Inhibition of MG-63 cell cycle progression by synthetic vitamin D3 analogs mediated by p27, Cdk2, cyclin E, and the retinoblastoma protein.
Progression through eukaryotic cell division cycle is regulated by synergistic activities of both positive and negative regulatory factors. The active form of vitamin D(3) (1alpha,25(OH)(2)D(3), 1,25D) and a number of its synthetic analogs have been shown to arrest cells in the G(1) phase of the cell cycle. In the present study, 1alpha,25(OH)(2)D(3) and the analogs KH1060, EB1089, and CB1093 were used to study the mechanism of the cell cycle arrest and to compare the effectiveness of these compounds in human MG-63 osteosarcoma cells. The 20-epi analogs KH1060 and CB1093, as well as the 20-normal analog EB1089, were found to be more potent than 1alpha,25(OH)(2)D(3) in inhibiting cell proliferation and arresting the MG-63 cells in the G(1) phase. These analogs were more active than 1alpha,25(OH)(2)D(3) in increasing the cyclin dependent kinase inhibitor p27 protein levels (approximately 2.3-2.5-fold compared to 1alpha,25(OH)(2)D(3)) by both increasing its formation and decreasing its degradation rate. The increased p27 formation was accompanied by stabilization of binding of nuclear proteins to the Sp1+NF-Y responsive promoter region of the p27 gene. The increase in p27 protein levels and the simultaneous decrease in cyclin E protein levels was accompanied by decreased Cdk2 kinase activity, retinoblastoma (Rb) protein hypophosphorylation and, finally, cell cycle arrest in the G(1) phase. In summary, the analogs KH1060, EB1089, and CB1093 keep Rb protein in its growth-suppressing, hypophosphorylated form and prevent cell cycle progression through the restriction point. Therefore, these synthetic vitamin D(3) analogs may be potential candidates for treating diseases, where cell cycle regulation is needed.


Red blood cell-derived microparticles: An overview.
The red blood cell (RBC) is historically the original parent cell of microparticles (MPs). In this overview, we describe the discovery and the early history of red cell-derived microparticles (RMPs) and present an overview of the evolution of RMP. We report the formation, characteristics, effects of RMP and factors which may affect RMP evaluation. The review examines RMP derived from both normal and pathologic RBC. The pathologic RBC studies include sickle cell anemia (SCA), sickle cell trait (STr), thalassemia intermedia (TI), hereditary spherocytosis (HS), hereditary elliptocytosis (HE), hereditary stomatocytosis (HSt) and glucose-6-phosphate dehydrogenase deficiency (G6PD).


Bacillus cereus, an unusual cause of fulminant liver failure: diagnosis may prevent liver transplantation.
Bacillus cereus is a well-known cause of foodborne disease usually of benign course. Here, we present the case of a 15-year-old boy who developed reversible fulminant liver failure associated with rhabdomyolysis after pasta consumption. Suspecting B. cereus as the aetiological agent may prevent unnecessary liver transplantation.


A universal predictive and mechanistic urinary peptide signature in acute kidney injury.
The delayed diagnosis of acute kidney injury (AKI) episodes and the lack of specificity of current single AKI biomarkers hamper its management. Urinary peptidome analysis may help to identify early molecular changes in AKI and grasp its complexity to identify potential targetable molecular pathways. In derivation and validation cohorts totalizing 1170 major cardiac bypass surgery patients and in an external cohort of 1569 intensive care unit (ICU) patients, a peptide-based score predictive of AKI (7-day KDIGO classification) was developed, validated, and compared to the reference biomarker urinary NGAL and NephroCheck and clinical scores. A set of 204 urinary peptides derived from 48 proteins related to hemolysis, inflammation, immune cells trafficking, innate immunity, and cell growth and survival was identified and validated for the early discrimination (< 4 h) of patients according to their risk to develop AKI (OR 6.13 [3.96-9.59], p < 0.001) outperforming reference biomarkers (urinary NGAL and [IGFBP7].[TIMP2] product) and clinical scores. In an external cohort of 1569 ICU patients, performances of the signature were similar (OR 5.92 [4.73-7.45], p < 0.001), and it was also associated with the in-hospital mortality (OR 2.62 [2.05-3.38], p < 0.001). An overarching AKI physiopathology-driven urinary peptide signature shows significant promise for identifying, at an early stage, patients who will progress to AKI and thus to develop tailored treatments for this frequent and life-threatening condition. Performance of the urine peptide signature is as high as or higher than that of single biomarkers but adds mechanistic information that may help to discriminate sub-phenotypes of AKI offering new therapeutic avenues.


Hierarchical pore structure of calcium phosphate scaffolds by a combination of gel-casting and multiple tape-casting methods.
The objective of this work was to design hierarchical pore structure scaffolds with potential applications in bone tissue regeneration. For that purpose, a bioceramic material such as biphasic calcium phosphate, which consists of a mixture of hydroxyapatite and beta-tricalcium phosphate, was selected. Multilayer pieces (MLP) with hierarchical pore structure were developed employing a new technique that combines gel casting and adding porogens, using multiple tape-casting methods. Pieces with functionally graded porosity were fabricated using porogens with different sizes. The porogens used were Porlat K85 and Porlat K86 with diameters <150 microm and 150-300 microm, respectively. Two types of sintered tapes, with different porosity, no cracking and enough interconnection size were selected. MLP with hierarchical pore structure were designed by the multiple tape-casting method. Interconnected pores whose sizes increase from interior tapes (1.6-3.6 microm) towards exterior tapes (20-51.5 microm) and interpenetration between tapes were achieved. Delamination or cracking were not observed after heat treatment. The flexural strength of pieces was investigated by the three-point bending test. This new combination of methods offers the possibility of manufacturing scaffolds with interconnected pore sizes ranging from 1.6 to 51.5 microm.


Surface enhanced Raman spectroscopy as a new spectral technique for quantitative detection of metal ions.
Four newly synthesized poly (propylene amine) dendrimers from first and second generation modified with 1,8-naphthalimide units in the dendrimer periphery have been investigated as ligands for the detection of heavy metal ions (Al(3+), Sb(2+), As(2+), Cd(2+) and Pb(2+)) by surface-enhanced Raman spectroscopy. Calibration curves were established for all metal ions between the concentration ranges of 1 x 10(-6) to 5 x 10(-4) M. It has been shown that these dendrimers can be coordinated, especially with different metal ions. Using dendrimer molecules and silver colloids at the same time allowed us to obtain an SERS signal from the abovementioned metal ions at very low concentrations. Principle component analysis (PCA) analysis was also applied to the collected SERS data. Four different PCA models were developed to accomplish the discrimination of five metal ions, which interacted with each of the four dendrimer molecules, separately. A detailed investigation was performed in the present study to provide the basis of a new approach for heavy metal detection.


[Analysis a family with partial Xq deletion].
To analyze partial deletion of the long arm of X chromosome in a family and explore the mechanism underlying its phenotypes. G-banding technique was employed to analyze the karyotypes of the subjects, and fluorescence in situ hybridization (FISH) was used to analyze their X chromosomes with Xpter, Xqter and WCPX probes. The karyotypes of the proband, her mother and her fetus were all 46,X,del(X)(q24). Combined FISH and karyotyping analysis suggested that the proband and her fetus both carried a Xq24q27.3 deletion. The Xq24q27.3 deletion carried by the family is closely related with premature ovarian failure but not with short stature, gonadal dysgenesis and primary amenorrhea.


Design of biosolvents through hydroxyl functionalization of compounds with high dielectric constant.
We proposed basic principles for biosolvent design on the viewpoint of ionization. Two classes of biosolvents, based on cyclic carbonate moiety and amide moiety, were designed through hydroxyl functionalization of highly dielectric compound. The newly designed compounds, glycerol carbonate (GC) and N-hydroxymethyl formamide (HOF), were synthesized for the development of soluble enzymatic systems and characterized by (13)C NMR and (1)H NMR. All the characterization data were consistent with the expected structures. Using conductance measurements, the pK (a) values of trichloroacetic acid in GC and HOF were determined as 0.80 and 0.85 at 25.0 °C, which was very close to that in water (pK (a) = 0.70), suggesting that the ionizing and dissociating abilities of GC and HOF are similar to those of water. The effects of various reaction parameters on activity and stability of Candida antarctica lipase B and lipase from Pseudomonas cepacia were investigated using the transesterification of ethyl butyrate with n-butanol as a model reaction. The activities of lipases in GC and HOF were comparable to those in water, indicating that the newly designed compounds were biocompactible. Biosolvent design is a promising and versatile method for developing new biosolvents.


Critical review of non-invasive respiratory monitoring in medical care.
Respiratory failure can be difficult to predict. It can develop into a life-threatening condition in just a few minutes, or it can build up more slowly. Thus continuous monitoring of respiratory activity should be mandatory in clinical, high-risk situations, and appropriate monitoring equipment could be life-saving. The review considers non-invasive methods and devices claimed to provide information about respiratory rate or depth, or gas exchange. Methods are categorised into those responding to movement, volume and tissue composition detection; air flow; and blood gas concentration. The merits and limitations of the methods and devices are analysed, considering information content and their ability to minimise the rate of false alarms and false non-alarms. It is concluded that the field of non-invasive respiratory monitoring is still in an exploratory phase, with numerous reports on specific device solutions but less work on evaluation and adaptation to clinical requirements. Convincing evidence of the clinical usefulness of respiratory monitors is still lacking. Devices responding only to respiratory rate, and lacking information about actual gas exchange, will have limited clinical value. Furthermore, enhancement in specificity and sensitivity to avoid false alarms and non-alarms will be necessary to meet clinical requirements. Miniature CO2 sensors are identified as one route towards substantial improvement.


[Relation of hypertension to diabetic nephropathy in patients with non-insulin-dependent diabetes mellitus--a pair-matched case-control study].
The study aimed to assess the role of hypertension in the cause of nephropathy in patients with NIDDM. A retrospective analysis was done on two groups of non-insulin-dependent diabetes mellitus (NIDDM) patients, one group without proteinuria (< 300 mg/24 h, n = 106) and the other group with proteinuria (> or = 500 mg/24 h, n = 106). The groups were matched by age (< or = +/- 3) years, sex, race, and resident place. Some information of these subjects including demographic, history of disease, family history of diseases, life and behavior style variables were obtained by questionnaire, some variables were measured including systolic blood pressure(SBP), diastolic blood pressure(DBP), fasting blood glucose, and quantity of protein in 24 h urine. Finally the conditional logistic regression analysis was done. Some factors were independently associated with the occurrence risk of diabetic nephropathy (DN) associated history of hypertension, longer duration of hypertension, higher levels of the past highest SBP and DBP. Their corresponding odd ratios(OR) with 95% confidence intervals(CI) were 2.00(1.17-3.43), 1.25(1.08-1.46), 1.38(1.15-1.66), and 1.33(1.09-1.62) respectively. But family history of hypertension was not significantly associated with the development of DN. When the above-mentioned relations were adjusted by some relevant confounding factors, the associations were still present. History and longer duration of hypertension, history of the highest SBP and DBP are independent risk factors for DN.


