Modified Blalock shunts utilizing pericardial tube grafts.
In the last decade, 14 patients underwent an aorticpulmonary shunt for cyanotic heart disease, at which time the subclavian artery was either deemed too small or too short to function satisfactorily as a Blalock shunt. In each case a rectangular piece of pericardium was excised, rolled into a tube, and sutured down one edge to create a tube graft. One end of the graft was sutured to the stump of the subclavian artery near its takeoff and the other end was sutured end-to-side to the corresponding pulmonary artery. During the same period, 5 children had azygos vein grafts and 2 had Teflon grafts inserted to create a modified Blalock shunt. This article will discuss the indications, techniques, and long term results of aorticpulmonary shunts of all types, and more specifically the complications and long term results in patients where these grafts were used.


Metabolic correlates of lesion-specific plasticity: an in vivo imaging study.
High-resolution positron emission tomography (microPET) allows for repeated observations of brain function in the same animal. In a previous study, using [(18)F] fluorodeoxyglucose (FDG) microPET, we demonstrated diminished glucose metabolism and subsequent recovery in the Neostriatum and thalamus ipsilateral to cortical aspiration (ASP) lesions. Thermocoagulation (TCL) of pial vessels has been shown to result in the same degree of cortical injury but induce more compensatory re-organization than ASP. In the present work, FDG microPET was used to compare glucose metabolism following both TCL and ASP lesions in order to determine whether metabolic differences correlate with the previously described anatomical and functional changes in the two lesion models. Animals were scanned 3-day, 10-day and 1-month post-injury. Estimated cortical lesion size did not differ between the two models at 1 month following injury. Both lesions induced ipsilateral neostriatal and thalamic hypometabolism 3-day post-injury, with subsequent metabolic improvement over time. However, complete recovery was not observed by 1 month in either group. ASP lesions resulted in an overall greater metabolic deficit in the subcortical structures and a greater cortical deficit 1 month following injury when compared to the TCL. Contralateral cortical glucose metabolism at 3 days following injury was not different in the two lesions. These data demonstrate that the two lesions differ somewhat in their metabolic response to injury, and that the relative hypometabolism observed following ASP may be a reflection of the diminished capacity of the contralateral cortex to compensate for ASP as compared to TCL.


Adult coeliac disease, osteomalacia, hyperparathyroidism and acromegaly. Evidence for urinary losses of hydrosoluble metabolites of vitamin D3.
Vitamin D-deficient osteomalacia with pronounced secondary hyperparathyroidism was observed in an acromegalic patient suffering from adult celiac disease. Two oral tests with tritiated vitamin D3 showed a nearly normal absorption coefficient, contrasting with a marked steatorrhea mainly due to functional and reversible pancreatic insufficiency. The urinary excretion of the radioactive label was strikingly increased and accounted for the completely flat curve of plasma radioactivity. This urinary loss of mainly water-soluble metabolite(s) of vitamin D3 represents a unique and presently unexplained feature.


Mesenchymal Stem Cells Promote Wound Healing and Effects on Expression of Matrix Metalloproteinases-8 and 9 in the Wound Tissue of Diabetic Rats.
Diabetic foot ulcer (DFU) is a multifactorial complication of diabetes, mainly manifested as infection, ulcer, or destruction of deep tissue, and there is currently no effective treatment. Several preclinical and clinical studies have proved that the transplantation of mesenchymal stem cells (MSCs) improved wound healing. In this study, we evaluated the therapeutic efficacy of human umbilical cord (hUC-MSCs) in DFU rat model. One dose of hUC-MSCs (1 × 106 cells) was subcutaneously injected around wounds in male Sprague-Dawley rats. Wound healing was evaluated macroscopically (wound closure) every 3 days. In addition, we measured growth factors and specific proteins [matrix metalloproteinases (MMPs)-9 and MMP-8] on Day 14 post hUC-MSC transplantation. Results showed significant differences in the wound healing kinetics of lesions that received hUC-MSCs compared to lesions that received vehicle (phosphate buffered saline; P < 0.05). Enzyme-linked immunosorbent assay analyses indicated that MMP-9 protein contents were significantly upregulated in DFU animals, while MMP-8 was downregulated compared to the diabetic rats (P < 0.05). After MSC treatment, the level of MMP-9 and MMP-8 decreased and increased compared to the vehicle group, respectively. These findings suggest that hUC-MSC transplantation can ameliorate the healing process of DFU rats and a potential mechanism through which MSCs enhance DFU wound healing by decreasing MMP-9 expression and increasing MMP-8 expression. This study represents a promising opportunity to gain insight into how MSCs mediate wound healing.


Changes in the glycosaminoglycans distribution pattern in the human uterine cervix during pregnancy and labor.
The glycosaminoglycans distribution pattern of uterine cervix samples obtained from 42 women of reproductive age was determined by means of proteolytic digestion and subsequent chromatographic separation. The following glycosaminoglycans were detected: chondroitin 4- and 6-sulfates, dermatan sulfate, hyaluronate, chondroitin, and keratan sulfate. The connective tissue of the uterine cervix shows a characteristic distribution pattern with regard to glycosaminoglycans which does not correspond to that found in any other tissue studied so far. Based on dry weight, the content of keratan sulfate increases during pregnancy while the concentration of chondroitin remains unchanged. The chondroitin sulfates and dermatan sulfate drop simultaneously. During labor chondroitin increases threefold. The hyaluronate content of the postpartum cervix is higher than that of the cervix in nonpregnant women. Both changes in the solubility of collagen as well as in the distribution pattern of the glycosaminoglycans seem to be related to cervical dilatation.


