They can be identified and addressed through planning and preparation. Hopefully, the acquisition rapid response light components will equip commanders with more effective options with which to conduct Pacific HA/DR operations and be a focal point for effective joint operations.


Acute and subacute pulmonary toxicity of low dose of ultrafine colloidal silica particles in mice after intratracheal instillation.
To study the acute and subacute lung toxicity of low dose of ultrafine colloidal silica particles (UFCSs), mice were intratracheally instilled with 0, 0.3, 3, 10, 30 or 100 microg of UFCSs. Cellular and biochemical parameters in bronchoalveolar lavage fluid (BALF), histological alteration and the body weight were determined at 3 days after instillation. Exposure to 30 or 100 microg of UFCSs produced moderate to severe pulmonary inflammation and tissue injury. To investigate the time response, mice were instilled with 30 microg of UFCSs and sacrificed at intervals from 1 to 30 days post-exposure. UFCSs induced moderate pulmonary inflammation and injury on BALF indices at acute period; however, these changes gradually regressed until recovery during the experiment. Concomitant histopathological and laminin immunohistochemical findings generally correlated to BALF data. TUNEL analyses in UFCSs-treated animals showed a significant increase of the apoptotic index in lung parenchyma at all observation times. 8-OHdG expression occurred in lung epithelial cells and activated macrophages, which correlated to lung lesions in UFCSs-treated mice. These findings suggest that instillation of a small dose of UFCSs causes transient acute moderate lung inflammation and tissue damage. Oxidative stress and apoptosis may underlie the lung tissue injury induction.


Integration of summary data from GWAS and eQTL studies identified novel risk genes for coronary artery disease.
Several genetic loci have been reported to be significantly associated with coronary artery disease (CAD) by multiple genome-wide association studies (GWAS). Nevertheless, the biological and functional effects of these genetic variants on CAD remain largely equivocal. In the current study, we performed an integrative genomics analysis by integrating large-scale GWAS data (N = 459,534) and 2 independent expression quantitative trait loci (eQTL) datasets (N = 1890) to determine whether CAD-associated risk single nucleotide polymorphisms (SNPs) exert regulatory effects on gene expression. By using Sherlock Bayesian, MAGMA gene-based, multidimensional scaling (MDS), functional enrichment, and in silico permutation analyses for independent technical and biological replications, we highlighted 4 susceptible genes (CHCHD1, TUBG1, LY6G6C, and MRPS17) associated with CAD risk. Based on the protein-protein interaction (PPI) network analysis, these 4 genes were found to interact with each other. We detected a remarkably altered co-expression pattern among these 4 genes between CAD patients and controls. In addition, 3 genes of CHCHD1 (P = .0013), TUBG1 (P = .004), and LY6G6C (P = .038) showed significantly different expressions between CAD patients and controls. Together, we provide evidence to support that these identified genes such as CHCHD1 and TUBG1 are indicative factors of CAD.


Sperm Dysfunction in the Testes and Epididymides due to Overweight and Obesity Is Not Caused by Oxidative Stress.
Obesity is a condition that has been linked to male infertility. The current hypothesis regarding the cause of infertility is that sperm are highly sensitive to reactive oxygen species (ROS) during spermatogenesis in the testes and transit through the epididymides, so the increase in ROS brought on by obesity could cause oxidative stress. The aim of this study was to evaluate whether the activity of the enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX) is capable of counteracting oxidative stress in sperm. The male Wistar rat was used as an overweight and obesity model, and analysis of fertility in these groups was carried out including the control group. Serum testosterone levels were determined, and the scrotal fat, testes, and epididymides were extracted. The epididymides were separated ini0 3 principal parts (caput, corpus, and cauda) before evaluating sperm viability, sperm morphology, damage to desoxyribonucleic acid of the sperm, and ROS production. The protein content and specific activity of the three enzymes mentioned above were evaluated. Results showed a gain in body weight and scrotal fat in the overweight and obese groups with decreased parameters for serum testosterone levels and sperm viability and morphology. Fertility was not greatly affected and no DNA integrity damage was found, although ROS in the epididymal sperm increased markedly and Raman spectroscopy showed a disulfide bridge collapse associated with DNA. The specific activities of CAT and GPX increased in the overweight and obesity groups, but those of SOD did not change. The amounts of proteins in the testes and epididymides decreased. These findings confirm that overweight and obesity decrease concentrations of free testosterone and seem to decrease protein content, causing poor sperm quality. Implications. An increase in scrotal fat in these conditions fosters an increase of ROS, but the increase of GPX and CAT activity seems to avoid oxidative stress increase in the sperm without damaging your DNA.


Tuberculosis in patients with myelodysplastic syndromes.
The purpose of our study was to describe radiological manifestations of tuberculosis in patients with myelodysplastic syndromes. Chest radiographs and CTs of 12 patients with tuberculosis among 195 consecutive patients with myelodysplastic syndrome, proved by bone marrow biopsy, were reviewed. Six of the 12 patients presented with tuberculosis and were subsequently found to have myelodysplastic syndrome. Chest radiographs and CTs revealed pulmonary tuberculosis in all 12 patients and extrapulmonary tuberculous involvement in six (50%). Initial chest radiographic findings of pulmonary tuberculosis included a primary pattern (n = 6), a post-primary pattern (n = 3), a miliary pattern (n = 1), atypical infiltrates (n = 1) and normal radiograph (n = 1). Tuberculosis involved extrathoracic lymph nodes (n = 5), liver (n = 2), spleen (n = 2), kidney (n = 2), bowel (n = 2), pericardium (n = 2) peritoneum (n = 1) and rib (n = 1). Tuberculosis is a relatively common cause of infection in patients with myelodysplastic syndromes. The radiological appearance of pulmonary tuberculosis in myelodysplastic syndromes is often a primary pattern, and there is frequently extrapulmonary involvement.


Evolution of associating liver partition and portal vein ligation for staged hepatectomy: Simpler, safer and equally effective methods.
Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been recently demonstrated as a method to induce rapid and extensive hypertrophy within a short time and has been employed for a variety of primary and metastatic liver tumors. However, controversies remain due to its high morbidity and mortality. To enable safer surgery, liver surgeons have searched for better technical modifications, such as partial ALPPS, mini-ALPPS, minimally invasive ALPPS, and Terminal branches portal vein Embolization Liver Partition for Planned hepatectomy (TELPP). It seems that TELPP is very promising, because it has the main advantage of ALPPS - the rapid increase of future liver remnant volume, but the morbidity and mortality are much lower because only one surgical operation is required.


Diversity of Blastocystis subtypes in dogs in different geographical settings.
Blastocystis is a ubiquitous, globally distributed intestinal protist infecting humans and a wide range of animals. Several studies have shown that Blastocystis is a potentially zoonotic parasite. A 1996 study reported a 70% Blastocystis prevalence in Brisbane pound dogs while another study found that pet dogs/cats of 11 symptomatic Blastocystis infected patients harboured at least one Blastocystis subtype (ST) in common with the patient. These results raised the possibility that dogs might be natural hosts of Blastocystis. In this study, we aimed to investigate this hypothesis by estimating the prevalence of Blastocystis carriage and characterising the diversity of STs in dogs from three different environmental settings and comparing these STs with the range that humans harbour. Two hundred and forty faecal samples from dogs from three different geographical regions with varying levels of socio-economic development and sanitation, namely i) 80 pet and pound dogs from Brisbane, Australia, ii) 80 semi-domesticated dogs from Dong Village, Cambodia and iii) 80 stray dogs from the densely populated cities of Sikkim, Delhi and Mumbai in India, were screened for Blastocystis using PCR and subtyped based on the "barcode region" of the small subunit ribosomal RNA (SSU rRNA) gene. The prevalence of Blastocystis in dogs from Brisbane and Cambodia was 2.5% (2/80) and 1.3% (1/80), respectively, in contrast to 24% (19/80) in stray dogs from India. Stray dogs in India carried a diverse range of Blastocystis STs including ST 1, 4, 5 and 6 while the dogs from Brisbane carried only ST1 and one Cambodian dog carried ST2. The results suggest there is geographical variation in Blastocystis prevalence and STs between dog populations as reported in human studies. In addition, the greater diversity of STs and higher prevalence of Blastocystis in Indian stray dogs compared to pet/pound and community dogs in Australia and Cambodia could reflect close proximity to humans and other animals and exposure to their faeces. It appears that dogs are not natural hosts for Blastocystis but rather are transiently and opportunistically infected with a diversity of STs.


An evaluation of the humaneness of puntilla in cattle.
Slaughter by puntilla followed by neck sticking was examined in 309 cattle, to assess the humaneness of this method. After the neck stab, brain and spinal function as well as presence of selected cognitive responses were measured. In addition breed, sex, live weight, body condition score, number of stabs given and level of experience of the slaughterman were recorded. Repeat stabbing was needed to penetrate the foramen ovale in 24% of the animals, and was significantly less frequent in slaughtermen who were experienced, and more frequent in heavy weight animals (>380 kg). Prevalence of brain and spinal function was 91%. When animals attempted to stand after the neck stab they were more likely to have rhythmic breathing, positive palpebral response and responsiveness to threat, noise and short air stimulus. These findings indicate that nerve pathways are often functional after neck stab and therefore it is highly likely that the animals are still conscious.


ADAPTATION AND SPECIALIZATION IN A TWO-RESOURCE ENVIRONMENT IN DROSOPHILA SPECIES.
We assayed two components of performance (development time and survivorship), on food medium with and without ethanol, in laboratory populations of Drosophila simulans and D. melanogaster for which ethanol-medium was a novel food resource. These assays were done before and after 12 generations of rearing in either one-(regular medium only) or two-resource (regular medium and ethanol medium) environments. Initially, D. simulans was highly susceptible to ethanol, whereas D. melanogaster was relatively unaffected. After 12 generations in the two-resource environment, D. simulans showed significantly improved mean performance on ethanol medium; mean performance of D. melanogaster did not significantly change. Variation among families for both traits was higher on ethanol medium in D. simulans. Variation in D. melanogaster was not significantly affected by ethanol level, suggesting that resource quality was more important than novelty per se. In both species, the least variation was seen in populations after 12 generations in the two-resource environment. For development time in D. simulans, the decrease in variation was largely due to reduced variation within families, suggesting the evolution of canalization. Development time on the two media was not negatively correlated. In D. simulans, correlations measured before and after the experiment were not heterogeneous, suggesting that trade-offs in performance did not block diet expansion. In D. melanogaster, correlations became significantly less positive after 12 generations in the two-resource environment, supporting the view that correlations between performance on different resources may become less positive over time through selection.