Optimization of Toxoplasma gondii DNA extraction from amniotic fluid using NucliSENS easyMAG and comparison with QIAamp DNA minikit.
Antenatal diagnosis of congenital toxoplasmosis relies on PCR in amniotic fluid. Because parasitic load is often low, DNA extraction must be optimized. Manual methods remain widespread although automated methods appear more effective. This study aimed at optimizing an automated method and at comparing it with a widespread manual method: QIAamp DNA minikit. To optimize NucliSens easyMAG, we evaluated the addition of proteinase K pre-treatment and the increase of the amount of silica particles used for the extraction. The optimized method was then compared to QIAamp DNA minikit on samples containing less than 25 tachyzoites/ml. NucliSens easyMAG DNA yield was improved after proteinase K pre-treatment (p < 0.01), but not with a higher silica particle input. The optimized method yielded more positive PCRs than the manual method, especially for samples containing 5 tachyzoites/ml or less (71% vs 26%, p < 10(-4)). The DNA amount in samples found positive by PCR was higher after optimized automated extraction than after manual extraction (p < 10(-4)). Proteinase K pre-treatment should be added to extract DNA from amniotic fluid using NucliSens easyMAG. Using this optimized automated method rather than manual methods would improve the sensitivity of Toxoplasma PCR and simplify the daily workflow.


Laparoscopic mediastinal dissection via an open left diaphragm approach for advanced Siewert type II adenocarcinoma.
Around the lower esophagus, the diaphragm obstructs the laparoscopic dissection of mediastinal lymph nodes in surgery for Siewert type II cancer. To address this problem, we developed the open left diaphragm approach. After dissecting the esophageal hiatus along the diaphragm, the anterior mediastinum is dissected along the pericardium. The left side of the mediastinal pleura is then opened and the left diaphragm is incised with a 60-mm linear stapler to create sufficient working space in the lower mediastinum for the lower mediastinal lymph nodes to be resected with a good view. Six patients who received neoadjuvant chemotherapy underwent mediastinal dissection using this technique. The median operative time and estimated blood loss were 479 (390-750) min and 250 (130-500) ml, respectively, and there were no deaths or severe complications. The open left diaphragm approach provides clear surgical space and a good view for performing mediastinal lymph node dissection and is useful for laparoscopic mediastinal dissection and reconstruction.


Selected organizational features of certain Polish health care institutions.
A special feature of the Polish health care system in the 70s was the process toward organizational centralization. This consisted in integrating independent organizational units into larger, more complex ones, and transferring the processes of decision-making to higher management levels. This transition was introduced in 1975. One of its effects was incorporating into one organization all health care systems in a given area, primary care hospitals, specialist care units, laboratory bases, emergency and social welfare agencies and subsuming all these institutions under one management. The ensuing organization was named the Health Care Complex (HCC). It is interesting that in the HCC area other organizations were founded to cover industrial workers. These were called Occupational Health Care Complexes (OHCC). This paper deals with a description of a variety of OHCC organizational structures, an analysis of the relationships between different parameters of organizational structures (leaving aside, however, their casual interpretation), and an examination of the possibilities for applying empirical data to OHCC organizational structural analysis.


Implementation of a universal cervical length screening program: identifying factors associated with decline rates.
Cervical length (CL) measurement is now accepted as a screening strategy for identifying women at risk for preterm birth (PTB). However, patient acceptability may limit its implementation. Our objective was to identify characteristics associated with women who decline this screening. This is a secondary analysis of a prospective cohort study of women offered UCL screening from January 2012 to June 2012. Women with a singleton gestation 18 0/7-23 6/7 weeks at the time of anatomy scan were included. Trained sonographers were instructed to perform UCL screening on all eligible patients using an "opt-out" approach. Chi square statistics and Wilcoxon rank sum tests were used to compare categorical and continuous data, where appropriate. Logistic regression was used to calculate odds ratio for factors associated with declining UCL screening Results: 1348 women were offered CL screening; 131 (9.7%) declined. Overall, multiparous women were more than twice as likely to decline UCL screening compared to primiparous women [OR 2.4 (1.6-3.8)]. Patient acceptance of screening was significantly dependent on the sonographer (p < .05). Multiparous women are less likely to accept this strategy of PTB prevention. A standardized counseling approach may improve patient acceptance and mitigate variability in acceptance rates observed amongst sonographers.


Isolated Metastasis to Spleen-Stomach Space From Follicular Thyroid Cancer Combined With a Benign Subcutaneous Nodule on 18F-FDG PET/CT and 131I Scintigraphy.
A 40-year-old woman with follicular thyroid cancer underwent a systemic PET/CT evaluation before operation and then received total thyroidectomy and radioactive 131I ablation therapy. Posttreatment imaging of 131I whole-body scan with SPECT/CT showed that metastasis on the spleen-stomach space coexists with mimicking subcutaneous metastasis, considering their level of 131I accumulation and morphological changes on PET/CT. However, histopathology confirmed the subcutaneous lesion of fibrous hyperplasia by fine-needle aspiration. This case demonstrates a vital role of SPECT/CT in the diagnosis of metastatic thyroid cancer and mimicking metastasis.


Time-dependent dynamical Bragg diffraction in deformed crystals by the beam propagation method.
This paper describes how to efficiently solve time-dependent X-ray dynamic diffraction problems in distorted crystals with a fast Fourier transform based beam propagation method. Examples are given of using the technique to simulate the propagation of X-ray beams in deformed crystals in space and time domains relevant to the cavity-based X-ray free-electron lasers and X-ray free-electron laser self-seeding systems.


Racial Disparities in Clinical Characteristics and Outcomes of Women Undergoing Percutaneous Coronary Intervention.
Women are underrepresented in cardiovascular clinical studies. Black women have a higher ischemic heart disease mortality risk than their white counterparts. However, there exist limited outcome data comparing black women and white women after percutaneous coronary intervention (PCI). The aim of this retrospective analysis was to evaluate for racial disparities in 1-year major adverse cardiovascular events (MACE) in women undergoing PCI. Within our PCI database, we identified 4776 female patients who underwent PCI between 2003 and 2016. Of those, 1916 were black and 2860 were white. Endpoints included MACE, death, myocardial infarction, target vessel revascularization (TVR) and stent thrombosis (ST) at 30 days and 1 year. A proportional Cox hazard model analysis was performed to assess outcomes after adjustment for confounding factors. Black women presented at a younger age and had a significantly higher prevalence of risk factors. Periprocedural and in-hospital outcomes were similar in the 2 groups. At 30 days and 1 year, the rates of myocardial infarction, TVR and ST were significantly higher in black women. After adjustment for baseline differences, only ST appears to be more likely to occur in black women than in white women. In this large cohort of women with coronary artery disease undergoing PCI, we observed racial disparities primarily in baseline characteristics indicative of need for interventions to achieve early diagnosis and better prevention in black women. Future directions should include efforts to identify and better characterize the factors underlying and contributing to cardiovascular outcomes in women after PCI. In this real-world analysis from a large cohort of women with coronary artery disease undergoing percutaneous coronary intervention at a US tertiary-care center, racial disparities were observed, especially in baseline characteristics, indicating late presentation.


The toxicity of seed extracts and their fractions from Lupinus angustifolius L. and Lupinus albus L.
Seed extracts obtained from Lupinus albus and Lupinus angustifolius by treatment with 48% ethanol contained ca. 10% alkaloids (on a dry weight basis) and were non-toxic. Their acute toxicity (LD50) in the mouse is > 4000 mg kg-1 body wt. After fractionation, the extract from L. angustifolius seeds afforded several fractions with differing toxicities (LD50 750-4000 mg kg-1 body wt.). None of the fractions tested in vitro were toxic. The results obtained showed that, in spite of the alkaloids, other low-molecular-weight constituents present significantly modified the toxicity of the lupin extracts.


Neonatal Manifestations of Chronic Granulomatous Disease: MAS/HLH and Necrotizing Pneumonia as Unusual Phenotypes and Review of the Literature.
Chronic granulomatous disease (CGD) is a rare inborn error of immunity (IEI), characterized by a deficient phagocyte killing due to the inability of NADPH oxidase to produce reactive oxygen species in the phagosome. Patients with CGD suffer from severe and recurrent infections and chronic inflammatory disorders. Onset of CGD has been rarely reported in neonates and only as single case reports or small case series. We report here the cases of three newborns from two different kindreds, presenting with novel infectious and inflammatory phenotypes associated with CGD. A girl with CYBA deficiency presented with necrotizing pneumonia, requiring a prolonged antibiotic treatment and resulting in fibrotic pulmonary changes. From the second kindred, the first of two brothers developed a fatal Burkholderia multivorans sepsis and died at 24 days of life. His younger brother had a diagnosis of CYBB deficiency and presented with Macrophage Activation Syndrome/Hemophagocytic Lympho-Histiocytosis (MAS/HLH) without any infection, that could be controlled with steroids. We further report the findings of a review of the literature and show that the spectrum of microorganisms causing infections in neonates with CGD is similar to that of older patients, but the clinical manifestations are more diverse, especially those related to the inflammatory syndromes. Our findings extend the spectrum of the clinical presentation of CGD to include unusual neonatal phenotypes. The recognition of the very early, potentially life-threatening manifestations of CGD is crucial for a prompt diagnosis, improvement of survival and reduction of the risk of long-term sequelae.


Circulatory adjuncts. Newer methods of cardiopulmonary resuscitation.
Principles of cardiovascular physiology tell us that during cardiac arrest and CPR, forward flow of blood can be generated by external compression or decompression of either the chest or the abdomen. Standard CPR utilizes only one of these modes--chest compression--and generates roughly 1 L/min forward flow in an adult human, which is 20% of normal cardiac output. IAC-CPR uses two of these modes--chest compression and abdominal compression--and generates roughly twice the forward flow, or 2 L/min in an adult human. ACD-CPR uses two of these modes--chest compression and chest decompression--and also generates roughly twice the forward flow as standard CPR, although the results are somewhat model dependent. The studies by Sack et al with IAC-CPR and by Plaisance et al with ACD-CPR suggest that when methods that double perfusion are employed methodically, resuscitation outcome in terms of short- and long-term survival are also roughly doubled. This state of affairs is fortunate, because it is possible that factors, such as severe underlying disease or the quality of postresuscitation care, could blunt or cancel positive effects of improved blood flow during the brief resuscitation period. Theoretically, full four-phase CPR, including active compression and decompression of both chest and abdomen, is capable of generating 4 L/min forward flow or greater, which is 80% of normal, and there is a reasonable prospect of achieving 100% of normal flow under conditions in which all four phases are optimized. Standard CPR is clearly not the ultimate form of external CPR. There is real, credible evidence that substantial improvements in resuscitation methods and results will be possible in the next decade.