The Australian Trauma Registry (ATR): a leading clinical quality registry.
Operating since 2012 under the auspices of the Australian Trauma Quality Improvement Program (AusTQIP), the Australian Trauma Registry (ATR) has established itself as a leading clinical quality registry (CQR). Initially developed as a national program for improved safety and quality trauma care across Australian trauma centers, it has since expanded to include New Zealand, becoming one of the few bi-national trauma registries. The registry has recorded close to 100,000 episodes of care for severely injured patients since its inception, with 10.7% growth in annual inclusions. The ATR, administered by the National Trauma Research Institute (NTRI), monitors the continuum of trauma care from pre-hospital settings, to discharge from definitive care. Collection and analysis of data about severely injured trauma patients, their injuries, management and outcomes, aims to inform future improvements to health service provision and reduce preventable morbidity and mortality.


Novel nuclear hENT2 isoforms regulate cell cycle progression via controlling nucleoside transport and nuclear reservoir.
Nucleosides participate in many cellular processes and are the fundamental building blocks of nucleic acids. Nucleoside transporters translocate nucleosides across plasma membranes although the mechanism by which nucleos(t)ides are translocated into the nucleus during DNA replication is unknown. Here, we identify two novel functional splice variants of equilibrative nucleoside transporter 2 (ENT2), which are present at the nuclear envelope. Under proliferative conditions, these splice variants are up-regulated and recruit wild-type ENT2 to the nuclear envelope to translocate nucleosides into the nucleus for incorporation into DNA during replication. Reduced presence of hENT2 splice variants resulted in a dramatic decrease in cell proliferation and dysregulation of cell cycle due to a lower incorporation of nucleotides into DNA. Our findings support a novel model of nucleoside compartmentalisation at the nuclear envelope and translocation into the nucleus through hENT2 and its variants, which are essential for effective DNA synthesis and cell proliferation.


The role of bedside assistant during robot assisted radical prostatectomy: Is more experience better? Analysis on perioperative and clinical outcomes.
To analyze the impact of the bedside assistant's experience during RARP. It is believed that the outcome of robotic surgery during Robot Assisted Radical Prostatectomy (RARP) for prostate cancer depends not only on the console surgeon's experience. All consecutive RARPs from January 2017 to March 2018 were sourced from a prospectively maintained database. All cases were performed by the same surgeon. He was supported by three bedside assistants: one with bedside and console experience, one only with relevant bedside experience, one basically inexperienced. The patient's parameters analyzed: age, Body Mass Index (BMI), previous abdominal surgery, prostate volume (by TRUS), pre-operative PSA, bioptic grading. Surgical outcomes analyzed included skin-to-skin operative time and estimated blood loss; clinical outcomes included length of hospital stay and time to catheter removal; the oncological outcome was represented by positive surgical margin rate. A total of 116 RARPs were identified: 38 RARPs were performed with the console experienced bedside assistant, 38 with the experienced one, 40 with the novice one. The variables were similar between the three groups. As far as outcomes are concerned, there were no statistically significant differences between the three bedside assistants in terms of operative time, estimated blood loss, length of stay, days of catheterization, positive surgical margin rate.


Extraspinal ependymoma.
Two cases of extraspinal ependymoma are described. This is a low-grade tumor that recurs locally unless wide local excision is performed. It does metastasize, mainly to lymph nodes and lung. Its origin is likely from heterotopic ependymal cells called the coccygeal medullary vestige.


Safety and efficacy of software-assisted MRI-TRUS fusion-guided transperineal prostate biopsy in an outpatient setting using local anaesthesia.
To evaluate diagnostic accuracy, safety, and efficiency of an MRI-TRUS fusion-guided transperineal prostate biopsy method in an outpatient setting under local anaesthesia. Patients undergoing transperineal prostate biopsy were included from March 2021 to May 2022. Biopsies were performed under local anaesthesia in an outpatient setting, using specialised fusion software. Primary outcome was (clinically significant) cancer detection rate. Secondary outcomes were procedure time, patient discomfort during the procedure and complication rate. We included 203 male patients (69 years +-SD 8.2) with PI-RADS score > 2. In total 223 suspicious lesions were targeted. Overall cancer detection rate and clinically significant cancer detection rate were 73.5% and 60.1%, respectively. (Clinically significant) cancer detection rates in PI-RADS 3, 4 and 5 lesions were 46.4% (23.2%), 78.5% (66.1%) and 93.5% (89.1%), respectively. Mean duration of the procedure including fusion, targeted and systematic biopsies was 22.5 min. Patients rated injection of local anaesthesia on a numeric pain rating scale on average 3.7/10 (SD 2.09) and biopsy core sampling 1.6/10 (SD 1.65). No patient presented with acute urinary retention on follow-up consultation. Two (1%) patients presented with infectious complications. Four (2%) patients experienced a vasovagal reaction. Transperineal targeted biopsy with MRI-TRUS fusion software has high overall and clinically significant cancer detection rates. The method is well tolerated under local anaesthesia and in an outpatient setting.