Heterozygous carriers of classical homocystinuria tend to have higher fasting serum homocysteine concentrations than non-carriers in the presence of folate deficiency.
Many studies have reported that serum total homocysteine (tHcy) levels in cystathionine-beta-synthase (CBS) carriers are usually normal and only elevated after a methionine load. However, the amount of methionine required for a loading test is non-physiological and is never reached with regular feeding. Therefore, CBS carriers do not seem to be at an increased risk of cardiovascular diseases. However, the risk of cardiovascular diseases of CBS carriers with folate deficiency has not been studied. We recently found an extraordinarily high carrier rate (1/7.78) of a novel CBS mutation (p.D47E, c.T141A) in an Austronesian Taiwanese Tao tribe who live in a geographic area with folate deficiency. We evaluated if the CBS carriers tend to have higher fasting serum tHcy concentrations than non-carriers in presence of folate deficiency. The serum tHcy and folate levels before and after folate replacement were measured in 48 adult Tao carriers, 40 age-matched Tao non-carriers and 40 age-matched Han Taiwanese controls. The serum tHcy level of the Tao CBS carriers (17.9 ± 3.8 μmol/l) was significantly higher than in Tao non-carriers (15.7 ± 3.5 μmol/l; p < 0.008) and Taiwanese controls (11.8 ± 2.9 μmol/l; p < 0.001). Furthermore, a high prevalence of folate deficiency in the Tao compared with the Taiwanese controls (4.9 ± 1.8 ng/ml vs. 10.6 ± 5.5 ng/ml; p < 0.001) was also noted. Of note, the difference in tHcy levels between the carriers and non-carriers was eliminated by folate supplementation. (carriers:13.65 ± 2.13 μmol/l; non-carriers:12.39 ± 3.25 μmol/l, p = 0.321). CBS carriers tend to have a higher tHcy level in the presence of folate deficiency than non-carriers. Although many reports have indicated that CBS carriers are not associated with cardiovascular disease, the risk for CBS carriers with folate deficiency has not been well studied. Owing to a significantly elevated level of fasting tHcy without methionine loading, it is important to evaluate the risk of cardiovascular disease in CBS carriers with folate deficiency.


O-Protected 3-hydroxy-oxazolidin-2,4-diones: novel precursors in the synthesis of alpha-hydroxyhydroxamic acids.
O-Protected 3-hydroxyoxazolidin-2,4-diones have been prepared in a novel one-pot reaction by subsequent treatment of cyanohydrins with 1,1'-carbonyldiimidazole and O-protected hydroxylamines followed by acidic hydrolysis of the intermediate 4-imino-oxazolidin-2-ones. Decarbonylation of O-protected 3-hydroxyoxazolidin-2,4-diones by catalytic amounts of sodium methoxide, lithium hydroxide, sodium carbonate and caesium carbonate in methanol afforded O-protected alpha-hydroxyhydroxamic acids in excellent yields. Their deprotection provided a series of novel alpha-hydroxyhydroxamic acids.


fMLP-stimulated release of reactive oxygen species from adherent leukocytes increases microvessel permeability.
Our previous study (Am J Physiol Heart Circ Physiol 288: H1331-H1338, 2005) demonstrated that TNF-alpha induced significant leukocyte adhesion without causing increases in microvessel permeability, and that formyl-Met-Leu-Phe-OH (fMLP)-stimulated neutrophils in the absence of adhesion increased microvessel permeability via released reactive oxygen species (ROS). The objective of our present study is to investigate the mechanisms that regulate neutrophil respiratory burst and the roles of fMLP-stimulated ROS release from adherent leukocytes in microvessel permeability. A technique that combines single-microvessel perfusion with autologous blood perfusion was employed in venular microvessels of rat mesenteries. Leukocyte adhesion was induced by systemic application of TNF-alpha. Microvessel permeability was assessed by measuring hydraulic conductivity (L(p)). The 2-h autologous blood perfusion after TNF-alpha application increased leukocyte adhesion from 1.2 +/- 0.2 to 13.3 +/- 1.6 per 100 microm of vessel length without causing increases in L(p). When fMLP (10 microM) was applied to either perfusate (n = 5) or superfusate (n = 8) in the presence of adherent leukocytes, L(p) transiently increased to 4.9 +/- 0.9 and 4.4 +/- 0.3 times the control value, respectively. Application of superoxide dismutase or an iron chelator, deferoxamine mesylate, after fMLP application prevented or attenuated the L(p) increase. Chemiluminescence measurements in isolated neutrophils demonstrated that TNF-alpha alone did not induce ROS release but that preexposure of neutrophils to TNF-alpha in vivo or in vitro potentiated fMLP-stimulated ROS release. These results suggest a priming role of TNF-alpha in fMLP-stimulated neutrophil respiratory burst and indicate that the released ROS play a key role in leukocyte-mediated permeability increases during acute inflammation.


Protein and genetic expression of CDKN1C and IGF2 and clinical features related to human umbilical cord length.
Umbilical cord (UC) abnormalities are related to neurological outcome and death; specific molecular factors that might be involved are, as yet, unknown; however, protein-coding genes insulin-like growth factor 2 (IGF2) and cyclin-dependent kinase inhibitor 1C (CDKN1C) have been identified as potential candidates. An analytical observational study was carried out. Newborn UCs were collected, along with their clinical and morphological features. Immunohistochemical analysis was made on paraffin-embedded sections and quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed in fresh UC tissue for the assessment of gene expression. A total of 100 newborns were included. A significant association was found between long UC and prematurity [odds ratio (OR) 9] and long UC and respiratory distress (OR 4.04). Gestational diabetes (OR 8.55) and hypertensive disorders of pregnancy (HDP) (OR 4.71) were found to be related to short UCs. The frequency for abnormal UC length was higher than expected. UC length was positively correlated with maternal, newborn and placental weight. No statistical association was found between IGF2 and CDKN1C (p57) expression and UC length; however, there was a tendency for higher CDKN1C expression in short UCs, while, on the contrary, higher IGF2 expression for long UCs. UC length was observed to be associated with maternal and newborn complications. Protein expression, messenger RNA (mRNA) activity and the activity of said genes seem to be related to UC length.


Carbon-13 and deuterium isotope effects on oxalacetate decarboxylation by pyruvate carboxylase.
Deuterium and 13C isotope effects for the enzymic decarboxylation of oxalacetate showed that both deuterium- and 13C-sensitive steps in the reaction are partially rate limiting. A normal alpha-secondary effect of 1.2 per deuterium was calculated for the reaction in which pyruvate-d3 was the substrate, suggesting that the enolate of pyruvate was an intermediate in the reaction. The large normal alpha-secondary deuterium isotope effect of 1.7 when oxalacetate-d2 was the substrate suggests that the motions of the secondary hydrogens are coupled to that of the primary hydrogen during the protonation of the enolate of pyruvate. The reduction in the magnitude of the 13C isotope effect for the oxamate-dependent decarboxylation of oxalacetate from 1.0238 to 1.0155 when the reaction was performed in D2O (primary deuterum isotope effect = 2.1) clearly indicates that the transfer of the proton and carboxyl group between biotin and pyruvate does not occur via a single concerted reaction. Mechanisms in which biotin is activated to react with CO2 (prior to transfer of the proton on N-1) by bond formation between the sulfur and the ureido carbon, or in which the sequence of events is decarboxylation of oxalacetate, proton transfer from biotin to enolpyruvate, and carboxylation of enolbiotin, predict that the 13C isotope effect in D2O should be substantially lower than the observed value. A stepwise mechanism that does fit the data is one in which a proton is removed from biotin by a sulfhydryl group on the enzyme prior to carboxyl transfer, as long as the sulfhydryl group has an abnormally low pK.(ABSTRACT TRUNCATED AT 250 WORDS)


Cloning of an early sporulation gene in Bacillus subtilis.
A 0.8-megadalton BglII restriction fragment of Bacillus licheniformis cloned into the BglII site of plasmid pBD64 can complement spo0H mutations of Bacillus subtilis. The clone was isolated by selecting for the Spo+ phenotype and antibiotic resistance, using the helper system described by Gryczan et al. (Mol. Gen. Genet. 177:459-467, 1980). The insert is functional in both orientations and thus presumably has its own promoter. A deletion generated within the 0.8-megadalton insert by HindIII restriction and subsequent religation eliminates the ability of the cloned fragment to complement spo0H mutations. The cloned B. licheniformis deoxyribonucleic acid segment specifies the synthesis, in minicells, of a polypeptide of approximately 27,000 daltons. This protein is observed with both orientations, but not when the HindIII deletion is present in the cloned B. licheniformis chromosomal fragment. We have also demonstrated that ribonucleic acid complementary to the cloned B. licheniformis sporulation gene is transcribed in B. licheniformis both during vegetative growth and sporulation.


Spontaneous production of gamma interferon and induced production of beta interferon by human T-lymphoblastoid cell lines.
Two human T-lymphoblastoid cell lines, CCRF/CEM and Molt 4, produced beta interferon (IFN-beta) upon infection with Sendai virus. Molt 4, but not CCRF/CEM, spontaneously produced up to 300 U of IFN-gamma per ml, apparently not contaminated with IFN-alpha or -beta. Phytohemagglutinin, a T-cell mitogen, did not stimulate IFN production in these lines. A third T-lymphoblastoid line, CCRF/HSB2, produced no IFN either spontaneously or after infection with Sendai virus or treatment with phytohemagglutinin. The Molt 4 cells contained an mRNA which could be translated by oocytes to give IFN-gamma. Molt 4 cells therefore provide a convenient source of human IFN-gamma and its mRNA for experimental purposes.