Imbalance of different types of CD4(+) forkhead box protein 3 (FoxP3)(+) T cells in patients with new-onset systemic lupus erythematosus.
The aim of this study was to examine the numbers of CD4(+) CD25(-) forkhead box protein 3 (FoxP3)(+) , CD4(+) CD25(+) FoxP3(+) and CD4(+) CXCR5(+) FoxP3(+) T cells in patients with new-onset systemic lupus erythematosus (SLE). The numbers of CD4(+) CD25(-) FoxP3(+) , CD4(+) CD25(+) FoxP3(+) and CD4(+) CXCR5(+) FoxP3(+) T cells and the concentrations of serum interleukin (IL)-10 in 23 patients and 20 healthy controls (HC) were measured. The potential correlations between CD4(+) FoxP3(+) T cells, serum IL-10 and clinical measures in SLE patients were analysed. In comparison with that in the HC, significantly reduced numbers of CD4(+) CD25(+) FoxP3(+) and CD4(+) CXCR5(+) FoxP3(+) T cells, but increased numbers of CD4(+) CD25(-) FoxP3(+) T cells, were detected, accompanied by significantly lower levels of serum IL-10 in the patients. Stratification analysis indicated the numbers of CD4(+) CD25(+) FoxP3(+) and CD4(+) CXCR5(+) FoxP3(+) T cells and serum IL-10 levels in the patients with seropositive anti-dsDNA were significantly less than that in those with seronegative anti-dsDNA. Treatment with the anti-SLE therapy, particularly with prednisone, leflunomide and methotrexate, significantly improved the imbalance of these types of FoxP3(+) T cells and increased the concentrations of serum IL-10 in the drug-responding patients. The numbers of CD4(+) CD25(+) FoxP3(+) T cells were correlated negatively with the values of SLE disease activity index (SLEDAI), whereas the numbers of CD4(+) CD25(-) FoxP3(+) T cells were correlated positively with the values of SLEDAI, erythrocyte sedimentation rate (ESR) and serum C3. In addition, the concentrations of serum IL-10 were correlated positively with the numbers of CD4(+) CD25(+) FoxP3(+) T cells, but negatively with the values of SLEDAI, serum C3, CRP and ESR in these patients. Our data indicate that the imbalance of different types of FoxP3(+) CD4(+) T cells may contribute to the development of SLE in Chinese patients.


Complexities of Simultaneously Improving Quality and Lowering Costs in Hospitals Comment on "Hospitals Bending the Cost Curve With Increased Quality: A Scoping Review Into Integrated Hospital Strategies".
As health systems transition to value-based care delivery models, reducing costs and improving quality of care without sacrificing either remains a challenge for many healthcare organizations. There is extensive research on hospital costs, however, works addressing the complex relationship between hospital costs and the quality of care have been limited. In this commentary, I expound on the scoping review on integrated hospital strategies by Wackers et al that aim to improve quality while lowering costs. Specifically, I reiterate the complexity of the relationship between cost and quality and delve into major interdependent themes identified by the authors as relevant for the implementation of hospitals' integrated strategy.


Immunochemical and immunocytochemical studies of the crustacean vitellogenesis-inhibiting hormone (VIH).
Immunochemical investigations, using dot immunobinding assay (DIA) and enzyme-linked immunosorbent assay (ELISA), and immunocytochemical studies reveal the following new information about crustacean vitellogenesis-inhibiting hormone (VIH): (1) The structure of VIH is sufficiently different from that of the other sinus gland neuropeptides to allow a selective recognition of VIH by polyclonal antibodies. (2) From immunochemical criteria, VIH does not seem strictly species specific. The antisera raised against VIH of Homarus americanus cross-react with sinus gland extracts of Palaemonetes varians, Palaemon serratus, Macrobrachium rosenbergii, Carcinus maenas, and Porcellio dilatatus. (3) In the sinus gland of H. americanus, VIH immunoreactivity is localized mainly in electron-dense granules of medium size (110-185 nm in diameter) while, in P. dilatatus, the labeling is mostly on the largest granules (200-270 nm in diameter).


Impact of mild traumatic brain injury on cingulate functions.
Mild traumatic brain injury (mTBI) is a condition of normal neuroimaging, because conventional MRI is not sensitive to brain lesions. Neurocognitive deficits persist for years after injury in 15% of patients. Persistent TAI can continue after the trauma and contribute to progressive disability. Neuropathologic studies underestimate the total axonal damage, by failure to identify fine-caliber unmyelinated fiber. Swollen axons represent the "tip of the iceberg" of damage. Progression of molecular changes, including mitochondrial dysfunction, leads to secondary injuries. Primary low-intensity "invisible injury" is solely detectable at ultrastructural levels. Over the long term, mTBI is not a static event but a progressive injury, increasing risk of neurodegenerative diseases. Lack of evidence of brain injury has led to the development of more sensitive methods: morphometric MRI (VBM, DTI) and functional techniques (fMRI, PET, SPECT). By deformation of the surface of gray matter cingulate gyrus and disruption of long-coursing WM of CB structures, striking the falx, mTBI causes alteration of cingulate functions. Postconcussion, blast, and whiplash-associated disorders are the main mechanisms providing behavior and cognitive symptoms after mTBI.


Gene expression profiling in the cerebral cortex of patients with cirrhosis with and without hepatic encephalopathy.
Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis and is seen as the clinical manifestation of a low-grade cerebral edema associated with oxidative-nitrosative stress. However, comprehensive data on HE-associated molecular derangements in the human brain are lacking. In the present study, we used a whole human genome microarray approach for gene expression profiling in post mortem brain samples from patients with cirrhosis with or without HE and controls without cirrhosis. Altered expression levels were found for a total of 1,012 genes in liver cirrhosis patients without and with HE, and HE-characteristic gene expression changes were identified. Genes with altered expression pattern in HE were related to oxidative stress, microglia activation, receptor signaling, inflammatory pathways, cell proliferation, and apoptosis. Despite an up-regulation of genes associated with microglia activation, pro-inflammatory cytokine messenger RNA profiles remained unchanged in the brains of patients with liver cirrhosis and HE compared with controls. Interestingly, many genes counteracting pro-inflammatory signaling and inflammatory cytokine expression were up-regulated in the cerebral cortex of patients with liver cirrhosis and HE. Pathogenetic mechanisms of HE deduced from cell culture and animal experiments, such as oxidative stress, altered Zn(2+) homeostasis and microglia activation also apply to human brain from patients with liver cirrhosis and HE. The study also revealed a not-yet recognized increased expression of genes antagonizing proinflammatory signaling and inflammatory cytokine expression. (HEPATOLOGY 2013;57:2436-2447).


Metallothionein deficiency in the injured peripheral nerves of complex regional pain syndrome as revealed by proteomics.
Complex regional pain syndrome (CRPS) is characterized by persistent and severe pain after trauma or surgery; however, its molecular mechanisms in the peripheral nervous system are poorly understood. Using proteomics, we investigated whether injured peripheral nerves of CRPS patients have altered protein profiles compared with control nerves. We obtained nerve samples from 3 patients with CRPS-2 who underwent resection of part of an injured peripheral nerve. Sural nerves from fresh cadavers with no history of trauma or neuropathic pain served as controls. Proteomic analysis showed that the number and functional distribution of proteins expressed in CRPS and control nerves was similar. Interestingly, metallothionein was absent in the injured nerves of CRPS-2, although it was readily detected in control nerves. Western blotting further confirmed the absence of metallothionein in CRPS-2 nerves, and immunohistochemistry corroborated the deficiency of metallothionein expression in injured nerves from 5 of 5 CRPS patients and 2 of 2 patients with painful neuromas. In contrast, all control nerves, including 5 sural nerves from fresh cadavers and 41 nerves obtained from surgically resected tumors, expressed MT. Furthermore, expression of S100 as a marker for Schwann cells, and neurofilament M as a marker of axons was comparable in both CRPS-2 and controls. Metallothioneins are zinc-binding proteins that are probably involved in protection against injury and subsequent regeneration after CNS damage. Their absence from the injured peripheral nerves of patients with CRPS-2 suggests a potential pathogenic role in generating pain in the damaged peripheral nerves.


Effect of 2-month detraining on body composition and insulin sensitivity in young female dancers.
To investigate the effect of 2-month detraining on body composition and glucose tolerance for female collegiate dancers. Longitudinal study of dancers who stopped their regular training for 2 months. 16 female collegiate dancers (age: 19.7 +/-0.11 year, body mass index (BMI): 20.7 +/- 0.56 kg/m(2)). BMI, waist-to-hip ratio (WHR), oral glucose tolerance test (OGTT), insulin response during OGTT, and blood lipids at baseline and after a 2-month detraining. Glucose tolerance was not significantly affected by the detraining, but the fasted insulin and insulin levels during OGTT were significantly elevated. Fasted free fatty acid (FFA) and triglyceride levels were significantly elevated without change in cholesterol level. BMI was not significantly altered during this detraining period, but the waist circumference and WHR ratio were significantly elevated. Only a 2-month cessation of regular training in female dancers significantly elevated basal and postprandial insulin levels and triglycerides, and were associated with increased basal FFA. This result appears to be partly related to the increased central fatness but not body mass, indicating that the early development of obesity due to reduced physical activity may not necessarily reflect on weight status. A warning is thus warranted for those young women who depend on weight measurement for body fat status monitoring.


Preparation of NanoMEDIC Extracellular Vesicles to Deliver CRISPR-Cas9 Ribonucleoproteins for Genomic Exon Skipping.
The CRISPR-Cas9 system has quickly become the standard tool for genome editing. To deliver this system to target cells, adeno-associated virus (AAV) vectors are commonly used. In fact, AAV vectors have been utilized to deliver the CRISPR-Cas9 system to induce genomic exon skipping and restore the dystrophin protein in various Duchenne muscular dystrophy model animals. Despite the high transduction efficiency, AAV vector-mediated delivery has several limitations, such as the packaging size, prolonged overexpression of Cas9, immunogenicity against the AAV capsid, and the risk of integrating a part of the AAV genomic sequence into the host cell. To overcome these issues, we have recently engineered a transient delivery system utilizing VSV-G pseudotyped extracellular vesicles (EVs) termed NanoMEDIC (nanomembrane-derived extracellular vesicles for the delivery of macromolecular cargo). NanoMEDIC utilizes an HIV-derived Gag protein to package Cas9 protein and gRNA into EVs. The Cas9 and Gag proteins are fused to a heterodimerizer and conditionally dimerized by the addition of an inducible chemical ligand to recruit Cas9 protein into EVs. sgRNA is packaged into EVs through an HIV-derived RNA packaging signal and is subsequently released by two self-cleaving ribozymes. Utilizing these features, NanoMEDIC can achieve highly efficient packaging of the Cas9 protein and gRNA for genome editing into a variety of target cells and in vivo. Here, we describe a step-by-step protocol, including the gRNA-expressing vector construction and large-scale NanoMEDIC production, for in vivo genome editing.