Combined adjuvant radiation and interferon-alpha 2B therapy in high-risk melanoma patients: the potential for increased radiation toxicity.
Surgically resected melanoma patients with high-risk features commonly receive adjuvant therapy with interferon-alpha 2b combined with radiation therapy; the purpose of our study was to evaluate the potential enhancement of radiation toxicity by interferon. Patients at LDS Hospital and the University of Utah Medical Center in Salt Lake City treated with interferon during radiotherapy or within 1 month of its completion were retrospectively identified, and their charts were reviewed. If possible, the patients were asked to return to the LDS Hospital radiation therapy department for follow-up. Five of 10 patients receiving interferon-alpha 2b therapy during radiation therapy or within 1 month of its completion experienced severe subacute/late complications of therapy. Severe subacute/late complications included two patients with peripheral neuropathy, one patient with radiation necrosis in the brain, and two patients with radiation necrosis in the s.c. tissue. One patient with peripheral neuropathy and one patient with radiation necrosis also developed lymphedema. In vitro studies have identified a radiosensitizing effect by interferon-alpha on certain cell lines, which suggests the possibility that patients treated with interferon and radiation therapy may experience more severe radiation toxicities. We have observed severe subacute/late complications in five of 10 patients treated with interferon-alpha 2b during radiation therapy or within 1 month of its completion. Although an observational study of 10 patients lacks the statistic power to reach conclusions regarding the safety and complication rates of combined interferon and radiation therapy, it is sufficient to raise concerns and suggest the need for prospective studies.


Effect of estrogen upon methamphetamine-induced neurotoxicity within the impaired nigrostriatal dopaminergic system.
In the present study, we investigated whether estrogen remains effective as a neuroprotectant within an impaired nigrostriatal dopaminergic (NSDA) system of gonadectomized female and male mice. In Experiment 1, mice were treated with four different regimens of methamphetamine (MA) to establish a protocol for an impaired NSDA system to be used in subsequent experiments. Based upon the results of Experiment 1, in Experiment 2 gonadectomized female mice received a treatment with either control (saline), low- or high-dose of MA to produce an initial NSDA impairment. At one week post-MA, mice received either estradiol benzoate (10 microg) or vehicle followed 24 h later with low-MA or saline. Estrogen altered the toxic effects of the second invasion of MA as indicated by a significant decrease in striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations. In addition, DA and DOPAC depletion was greater in high- vs. low-dose MA. In gonadectomized male mice (Experiment 3), striatal DA and DOPAC concentrations showed greater decreases following high-, vs. low-doses of MA; however, estrogen did not alter these responses. These results demonstrate that the capacity for estrogen to protect or worsen MA-induced neurotoxicity of dopaminergic neurons is limited to female mice and depends on the condition of the NSDA system.


Frontostriatal deficits in unipolar major depression.
Recent accounts of major depression have tended to focus on dysfunction of frontothalamic-striatal reentrant circuits as a possible source of the disorder. Evidence of frontostriatal involvement in unipolar major depression from lesion and neuropsychological studies, and functional and structural imaging studies is examined. The high incidence of depressive symptomatology following left frontal and basal ganglia lesions implicate these as possible sites of dysfunction. Neuropsychological evidence indicates similar deficits in patients with major depression, perhaps with dorsolateral prefrontal deficits most prominent. Structural imaging studies report frontal and basal ganglia (BG) abnormalities particularly in cases of late-age onset depression. Resting state functional imaging studies show deficits in dorsolateral, anterior cingulate (medial frontal), and BG structures. Activation imaging studies show less consistent evidence of dorsolateral deficit, while anterior cingulate deficit is more consistently demonstrated. Variability in findings across studies may reflect differences between subtypes of depression and differences in methodology. Possible involvement of the BG in the psychomotor retardation of depression is examined. It is concluded that, while there is evidence of frontostriatal deficit in major depression, the exact nature of such deficits is uncertain. Issues such as component vs. system dysfunction need to be addressed.


The contribution of prostaglandins in the muscle of human isolated small intestine to neurogenic responses.
1. In stris cut parallel to the longitudinal or circular muscle, indomethacin (2--10 microgram/ml) usually lowered the tone, thus probably accounting for the reduction of nerve-mediated relaxations to electrical field stimulation. 2. In longitudinal muscle strips, indomethacin enhanced contractions which occurred during electrical stimulation, probably because tone fell, but antagonized after-contractions. By contrast, in the circular muscle indomethacin reduced initial contractions but enhanced after-contractions. 3. Prostaglandin E2 counteracted all of the effects of indomethacin in the longitudinal muscle and most of those in the circular muscle; prostaglandin F2alpha restored circular muscle tone. 4. The results suggest that prostaglandins affect the muscle directly and contribute to the regulation of tone. They may also mediate non-cholinergic contraction in longitudinal muscle and suppress contractility in the circular muscle.


c-Jun N-terminal kinase upregulation as a key event in the proapoptotic interaction between transforming growth factor-beta1 and 4-hydroxynonenal in colon mucosa.
Cells of colonic mucosa are sensitive to the Smad-mediated growth-inhibitory effect of transforming growth factor-beta1 (TGF-beta1). Another important cell growth inhibitor is the polyunsaturated lipid peroxidation end product, 4-hydroxynonenal (HNE), which triggers apoptosis through c-Jun N-terminal kinase (JNK) activation. Interestingly, a close association between TGF-beta1 and HNE was found in the progression of human colon cancer, with concentration of both molecules inversely related to the malignancy. We investigated the cross talk between Smads and JNK signal transduction pathways in inducing apoptosis. To this purpose TGF-beta1 and HNE were added singly or in combination to CaCo-2 human colon adenocarcinoma cells. The cotreatment induced a marked enhancement of apoptosis and of JNK and Smad4 activities much more than either individual molecule. Cell preincubation with the JNK inhibitor SP600125 significantly prevented JNK and Smad4 enhancement and, subsequently, the cooperative proapoptotic effect was abolished. The primary role of JNK activity in TGF-beta1/HNE cooperative signaling was fully confirmed in a second set of experiments by using JNKi I, a more selective kinase inhibitor. Hence, in tumor cells becoming resistant to TGF-beta1-mediated growth inhibition, increased induction of the remaining TGF-beta1 pathways by interaction with other antiproliferative molecules, such as HNE, could help in inhibiting tumor growth.