Co-treatment of breast cancer cells with pharmacologic doses of 2-deoxy-D-glucose and metformin: Starving tumors.
A characteristic of tumor cells is the increased aerobic glycolysis for energy production. Thus, inhibition of glycolysis represents a selective therapeutic option. It has been shown that glycolysis inhibitor 2-deoxy-D-glucose (2DG) induces apoptotic cell death in different tumor entities. In addition, the antitumor activity of the anti-diabetic drug metformin has been demonstrated. In the present study, we aimed to ascertain whether the combination of pharmacologic doses of 2DG with metformin increases the antitumor efficacy. Cell viability of MDA-MB-231 and HCC1806 triple-negative breast cancer (TNBC) cells treated without or with 2DG or with metformin alone or with the combination of both agents was measured using Alamar Blue assay. Induction of apoptosis was quantified by measurement of the loss of mitochondrial membrane potential and cleavage of PARP. Treatment of breast cancer cells with glycolysis inhibitor 2DG or with the anti-diabetic drug metformin resulted in a significant decrease in cell viability and an increase in apoptosis. Treatment with 2DG in combination with metformin resulted in significantly reduced viability compared with the single agent treatments. The observed reduction in viability was due to induction of apoptosis. In addition, in regards to apoptosis induction a stronger effect in the case of co-treatment compared with single agent treatments was observed. The glycolytic phenotype of human breast cancer cells can be targeted for therapeutic intervention. Co-treatment with doses of the glycolysis inhibitor 2DG and anti-diabetic drug metformin is tolerable in humans and may be a suitable therapy for human breast cancers.


The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) induces apoptosis in Mycosis fungoides/Sézary syndrome cells.
The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) can serve as a ligand for the peroxisome proliferator activator receptor-gamma (PPAR-gamma) and has been shown to inhibit cell proliferation, and to induce differentiation and apoptosis in tumor cell lines. Bexarotene is an RXR-selective retinoid that can induce apoptosis of mycosis fungoides (MF) and Sézary syndrome (SS) cells. Since the PPAR-gamma and RXR receptors can form heterodimers, we studied the effects of CDDO and its synergism with bexarotene on apoptosis in MF/SS cell lines (MJ, Hut78, and HH) and freshly isolated peripheral blood lymphocytes (PBL) from SS patients with circulating atypical T cells (CD4+CD26-). CDDO treatment at 1-5 microM for 48 h caused a concentration-dependent apoptosis in three MF/SS cell lines and patients' PBL compared to vehicle controls. Bexarotene augmented CDDO-induced apoptosis in these cells. PPAR-gamma was expressed but decreased by 47% in MJ, 42% in Hut78, and 77% in HH cells following CDDO treatment. The anti-apoptotic protein bcl-xL, but not bcl-2, was decreased by 69% in MJ, 31% in Hut78, and 59% in HH cells and caspase-3 was activated following CDDO treatment. Interestingly, the PPAR-gamma antagonist T007 did not block CDDO-induced apoptosis, and the more potent PPAR-gamma agonist rosiglitazone required much higher concentrations (>50 microM) than CDDO to induce apoptosis in MF/SS cells. In summary, CDDO induces apoptosis that is further enhanced by bexarotene and decreases the PPAR-gamma and bcl-xL proteins in MF/SS cells. CDDO's effects on MF/SS cells may be at least partly mediated through a PPAR-gamma-independent mechanism. Our findings suggest the rationale for further investigation of the clinical potential of CDDO, either alone or in combination with bexarotene for MF/SS patients.


Rearrangement of the p53 gene in human breast tumours.
Rearrangement of the p53 gene is frequent in virus transformed cell lines and in chronic myelogenous leukemia. It is a rare event in solid tumours and has been reported only in osteosarcomas. In this study we have examined rearrangement of the p53 gene in human breast tumours. We found rearrangement in 35% of the patients (7 of 20 tumours examined). Normal tissue from these patients had an unrearranged gene, indicating that the genetic abnormality in the tumour is acquired during the natural process of tumorigenesis. No intronic rearrangement or allelic loss of the p53 gene was found in the breast tumour samples studied. Further, rearrangement of the p53 gene has been correlated with the p53 transcriptional status. Only two patients with rearranged p53 showed a high level of p53 RNA as well as protein expression. Thus, for the first time we report the rearrangement of the p53 gene in breast tumours, which may play a role in the process of tumorigenesis.


A clinical study on the management of inguinal hernias in children on the general surgical practice.
Inguinal and scrotal swellings are frequently encountered in the surgical practice, especially in children. It is also important to study the factors which are associated with inguinal hernia, especially in children, for its effective management. To study the factors which are associated with inguinal hernia in children. A prospective hospital based study was undertaken in the Department of Surgery for a period of one year between 2001 to 2002. Children who were aged one day to 12 years were selected for the study. Out of 960 children who were admitted to the surgical ward, 50 children had inguinal hernia and they constituted the sample. The details regarding the clinical history and the examination details were collected by using a predesigned proforma. The data which was thus collected was analyzed by using the appropriate statistical tests. The inguinal hernia in the study group was common in the 1-5 years age group. 90% of the study group was males; a swelling in the inguinal region was the commonest symptom. 70% of the study group was term deliveries; the swelling of the inguinal hernia was elastic in consistency in 35 cases. The swelling of the inguinal hernia was irreducible in two cases. The testis was palpable in 48 cases; a cough impulse was seen and felt in 48 cases. Tenderness of the swelling was present in 2 cases. Inguinal hernia is a common congenital condition in children. Difficulties are commonly encountered by the surgeons to identify and to confirm the presence of inguinal hernia. This study will help in a better management of hernia in the paediatric age group by understanding the features of inguinal hernia.


Systematic In Vitro Evaluation of a Library of Approved and Pharmacologically Active Compounds for the Identification of Novel Candidate Drugs for KMT2A-Rearranged Leukemia.
Patients whose leukemias harbor a rearrangement of the Mixed Lineage Leukemia (MLL/KMT2A) gene have a poor prognosis, especially when the disease strikes in infants. The poor clinical outcome linked to this aggressive disease and the detrimental treatment side-effects, particularly in children, warrant the urgent development of more effective and cancer-selective therapeutics. The aim of this study was to identify novel candidate compounds that selectively target KMT2A-rearranged (KMT2A-r) leukemia cells. A library containing 3707 approved drugs and pharmacologically active compounds was screened for differential activity against KMT2A-r leukemia cell lines versus KMT2A-wild type (KMT2A-wt) leukemia cell lines, solid tumor cells and non-malignant cells by cell-based viability assays. The screen yielded SID7969543, an inhibitor of transcription factor Nuclear Receptor Subfamily 5 Group A Member 1 (NR5A1), that limited the viability of 7 out of 11 KMT2A-r leukemia cell lines including 5 out of 7 lines derived from infants, without affecting KMT2A-wt leukemia cells, solid cancer lines, non-malignant cell lines, or peripheral blood mononuclear cells from healthy controls. The compound also significantly inhibited growth of leukemia cell lines with a CALM-AF10 translocation, which defines a highly aggressive leukemia subtype that shares common underlying leukemogenic mechanisms with KMT2A-r leukemia. SID7969543 decreased KMT2A-r leukemia cell viability by inducing caspase-dependent apoptosis within hours of treatment and demonstrated synergy with established chemotherapeutics used in the treatment of high-risk leukemia. Thus, SID7969543 represents a novel candidate agent with selective activity against CALM-AF10 translocated and KMT2A-r leukemias that warrants further investigation.


Non-adiabatic molecular dynamic simulations of opening reaction of molecular junctions.
We report non-adiabatic molecular dynamic simulations of the ring opening reaction of diarylethene (DAE) derivative molecules, both free standing and embedded between gold electrodes. Simulations are performed by the surface hopping method employing density functional theory. Typically, the free-standing molecules exhibit large quantum yields to open and close; however the process is quenched for the molecules embedded between electrodes. Our simulations reveal the importance of the DAE side chemical groups, which explain the efficiency of the quenching process. Namely, delocalization of the LUMO state contributes to electronic coupling between the molecule and electrodes, suppressing or enhancing the reaction process. The simulations indicate that a proper choice of the chemical side group, which provides the strong localization of the LUMO state, can substantially diminish the quenching mechanism. Additionally, we analyze a strong dependency of the quantum yield of the opening reaction coming from the mechanical strength of the molecules.


Levator resection for congenital ptosis: Does pre-operative levator function or degree of ptosis affect successful outcome?
The aim of this study was to determine whether pre-operative levator function and degree of ptosis affect surgical outcomes in children with congenital ptosis undergoing anterior levator resection under general anaesthesia. Retrospective cohort study. Children with 'simple' congenital ptosis who underwent anterior levator resection under general anaesthesia. Consecutive cases were reviewed with regards to achievement of the desired lid height (surgical success), and the influence of preoperative levator function and degree of ptosis. The amount of pre-operative levator function and degree of ptosis, with corresponding surgical outcomes. Forty-two lids (37 patients) were included in the study: 36 primary and 6 revision cases (which were excluded from analysis due to small sample size). Mean age was 7 years (range 3-17 years), with similar male to female ratio (1.2:1). The overall success rate for primary was 86%. There were small to moderate trends towards greater amount of levator resection for lower levator function (r2 = -0.25, p < 0.05) and higher degree of ptosis (r2 = 0.38, p < 0.05). All successful primary cases (n = 31) had pre-operative levator function of at least 8 mm. Levator resection in children under general anaesthesia continues to be an imprecise science. Degree of ptosis and levator function were poorly correlated to each other; however, there was an expected small to moderate correlation between resection amount and levator function (negative correlation) or degree of ptosis (positive correlation). Patients with levator function of 8mm or more are likely to have a successful outcome.


The role of fine needle aspiration cytology in the diagnosis of lymphoma.
The accuracy of fine needle aspiration (FNA) cytology for the diagnosis of lymphoma and other hematolymphoid malignancies was investigated by a review of 158 FNA specimens from 143 patients. Patients included in the study had either a diagnosis of a hematolymphoid malignancy by FNA cytology or a biopsy diagnosis of lymphoma that was preceded by FNA cytology. Biopsy specimens were obtained from 85% of the patients. Of the 158 needle aspirates, 118 (75%) were diagnosed as lymphoma, 13 (8%) as suspicious of lymphoma, 8 (5%) as myelomas, 3 (2%) as leukemias, 12 (8%) as positive for malignancy and 4 (2%) as negative for malignancy. Two of the 118 needle aspirates diagnosed as lymphoma were false positives while 3 of 13 diagnosed as suspicious for lymphoma were found to be benign. Overall, there were four false negatives. Morphologic subclassification of the lymphomas, originally attempted for 60 needle aspirates, was identical to the histologic subclassification in 51 cases (85%). FNA cytology provided the initial diagnosis of a hematolymphoid malignancy in 51% of the cases and allowed the documentation of recurrent disease in 49%. The results demonstrate the usefulness of FNA cytology for the diagnosis and management of patients with lymphoma.