Resilience to urban poverty: theoretical and empirical considerations for population health.
To better understand the trajectory that propels people from poverty to poor health, we investigated health resilience longitudinally among African American families with incomes below 250% of the federal poverty level. Health resilience is the capacity to maintain good health in the face of significant adversity. With higher levels of tooth retention as a marker of health resilience, we used a social-epidemiological framework to define capacity for health resilience through a chain of determinants starting in the built environment (housing quality) and community context (social support) to familial influences (religiosity) and individual mental health and health behavior. Odds of retaining 20 or more teeth were 3 times as likely among adults with resilience versus more-vulnerable adults (odds ratio=3.1; 95% confidence interval [CI]=1.3, 7.4). Children of caregivers with resilience had a lower incident rate of noncavitated tooth decay at 18- to 24-month follow-up (incidence risk ratio=0.8; 95% CI=0.7, 0.9) compared with other children. Health resilience to poverty was supported by protective factors in the built and social environments. When poverty itself cannot be eliminated, improving the quality of the built and social environments will foster resilience to its harmful health effects.


Change in Objectively Measured Activity Levels Resulting from the EMPOWER Study Lifestyle Intervention.
To examine changes in physical activity (PA) during a behavioral weight-loss intervention and determine baseline factors associated with PA goal achievement. Overweight/obese community-dwelling adults with valid PA accelerometer data (N=116; mean age 51.7 years; 89% female; 83% non-Hispanic White) were recruited into a single-arm prospective cohort study examining the effects of a 12-month intervention that included 24 in-person group sessions, weight-loss, calorie, fat gram, and PA goals, self-monitoring, and feedback. Minutes of moderate-to-vigorous (MV) PA and steps were measured using a waist-worn accelerometer (ActiGraph GT3x) at baseline, 6 months, and 12 months. Achievement of the 150 minute/week MVPA goal was examined using total minutes and bout minutes (i.e., counting only PA occurring in bouts ≥10 minutes in length). Change in PA was analyzed using non-parametric tests for multiple comparisons. Associations of factors with meeting the PA goal were modeled using binary logistic regression. At 6 months, there were increases from baseline in MVPA (median [p25, p75]: 5.3 [-0.9, 17.6] minutes/day) and steps (863 [-145, 2790] steps/day), both p<0.001. At 12 months, improvements were attenuated (MVPA: 2.4 [-2.0, 11.4] minutes/day, p=0.047; steps: 374[-570, 1804] p=0.14). At 6 months, 33.6% of individuals met the PA goal (using total or bout minutes). At 12 months, the percent meeting the goal using total MVPA [31%] differed from bout MVPA [22.4%]. Male gender (OR=4.14, p=0.027) and an autumn program start (versus winter; OR=3.39, p=0.011) were associated with greater odds of goal achievement at 6 months. The intervention increased PA goal achievement at 6 and 12 months with many making clinically meaningful improvements. Our results suggest female participants may require extra support toward improving PA levels.


Effect of cardiac resynchronization therapy on the incidence of ventricular arrhythmias in patients with an implantable cardioverter-defibrillator.
Cardiac resynchronization therapy (CRT) reduces mortality in selected patients with heart failure. However, this result may not be entirely related to the beneficial hemodynamic effects of CRT. The purpose of this study was to assess retrospectively the effect of CRT on the incidence of appropriate therapy in patients with an implantable cardioverter-defibrillator (ICD). Sixty-five patients (48 men and 17 women; mean age 58 +/- 13 years) with an ICD (31 biventricular, 34 dual-chamber) were included in the study. Clinical, ECG, and ICD stored data and electrograms were collected. Biventricular and dual-chamber ICDs were implanted in 31 and 34 patients, respectively, who had either ischemic (n = 36) or dilated cardiomyopathy (n = 29). Thirty-two (49%) patients received > or =1 appropriate ICD therapy during follow-up of 11 +/- 8 months. Thirty-five percent and 62% of patients with biventricular (n = 11) and dual-chamber ICDs (n = 21), respectively, received appropriate ICD therapy during the follow-up period (odds ratio = 0.340, P = .048). Stratifying the patients according to underlying heart disease and ejection fraction resulted in an adjusted odds ratio = 0.239 (P = .029). Comparing the rate of > or =1 appropriate ICD therapy between the two groups by Kaplan-Meier analysis and the log rank test resulted in P = .027. In this retrospective analysis, biventricular pacing was associated with a decreased incidence of sustained ventricular arrhythmias requiring ICD therapy. The antiarrhythmic effect of biventricular pacing could contribute to the reduction in mortality reported in recent large-scale clinical trials on CRT. However, further prospective studies are warranted to clarify this issue.


Stimulation of epidermal hyperplasia and tumorigenesis by resident p16INK4a-expressing cells.
p16INK4a (CDKN2A) is a central tumor-suppressor and activator of senescence. We recently found that prolonged expression of p16INK4a in epidermal cells induces hyperplasia and dysplasia through Wnt-mediated stimulation of neighboring keratinocytes. The study suggests a pro-tumorigenic function of p16INK4a in early epidermal lesions, which could potentially be targeted by senolytic therapy.


A single-molecule dissection of ligand binding to a protein with intrinsic dynamics.
Protein dynamics have been suggested to have a crucial role in biomolecular recognition, but the precise molecular mechanisms remain unclear. Herein, we performed single-molecule fluorescence resonance energy transfer measurements for wild-type maltose-binding protein (MBP) and its variants to demonstrate the interplay of conformational dynamics and molecular recognition. Kinetic analysis provided direct evidence that MBP recognizes a ligand through an 'induced-fit' mechanism, not through the generally proposed selection mechanism for proteins with conformational dynamics such as MBP. Our results indicated that the mere presence of intrinsic dynamics is insufficient for a 'selection' mechanism. An energetic analysis of ligand binding implicated the critical role of conformational dynamics in facilitating a structural change that occurs upon ligand binding.


The poor recovery of neuromyelitis optica spectrum disorder is associated with a lower level of CXCL12 in the human brain.
Neuromyelitis optica spectrum disorders (NMOSDs) are blindness-causing neuritis. In NMOSD patients, NMO-IgG evokes astrocytopathy that in turn causes demyelination. While measurement of NMO-IgG titer will help neurologists make the diagnosis of NMOSDs, it is not sufficient to evaluate the severity of astrocytopathy. In this study, we compared the different levels of an astrocyte biomarker in cerebrospinal fluid of NMOSD patients with good or poor recovery, and then linked their differences to the changes in remyelinating promoter (CXCL12) levels. Our results indicate that NMO-IgG down-regulated CXCL12 and impaired the remyelinating process, this may be a mechanism contributing to the poor recovery of NMOSDs.


Dual chamber epicardial pacing for the failing atriopulmonary Fontan patient.
The atriopulmonary Fontan circulation leads to arrhythmias, heart failure, or protein-losing enteropathy, eventually requiring conversion. In hesitant patients, we evaluated the effect of dual chamber pacing as a time-buying measure. Between 1997 and 2004, 9 patients (aged, 6 to 18 years) with an atriopulmonary Fontan connection and sinus node dysfunction received dual chamber epicardial pacemaker systems. Indications included refractory arrhythmias (n = 5), protein-losing enteropathy (n = 2), heart failure with effusions (n = 1), and exercise intolerance (n = 2). Data were compared between hospital discharge after pacemaker implantation and last follow-up. There was no mortality or morbidity. At a follow-up of 3.3 +/- 1.0 years, lead survival was 100%. Both atrial (impedance = 683 +/- 40 Ohm; threshold = 0.8 +/- 0.1 V at 0.5 ms; sensing P waves = 3.3 +/- 0.8 mV) and ventricular (impedance = 630 +/- 68 Ohm; threshold = 1.3 +/- 0.3 V at 0.5 ms; sensing R waves = 8.7 +/- 2.5 mV) leads retained satisfactory pacing characteristics at last control, better than those at discharge. Arrhythmias subsided in all instances and no longer required medication in 3 patients. Protein-losing enteropathy improved temporarily in 1 patient and disappeared in another. Exercise intolerance diminished, and heart failure was controlled. Although most atriopulmonary Fontan circulations will need conversion with arrhythmia surgery, patients may delay out of fear. Dual chamber pacing improves single ventricle hemodynamics and can help decompensated Fontan patients. In a multiple-redo setting, a left lateral thoracotomy provides safe access and allows for quantitatively reliable and durable epicardial pacing.


Nephron endowment and renal filtration surface area in young spontaneously hypertensive rats.
A reduction in nephron endowment leading to reduced renal filtration surface area has been implicated in the development of hypertension. The aim of this study was to compare glomerular (and thereby nephron) number and renal filtration surface area in young Wistar-Kyoto rats (WKY) with young spontaneously hypertensive rats (SHR), prior to the development of hypertension in this model. Using unbiased stereological methods the number and size of glomeruli, as well as total renal filtration surface area were determined in perfusion-fixed kidneys of 4-week-old WKY and SHR. At 4 weeks of age, in weight-matched animals, there was no significant difference in the number of glomeruli in the kidneys of SHR compared to WKY (28,620 +/- 1,643 and 25,670 +/- 1,263 glomeruli/kidney, respectively). Similarly, there was no difference in mean glomerular volume (SHR: 4.70 +/- 0.31 x 10(-4) mm(3); WKY: 4.28 +/- 0.20 x 10(-4) mm(3)). Surprisingly, total renal filtration surface area was significantly greater in SHR than WKY (3,867 +/- 116 and 3,176 +/- 83 mm(2), respectively). The renal abnormality underlying the development of hypertension in the SHR is not due to inborn deficits in nephron endowment and/or filtration surface area.


Dependence of position-effect variegation in Drosophila on dose of a gene encoding an unusual zinc-finger protein.
Position-effect variegation is the inactivation in some cells of a gene translocated next to heterochromatin, the region of the chromosome that is permanently condensed. The number of copies of the Drosophila gene Suvar(3)7 is a dose-limiting factor in this phenomenon, and seems from its sequence that it encodes a protein with five widely spaced zinc-fingers. This novel arrangement of zinc-fingers could help in packaging the chromatin fibre into heterochromatin, and also reflect a novel method of controlling the expression from DNA domains.