Enhancement of IGE-induced mediator release from rat peritoneal mast cells by serum-treated zymosan.
Phagocytosis of zymosan (Z) treated with rat serum (ZX) by rat peritoneal mast cells caused only a small amount of [3H]serotonin release, and prior release of mediators from mast cells did not affect phagocytosis of sheep erythrocytes bearing IgG and C3b, indicating the independence of these two phenomena. When, however, mast cells were exposed to ZX, subsequent IgE-mediated release of histamine, [3H]serotonin, and beta-hexosaminidase was greatly enhanced. Prevention of complement activation by the presence of EDTA during the treatment of Z with the serum or prior heating of the serum at 56 degrees C for 30 min only slightly impaired the ability of ZX to augment mediator release, whereas prior absorption of the serum with zymosan at 0 degree C greatly diminished the enhancement. Exposure of fresh Z to variable amounts of either the acid or the high-salt eluate of ZX also generated ZX capable of enhancing [3H]serotonin release in a dose-dependent fashion. IgG, IgM, C3, and albumin were detected in the eluates by immunodiffusion. When IgG was depleted from the high-salt eluate by treating with Sepharose-anti-IgG, the enhancement was significantly reduced, indicating that IgG but not C3 or other immunoglobulins was required for the enhancement.


Fentiazac as a therapeutic aid in the treatment of tuberculosis.
The authors point out the clinical usefulness and optimal tolerability of Fentiazac in patients suffering from tuberculosis and whose condition requires therapeutic intervention with non-steroid anti-inflammatory drugs.


On-line immunoanalysis of monoclonal antibodies during a continuous culture of hybridoma cells.
The monoclonal-antibody production of an immobilized hybridoma cell line cultivated in a fluidized-bed reactor was monitored on-line for nearly 900 h. The monoclonal antibody concentration was determined by an immuno affinity-chromatography method (ABICAP). Antibodies directed against the product, e.g. IgG, were immobilized on a micro-porous gel and packed in small columns. After all IgG present in the sample was bound to the immobilized antibodies, unbound proteins were removed by rinsing the column. Elution of the bound antibodies followed and the antibodies were determined by fluorescence. The analytical procedure was automated with a robotic device to enable on-line measurements. The correlation between the on-line determined data and antibody concentrations measured by HPLC was linear.A sampling system was constructed, which was based on a pneumatically actuated in-line membrane valve integrated into the circulation loop of the reactor. Separation of the cells from the sample stream was achieved by a depth filter made of glass-fibre, situated outside the reactor. Rapid obstruction of the filter by cells or cell debris and contamination of the sample system was avoided by intermittent rinsing of the sample system with a chemical solution. The intermittent rinsing of the filter, which had a surface of 4.8 cm(2), resulted in an operational capacity of up to 40 samples (1.0 l total sample volume). Both the sampling system and the analytical device functioned without failure during this long-term culture.The culture temperature was varied between 34 and 40 °C. Raising the temperature from 34 up to 37 °C resulted in a simultaneous increase of growth and specific antibody production rate. Specific metabolic rates of glucose, lactate, glutamine and ammonium stayed constant in this temperature range. A further enhancement of temperature up to 40 °C had a negative effect on the growth rate, whereas the specific monoclonal antibody production rate showed a small increase. The other specific metabolic rates also increased in the temperature range between 38 to 40 °C.


Imaging of pH distribution inside individual microdroplet by stimulated Raman microscopy.
Aerosol microdroplets as microreactors for many important atmospheric reactions are ubiquitous in the atmosphere. pH largely regulates the chemical processes within them; however, how pH and chemical species spatially distribute within an atmospheric microdroplet is still under intense debate. The challenge is to measure pH distribution within a tiny volume without affecting the chemical species distribution. We demonstrate a method based on stimulated Raman scattering microscopy to visualize the three-dimensional pH distribution inside single microdroplets of varying sizes. We find that the surface of all microdroplets is more acidic, and a monotonic trend of pH decreasing is observed in the 2.9-μm aerosol microdroplet from center to edge, which is well supported by molecular dynamics simulation. However, bigger cloud microdroplet differs from small aerosol for pH distribution. This size-dependent pH distribution in microdroplets can be related to the surface-to-volume ratio. This work presents noncontact measurement and chemical imaging of pH distribution in microdroplets, filling the gap in our understanding of spatial pH in atmospheric aerosol.


Lipocalin-2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high-fat diet-fed Ob/Ob mice.
In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of NASH via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH. Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. The LX-2 human HSCs and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic α-SMA/matrix metalloproteinase 9 (MMP9)/signal transducer and activator of transcription 3 (STAT3) protein levels. HFD-fed DKO mice showed a marked reduction of α-SMA protein compared with HFD-fed ob/ob mice. In particular, the colocalization of LCN2 and α-SMA was increased in HSCs from HFD-fed ob/ob mice. In primary HSCs from ob/ob mice, exogenous LCN2 treatment induced HSC activation and MMP9 secretion. By contrast, LCN2 receptor 24p3R deficiency or a STAT3 inhibitor reduced the activation and migration of primary HSCs. LCN2 acts as a key mediator of HSC activation in leptin-deficient obesity via α-SMA/MMP9/STAT3 signaling, thereby exacerbating NASH.