Voltage mapping for slow-pathway visualization and ablation of atrioventricular nodal reentry tachycardia in pediatric and young adult patients.
Voltage guidance for the ablation of the slow pathway in atrioventricular nodal reentry tachycardia (AVNRT) is a dramatic shift from the traditional anatomy-guided approach within the triangle of Koch. The use of voltage gradient mapping has been evaluated in adults as an aid to identification of the slow pathway guiding placement of ablation applications. This study aimed to evaluate this technique of voltage-guided ablation of AVNRT in pediatric and young adult patients, who have a smaller, more compact triangle of Koch. A retrospective cohort study evaluated patients 20 years of age or younger with AVNRT who underwent voltage mapping. Using NavX, three-dimensional voltage maps of the right atrium were created during sinus rhythm, focusing primarily on the triangle of Koch. The voltage map gradients were adjusted to uncover a "voltage bridge" of lower voltage signals. This bridge was used as a surrogate of the slow pathway to guide cryoablation at this site. Of the 31 patients who underwent voltage mapping, three were excluded from the study due to inadequate mapping. All the patients experienced procedural success. In 86 % of the patients, there was an adequate voltage bridge to allow guided ablation. The successful ablation site was within the first three lesions for 60 % of the patients. Two patients experienced recurrence during a median follow-up period of 14 months. It appears that voltage-guided ablation of a voltage bridge in AVNRT can be used effectively and safely in the pediatric population.


Increased phasic activity of dopaminergic neurones in the rat ventral tegmental area following pharmacologically elevated levels of endogenous kynurenic acid.
Kynurenic acid (KYNA) is an antagonist of ionotropic glutamate receptors, preferentially blocking the glycine-site of the N-methyl-D-aspartate (NMDA) receptor. In the present electrophysiological study, the firing pattern of dopamine (DA) neurones of rat ventral tegmental area (VTA) was investigated following pharmacologically elevated endogenous levels of KYNA by means of an inhibitor of kynurenine 3-hydroxylase (PNU 156561A). Pre-treatment with PNU 156561A (40 mg kg-1, i.v., 5-9 h) caused a threefold increase in endogenous KYNA in whole brain levels and also evoked a significant increase in firing rate and bursting activity of VTA DA neurones. Administration of D-cycloserine (2-128 mg kg-1, i.v.), a partial agonist at the glycine-site of the NMDA-receptor, was found to reverse the increase in firing rate and bursting activity as induced by elevated concentrations of KYNA. The electrophysiological effects of elevated KYNA levels were in all essential mimicked by administration of the NMDA-receptor antagonist MK 801 (0.05-1.6 mg kg-1, i.v.). Thus, the effects of elevated endogenous brain KYNA observed in the present study are likely to be carried out by NMDA receptor antagonism. In conclusion, this study shows that an increase in endogenous KYNA levels produces significant actions on the tonic afferent control of the firing pattern of VTA DA neurones. Given the psychotomimetic effects of NMDA-receptor antagonists, e.g. phencyclidine and ketamine, the state of hyperactivity of mesocorticolimbic DA system induced by elevated levels of KYNA may represent a pathophysiological condition analogous to that seen in schizophrenic patients.


Exercise-based oncology rehabilitation: leveraging the cardiac rehabilitation model.
The value of exercise and rehabilitative interventions for cancer survivors is increasingly clear, and oncology rehabilitation programs could provide these important interventions. However, a pathway to create oncology rehabilitation has not been delineated. Community-based cardiac rehabilitation (CR) programs staffed by health care professionals with experience in providing rehabilitation and secondary prevention services to individuals with coronary heart disease are widely available and provide a potential model and location for oncology rehabilitation programs. Our purpose was to outline the rehabilitative needs of cancer survivors and demonstrate how oncology rehabilitation can be created using a CR model. We identify the impairments associated with cancer and its therapy that respond to rehabilitative interventions. Components of the CR model that would benefit cancer survivors are described. An example of an oncology rehabilitation program using a CR model is presented. Cancer survivors have impairments associated with cancer and its therapy that improve with rehabilitation. Our experience demonstrates that effective rehabilitation services can be provided utilizing an existing CR infrastructure. Few adjustments to current CR models would be needed to provide oncology rehabilitation. Preliminary evidence suggests that cancer survivors participating in an oncology rehabilitation program experience improvements in psychological and physiologic parameters. Utilizing the CR model of rehabilitative services and disease management provides a much needed mechanism to bring oncology rehabilitation to larger numbers of cancer survivors.


Continuous molecular enrichment in microfluidic systems.
Highly efficient molecular extractions in continuous flow microfluidic systems are demonstrated utilising the rapid mixing properties of biphasic segmented flow in conjunction with suspended micro-particulate adsorbents. A continuous flow technique providing potential for continual on-line sample enrichment, purification and clean-up in chemical synthesis, and sample preparation.


Iron Binding Properties of Recombinant Class A Protein Disulfide Isomerase from Arabidopsis thaliana.
The protein disulfide isomerase (PDI) family comprises a wide set of enzymes mainly involved in thiol-disulfide exchange reactions in the endoplasmic reticulum. Class A PDIs (PDI-A) constitute the smallest members of the family, consisting of a single thioredoxin (TRX) module without any additional domains. To date, their catalytic activity and cellular function are still poorly understood. To gain insight into the role of higher-plant class A PDIs, the biochemical properties of rAtPDI-A, the recombinant form of Arabidopsis thaliana PDI-A, have been investigated. As expressed, rAtPDI-A has only little oxidoreductase activity, but it appears to be capable of binding an iron-sulfur (Fe-S) cluster, most likely a [2Fe-2S] center, at the interface between two protein monomers. A mutational survey of all cysteine residues of rAtPDI-A indicates that only the second and third cysteines of the CXXXCKHC stretch, containing the putative catalytic site CKHC, are primarily involved in cluster coordination. A key role is also played by the lysine residue. Its substitution with glycine, which restores the canonical PDI active site CGHC, does not influence the oxidoreductase activity of the protein, which remains marginal, but strongly affects the binding of the cluster. It is therefore proposed that the unexpected ability of rAtPDI-A to accommodate an Fe-S cluster is due to its very unique CKHC motif, which is conserved in all higher-plant class A PDIs, differentiating them from all other members of the PDI family.


Intravenous Thrombolysis after Reversal of Dabigatran by Idarucizumab: A Case Report.
We describe a 75-year-old female patient with nonvalvular atrial fibrillation who presented with acute ischemic stroke during treatment with dabigatran 2 × 110 mg per day. After informed consent, we reversed the anticoagulant effects of dabigatran using idarucizumab and applied an intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (off-label use). An intracerebral hemorrhage was excluded after systemic thrombolysis. Despite the IVT, the patient's clinical condition deteriorated and she developed an ischemic lesion in the right pons, the right thalamus and right cerebellum. To date, the literature lacks data concerning the thrombolytic treatment of acute ischemic stroke in patients after specific reversal of the non-vitamin K oral anticoagulant dabigatran using idarucizumab. Given the rapid and sustainable efficacy of idarucizumab, the reversal of dabigatran followed by thrombolysis seems to be safe, but further studies and register data are still needed to confirm our preliminary observation, especially to provide additional data concerning the risk-benefit evaluation.


Inflammation-driven activation of JAK/STAT signaling reversibly accelerates acute myeloid leukemia in vitro.
Acute myeloid leukemia (AML) is characterized by a high relapse rate and dismal long-term overall survival which is related to persistence of leukemia-initiating cells in their niche. Different animal models of myeloid malignancies reveal how neoplastic cells alter the structural and functional characteristics of the hematopoietic stem cell niche to reinforce malignancy. Understanding and disruption of the microenvironmental interactions with AML cells are a vital need. Malignant niches frequently go along with inflammatory responses, but their impact on cancerogenesis often remains unexplored. Here, we uncovered an aberrant production of inflammatory cytokines in untreated AML bone marrow that was proved to promote the proliferation of leukemia cells. This inflammatory response induced an activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in AML blasts as well as bone marrow stromal cells that also fostered leukemia proliferation. Inhibition of JAK/STAT signaling using the selective JAK1/2 inhibitor ruxolitinib resulted in significant antileukemic activity in AML in vitro which is mediated through both cell-autonomous and microenvironment-mediated mechanisms. However, in a xenograft transplantation model, monotherapy with ruxolitinib did not achieve substantial antileukemic activity, possibly suggesting a complementary function of JAK1/2 inhibition in AML.


Evaluation of multidrug resistance in 46 newly diagnosed patients with acute leukemia.
The aim of the present study was to assess the expression profile of multidrug resistance (MDR)-related proteins ABCB1, ABCC1 and LRP in 46 patients with acute leukemia (AL). The levels of MDR gene mRNA expression and protein expression at diagnosis were analyzed by semi-quantitative PCR and flow cytometry, respectively. In the adult group, higher expression levels of abcc1 gene were associated with older age and lower levels of lactate dehydrogenase (LDH). In the pediatric group, abcc1 gene expression levels were associated with higher CD34 expression and a higher ABCB1 protein expression was correlated with high WBC counts. The present data indicate that abcb1 gene overexpression may be associated with a poor prognosis in adults with AL and that ABCB1 and abcc1 expression correlates with different prognostic factors in pediatric patients with AL. Our findings demonstrate that the method of choice to evaluate chemotherapy resistance-related proteins is a major variable.