Competitive and substrate limited environments drive metabolic heterogeneity for comammox Nitrospira.
Nitrospira has been revealed as a high versatile genus. Although previously considered only responsible for the conversion of nitrite to nitrate, now we know that Nitrospira can perform complete ammonia oxidation to nitrate too (comammox). Comammox activity was firstly reported as dominant in extremely limited oxygen environments, where anaerobic ammonia oxidation was also occurring (anammox). To explain the comammox selection, we developed an Individual-based Model able to describe Nitrospira and anammox growth in suspended flocs assembled in a dynamic nitrogen and oxygen-limiting environment. All known and hypothesized nitrogen transformations of Nitrospira were considered: ammonia and nitrite oxidation, comammox, nitrate-reducing ammonia oxidation, and anaerobic nitrite-reducing ammonia oxidation. Through bioenergetics analysis, the growth yield associated to each activity was estimated. The other kinetic parameters necessary to describe growth were calibrated according to the reported literature values. Our modeling results suggest that even extremely low oxygen concentrations (~1.0 µM) allow for a proportional growth of anammox versus Nitrospira similar to the one experimentally observed. The strong oxygen limitation was followed by a limitation of ammonia and nitrite, because anammox, without strong competitors, were able to grow faster than Nitrospira depleting the environment in nitrogen. These substrate limitations created an extremely competitive environment that proved to be decisive in the community assembly of Nitrospira and anammox. Additionally, a diversity of metabolic activities for Nitrospira was observed in all tested conditions, which in turn, explained the transient nitrite accumulation observed in aerobic environments with higher ammonia availability.


Early pregnancy imaging predicts ischemic placental disease.
To characterize early-gestation changes in placental structure, perfusion, and oxygenation in the context of ischemic placental disease (IPD) as a composite outcome and in individual sub-groups. In a single-center prospective cohort study, 199 women were recruited from antenatal clinics between February 2017 and February 2019. Maternal magnetic resonance imaging (MRI) studies of the placenta were temporally conducted at two timepoints: 14-16 weeks gestational age (GA) and 19-24 weeks GA. The pregnancy was monitored via four additional study visits, including at delivery. Placental volume, perfusion, and oxygenation were assessed at both MRI timepoints. The primary outcome was defined as pregnancy complicated by IPD, with group assignment confirmed after delivery. In early gestation, mothers with IPD who subsequently developed fetal growth restriction (FGR) and/or delivered small-for gestational age (SGA) infants showed significantly decreased MRI indices of placental volume, perfusion, and oxygenation compared to controls. The prediction of FGR or SGA by multiple logistic regression using placental volume, perfusion, and oxygenation revealed receiver operator characteristic curves with areas under the curve of 0.81 (Positive predictive value (PPV) = 0.84, negative predictive value (NPV) = 0.75) at 14-16 weeks GA and 0.66 (PPV = 0.78, NPV = 0.60) at 19-24 weeks GA. MRI indices showing decreased placental volume, perfusion and oxygenation in early pregnancy were associated with subsequent onset of IPD, with the greatest deviation evident in subjects with FGR and/or SGA. These early-gestation MRI changes may be predictive of the subsequent development of FGR and/or SGA.


A first-principles study on strain engineering of monolayer stanene for enhanced catalysis of CO2 reduction.
Using first-principles calculations, we investigated the changes in the lattice structure, electronic structures and catalytic performance for CO2 reduction reaction (CO2RR) of stanene under applied strain. Our calculations showed that the initial buckled honeycomb structure of free-standing stanene becomes increasingly flat upon the increase of tensile strain. Stanene remains its gapless semiconductor characteristic within the strain range of -2% and 2%, beyond which a semiconductor-to-metal transition occurs. Under strain, the adsorption of CO is weakened, which can facilitate the desorption of product CO, enabling a strained stanene to be a better catalyst for CO2RR to CO than strain-free stanene. In particular, the stanene with 4% strain may give rise to the best performance because of the weakest CO adsorption (Eadsorp= -0.15 eV). The adsorption of intermediate product COOH on stanene is tunable with strain. We also evaluated the overall catalytic performance of the strained stanene based on the adsorption of CO and COOH and the selectivity against HER. If the reduction of COOH is governed by adsorption of the intermediate, a 10% strain may give a stronger COOH adsorption, weaker CO adsorption and better selectivity against HER, leading to an enhanced catalytic performance for CO2RR to CO. On the other hand, if the reduction of COOH is governed by desorption, a tensile strain higher than 4% may result in an enhanced catalytic performance. Our study here suggests that strain-tuned stanene might serve as an optimal electrocatalyst for CO2RR to CO with a high activity and selectivity.


Effects of pertussis toxin on behavioural responses of guinea-pigs to centrally administered substance P, quinpirole, carbachol, U-50,488H, morphine and morphine withdrawal.
The effects of pretreatment with pertussis toxin (PTX) on the sedative effect of morphine administered i.c.v. (200 nmol), and on the locomotor and behavioural activation precipitated by naloxone (15 mg/kg s.c.) following treatment with a single dose of morphine (i.c.v., 200 nmol), were investigated in guinea-pigs. Responses to i.c.v. administration of substance P (50 nmol), quinpirole (200 nmol), U50,488H (100 nmol) and carbachol (2 nmol) following PTX pretreatment were also investigated. Following PTX pretreatment, morphine induced mild agitation and the onset of sedation was delayed. Pretreatment with PTX also attenuated the locomotor and some components of behavioural activation induced by substance P, U50,488H, quinpirole and naloxone-precipitated morphine withdrawal, but failed to attenuate the effects induced by carbachol. These results suggest the involvement of PTX-sensitive G-protein-mediated mechanisms in the sedative effect of morphine in guinea-pigs and in the central stimulating actions of acute morphine withdrawal, U50,488H, substance P, and quinpirole.


Contribution of dectin-1 and granulocyte macrophage-colony stimulating factor (GM-CSF) to immunomodulating actions of beta-glucan.
beta-Glucans are major cell wall structural components in fungi. As they are not found in animals, these carbohydrates are considered to be classic pathogen-associated molecular patterns (PAMPs), and are recognized by the innate immune system. Although their immunomodulating activities have been shown to be associated with the recognition of some fungi, and with their medicinal properties in the field of cancer immunotherapy, it is still unclear how beta-glucans mediate their effects. Recent studies have started to shed some light on their cellular receptors, such as dectin-1, and their molecular mechanisms of action. We have extensively investigated the response of leukocytes to beta-glucan, focusing on cytokine induction by SCG, which is a major 6-branched 1,3-beta-d-glucan in Sparassis crispa Fr. There is a strain difference in the reactivity of mice to SCG, and DBA/1 and DBA/2 mice are highly sensitive strains. In the process of research on cytokine induction by SCG in DBA/2 mice, we found that GM-CSF plays a key biological role in this activity. Cytokine induction by SCG was completely abolished in dendritic cells from dectin-1 knockout mice. On the other hand, controlling the level of endogenous GM-CSF production and/or dectin-1 expression could regulate the reactivity to beta-glucan. These results indicate that the key factors in the responsiveness to beta-glucan are GM-CSF production and dectin-1 expression. In this review, we describe how the key molecules related to the expression of the immunomodulating activities of beta-glucan were identified, and how the response to beta-glucan is controlled.


Genotoxic effects of paracetamol in V79 Chinese hamster cells.
Paracetamol was studied for possible genotoxic effects in V79 Chinese hamster cells. Paracetamol (0.5 mM for 30 min) reduced the rate of DNA synthesis in exponentially growing V79 cells to about 50% of control. A further decrease in the DNA synthesis was seen during the first 30 min after termination of paracetamol exposure. Paracetamol (3 and 10 mM for 2 h) caused a small increase in DNA single-strand breaks, as measured by the alkaline elution technique. After 16 h elution, the amount of DNA retained on the filters was 79 and 70% of controls in cells treated with 3 and 10 mM paracetamol respectively. No indication of DNA damage was seen in measuring the effect of paracetamol (0.25-10 mM for 2 h) on unscheduled DNA synthesis in growth-arrested cultures of V79 cells. At the highest concentrations (3 and 10 mM paracetamol), decreased unscheduled DNA synthesis was observed. Also UV-induced DNA-repair synthesis was inhibited by 3 and 10 mM paracetamol. DNA-repair synthesis was, however, inhibited at a much higher concentration than that inhibiting replicative DNA synthesis. The number of sister-chromatid exchanges (SCE) increased in a dose-dependent manner on 2 h exposure to paracetamol from 1 mM to 10 mM. At the highest dose tested (10 mM), the number of SCE increased to 3 times the control value. Co-culturing the V79 cells with freshly isolated mouse hepatocytes had no further effect on the paracetamol induced sister-chromatid exchanges. The present study indicates that paracetamol may cause DNA damage in V79 cells without any external metabolic activation system added.


Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia.
Nilotinib is a BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (CML). The UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphism UGT1A1*28 (*28)/*28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib. Beside *28, UGT1A1*6 (*6) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan, metabolized by UGT1A1. We retrospectively investigated the association between severe toxicity of nilotinib and UGT1A1 polymorphisms (*6 and*28) in Japanese patients with CML. Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of UGT1A1 polymorphisms with severe nilotinib-related toxicity. Genotyping analyses were determined for *6 and *28. All 3 patients with the *6/*6 or *6/*28 genotype had severe toxicity, including QT interval prolongation (grade 3), elevated lipase levels (grade 3) plus hyperbilirubinemia (grade 2), and anemia (grade 3) plus hepatic cyst hemorrhage (grade 2) in 1 patient each. Among the 5 patients with the *6/*1 or *1/*1 genotype, 1 had elevated lipase levels (grade 3) and another had severe pain in the lower extremities (grade 3). These findings suggest that UGT1A1 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients.


Coping strategies mediate the association between stigma and fertility quality of life in infertile women undergoing in vitro fertilization-embryo transfer.
The mediating role of coping strategies and its relationship with psychological well-being and quality of life has been considered in the literature. However, there is little research to explore the mechanism of coping strategies on stigma and fertility quality of life (FertiQoL) in infertile women undergoing In Vitro Fertilization Embryo Transfer (IVF-ET). The aim of this study was to examine the mediating effect of coping strategies on the relationship between stigma and fertility quality of life (FertiQoL) in Chinese infertile women undergoing In Vitro Fertilization Embryo Transfer (IVF-ET). In this cross-sectional study, a total of 768 infertile women undergoing IVF-ET were recruited from Assisted Reproductive Center of Shaanxi Province, China. The personal information, infertility stigma scale, coping strategy scale and FertiQoL scale were measured using a set of questionnaires. The multiple mediator model was performed using AMOS 21.0. The model showed a significant negative direct effect between stigma on FertiQoL. There were significantly negative indirect effects of stigma on FertiQoL through active-avoidance, active-confronting and passive-avoidance, respectively. The meaning-based coping played a positive intermediary role. The model explained 69.4% of the variance in FertiQoL. Active-avoidance coping strategy is the most important mediator factor between stigma and FertiQoL in infertile women undergoing IVF-ET treatment. Meaning-based coping strategy plays a positive mediating role between stigma and FertiQoL.