Topoisomerases interlink genetic network underlying autism.
DNA topoisomerases belong to the group of proteins that play an important role in the organizational dynamics of the human genome. Their enzymatic activity solves topological strain rising from DNA supercoiling occurring during transcription. DNA topoisomerases are especially important for transcription of genes involved in neurodevelopment. Disruption of topoisomerase activity in animal models resulted in impaired neurodevelopment and changed brain architecture. Recent research revealed that topoisomerases induced expression of the same group of genes as those associated with autism. Transcriptional inhibition of neuronal genes during critical stages of brain development may be responsible for pathology of neurodevelopmental disorders such as autism. In this review we aim to outline the role of topoisomerase in neurodevelopment and its possible linkage to neuropathology of autism.


Peroxisome proliferator activated receptor (PPAR)-gamma concentrations in childhood obesity.
Peroxisome proliferator-activated receptors (PPARs) are nuclear proteins that regulate transcriptional responses to peroxisome proliferators. There has been limited research concerned with the childhood expression of these receptors. In this study, we aimed to evaluate PPAR-gamma (PPAR-γ) concentrations and their relationship to body mass index (BMI), ratio of waist and hip, blood pressure levels, insulin resistance and lipid profile in obese children and adolescents. Children aged 8-16 years old were included in the study; 44 obese children and 25 healthy children were taken into the study. Blood pressure and waist-hip circumference of obese patients were measured. Following a 12-hour nighttime fasting, venous blood samples were taken, including blood glucose, insulin, lipid profile, liver function tests and PPAR-γ concentrations, and all samples were analyzed at the same time. PPAR-γ concentrations were 0.226 + 0.128 in obese children and 0.547 + 0.546 in the control group. PPAR-γ concentrations were lower in obese children and this difference was statistically significant (p = 0.008). PPAR-γ concentrations of control children were 2.42-fold higher than obese children. There was a negative correlation between PPAR-γ concentrations and waist circumference, and a positive correlation between birth weight and PPAR-γ concentrations in obese children. In our study we found that PPAR-γ concentrations were low in obese children. In adults, treatment modalities aimed at enhancing the activation of PPAR in obesity lead to a decrease in obesity, insulin resistance, dyslipidemia and cardiovascular disease and this gives hope that similar treatment modalities can be used for children.


Directed vaccination against pneumococcal disease.
Immunization strategies against commensal bacterial pathogens have long focused on eradicating asymptomatic carriage as well as disease, resulting in changes in the colonizing microflora with unknown future consequences. Additionally, current vaccines are not easily adaptable to sequence diversity and immune evasion. Here, we present a "smart" vaccine that leverages our current understanding of disease transition from bacterial carriage to infection with the pneumococcus serving as a model organism. Using conserved surface proteins highly expressed during virulent transition, the vaccine mounts an immune response specifically against disease-causing bacterial populations without affecting carriage. Aided by a delivery technology capable of multivalent surface display, which can be adapted easily to a changing clinical picture, results include complete protection against the development of pneumonia and sepsis during animal challenge experiments with multiple, highly variable, and clinically relevant pneumococcal isolates. The approach thus offers a unique and dynamic treatment option readily adaptable to other commensal pathogens.


A rapid method for preparation of urinary bladder epithelium for flow cytometric analysis.
A rapid and reliable method is described for preparation of urinary bladder epithelium for flow cytometric analysis. This method has proven useful for measurement of cell cycle kinetics in bladder epithelium from normal fetal, neonatal and adult mice as well as animals that have been exposed to urinary bladder toxicants. A modified Vindelov 's propidium iodide stain was instilled directly into the urinary bladder through the urethra, allowing the propidium iodide to lyse the epithelial cells and stain the DNA in the liberated nuclei. The stained epithelial cell nuclei were then removed from the lumen and analyzed by flow cytometry without centrifugation or filtration techniques. This method allows examination of epithelial cell nuclei without contamination from other tissue elements due to the fact that the propidium iodide did not act beyond the epithelial basement membrane under our experimental conditions.


Synthesis of water-soluble poly(p-phenyleneethynylene) in neat water under aerobic conditions via Suzuki-Miyaura polycondensation using a diborylethyne synthon.
We report the synthesis, structure, and characterization of a novel ethyne synthon, 1,2-bis(4',4',5',5'-tetramethyl[1',3',2']dioxaborolan-2'-yl)ethyne (B2C2). We demonstrate the utility of B2C2 in the Suzuki-Miyaura polycondensation reaction, synthesizing a water-soluble poly(p-phenyleneethynylene) from [2,5-diiodo-1,4-bis(3-propoxy-sulfonicacid)benzene] sodium salt in neat water under an aerobic atmosphere.