Design, synthesis and anticancer evaluation of novel Se-NSAID hybrid molecules: Identification of a Se-indomethacin analog as a potential therapeutic for breast cancer.
A total of twenty-five novel carboxylic acid, methylester, methylamide or cyano nonsteroidal anti-inflammatory drug (NSAID) derivatives incorporating Se in the chemical form of selenoester were reported. Twenty Se-NSAID analogs exhibited an increase in cytotoxic potency compared with parent NSAID scaffolds (aspirin, salicylic acid, naproxen, indomethacin and ketoprofen). Top five analogs were selected to further study their cytotoxicity in a larger panel of cancer cells and were also submitted to the DTP program of the NCI's panel of 60 cancer cell lines. Compounds 4a and 4d stood out with IC50 values below 10 μM in several cancer cells along with a selectivity index higher than 5 in breast cancer cells. Remarkably, analog 4d was found to inhibit cell growth notably in two breast cancer cell lines by inducing apoptosis, and to be metabolized to release the parent NSAID along with the Se fragment. Taken together, our results show that Se-NSAID analog 4d could be a potential chemotherapeutic drug for breast cancer.


Linking data to models: data regression.
Mathematical models are an essential tool in systems biology, linking the behaviour of a system to the interactions between its components. Parameters in empirical mathematical models must be determined using experimental data, a process called regression. Because experimental data are noisy and incomplete, diagnostics that test the structural identifiability and validity of models and the significance and determinability of their parameters are needed to ensure that the proposed models are supported by the available data.


Phylogenetic diversity of sequences of cyanophage photosynthetic gene psbA in marine and freshwaters.
Many cyanophage isolates which infect the marine cyanobacteria Synechococcus spp. and Prochlorococcus spp. contain a gene homologous to psbA, which codes for the D1 protein involved in photosynthesis. In the present study, cyanophage psbA gene fragments were readily amplified from freshwater and marine samples, confirming their widespread occurrence in aquatic communities. Phylogenetic analyses demonstrated that sequences from freshwaters have an evolutionary history that is distinct from that of their marine counterparts. Similarly, sequences from cyanophages infecting Prochlorococcus and Synechococcus spp. were readily discriminated, as were sequences from podoviruses and myoviruses. Viral psbA sequences from the same geographic origins clustered within different clades. For example, cyanophage psbA sequences from the Arctic Ocean fell within the Synechococcus as well as Prochlorococcus phage groups. Moreover, as psbA sequences are not confined to a single family of phages, they provide an additional genetic marker that can be used to explore the diversity and evolutionary history of cyanophages in aquatic environments.


Variation and decomposition of the partial molar volume of small gas molecules in different organic solvents derived from molecular dynamics simulations.
The partial molar volumes, V(i), of the gas solutes H2, CO, and CO2, solvated in acetone, methanol, heptane, and diethylether are determined computationally in the limit of infinite dilution and standard conditions. Solutions are described with molecular dynamics simulations in combination with the OPLS-aa force field for solvents and customized force field for solutes. V(i) is determined with the direct method, while the composition of V(i) is studied with Kirkwood-Buff integrals (KBIs). Subsequently, the amount of unoccupied space and size of pre-formed cavities in pure solvents is determined. Additionally, the shape of individual solvent cages is analyzed. Calculated V(i) deviate only 3.4 cm(3) mol(-1) (7.1%) from experimental literature values. Experimental V(i) variations across solutions are reproduced qualitatively and also quantitatively in most cases. The KBI analysis identifies differences in solute induced solvent reorganization in the immediate vicinity of H2 (<0.7 nm) and solvent reorganization up to the third solvation shell of CO and CO2 (<1.6 nm) as the origin of V(i) variations. In all solutions, larger V(i) are found in solvents that exhibit weak internal interactions, low cohesive energy density and large compressibility. Weak internal interactions facilitate solvent displacement by thermal solute movement, which enhances the size of solvent cages and thus V(i). Additionally, attractive electrostatic interactions of CO2 and the solvents, which do not depend on internal solvent interactions only, partially reversed the V(i) trends observed in H2 and CO solutions where electrostatic interactions with the solvents are absent. More empty space and larger pre-formed cavities are found in solvents with weak internal interactions, however, no evidence is found that solutes in any considered solvent are accommodated in pre-formed cavities. Individual solvent cages are found to be elongated in the negative direction of solute movement. This wake behind the moving solute is more pronounced in case of mobile H2 and in solvents with weaker internal interactions. However, deviations from a spherical solvent cage shape do not influence solute-solvent radial distribution functions after averaging over all solvent cage orientations and hence do not change V(i). Overall, the applied methodology reproduces V(i) and its variations reliably and the used V(i) decompositions identify the underlying reasons behind observed V(i) variations.


Adherence with immunosuppressive treatment after transplantation: results from the French trial PREDICT.
Although immunosuppressive therapy after organ transplantation is paramount for long-term outcomes, patients do not comply with their immunosuppressive treatment as much as might be expected. In this observational study, patients having undergone a kidney or liver transplantation were enrolled. Adherence was evaluated by patients using the compliance evaluation test and by physicians using a visual analogic scale. A linear regression was performed to identify determinants of adherence. Less patients having undergone kidney transplantation (27%) described themselves as good compliers than liver transplanted patients (40%). Discrepancy was noted between the physician and patient assessments. Rates of good adherence were significantly different depending on gender, age at transplantation, retransplantation, and time elapsed since transplantation, in at least one of the groups evaluated (whole cohort, kidney liver transplantation groups). In all three groups, adherence decreased with the number of immunosuppressants prescribed. In the whole cohort, the rate of good adherence was significantly higher in patients taking lower number of immunosuppressive drugs (45% for 1 vs. 24% for 3 immunosuppressants; p = 0.02). In this study, which is the first study of this scale in France, we confirmed that adherence with immunosuppressant treatment was low and that simpler treatment regimens may favor adherence.


Seasonal, environmental and individual effects on hypoxia tolerance of eastern sand darter (Ammocrypta pellucida).
Metabolic rate and hypoxia tolerance are highly variable among individual fish in a stable environment. Understanding the variability of these measures in wild fish populations is critical for assessing adaptive potential and determining local extinction risks as a result of climate-induced fluctuations in temperature and hypoxic conditions. We assessed the field metabolic rate (FMR) and two hypoxia tolerance metrics, oxygen pressure at loss of equilibrium (PO2 at LOE) and critical oxygen tolerance (Pcrit) of wild-captured eastern sand darter (Ammocrypta pellucida), a threatened species in Canada, using field trials (June to October) that encompassed ambient water temperatures and oxygen conditions typically experienced by the species. Temperature was significantly and positively related to hypoxia tolerance but not FMR. Temperature alone explained 1%, 31% and 7% of the variability observed in FMR, LOE, and Pcrit, respectively. Environmental and fish-specific factors such as reproductive season and condition explained much of the residual variation. Reproductive season significantly affected FMR by increasing it by 159-176% over the tested temperature range. Further understanding the impact of reproductive season on metabolic rate over a temperature range is crucial for understanding how climate change could impact species fitness. Among-individual variation in FMR significantly increased with temperature while among-individual variation in both hypoxia tolerance metrics did not. A large degree of variation in FMR in the summer might allow for evolutionary rescue with increasing mean and variance of global temperatures. Findings suggest that temperature may be a weak predictor in a field setting where biotic and abiotic factors can act concurrently on variables that affect physiological tolerance.


Stimulation of rat liver mitochondrial fusion by an outer membrane-derived aluminum fluoride-sensitive protein fraction.
In normal livers, hepatocytes contain a large number of spheroidal mitochondria. Mitochondrial morphology changes drastically in liver disease, but the underlying fusion-fission mechanisms are not known. We detected GTP- and aluminum fluoride-dependent membrane fusion events between rat liver mitochondria. Separation of outer mitochondrial membrane-derived proteins led to a subfraction containing a 60-kDa protein band that is detected by specific antibodies directed to common amino acid sequences of the GTP-binding site or carboxyl-terminus of eukaryotic heterotrimeric G-protein alpha subunits. Addition of this subfraction and aluminum fluoride to permeabilized rat hepatocytes triggered a substantial morphological change in hepatic mitochondria, giving them the three-dimensional appearance of a tubulovesicular network. Comparative stereology using electron and confocal microscopy showed that these morphological changes represent true mitochondrial fusion. Addition of aluminum fluoride alone induces a more limited change in mitochondrial morphology, from spheroidal organelles to short rods. Mitochondria maintained their normal membrane potential and overall membrane ultrastructure after all these morphological changes. Our results reveal that mammalian liver mitochondria contain proteins that stimulate mitochondrial fusion and suggest that members of the GTPase superfamily control the normalcy of mitochondrial morphology, which is closely linked to physiological cellular energetics.


Bioactivity-guided identification and cell signaling technology to delineate the lactate dehydrogenase A inhibition effects of Spatholobus suberectus on breast cancer.
Aerobic glycolysis is an important feature of cancer cells. In recent years, lactate dehydrogenase A (LDH-A) is emerging as a novel therapeutic target for cancer treatment. Seeking LDH-A inhibitors from natural resources has been paid much attention for drug discovery. Spatholobus suberectus (SS) is a common herbal medicine used in China for treating blood-stasis related diseases such as cancer. This study aims to explore the potential medicinal application of SS for LDH-A inhibition on breast cancer and to determine its bioactive compounds. We found that SS manifested apoptosis-inducing, cell cycle arresting and anti-LDH-A activities in both estrogen-dependent human MCF-7 cells and estrogen-independent MDA-MB-231 cell. Oral herbal extracts (1 g/kg/d) administration attenuated tumor growth and LDH-A expression in both breast cancer xenografts. Bioactivity-guided fractionation finally identified epigallocatechin as a key compound in SS inhibiting LDH-A activity. Further studies revealed that LDH-A plays a critical role in mediating the apoptosis-induction effects of epigallocatechin. The inhibited LDH-A activities by epigallocatechin is attributed to disassociation of Hsp90 from HIF-1α and subsequent accelerated HIF-1α proteasome degradation. In vivo study also demonstrated that epigallocatechin could significantly inhibit breast cancer growth, HIF-1α/LDH-A expression and trigger apoptosis without bringing toxic effects. The preclinical study thus suggests that the potential medicinal application of SS for inhibiting cancer LDH-A activity and the possibility to consider epigallocatechin as a lead compound to develop LDH-A inhibitors. Future studies of SS for chemoprevention or chemosensitization against breast cancer are thus warranted.