Evaluation of the American College of Sports Medicine submaximal treadmill running test for predicting VO2max.
The purpose of this study was to assess the validity of the American College of Sports Medicine's (ACSM's) submaximal treadmill running test in predicting VO2max. Twenty-one moderately well-trained men aged 18-34 years performed 1 maximal treadmill test to determine maximal oxygen uptake (M VO2max) and 2 submaximal treadmill tests using 4 stages of continuous submaximal exercise. Estimated VO2max was predicted by extrapolation to age-predicted maximal heart rate (HRmax) and calculated in 2 ways: using data from all submaximal stages between 110 b·min(-1) and 85% HRmax (P VO2max-All), and using data from the last 2 stages only (P VO2max-2). The measured VO2max was overestimated by 3% on average for the group but was not significantly different to predicted VO2max (1-way analysis of variance [ANOVA] p = 0.695; M VO2max = 53.01 ± 5.38; P VO2max-All = 54.27 ± 7.16; P VO2max-2 = 54.99 ± 7.69 ml·kg(-1)·min(-1)), although M VO2max was not overestimated in all the participants--it was underestimated in 30% of observations. Pearson's correlation, standard error of estimate (SEE), and total error (E) between measured and predicted VO2max were r = 0.646, 4.35, 4.08 ml·kg(-1)·min(-1) (P VO2max-All) and r = 0.642, 4.21, 3.98 ml·kg(-1)·min(-1) (P VO2max-2) indicating that the accuracy in prediction (error) was very similar whether using P VO2max-All or P VO2max-2, with up to 70% of the participants predicted scores within 1 SEE (∼4 ml·kg(-1)·min(-1)) of M VO2max. In conclusion, the ACSM equation provides a reasonably good estimation of VO2max with no difference in predictive accuracy between P VO2max-2 and P VO2max-All, and hence, either approach may be equally useful in tracking an individual's aerobic fitness over time. However, if a precise knowledge of VO2max is required, then it is recommended that this be measured directly.


Parental and Peer Support are Associated with Physical Activity in Adolescents: Evidence from 74 Countries.
Although parental and peer support can influence adolescents' physical activity (PA), these associations have not been fully examined through a global assessment. This study examined the associations of parental and peer support with PA among adolescents from 74 countries. The Global School-based Student Health Survey data from 250,317 adolescents aged 11-17 years (48.8% girls), collected between 2007 and 2016, were analysed. Adolescents were asked how many days/week they were physically active and about their parental and peer support. Meta-analysis showed that adolescents who had high parental or peer support had higher odds of attaining sufficient PA (odds ratio (OR): 1.40, 95% confidence interval (CI): 1.34-1.46; OR: 1.57, 95% CI: 1.49-1.65, respectively). Pooled estimates of association were significant across all World Health Organization (WHO) regions and country-income categories with the highest estimate from the low-income countries. The Western Pacific region showed the highest association between parental support and adolescents' PA (OR: 1.49, 95% CI: 1.41-1.59), while South-East Asia exhibited the highest association between peer support and adolescents' PA (OR: 1.80, 95% CI: 1.59-2.04). Country-level estimates of associations are presented. Future studies should use robust assessment of PA and PA-specific parental and peer support with emphasis on qualitative investigation to understand the complexity of the relationships.


Epidermal growth factor is not the major growth-promoting agent in extracts of prostatic tissue.
Extracts of benign prostatic hyperplasia (BPH) contain a factor which is mitogenic for human foreskin fibroblasts in culture. Because of the similarity of BPH extract and epidermal growth factor (EGF) in stimulating quiescent fibroblasts to divide, it was of interest to determine if the prostate-associated growth factor competes for EGF receptor binding. BPH extract was found to compete poorly for 125I-EGF-receptor binding, did not influence the dissociation of cell-bound 125I-EGF and caused only a slight down-regulation of the EGF receptor. These findings indicate that EGF and BPH extract do not recognize the same receptor and that the major growth stimulating activity of BPH extract is not due to EGF.


Five-year outcomes of ADHD diagnosed in adulthood.
There is a dearth of long-term follow-up studies of adults diagnosed with ADHD. Here, the aim was to evaluate long-term outcomes in a group of ADHD patients diagnosed in adulthood and receiving routine psychiatric health care. Adults diagnosed with any type of ADHD (n = 52) and healthy controls (n = 73) were assessed at baseline and at a 5-year follow-up, using Global Assessment of Functioning (GAF), Clinical Global Impression (CGI), Brown ADD Scale (BADDS) and Adult ADHD Self-Report Scale (ASRS). A multivariate regression method was used to identify factors predicting 5-year outcomes, including baseline ratings, medication intensity, comorbidity, intelligence quotient (IQ), age, and sex. After 5 years, ADHD patients reported fewer and/or less severe symptoms compared to baseline, but remained at clinically significant symptom levels and with functional deficits. Baseline self-reports of ADHD symptoms predicted their own 5-year outcome and low baseline functioning level predicted improved global functioning at follow-up. Factors previously reported to predict short-term outcomes (i.e., medication, comorbidity, IQ, age, and sex) did not anticipate long-term outcomes in present study.


Recovery of positive future thinking within a high-risk parasuicide group: results from a pilot randomized controlled trial.
The research examined: (i) whether high risk parasuicide patients showed a deficit in positive future thinking but no increase in negative future thinking; and (ii) whether such a deficit could be remedied by a brief, manual-assisted psychological intervention (manual assisted cognitive-behaviour therapy; MACT). A cross-sectional, mixed model design was used to assess differences between a sample of high risk parasuicide patients and matched controls on future thinking. A longitudinal mixed model design was used to assess changes in future thinking in the different groups over time. Parasuicide patients with a history of previous suicidal behaviour and personality disturbance were compared with a matched group of community controls on an adapted fluency measure of future thinking, which measured both quantitative and qualitative aspects of anticipated experiences. Patients were then randomly allocated to either the specific intervention (MACT) or treatment as usual (TAU) and assessed again at 6 month follow-up. Parasuicide patients showed reduced positive future thinking but no increased negative future thinking. Patients who received MACT showed a significant improvement in positive future thinking over the follow-up period whereas the TAU group showed no such improvement. However, interpretation of this finding was made more difficult by the control group also showing a significant improvement in positive future thinking. The results confirm that parasuicide patients exhibit a relative deficit in positive future thinking and suggest that this lack of positive future thinking may be remedied, at least partly, by a brief intervention.


Traditional threads tied on children in india trigger dermatitis and may contain carcinogens.
It is a common Indian custom to tie threads on the hip, neck, or wrist of infants and children. A retrospective registry review was performed for 23 children (age range 5-18 months) with threads tied around the hip/neck/forearm who presented with dermatitis. Analysis of one of the threads revealed the presence of three banned azo dyes and disperse yellow 3 (category 2B possible carcinogens). Thread dermatitis is a unique cultural dermatosis. Dermatitis caused by threads may have multifactorial causes including friction, maceration, and contact dermatitis (allergic and/ or irritant) to the thread contents. Use of banned dyes still used to color these threads may be contributory to dermatitis, but there is also concern for health and environmental hazards to children. Strict regulation is needed in the manufacture of these threads to protect the health and welfare of young children.


Molecularly imprinted polymer dual electrochemical sensor for the one-step determination of albuminuria to creatinine ratio (ACR).
The urinary albumin to creatinine ratio (ACR) is a convenient and accurate biomarker of chronic kidney disease (CKD). An electrochemical sensor for the quantification of ACR was developed based on a dual screen-printed carbon electrode (SPdCE). The SPdCE was modified with carboxylated multiwalled carbon nanotubes (f-MWCNTs) and redox probes of polymethylene blue (PMB) for creatinine and ferrocene (Fc) for albumin. The modified working electrodes were then molecularly imprinted with coated with polymerized poly-o-phenylenediamine (PoPD) to form surfaces that could be separately imprinted with creatinine and albumin template molecules. The seeded polymer layers were polymerized with a second coating of PoPD and the templates were removed to form two different molecularly imprinted polymer (MIP) layers. The dual sensor presented recognition sites for creatinine and albumin on different working electrodes, enabling the measurement of each analyte in one potential scan of square wave voltammetry (SWV). The proposed sensor produced linear ranges of 5.0-100 ng mL-1 and 100-2500 ng mL-1 for creatinine, and 5.0-100 ng mL-1 for albumin. LODs were 1.5 ± 0.2 ng mL-1 and 1.5 ± 0.3 ng mL-1, respectively. The dual MIP sensor was highly selective and stable for seven weeks at room temperature. The ACRs obtained using the proposed sensor compared well (P > 0.05) with the results from immunoturbidimetric and enzymatic methods.


Mutagenicity of some monoaromatic hydroxamic acids.
The mutagenicity of some monoaromatic hydroxamic acids was tested in the presence and absence of rat liver S-9 with Salmonella typhimurium tester strains TA98 and TA100. Of the five N-(chlorophenyl)-substituted hydroxamic acids and seven N-arylformohydroxamic acids tested, 2 of the first and 4 of the latter series were mutagenic to both strains upon metabolic activation. None of the four N-acetyl-type hydroxamic acids was mutagenic to either strain, even upon activation. Because some of the N-acetyl-derived hydroxamic acids were inactive, whereas the same aromatic nucleus possessing a formyl group displayed significant activity, a consideration of the nature of the aryl group in hydroxamic acid mutagenicity is important.


A method for demonstrating the heterogeneity of pigeon red cell membrane vesicles based on their glycine transport activity.
A procedure is described which is capable of detecting the changes in size and/or density of small membrane vesicles resulting from solute uptake. Vesicles which have taken up solute sediment more slowly in a density gradient, the ratio of glycine uptake/vesicle-trapped space is not uniform in the vesicle population, and vesicles with higher uptake/space ratios are preferentially retarded upon centrifugation. Alanine transport activity is associated with glycine transport activity in that retardation of vesicles due to glycine uptake equally retards vesicles possessing alanine uptake activity.