Effects of redecoration of a hospital isolation room with natural materials on stress levels of denizens in cold season.
We investigated the effects of redecoration of a hospital isolation room with natural materials on thermoregulatory, cardiovascular and hormonal parameters of healthy subjects staying in the room. Two isolation rooms with almost bilaterally-symmetrical arrangements were used. One room (RD) was redecorated with wood paneling and Japanese paper, while the other (CN) was unchanged (with concrete walls). Seven healthy male subjects stayed in each room for over 24 h in the cold season. Their rectal temperature (T(re)) and heart rate, and the room temperature (T(a)) and relative humidity were continuously measured. Arterial blood pressures, arterial vascular compliance, thermal sensation and thermal comfort were measured every 4 h except during sleeping. Blood was sampled after the stay in the rooms. In RD, T(a) was significantly higher by about 0.4 degrees C and relative humidity was lower by about 5% than in CN. Diurnal T(re) levels of subjects in RD significantly differed from those in CN, i.e., T(re)s were significantly higher in RD than in CN especially in the evening. In RD, the subjects felt more thermally-comfortable than in CN. Redecoration had minimal effects on cardiovascular parameters. Plasma levels of catecholamines and antidiuretic hormone did not differ, while plasma cortisol level was significantly lower after staying in RD than in CN by nearly 20%. The results indicate that, in the cold season, redecoration with natural materials improves the thermal environment of the room and contributes to maintaining core temperature of denizens at preferable levels. It also seems that redecoration of room could attenuate stress levels of isolated subjects.


Cabazitaxel-conjugated nanoparticles for docetaxel-resistant and bone metastatic prostate cancer.
Effective treatment of metastatic castration resistant prostate cancer (mCRPC) remains an unmet challenge. Cabazitaxel (CBZ) is approved for mCRPC after docetaxel (DTX) failure, but the improvement in survival is only moderate (∼2 months) and patients suffer from significant side effects. Here, we report the development of a polymer based delivery system for CBZ to improve its safety and efficacy against DTX-resistant mCRPC. CBZ was conjugated to a carboxymethylcellulose-based polymer (Cellax-CBZ), which self-assembled into ∼100 nm particles in saline and exhibited sustained drug release in serum at 10%/day. Cellax-CBZ delivered 157-fold higher CBZ to PC3-RES prostate tumor in mice and could be safely administered at a 25-fold higher dose compared to free CBZ, resulting in superior tumor inhibition in multiple mice models of DTX-resistant CRPC. In a metastatic bone model of CRPC, Cellax-CBZ significantly improves overall survival with a 70% long-term survival rate to day 120, while mice treated with free CBZ had a median survival of 40 days. Cellax-CBZ induced mild and reversible neutropenia in mice but no other tissue damage. Cellax-CBZ showed significant potential for improving therapy of mCRPC over clinically approved CBZ.


Unusual presentation of osteoid osteoma of the scaphoid.
The small carpal bones are infrequent sites for osteoid osteomas, and their clinical and imaging pictures may be quite confusing leading to suspect other etiologies. The authors present herein an unusual case of osteoid osteoma of the scaphoid superimposed on a wrist injury caused by a fall on the outstretched hand.


Confocal laser endomicroscopy for the diagnosis of colorectal cancer in vivo.
To evaluate the feasibility and accuracy of confocal laser endomicroscopy (CLE) for the in vivo diagnosis of colorectal cancer (CRC) compared with conventional histology. Consecutive patients who had undergone CLE examination for screening or surveillance colonoscopy were recruited. Suspected malignant lesions and adjacent mucosal sites were first examined by confocal imaging and then biopsied specimens of these sites were obtained. The confocal images were independently interpreted by two endoscopists. The diagnosis made with CLE was compared with the conventional histological diagnosis in a prospective and blinded fashion. In total, 71 patients with suspected malignant lesions were included in the study. A total of 74 lesions and 92 adjacent mucosal sites were observed. The sensitivity, specificity and accuracy of CLE in diagnosing CRC were 97.1%, 99.0% and 98.2% for endoscopist A, and 98.6%, 96.9% and 97.6% for endoscopist B, respectively. The interobserver agreement between the two endoscopists was excellent (κ = 0.950). The accuracy of diagnosing poorly differentiated CRC using CLE was 97.0% for endoscopist A and 95.6% for endoscopist B. CLE has the potential to enable an immediate diagnosis of CRC and the degree of differentiation of CRC during ongoing endoscopy in vivo.


Correction: Wilk et al. "The Effects of High Doses of Caffeine on Maximal Strength and Muscular Endurance in Athletes Habituated to Caffeine" Nutrients, 2019, 11(8), 1912.
The authors wish to make a correction to the published version of their paper [...].


Type 2 cytokines promote angiogenesis in ischemic muscle via endothelial IL-4Rα signaling.
Peripheral arterial disease (PAD) is one of the leading causes of cardiovascular morbidity and mortality worldwide, yet current trials on therapeutic angiogenesis remain suboptimal. Type 2 immunity is critical for post-ischemic regeneration, but its regulatory role in revascularization is poorly characterized. Here, we show that type 2 cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13), are the key mediators in post-ischemic angiogenesis. IL-4/IL-13-deficient mice exhibit impaired reperfusion and muscle repair in an experimental model of PAD. We find that deletion of IL-4Rα in the endothelial compartment, rather than the myeloid compartment, leads to remarkable impairment in revascularization. Mechanistically, IL-4/IL-13 promote endothelial cell proliferation, migration, and tube formation via IL-4Rα/STAT6 signaling. Furthermore, attenuated IL-4/IL-13 expression is associated with the angiogenesis deficit in the setting of diabetic PAD, while IL-4/IL-13 treatment rescues this defective regeneration. Our findings reveal the therapeutic potential of type 2 cytokines in treating patients with muscle ischemia.