Two unusual budding bacteria isolated from a swimming pool.
Two unusual strains of budding bacteria were isolated on a Millipore Pseudomonas Count Water Tester during routine monitoring of Pseudomonas aeruginosa counts in a swimming pool. The first isolate has been identified as Blastobacter sp. It was a yellow-pigmented, Gram negative rod-shaped organism with a polar holdfast by which it attached to solid surfaces or other cells to form rosettes. The cells reproduced by asymmetric division or budding at the free pole of the cell, producing motile daughter cells with a single polar flagellum. The second isolate, which has not yet been identified, was a red-pigmented, Gram negative rod-shaped organism which produced one or more buds at each pole of the cell. Cell division appears to occur by both binary fission and by budding. Both organisms were strict aerobes, catalase and oxidase positive and did not produce acid from glucose in Hugh and Leifson medium.


Suppression of bremsstrahlung losses from relativistic plasma with energy cutoff.
We study the effects of redistributing superthermal electrons on bremsstrahlung radiation from hot relativistic plasma. We consider thermal and nonthermal distribution of electrons with an energy cutoff in the phase space and explore the impact of the energy cutoff on bremsstrahlung losses. We discover that the redistribution of the superthermal electrons into lower energies reduces radiative losses, which is in contrast to nonrelativistic plasma. Finally, we discuss the possible relevance of our results for open magnetic field line configurations and prospects of the aneutronic fusion based on proton-boron-11 (p-B11) fuel.


Adnexal masses and pregnancy: a 12-year experience.
Our purpose was to describe pregnancy-associated adnexal masses in eastern North Carolina. A retrospective study was performed of 60 adnexal masses resected during pregnancy at a regional referral hospital from January 1990 to March 2002. Adnexal masses occurred in 0.15% of pregnancies. Average gestational age at diagnosis and surgery was 12 and 20 weeks, respectively. Fifty percent of ovarian tumors were mature cystic teratomas, 20% were cystadenomas, and 13% were functional ovarian cysts. Malignancy occurred in 13%. Tumors with low malignant potential comprised 63% of malignancies. Average cyst size was 11.5 cm for malignancies and 7.6 cm for benign lesions (P value <.05). The preterm birth rate was 9%, the miscarriage rate was 4.7% after elective cases, and average Apgar scores were 7.5 and 8.7 at 1 and 5 minutes. The incidence of malignancy in pregnancy-associated adnexal masses was high. Ultrasonography detected internal excrescences in the majority of tumors with low malignant potential. Fetal outcomes were not affected.


Implementation of an intervention to improve the adoption of asthma self-management practices in Peru: Asthma Implementation Research (AIRE) randomized trial study protocol.
Asthma is the most common chronic disease among children worldwide, with 80% of asthma-related deaths occurring in low- and middle-income countries (LMICs). While evidence-based guidelines exist for asthma treatment and management, adoption of guideline-based practices is low in high-income country and LMIC settings alike. While asthma prevalence among children and adolescents in Lima, Peru is in the range of 13%-19.6%, our data suggest that < 5% of children in low-resource communities are currently taking guideline-based therapies. There is an urgent need for effective, locally tailored solutions to address the asthma treatment gap in low-income communities in Peru. This study aims to develop and test a locally adapted intervention package to improve adoption of self-management practices and utilization of preventive health services for asthma among children in Lima Norte. The intervention package was designed using a systematic, theory-based framework (Capability, Opportunity, Motivation - Behavior Framework) and is rooted in a multi-phased formative research approach. The main study design is an individually randomized implementation-effectiveness hybrid trial enrolling 110 children aged 5-17 years with asthma and their caregivers. Families allocated to the treatment group receive the supported self-management intervention package, while families allocated to the control group receive the standard of care plus asthma education. We will follow participants monthly for six months and evaluate asthma control (Asthma Control Test), healthcare utilization, and medication adherence (Adherence to Refills and Medications Scale). Disease-specific quality of life for children (Pediatric Asthma Quality of Life Questionnaire) and caregivers (Pediatric Asthma Caregiver's Quality of Life Questionnaire) will be evaluated at baseline, 3 months, and 6 months. We will also evaluate acceptability, feasibility, and fidelity of the intervention using mixed methods approaches. The long-term goal of this study is to disseminate locally appropriate asthma management strategies in LMIC settings. This study will contribute to the body of knowledge surrounding approaches for developing and evaluating intervention strategies for asthma using systematic, theory-based approaches grounded in local context. Such strategies have the potential to inform the development and adaptation of appropriate and scalable solutions for asthma management in LMIC settings. ClinicalTrials.gov, NCT03986177. Registered on 14 June 2019.


Extent of transcription of mouse sarcoma-leukemia virus by RNA-directed DNA polymerase.
The DNA product obtained from the endogenous RNA-directed DNA polymerase (deoxynucleosidetriphosphate:DNA deoxynucleotidyltransferase, EC 18.104.22.168) reaction of the Moloney sarcoma:leukemia viruses produced by the 78 A-1 cell line was analyzed and characterized. The extent of transcription of viral 70S RNA was measured by RNA.DNA hybridization ((32)P-viral RNA-(3)H product DNA). No double-stranded DNA was obtained. The product consisted of 95-99% single-stranded DNA with an average length of 200 nucleotides. In contrast to the results reported with avian and other RNA oncogenic viruses, it was found that the entire 70S viral RNA genome was transcribed into DNA pieces and that a small excess of the product DNA was sufficient to anneal the 70S RNA and render it totally resistant to single-stranded-specific enzyme digestion.


Mitogenic effect of L-dopa on human periodontal ligament fibroblast cells.
In cases of tooth avulsion, immediate replantation is the treatment of choice. In the event of any problem, the tooth should be stored in a medium that supports the periodontal ligament cell viability. Theoretically, mitotic promoting agents may be of use to preserve cell viability. It has previously been reported that levodopa (L-dopa) accelerates healing by increasing the growth hormone level. In this study, the direct effect of L-dopa was investigated on human periodontal ligament fibroblast (HPLF) cells. Cell culture methods were used to assess the potential mitogenic effect of L-dopa. Results show that in low concentrations of L-dopa (1 microgram/microl in this study), the number of HPLF cells were remarkably higher than the control group, and the number of viable cells were not affected by increasing the L-dopa concentration in the range of the study. These results suggest that L-dopa can also have a direct local effect on the growth of HPLF cells. These results may be of use clinically to increase the viability of HPLF cells in cases of an avulsed tooth preserved in storing medium.


Main Aspects of Pharmaceutical Development of In situ Immunobiological Drugs for Intranasal Administration.
The review presents the latest developments in the area of intranasal in situ delivery systems of immunobiological drugs (IBDs). Interest in intranasal administration for IBDs has increased significantly due to the COVID-19 pandemic. However, not only intranasal delivery of vaccines is developing, but also bacteriophages, interferons, etc. In situ systems that make a selective phase transition can be a modern solution to intranasal delivery problems caused by mucociliary clearance. In addition, smart-polymers used as the main excipients in in situ systems can be used as specific adjuvants. A scientific search was conducted on the PubMed database of medical publications for the period from 2000 to 2022, using the keywords "intranasal in situ vaccine"; "intranasal in situ immunization". There were analyzed in detail more than 70 scientific studies on intranasal in situ delivery of IBDs. Despite the large number of new studies, the potential of possibilities of intranasal in situ systems is not being realized. Based on the results of the literature review an algorithm was created for the development of in situ systems for intranasal delivery of IBDs. Such algorithms and the methods of study design organization described in the review will help to facilitate the R&D process and bring the drug to commercial market, which will help to improve the quality of medical care.


[Aids in Madagascar. II. Intervention policy for maintaining low HIV infection prevalence].
The HIV seroprevalence per 100,000 adults Malagasy rose from 20 in 1989, to 30 in 1992, and to 70 in 1995. In that year, the total number of HIV infected people in the Big Island was estimated at 5,000, the number of people sick with AIDS at 130, and the people at risk at more than 1,000,000. The latter are the persons infected with other STDs and individuals (or their partners) with risky sexual behaviour (e.g. numerous sexual partners, occasional sexual partners, and/or sexual contacts with commercial sex workers). The HIV prevalence rate is low as compared with those of other countries. Nevertheless, the spread of the HIV infection is alarming in some parts of the country and the risk factors are also present, namely: the high prevalence of STDs, numerous sexual partners, the low use of condoms in all groups, the development of tourism, the development of prostitution associated with social and economical problems, and internal and international migrations (with risky sexual contacts). Therefore, the still low but rising HIV prevalence in 1995 does not warrant complacency. To estimate the trend of HIV prevalence within the population, it is useful to know two different assumptions, as follows: firstly, a controlled evolution of the epidemic (low epidemic) and secondly, a very fast spread of the epidemic (high epidemic). If we consider the 5,000 individuals seropositive in July 1995, the Aids Impact Model (AIM) projection model shows that HIV seroprevalence rates among adults in 2015 might be between 3% (when the progression course of HIV epidemic is low) and 15% (when the progression course of HIV epidemic is high). By 2015 AIDS could have severe demographic, social, and economic impacts. Then, it is necessary to take measures to prevent contamination. Five major interventions are required: public information about AIDS, HIV transmission mechanism, and its prevention, communities education via the respected people and the notabilities to promote moral values, reduce the number of sexual partners, delay visit of sexual activity, and advice for infected couples; screening of blood donors and the supposed high risk group; control of STDs; reduction of the number of sexual partners; promotion of condom use, abstinence, and fidelity. To sum up, the fight against AIDS is not only the health professional workers' problem. It concerns all Malagasy people. Therefore, successfullness in prevention efforts to slow the epidemic needs concerted, collective, and long lasting actions from all sectors of the society for the nation's future and the well-being of the rising generations.