A novel staging system based on deep learning for overall survival in patients with esophageal squamous cell carcinoma.
We developed DeepSurv, a deep learning approach for predicting overall survival (OS) in patients with esophageal squamous cell carcinoma (ESCC). We validated and visualized the novel staging system based on DeepSurv using data from multiple cohorts. Totally 6020 ESCC patients diagnosed from January 2010 to December 2018 were included in the present study from the Surveillance, Epidemiology, and End Results database (SEER), randomly assigned to the training and test cohorts. We developed, validated and visualized a deep learning model that included 16 prognostic factors; then a novel staging system was further constructed based on the total risk score derived from the deep learning model. The classification performance at 3-year and 5-year OS was assessed by the receiver-operating characteristic (ROC) curve. Calibration curve and the Harrell's concordance index (C-index) were also used to comprehensively assess the predictive performance of the deep learning model. Decision curve analysis (DCA) was utilized to assess the clinical utility of the novel staging system. A more applicable and accurate deep learning model was established, which outperformed the traditional nomogram in predicting OS in the test cohort (C-index: 0.732 [95% CI 0.714-0.750] versus 0.671 [95% CI 0.647-0.695]). The ROC curves at 3-year and 5-year OS for the model also showed good discrimination ability in the test cohort (Area Under the Curve [AUC] at 3-/5-year OS = 0.805/0.825). Moreover, using our novel staging system, we observed a clear survival difference among different risk groups (P < 0.001) and a significant positive net benefit in the DCA. A novel deep learning-based staging system was constructed for patients with ESCC, which performed a significant discriminability for survival probability. Moreover, an easy-to-use web-based tool based on the deep learning model was also implemented, offering convenience for personalized survival prediction. We developed a deep learning-based system that stages patients with ESCC according to their survival probability. We also created a web-based tool that uses this system to predict individual survival outcomes.


Bilateral patellar fractures from indirect trauma. A case report.
Bilateral simultaneous fractures of the patella occurred in a 17-year-old basketball player. This rare occurrence is, for the first time, linked to apparent stress reactions in each patella.


Injury Mechanism of Acute Anterior Shoulder Dislocation Associated with Glenoid and Greater Tuberosity Fractures: A Study Based on Fracture Morphology.
Based on the morphological characteristics of glenoid and greater tuberosity (GT) fractures and the relationship between them, we explored the injury mechanism of acute anterior shoulder dislocation associated with glenoid and GT fractures. From December 2013 to December 2019, we retrospectively reviewed the clinical data of patients who were diagnosed with acute anterior shoulder dislocation associated with glenoid and GT fractures in our hospital. According to the fracture site, a glenoid fracture group and a greater tuberosity fracture (GT) group were established, and the morphological characteristics of both glenoid and GT fractures were measured and statistically analyzed. A total of 41 patients (43 shoulders) met the inclusion criteria (39 unilateral shoulders and 2 bilateral shoulders). The mean age was 50.21 years (range, 22-71 years). A total of 27 shoulder injuries (62.8%) were split GT fractures and 33 shoulder injuries (76.7%) were combined with rotator cuff tears. The mean size of glenoid fragments was 30.16% and the mean displacement was 8.85 mm. The mean size of GT fragments was 28.43 mm. The mean superoinferior and anteroposterior displacements of the GT fragment were 6.77 mm and 4.96 mm, respectively. There was a negative correlation between the size of glenoid and GT fracture fragments (r = -0.64, P < 0.05). The glenoid fragments in the Ideberg type Ia glenoid fracture group were smaller than those in the Ideberg type II glenoid fracture group (28.41% and 40.95%, respectively), while the size of GT fragments in the type Ia group were larger than those in the type II group (29.77 mm and 20.21 mm, respectively) (P < 0.05). The GT fragments in the split GT fracture group were larger than those in the avulsion or depression GT fracture group (33.69 mm, 19.07 mm and 21.12 mm, respectively), while the size of glenoid fragments in the split GT fracture group were smaller than those in the avulsion or depression GT fracture group (23.57%, 41.37%, and 43.42%, respectively) (P < 0.05). As for the displacement direction of GT fragments, depression fractures were mainly inferior displacements, avulsion fractures were mainly anterosuperior displacements, while split fractures were mainly posteroinferior displacements (P < 0.05). Multiple regression analysis suggested that the type and the fragment size of GT fractures have a significant influence on the size of glenoid fragments. Acute anterior shoulder dislocations associated with glenoid and GT fractures are often combined with rotator cuff tears. There is a negative correlation between the size of glenoid and GT fragments, and split GT fractures are most common. Such injuries are highly correlated to the relative spatial location between the GT and the glenoid when the shoulder dislocates.


SIRT4 silencing in tumor-associated macrophages promotes HCC development via PPARδ signalling-mediated alternative activation of macrophages.
The activation of tumour-associated macrophages (TAMs) contributes to the progression of hepatocellular carcinoma (HCC). SIRT4 acts as a tumour suppressor of tumour growth by regulating cell metabolism, inflammation, and anti-tumourigenesis. However, the involvement of SIRT4 in the activation of TAMs is unknown. Based on previous findings, the expression of SIRT4 in distinct groups of TAMs as well as the effect of SIRT4 silencing on macrophage polarization was investigated. The expression of SIRT4 in HCC tissues and peritumour tissues was tested by qRT-PCR, western blotting and histological analysis. A Kaplan-Meier survival curve was generated based on the expression of SIRT4 in the HCC samples. Next, immunofluorescence staining was used to evaluate distinct groups of TAMs in human HCC samples, and the expression of SIRT4 in M1 and M2 TAMs was examined by flow cytometry. A homograft mouse model was used to assess the effect of SIRT4 silencing in TAMs on the development of HCC cells. SIRT4 was significantly downregulated in HCC tumour tissues, and the expression of SIRT4 in peritumour tissues was positively associated with survival in patients. We further found that downregulation of SIRT4 was associated with increased macrophage infiltration and a high ratio of M2/M1 macrophages in HCC peritumour tissues. Using gene interference, we found that SIRT4 silencing in TAMs significantly modulated the alternative activation of macrophages and promoted in vitro and in vivo HCC cell growth. Mechanistically, we revealed that HCM restricted the expression of SIRT4 in macrophages and promoted alternative activation of macrophages via the FAO-PPARδ-STAT3 axis. Furthermore, we also revealed that elevated MCP-1 expression induced by SIRT4 downregulation was responsible for increased TAM infiltration in peritumour tissues. Overall, our results demonstrate that downregulation of SIRT4 in TAMs modulates the alternative activation of macrophages and promotes HCC development via the FAO-PPARδ-STAT3 axis. These results could provide a new therapeutic target for the treatment of HCC.


Canine Mobility Maintenance and Promotion of a Healthy Lifestyle.
This article highlights the recommendations and considerations for maintaining a healthy canine lifestyle. A key component of a healthy lifestyle is the enhancement and optimization of mobility. Mobility is essential in maintaining a high quality of life and involves the interplay of a dog's structure, posture, body condition score, physical exercise, and a healthy human-animal bond throughout a dog's lifetime.


Treatment of psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome) using lithium and phenytoin.
Six patients [5 men and 1 woman, mean age 37.3 +/- 8.2 (SD) years] with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome) underwent a sequence of treatments in an effort to normalize basal serum sodium levels and thereby protect the patients against complications, including hyponatremic seizures and coma. The morning baseline group mean basal serum sodium value was 132.5 +/- 3.8 meq/liter. Over a 20-month period, the sequence of treatments was salt-added diet, lithium and phenytoin, and lithium alone. Each treatment program yielded morning group mean basal serum sodium determinations superior to baseline values, except for the program of lithium alone, which could not be tolerated. The combination of lithium and phenytoin provided a morning group mean basal serum sodium level of 140.6 +/- 3.2 meq/liter, which was superior (p less than 0.01) to all other treatment modalities. Early morning hyposthenuria persisted throughout the 20-month period of observation.


Isolation and characterization of novel glycolipids with blood group A-related structures: galactosyl-A and sialosylgalactosyl-A.
Two glycosphingolipids with the following novel structures have been isolated from human blood cells and characterized by NMR, direct probe mass spectrometry, fast atom bombardment-mass spectrometry, and methylation analysis: (Formula: see text). Both structure i and structure ii are characterized by substitution of beta-galactosyl or sialosyl-beta-galactosyl residue at the terminal alpha-GalNAc residue of blood group A determinant and are therefore specific products associated with the blood group A phenotype.


Predictive performances of animal models using different multibreed relationship matrices in systems with rotational crossbreeding.
In livestock breeding, selection for some traits can be improved with direct selection for crossbred performance. However, genetic analyses with phenotypes from crossbred animals require methods for multibreed relationship matrices; especially when some animals are rotationally crossbred. Multiple methods for multibreed relationship matrices exist, but there is a lack of knowledge on how these methods compare for prediction of breeding values with phenotypes from rotationally crossbred animals. Therefore, the objective of this study was to compare models that use different multibreed relationship matrices in terms of ability to predict accurate and unbiased breeding values with phenotypes from two-way rotationally crossbred animals. We compared four methods for multibreed relationship matrices: numerator relationship matrices (NRM), García-Cortés and Toro's partial relationship matrices (GT), Strandén and Mäntysaari's approximation to the GT method (SM), and one NRM with metafounders (MF). The methods were compared using simulated data. We simulated two phenotypes; one with and one without dominance effects. Only crossbred animals were phenotyped and only purebred animals were genotyped. The MF and GT methods were the most accurate and least biased methods for prediction of breeding values in rotationally crossbred animals. Without genomic information, all methods were almost equally accurate for prediction of breeding values in purebred animals; however, with genomic information, the MF and GT methods were the most accurate. The GT, MF, and SM methods were the least biased methods for prediction of breeding values in purebred animals. For prediction of breeding values with phenotypes from rotationally crossbred animals, models using the MF method or the GT method were generally more accurate and less biased than models using the SM method or the NRM method.


Time-dependent change of relative apical longitudinal strain index in patients with wild-type transthyretin amyloid cardiomyopathy.
This study was conducted to investigate the meaning of left ventricular (LV) apical sparing in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). 165 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from January 2002 to December 2020 and had sufficient data for two-dimensional speckle tracking echocardiography were enrolled. Of these, 86 patients (52 %) had LV apical sparing (relative apical longitudinal strain index (RapLSI) > 1.0). Multivariable logistic regression analysis revealed the following variables were significantly associated with LV apical sparing: interventricular septal thickness in diastole (odds ratio (OR), 1.19; 95 % confidence interval (CI), 1.01-1.41; p < 0.05); E/e' ratio (OR, 1.06; 95 % CI, 1.00-1.11; p < 0.05); and heart-to-contralateral ratio by 99mTc-labeled pyrophosphate scintigraphy (OR, 3.40; 95 % CI, 1.07-10.83; p < 0.05).Next, we compared RapLSI at the time of diagnosis with that during the follow-up period (396 days (346-458) after diagnosis) in 92 patients. RapLSI increased significantly during the follow-up period compared with RapLSI at diagnosis in the non-LV apical sparing group (0.89 ± 0.32 vs 0.74 ± 0.18, p < 0.01) but not in the LV apical sparing group (1.33 ± 0.53 vs 1.39 ± 0.45, p = 0.46). A total of 12 patients (29 %) in the non-LV apical sparing group developed LV apical sparing and 11 patients (22 %) in LV apical sparing group diminished LV apical sparing during the follow-up period. Approximately half of ATTRwt-CM patients did not have LV apical sparing at diagnosis. Because RapLSI in ATTRwt-CM significantly changed over time, repeated two-dimensional speckle tracking analysis is important for suspected ATTR-CM patients.