Non-intubated video-assisted thoracoscopic surgery under combination of erector spinae plane block and thoracic paravertebral block.
The use of anesthetics and analgesic drugs and techniques in combination yields a multimodal effect with increased efficiency. In this case series, we aimed to evaluate the anesthetic effect of the thoracic paravertebral block (TPVB) and erector spinae plane block (ESPB) combination in patients, who underwent non-intubated video-assisted thoracoscopic surgery (NIVATS). Medical records of 16 patients, who underwent NIVATS for wedge resection under the combination of ESPB and TPVB were reviewed retrospectively. Demographic data of patients, duration of the sensory block, amount of the anesthetic agent used for premedication and sedo-analgesia, any presence of perioperative cough, operative times, postoperative visual analog scale (VAS) scores in the postoperative follow-up period, the need for additional analgesia, and patient satisfaction were reviewed. Of the patients included in the study, 12 were men and 4 were women. The mean age was 48.6 years and the mean BMI was 24.7 kg/m2. The mean time needed for the achievement of the sensorial block was 14 min and the mean skin-to-skin operative time was 21.4 min. During the procedure, patients received 81.5 ± 27.7 mg of propofol and 30 ± 13.6 micrograms of remifentanil infusions, respectively. The mean dose of ketamine administered in total was 58.1 ± 12.2 mg. Only 2 patients needed an extra dose of remifentanil because of recurrent cough. No patients developed postoperative nausea vomiting. During the first 24 h, the VAS static scores of the patients were 3 and below, while VAS dynamic scores were 4 and below. Morphine consumption in the first postoperative 24 h was 13.2 mg. In conclusion, combined ESPB and TPVB with added intravenous sedo-analgesia in the presence of good cooperation between the surgical team and the anesthesiologist in the perioperative period can provide optimal surgical conditions including the prevention of cough in NIVATS. It is not sufficient to state that this combination is superior to alone ESPB or alone TPVB, as it is a preliminary study with a limited number of cases.


Midazolam versus diazepam as premedication for upper gastrointestinal endoscopy: a randomized, double-blind, crossover study.
The effectiveness of midazolam as premedication for upper gastrointestinal endoscopy was examined and compared with that of diazepam in a double-blind crossover study involving 23 patients. The degree of sedation and cooperation of patients during the procedure and the speed of recovery from sedation were comparable for the two drugs. The effects of both compounds on arterial blood pressure and heart rate were quite similar. However, midazolam induced significantly more amnesia than diazepam (91% vs. 39%). Also, patients' acceptability for the procedure was significantly higher in the midazolam than in the diazepam group (78% vs. 26%). Therefore, when amnesia is desirable, as in the case of repeated endoscopies, midazolam should be the drug of choice.


Two opposing gene expression patterns within ATRX aberrant neuroblastoma.
Neuroblastoma is the most common extracranial solid tumor in children. A subgroup of high-risk patients is characterized by aberrations in the chromatin remodeller ATRX that is encoded by 35 exons. In contrast to other pediatric cancer where ATRX point mutations are most frequent, multi-exon deletions (MEDs) are the most frequent type of ATRX aberrations in neuroblastoma. 75% of these MEDs are predicted to produce in-frame fusion proteins, suggesting a potential gain-of-function effect compared to nonsense mutations. For neuroblastoma there are only a few patient-derived ATRX aberrant models. Therefore, we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid and performed total RNA-sequencing on these and the patient-derived models. Gene set enrichment analysis (GSEA) showed decreased expression of genes related to both ribosome biogenesis and several metabolic processes in our isogenic ATRX exon 2-10 MED model systems, the patient-derived MED models and in tumor data containing two patients with an ATRX exon 2-10 MED. In sharp contrast, these same processes showed an increased expression in our isogenic ATRX knock-out and exon 2-13 MED models. Our validations confirmed a role of ATRX in the regulation of ribosome homeostasis. The two distinct molecular expression patterns within ATRX aberrant neuroblastomas that we identified imply that there might be a need for distinct treatment regimens.


Effect of linocmycin on the chlorophyll protein complex I content and photosystem I activity of greening leaves.
1. Greening barley and pea leaves treated with lincomycin have a reduced chlorophyll content. Lincomycin dose not alter the proportion of chlorophyll in chlorophyll-protein complex II (CPII) but greatly reduces that in chlorophyll-protein complex I (CPI). 2. Difference spectra show that chloroplasts from lincomycin-treated leaves are deficient in at least two long wavelength forms of chlorophyll ratio of chloroplasts is unaffected by lincomycin but the photochemical P-700/chlorophyll ratio is less than half of that of the control. It is less affected than the chlorophyll-protein complex I content. 4. Photosystem I activity expressed on a chlorophyll basis is unaffected by linocomycin but the light intensity for half saturation is increased 8-fold. 5. Chlorophyll-protein complex I apoprotein content is reduced by lincomycin. No evidence was found for an accumulation of its precursor(s). The relative abundance of major peptides of 18 000, 15 000 and 12 000 daltons in lincomycin-treated chloroplasts is attributed to a general inhibition of greening and associated membrane of formation.


Body Mass Index standards based on agreement with health-related body fat.
Multiple screening tools, such as BMI and skinfold-derived percent body fat (%BF), are available to identify youth at risk of excess adiposity. However, poor classification agreement among these tools can be problematic for those interpreting test results. The purpose of this study was to investigate the validity of using BMI as an estimate of %BF in youth and to identify optimal BMI thresholds for identifying at-risk children and adolescents based on %BF. Percent body fat was derived from the skinfold thicknesses of children aged 5-18 years from three cross-sectional waves of the National Health and Nutrition Examination Survey (NHANES [1999-2004]; N=8269). Stature and body mass from the same data set were used to calculate BMI. Receiver operating characteristic (ROC) analysis was employed to determine the optimal BMI thresholds for detecting previously created %BF standards. The optimal BMI percentile associated with the low risk %BF threshold was the 83 rd and 80th in boys and girls, respectively. The selected BMI percentiles associated with the higher risk threshold were the 92 nd and 90th in boys and girls, respectively. Overall, classification accuracy when using BMI percentiles to identify the two %BF risk groups ranged from 86.9% to 89.1%. BMI and skinfold-derived %BF demonstrate reasonable agreement when used to classify adiposity status in children and adolescents.