Prevalence and determinants of iron deficiency in cardiac amyloidosis.
Iron deficiency (ID) is common in patient with chronic heart failure (HF) and has been widely studied. In contrast, data concerning ID in cardiac amyloidosis (CA) are limited. Amyloidosis is a severe and fatal systemic disease, characterized by an accumulation of amyloid fibrils in various tissues/organs, including nerves, kidneys, gastrointestinal tract, and heart. Amyloid deposits in the heart eventually cause HF. The main subtypes of CA are light chain (AL), hereditary transthyretin (ATTRv), and wild-type transthyretin (ATTRwt). We performed this study to determine the prevalence, clinical outcome (all-cause mortality), and determinants of ID among the three main subtypes of CA. Iron deficiency status were analysed in 816 CA patients enrolled at the French Referral Centre for Cardiac Amyloidosis: 271 (33%) had AL, 164 (20%) ATTRv, and 381 (47%) ATTRwt. ID affected 49% of CA patients, 45% with AL, 58% with ATTRv, and 48% with ATTRwt. We identified ATTR status (ATTRv P = 0.003, ATTRwt P = 0.037), diabetes (P = 0.003), aspirin treatment (P = 0.009), haemoglobin levels (P = 0.006), and altered global longitudinal strain (P = 0.02) as independent ID determinants. There is no difference in all-cause mortality considering ID status. Iron deficiency is common in patients with CA, irrespective of the subtype. Patients seem more likely to have ID if diagnosed with ATTR, if diabetic, and/or treated with aspirin. In CA, the benefit of intravenous iron therapy, for ID, on morbidity and mortality needs further study.


"In Vitro" Study About Variables that Influence in Arch Friction with Conventional and Self-Ligating Brackets.
Many advantages have been described surrounding self-ligating (SL) brackets compared to metallic conventional ligating (CL) brackets, such as: Less total treatment time, alignment efficiency, patient comfort, plaque retention, and low friction. The objective of this in vitro simulation was to know the variables that affect arch displacement in CL and SL brackets-active (ASL) and passive (PSL)-and analyze if static friction values are affected by bracket design, arch wire section, kind of ligature, and use of a friction reducer agent (FRA) in a wet state. Larger values of static friction were found in CL with metallic ligature (ML) (8.01 ± 1.08 N/mm) and elastic ligature (EL) (6.96 ± 0.48 N/mm). Lower values were found in PSL brackets combined with FRA (0.58 ± 0.21 N/mm). The study was carried out using different stereographical models of a maxillary upper right quadrant with canine, first and second premolar, and first molar bonded brackets. A section of 25 mm of 0.019 × 0.025" stainless steel arch with a rectangular section (SS) and hybrid section (HY) was inserted into the different bracket models. Static friction values were collected using a universal test machine in wet conditions and testing the effect of a friction reducer agent (FRA). To assure the reliability of the study, different wire combinations were repeated after two weeks by the same operator and a linear analysis of regression was done. Each bracket model analysis-with the different wires, use of the FRA, and comparison among brackets in similar conditions-was done using an ANOVA test with a confidence interval of 95% and comparative Post-Hoc tests (LSD). In this in vitro simulation we found higher static friction values in CL compared to ASL and PSL. In PSL, lower values were achieved. CL brackets using ML showed the highest static friction values with a great variability. In this setting, the use of HY wires did not reduce static friction values in ASL and PSL, while in CL brackets with EL friction the values were reduced significantly. An FRA combined with ASL reduced significantly static friction values but not with PSL. In the case of CL, the FRA effect was higher with SS and better than with HY wires. ML values were similar to ASL static friction. The direct extrapolation of the results might be inaccurate, since all these findings should be tested clinically to be validated.


The role of action readiness in motivated behavior.
According to many theories of motivation and decision making, the principal driver of human behavior is the valuation of actions. Action value is computed as the difference between stimulus value (the benefits and costs inherent in the stimulus that is the target of the action) and action costs (the effort required to perform the action). In the present work, we propose that action costs are crucially influenced by the readiness to perform a given action. We define action readiness as the ease with which an action may be initiated given the preaction launch state of the individual. An action that has been frequently or recently performed or rehearsed has a high level of action readiness, whereas an action that has not been frequently or recently performed or rehearsed has a low level of action readiness. By our account, if action readiness levels are high for a given action, decreased action costs may result in action even when the stimulus value is relatively low. Conversely, if action readiness levels are low for a given action, even action costs that appear negligible can dominate positive stimulus values, resulting in seemingly puzzling instances of inaction. We develop and test these ideas in 3 studies across 233 participants using an image-viewing decision context and a logistic prediction model.


Effectiveness of multiple-dose activated charcoal in lamotrigine poisoning: a case series.
Lamotrigine toxicity can cause coma, seizures, and intraventricular conduction disturbances, and treatment options include good supportive care. We report two cases of lamotrigine poisoning in which multiple-dose activated charcoal may have shortened the elimination half-life of lamotrigine. A 21-year-old woman ingested 15.6 g lamotrigine, 14 g levetiracetam, and 15 mg clonazepam. She became comatose and developed generalized tonic seizure. One hour post-ingestion, 50 g activated charcoal was administered. Starting 11 h post-ingestion, 25 g activated charcoal was administered every 4 h for 4 doses. The peak concentration of serum lamotrigine was 49.5 µg/mL, and the elimination half-life after commencement of multiple-dose activated charcoal was 6.5 h. A 46-year-old woman ingested 0.3 g lamotrigine and 0.1 g topiramate twice, 2 h apart. She became drowsy, complained of blurred vision, vertigo, nausea, and vomited. An initial dose of 50 g activated charcoal was administered at 4.5 h post-second ingestion, and subsequent doses of 25 g (total of 3 doses) were administered every 4 h, commencing at 8.5 h post-second ingestion. The peak concentration of serum lamotrigine was 19.9 µg/mL, and the elimination half-life after commencement of multiple-dose activated charcoal was 9.3 h. The mean elimination half-life of lamotrigine in healthy volunteers and epileptic patients receiving lamotrigine monotherapy is 22.8-37.4 h. In our two cases, multiple-dose activated charcoal may have shortened the elimination half-life of lamotrigine, possibly by inhibiting enterohepatic circulation. Multiple-dose activated charcoal should be considered an option for treating lamotrigine poisoning.


Phosphine-catalyzed formal Buchner [6+1] annulation: de novo construction of cycloheptatrienes.
An unprecedented phosphine-catalyzed formal Buchner [6+1] annulation of a newly designed allenoate has been developed, providing a series of cycloheptatriene derivatives in moderate to good yields (up to 99%). This reaction demonstrates that the introduction of an electrophilic allylic group to allenoates effectively extends the reaction scope of phosphine-catalyzed annulation, providing a concise route to cycloheptatrienes. Mechanistic study indicated that this reaction involves a [4+2] Diels-Alder reaction and ring expansion of the bicyclo[4.1.0] moiety, which is similar to the Buchner reaction. Notably, an enantioselective variant of this [6+1] annulation can also be performed using a chiral iminophosphine catalyst.


Pathophysiological interactions between sarcopenia and type 2 diabetes: A two-way street influencing diagnosis and therapeutic options.
This review will try to elucidate the interconnected pathophysiology of sarcopenia and type 2 diabetes (T2D) and will try to identify a common pathway to explain their development. To this end, the PubMed and Scopus databases were searched for articles published about the underlying pathophysiology, diagnosis and treatment of both sarcopenia and T2D. The medical subject heading (MeSH) terms 'sarcopenia' AND 'diabetes mellitus' AND ('physiopathology' OR 'diagnosis' OR 'therapeutics' OR 'aetiology' OR 'causality') were used. After screening, 32 papers were included. It was evident that sarcopenia and T2D share multiple pathophysiological mechanisms. Common changes in muscle architecture consist of a shift in myocyte composition, increased myosteatosis and a decreased capacity for muscle regeneration. Further, both diseases are linked to an imbalance in myokine and sex hormone production. Chronic low-grade inflammation and increased levels of oxidative stress are also known pathophysiological contributors. In the future, research efforts should be directed towards discovering common checkpoints in the development of T2D and sarcopenia as possible shared therapeutic targets for both diseases. Current treatment for T2D with biguanides, incretins and insulin may already convey a protective effect on the development of sarcopenia. Furthermore, attention should be given to early diagnosis of sarcopenia within the population of people with T2D, given the sizeable physical and medical burden it encompasses. A combination of simple diagnostic techniques could be used at regular diabetes check-ups to identify sarcopenia at an early stage and start lifestyle modifications and treatment as soon as possible.


AIDS susceptibility in a migrant population: perception and behavior.
Within the framework of the Health Belief Model, this paper examines correlates of perception of AIDS susceptibility among 846 drug-using migrant farm workers and their sex partners. Significant but relatively small differences by ethnicity and gender were found. The data showed a consistent significant statistical relationship between frequency of drug use, high-risk sexual behavior, and perception of AIDS susceptibility. Perception of AIDS susceptibility was significantly related to a subsequent reduction in sexual risk behaviors. Consistent with the Health Belief Model, the data suggest that increasing perception of AIDS susceptibility may be an important motivator in reducing high-risk behaviors.


Novel red phosphorescent polymers bearing both ambipolar and functionalized Ir(III) phosphorescent moieties for highly efficient organic light-emitting diodes.
A series of novel red phosphorescent polymers is successfully developed through Suzuki cross-coupling among ambipolar units, functionalized Ir(III) phosphorescent blocks, and fluorene-based silane moieties. The photophysical and electrochemical investigations indicate not only highly efficient energy-transfer from the organic segments to the phosphorescent units in the polymer backbone but also the ambipolar character of the copolymers. Benefiting from all these merits, the phosphorescent polymers can furnish organic light-emitting diodes (OLEDs) with exceptional high electroluminescent (EL) efficiencies with a current efficiency (η L ) of 8.31 cd A(-1) , external quantum efficiency (η ext ) of 16.07%, and power efficiency (η P ) of 2.95 lm W(-1) , representing the state-of-the-art electroluminescent performances ever achieved by red phosphorescent polymers. This work here might represent a new pathway to design and synthesize highly efficient phosphorescent polymers.