Pneumatosis Intestinalis in a Patient with Acute Promyelocytic Leukemia.
Pneumatosis Intestinalis is a rare condition characterized by the presence of gas within the intestinal wall. We describe a case of a 33-year-old woman with acute promyelocytic leukemia who developed nausea and nonbloody diarrhea. CT showed intramural air in transverse and descending colon. Patient clinically improved with conservative management.


Significance of anomalous thermoregulation in the pre-diabetic spiny mouse (Acomys cahirinus): cold tolerance: blood glucose and food consumption responses to environmental heat.
Decreased cold tolerance, reduced food requirement for body weight maintenance and comparative resistance to the hypoglycaemic effect of fasting in high ambient temperatures have been demonstrated in the spiny mouse. These phenomena could be related to anomalous spiny mouse thermoregulation, a phenomenon which is common in desert rodents and is simulated by mutant and artificially diabetic rodent species. The data can be interpreted as showing evidence for a survival advantage of genotypes with potential diabetic expression, and may provide an explanation of the geographic distribution of certain species.


Ultrasonography, HIDA scintigraphy or both in the diagnosis of acute cholecystitis?
The benefit of early surgery for patients with acute cholecystitis is now accepted but rapid accurate pre-operative diagnosis is important and the single best investigation has not yet been clearly established. All 47 patients with suspected acute cholecystitis admitted to a district general hospital during a 6 month period underwent ultrasonic examination and scintigraphy with HIDA within 48 h of admission. In 23 patients acute cholecystitis was proven. Ultrasound correctly diagnosed this in 21 patients but in 2, changes attributed to chronic cholecystitis only were detected. Two false positive ultrasound results also occurred, one in a patient with adenomyomatosis and acute pancreatitis, the other in a case of duodenitis. HIDA scan was diagnostic in 19 patients but in the remaining 4 the presence of abnormal liver function tests accounted for non-visualization of the biliary tree (a non-diagnostic result). In the absence of jaundice a HIDA scan is the more specific test for confirming acute cholecystitis.


A decision support system on the obesity management and consultation during childhood and adolescence using ontology and semantic rules.
Obesity is defined as abnormal or excessive fat accumulation that presents a risk to health according to the World Health Organization (WHO). Pediatric or childhood obesity is the most prevalent nutritional disorder among children and adolescents worldwide. In pediatric or childhood obesity, constant monitoring of the pediatric patients by health experts is required to provide efficient obesity management and treatment. Therefore, the patients are examined on a regular basis, the measurements are compared against predefined percentile values and the development of the pediatric patient is examined. This study discusses the design, implementation, and potential use of an ontology-based obesity management and consultation system which is a decision support system for health experts during treatments of the children and adolescent patients. The system does not only share instant gathered medical data to health experts but also examines the data as a smart medical assistant. The system includes an ontology-based inference engine module, which is a decision support module, and used to infer certain personalized suggestions for patients. Suggestions in four categories emerged as a result: (1) Development Feedback Suggestions, (2) Calorie Intake Suggestions and Physical Activities, (3) Mom Suggestions, and (4) Obesity Treatment Stage Suggestions. The methodologies applied and main technical contributions are discussed in three aspects: (1) Obesity Tracking Ontology, (2) Semantic Web Rule Knowledge base, and (3) Inference Engine Module. In this study, unlike other similar studies, ontology and rule based smart medical assistant which have different functionalities from adults' obesity management is considered especially for obesity management of children and adolescents. The system also includes intensive pediatric health care expert involvement. Eighty case studies from real anonymous pediatric patients are analyzed and discussed in this experimental study. The results retrieved from 80 case studies are promising in demonstrating the applicability, effectiveness and efficiency of the proposed approach. The inference engine module of the proposed system can be integrated semantically into intelligent and distributed decision support systems, and the system ontology can be used as a knowledge base in similar systems.


Prognosis of women with stage I endometrioid endometrial cancer and synchronous stage I endometrioid ovarian cancer.
Synchronous endometrial and ovarian cancer with endometrioid histology at two cancer sites typically presents with early-stage disease and is thought to have a good prognosis. We examined the survival of women with early-stage endometrioid endometrial cancer who had synchronous early-stage endometrioid ovarian cancer. This is a retrospective case-control study examining the Surveillance, Epidemiology, and End Result Program between 1973 and 2013. Survival of women with stage I endometrioid endometrial cancer with stage I endometrioid ovarian cancer (n=839) were compared to women with stage I endometrioid endometrial cancer without synchronous ovarian cancer (n=123,692) after propensity score matching. Women with synchronous stage I endometrioid ovarian cancer were more likely to be diagnosed recently, be younger, have stage IA disease, grade 1 tumors, to have undergone lymphadenectomy, and were less likely to receive radiotherapy compared to those without synchronous ovarian cancer (all, P<0.001). In a propensity score matched model, the presence of synchronous ovarian cancer was not associated with endometrial cancer-specific survival (10-year rates 96.0% versus 95.3%, P=0.97) or overall survival (85.6% versus 87.2%, P=0.10). Among tumors with concordant grades at the two cancer sites, survival was similar regardless of presence of synchronous ovarian tumors (grade 1 tumors, 10-year rate for overall survival, 88.2% versus 89.1%, P=0.40; and grade 2 tumors, 84.0% versus 85.8%, P=0.78). Women with stage I endometrioid endometrial cancer with synchronous stage I endometrioid ovarian cancer have a survival outcome similar to those with stage I endometrioid endometrial cancer without synchronous ovarian cancer.


Features of 164 bladder ruptures.
We reviewed 164 cases of bladder rupture from external trauma. Of these patients 145 (88 per cent) suffered blunt trauma, and 59 (35.5 per cent) suffered intraperitoneal, 93 (57.5 per cent) extraperitoneal and 12 (7 per cent) both types of rupture. Bladder rupture owing to blunt trauma was caused by a compression (burst) type of injury in all patients with intraperitoneal rupture and in 24 per cent of those with extraperitoneal rupture. In the remaining instances of extraperitoneal rupture pelvic bone fragments corresponded to the site of the injury. Although surgical repair has been the traditional method of management of all bladder ruptures, nonoperative (catheter) management of extraperitoneal rupture was successful in most cases.


Genotype-Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism.
Childhood and adolescent primary hyperparathyroidism (PHPT) is a very rare disease. Data on its molecular genetics are scarce. We performed a retrospective analysis (January 2000-January 2021) to determine the deleterious germline variants and genotype-phenotype correlations in children and adolescents < 20 years diagnosed with PHPT from a single referral center. Clinical features, biochemistry, imaging, management, and genetics (clinical exome analyzed for 11 PHPT and 7 pancreatitis-associated genes, MLPA for CDC73) were recorded. Thirty-six patients (20 males; median age 17 years) were classified into those with familial and/or syndromic (F/S) or apparently sporadic (AS) presentation. Sixteen (44.4%) harbored pathogenic/likely pathogenic germline variants in PHPT-associated genes. The genetic yield in F/S group was 90% (MEN1:8/10; CDC73:1/10), and AS group was 26.9% (CDC73:4/26; CASR:3/26). F/S group had frequent asymptomatic presentation (60% vs none; P < 0.001), lower serum PTH (237.5 vs 1369.1 pg/mL; P = 0.001), and maximum parathyroid dimension (0.9 vs 2.2 cm; P = 0.01) than AS group. Among the AS group, renal involvement was higher in those with molecular diagnoses (71.4% vs 10.5%; P = 0.01). All those with novel CASR variants (including one homozygous) had hypercalciuria and histology-proven parathyroid adenoma/carcinoma. A missense CTRC VUS occurred in one patient with chronic pancreatitis. In summary, Asian Indian children and adolescents with PHPT have high genetic yield, even with apparently sporadic presentation. The phenotypic spectrum of CASR variants is expanded to include childhood/adolescent PHPT with hypercalciuria and single gland neoplasia. The proposed roles for renal involvement to predict molecular diagnosis among those with apparently sporadic presentation require further elucidation.


Thyroid gland volume of schoolchildren in the North of Iran: Comparison with other studies.
Few studies have shown the limitation of the World Health Organization (WHO)/ International Council for the Control of Iodine Deficiency (ICCIDD)-adopted thyroid gland volume references as universal normative values for thyroid gland volume. So we decided to measure thyroid gland volume by sonography in schoolchildren in Rasht, Gilan Province, Iran - Rasht is a metropolitan city on the Caspian Sea coast - and compare them to WHO normative values. In a cross-sectional study, 2,522 schoolchildren, aged 6-13 years, in Rasht, Gilan Province, Iran were selected by multistage random sampling. Data were collected on their age, sex, weight, height, body surface area (BSA), and thyroid gland size by palpation and sonography. The terminal phalange of thumb finger volume was calculated with the same formula used in sonography, for the thyroid gland in 1,085 of these cases. Goiter prevalence was 64% (1613 cases) by palpation, 76.1% (1228 subjects) grade I and 23.9% (385 cases) grade II. The mean thyroid gland volume in girls was more than boys (3.67 ± 1.89 mL vs 3.41 ± 1.58 mL, P < 0.0001). According to the 1997 WHO thyroid gland volume reference, none of the children had goiter based on BSA and age even in those with grade II goiters (23.9%). In contrast, the median thyroid gland volume in our cases was larger than the 2004 WHO reference. The best single predictor of thyroid gland volume was age (R (2) = 0.391, P < 0.0001) followed by BSA (R (2) = 0.151, P < 0.0001). There was also a significant difference between thyroid gland and finger volume in all grades of goiter and grade II goiters (3 ± 1.4 mL vs 9.59 ± 2.4 mL; P < 0.0001. 4.3 ± 1.4 mL vs 9.3 ± 2.5 mL; P < 0.0001). The WHO standards for thyroid gland volume by sonography may underestimate or overestimate the goiter prevalence in many areas and populations. Finger volume was much larger than thyroid gland volume in even visible goiters.