Modeling static and dynamic thermography of the human breast under elastic deformation.
An abnormal thermogram has been shown to be a reliable indicator of increased risk of breast cancer. Numerical modeling techniques for thermography are proposed to quantify the complex relationships between the breast thermal behaviors and the underlying physiological/pathological conditions. Previous thermal modeling techniques did not account for gravity-induced elastic deformation arising from various body postures, nor did they suggest that a dynamic thermal procedure may be used to enhance clinical diagnosis. In this paper, 3D finite element method (FEM)-based thermal and elastic modeling techniques are developed to characterize comprehensively both the thermal and elastic properties of normal and tumorous breast tissues during static and dynamic thermography. In the steady state, gravity-induced breast deformation is found to cause an upper-lower asymmetric surface temperature contrast for sitting/standing up body posture, even though all the thermal and elastic properties are assumed uniform. Additionally, the tumor-induced surface temperature alterations are found to be caused primarily by shallow tumors and to be less sensitive to tumor size than to tumor depth. In the dynamic state, the breast exhibits distinctive temporal patterns that are associated with distinct thermal events: cold stress and thermal recovery induced by changes in the ambient temperature. Specifically, the tumor-induced thermal contrast shows an opposite initial change and delayed peak as compared with the deformation-induced thermal contrast. These findings are expected to provide a stronger foundation for, and greater specificity and precision in, thermographic diagnosis, and treatment of breast cancer.


Diabetes market grows ever more crowded.
Global prevalence of type-2 diabetes is expected to reach 330 million cases by 2022, with medication sales of $67.7 billion. The market is crowded with generic medications, and most products now in the development pipeline are "me-too" drugs.


A new cutthroat eel of the genus Synaphobranchus (Anguilliformes: Synaphobranchidae) from Taiwan.
A new species of the cutthroat eel genus Synaphobranchus is described from Taiwan on the basis of 12 types and 11 non-type specimens. The new species can be distinguished from its congeners in having most of its head and abdomen naked, except for a patch of scales behind the eye, dorsal surface of trunk naked or covered by scattered scales; scales oval in shape; dorsal fin slightly before to about opposite to origin of anal fin; mean vertebral formula 28-28-131, precaudal vertebrae 50-56, total vertebrae 124-135. Comments of the congeners occurred in adjacent regions are provided.


Distributed Online Learning With Multiple Kernels.
We consider the problem of learning a nonlinear function over a network of learners in a fully decentralized fashion. Online learning is additionally assumed, where every learner receives continuous streaming data locally. This learning model is called a fully distributed online learning (or a fully decentralized online federated learning). For this model, we propose a novel learning framework with multiple kernels, which is named DOMKL. The proposed DOMKL is devised by harnessing the principles of an online alternating direction method of multipliers and a distributed Hedge algorithm. We theoretically prove that DOMKL over T time slots can achieve an optimal sublinear regret O(√T) , implying that every learner in the network can learn a common function having a diminishing gap from the best function in hindsight. Our analysis also reveals that DOMKL yields the same asymptotic performance as the state-of-the-art centralized approach while keeping local data at edge learners. Via numerical tests with real datasets, we demonstrate the effectiveness of the proposed DOMKL on various online regression and time-series prediction tasks.


ICECAP: an integrated, general-purpose, automation-assisted IC50/EC50 assay platform.
IC50 and EC50 values are commonly used to evaluate drug potency. Mass spectrometry (MS)-centric bioanalytical and biomarker labs are now conducting IC50/EC50 assays, which, if done manually, are tedious and error-prone. Existing bioanalytical sample preparation automation systems cannot meet IC50/EC50 assay throughput demand. A general-purpose, automation-assisted IC50/EC50 assay platform was developed to automate the calculations of spiking solutions and the matrix solutions preparation scheme, the actual spiking and matrix solutions preparations, as well as the flexible sample extraction procedures after incubation. In addition, the platform also automates the data extraction, nonlinear regression curve fitting, computation of IC50/EC50 values, graphing, and reporting. The automation-assisted IC50/EC50 assay platform can process the whole class of assays of varying assay conditions. In each run, the system can handle up to 32 compounds and up to 10 concentration levels per compound, and it greatly improves IC50/EC50 assay experimental productivity and data processing efficiency.


Pulp Stones, Prevalence and Distribution in an Iranian Population.
This study determined the prevalence and distribution of pulp stones in the permanent dentition of an adult population using their periapical radiographs. The study followed a cross-sectional design. A total of 800 periapical radiographs collected from 412 patients attending dental clinics in Kerman, Islamic Republic of Iran, were examined using magnification. Pulp stones were present in 9.6% of all permanent teeth examined, being most common in maxillary first and second molars, followed by mandibular first and second molars. They were present in 31.5% of all adult patients, with a significantly increased prevalence in females compared with males (40.5 vs 23.9%, chi-squared test p < 0.001). There was also an increased prevalence with age. Based on the results of this study, clinicians should expect to encounter pulp stones most commonly in the pulp chambers of maxillary first and second molars, particularly in older female patients. Pulp stones depending on their size and location can pose challenges to endodontic treatment. They obstruct access to the canal orifices and thus complicate endodontic treatment. Knowing where and when pulp stones are likely to occur improves the quality of root canal treatments.


Mirvetuximab soravtansine for platinum-resistant epithelial ovarian cancer.
Mirvetuximab soravtansine (mirvetuximab) is an antibody drug conjugate (ADC) comprised of a humanized folate receptor alpha (FRα)-binding monoclonal antibody attached via a cleavable linker to the cytotoxic maytansinoid molecule, DM4. FRα is expressed in several epithelial cancers, including high grade serous ovarian cancer (HGSOC). Mirvetuximab received accelerated approval by the United States Food and Drug Administration (FDA) in November 2022 based on the results of the SORAYA trial, which tested mirvetuximab for the treatment of patients with recurrent platinum resistant HGSOC with high FRα expression and showed an overall response rate (ORR) of 32.4% and a median duration of response of 6.9 months. Mirvetuximab toxicities included low grade ocular and gastrointestinal toxicities. The National Comprehensive Cancer Network (NCCN) ovarian cancer 2023 guidelines adopted mirvetuximab as 2A, and mirvetuximab combined with bevacizumab as 2B, recommendations. This manuscript will review the preclinical and clinical development of mirvetuximab, the toxicities associated with mirvetuximab and mitigation strategies, and future applications of mirvetuximab. Mirvetuximab represents the first biomarker-directed therapy with an indication specifically for the treatment of PROC. The efficacy and favorable safety profile support further development of mirvetuximab and mirvetuximab combinations in platinum sensitive and newly diagnosed ovarian cancer.


Prevalence of cervical insufficiency in polycystic ovarian syndrome.
Pregnant women with polycystic ovarian syndrome (PCOS) experience a greater rate of adverse obstetrical outcomes compared with non-PCOS women. We examined the prevalence and incidence of cervical insufficiency (CI) in a community cohort of pregnant women with and without PCOS. A retrospective cohort study was conducted within a large integrated health care delivery system among non-diabetic PCOS women with second or third trimester delivery during 2002-2005 (singleton or twin gestation). PCOS was defined by Rotterdam criteria. A non-PCOS comparison group matched for delivery year and hospital facility was used to estimate the background rate of CI. Women were designated as having new CI diagnosed in the index pregnancy (based on cervical dilation and/or cervical shortening) and prior CI based on prior diagnosis of CI with prophylactic cerclage placed in the subsequent pregnancy. We identified 999 PCOS women, of whom 29 (2.9%) had CI. There were 18 patients with new CI and 11 with prior CI having prophylactic cerclage placement; four CI patients had twin gestation. In contrast, only five (0.5%) non-PCOS women had CI: two with new CI and three with prior CI. The proportion of newly diagnosed incident CI (1.8 versus 0.2%) or prevalent CI (2.9 versus 0.5%) was significantly greater for PCOS compared with non-PCOS pregnant women (both P < 0.01). Among PCOS women, CI prevalence was particularly high among South Asians (7.8%) and Blacks (17.5%) compared with Whites (1%) and significantly associated with gonadotropin use (including in vitro fertilization). Overall, the PCOS status was associated with an increased odds of prevalent CI pregnancy (adjusted odds ratio 4.8, 95% confidence interval 1.5-15.4), even after adjusting for maternal age, nulliparity, race/ethnicity, body mass index and fertility treatment. In this large and ethnically diverse PCOS cohort, we found that CI occurred with a higher than expected frequency in PCOS women, particularly among South Asian and Black women. PCOS women with CI were also more likely to have received gonadotropin therapy. Future studies should examine whether natural and hormone-altered PCOS is a risk factor for CI, the role of race/ethnicity, fertility drugs and consideration for heightened mid-trimester surveillance in higher risk subgroups of pregnant women with PCOS.


Lipid peroxidation and antioxidant status in the liver, erythrocytes, and serum of rats after methanol intoxication.
Lipid peroxidation products measured as a malondialdehyde and activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), and concentrations of ascorbic acid, alpha-tocopherol, and glutathione (GSH) were measured in the liver, erythrocytes, and serum of rats 6, 14, and 24 h and 2, 5, and 7 d after treatment with 3 g methanol/kg. GSH-Px and GSSG-R activities, GSH level, and ascorbate concentration in the liver, erythrocytes, and blood serum were significantly decreased. In addition, SOD and alpha-tocopherol in erythrocytes were diminished, while malondialdehyde (MDA) in liver, erythrocytes, and serum were elevated. Further, erythrocyte counts, hemoglobin levels, hematocrit, and mean corpuscular volume (MCV) were reduced. These results indicate that methanol intoxication in rats leads to an increase in the lipid peroxidation and impairment in the antioxidant mechanisms in liver, erythrocytes, and blood serum.


Effects of Face-to-Face and Telephone-Based Family-Oriented Education on Self-Care Behavior and Patient Outcomes in Type 2 Diabetes: A Randomized Controlled Trial.
Education of patients and their families is the cornerstone of effective diabetes care. The present study aimed to compare the effects of a face-to-face and telephone-based family-oriented educational program on self-care behavior and patient outcomes in type 2 diabetes patients. In the present randomized controlled trial, 90 type 2 diabetes patients were randomly divided into three groups of 30 participants: a face-to-face education group, a telephone-based education group, and a control group. The educational program lasted for 3 months. Outcomes evaluated included self-care, fasting blood sugar, hemoglobin A1c, cholesterol, and triglyceride. The overall self-care scores in the intervention groups were significantly higher than that in the control group (P = 0.0001). In addition, lipid profiles significantly improved in the interventions compared to the control (P < 0.05). Comparing the two interventions showed better results for the face-to-face group regarding dietary adherence and physical activity, but the latter group had comparable results in blood glucose monitoring, foot care, and cholesterol level. This study shows the beneficiary effects of a family-oriented education on self-care and patient outcomes. It also shows the potential value of low-cost telephone technology in delivering effective diabetes care.