Dietary habits contribute to define the risk of type 2 diabetes in humans.
Type 2 diabetes (T2D) is a frequent disorder largely preventable. The aim of this review was to summarize information on the association between dietary habits and the risk of developing T2D. We conducted a comprehensive literature search using the PubMed database from its inception to June, 2019. Articles were restricted to those written in English and concerning human subjects. Relevant manuscripts found in the list of references of the retrieved articles were also used in preparation for the review. Animal protein consumption increases the risk of T2D independently of body mass index. Intake of both unprocessed meat and processed meat is strongly and consistently associated with increased risk of developing T2D. In contrast, consumption of high-quality vegetable foods prevents the disease. High-quality plant foods include whole grains, nuts, legumes, fruits, and vegetables. Among less healthy plant-based foods are fruit juices, sweetened beverages, refined grains, potatoes, sweets, and desserts. Carbohydrate-restricted diets that encourage consumption of animal products promote T2D. Low intake of animal products is linked to high educational level so that well-informed individuals tend to consume diets with elevated content of vegetable food. According to the American Dietetic Association, "appropriately planned vegetarian diets including vegan diets are healthful, nutritionally adequate, and may provide health benefits in the prevention and treatment of certain diseases". restricting animal products while increasing healthy plant-based foods intake facilitates T2D prevention. To neutralize worldwide the burden of T2D and its devastating complications, animal products consumption should be limited or discontinued.


Ultrasonographic assessment of humeral retrotorsion in baseball players: a validation study.
Recently, clinicians and researchers started using diagnostic ultrasound to measure humeral torsion as an alternative to radiological assessments in overhead-throwing athletes and other clinical populations. Ultrasound appears to be a reliable, nonradiological alternative, but ultrasound assessment has not been validated against computed tomography (CT), the current gold standard. This study aimed to establish the validity of an ultrasound assessment of humeral torsion by comparing data obtained using both ultrasound and CT, the current standard. Cohort study (Diagnosis); Level of evidence, 2. Humeral torsion was measured using both ultrasound and CT in 24 collegiate-aged baseball players. Comparisons between the assessments were made using both regression and Bland-Altman plots. Reliability and precision were also established. A strong relationship existed between humeral torsion variables obtained with ultrasound and CT (R = .797, R (2) = .635, P < .001). The ultrasound assessment yielded reliability coefficients ranging from .991 to .997, with approximately 1° of measurement error. The CT method's reliability coefficients ranged from .805 to .933, with approximately 3.5° of measurement error. There was a strong relationship between humeral torsion obtained with ultrasound and CT, the current standard of assessment. Ultrasound provides a reliable, valid alternative to CT for obtaining an indication of the amount of humeral torsion in the upper extremity.


[Orbital cavity tumor with macular folds].
A 40-year-old patient presented with an orbital tumor of the right eye accompanied by visual impairment and macular folds. The diagnosis of mucocele was made through clinical and radiological investigations. The excision of the mucocele was performed immediately. As early as 8 weeks after the operation, an obvious increase in visual acuity was noticed. At this time, the macular folds were no longer detectable.


Provider and patient intervention to improve weight loss: a pilot study in a public hospital clinic.
To assess the efficacy of a literacy-appropriate weight loss intervention targeting providers and patients in improving physicians' weight loss counseling and patients' self-reported beliefs, and self-efficacy. The study took place in a public hospital nephrology clinic. The intervention included two physician workshops and a small group patient education. Physician-patient communication was observed and coded. Structured interviews assessed patient recall of weight loss recommendations, weight-related beliefs, and self-efficacy. 64 patient visits were observed before and after the intervention. 75% of patients were African American, 96% lacked private insurance, 71% had low literacy skills; mean body mass index (BMI) of 35 kg/m(2). Physician counseling improved significantly post-intervention, particularly in assessing, supporting and advising patients about weight loss and exercise. Patients reported increases in recall of weight loss recommendations and were more likely to report greater confidence about losing weight (52% vs. 70%, p<0.01). This pilot study offers promising directions to address provider and patient barriers to weight loss education and counseling in a public hospital. Hospital-based weight loss interventions need to target both physicians and patients.


Chemical carboxyl-terminal sequence analysis of peptides and proteins using tribenzylsilyl isothiocyanate.
A new derivatization reagent, tribenzylsilyl isothiocyanate (TBS-ITC), is applied to C-terminal peptide and protein sequencing. It has been successfully used to sequence six C-terminal residues of house apomyoglobin and a synthetic peptide at low nanomole levels. The chemistry involves activation with acetic anhydride, derivatization with TBS-ITC, and cleavage of derivatized C-terminal amino acid thiohydantoin with sodium hydroxide. The tribenzylsilyl is a bulky, electric donor group and is a good leaving group. It facilitates the nucleophilic attack of the NCS(-1) in the coupling reaction. The efficiency for C-terminal sequencing by TBS-ITC is about the same as that of acetyl isothiocyanate (AITC), which is a derivatizing reagent for C-terminal sequencing developed by our laboratory. TBS-ITC is much more stable than AITC and trimethylsilyl isothiocyanate (TMS-ITC). TBS-ITC is a solid with relatively long shelf life, whereas AITC and TMS-ITC are liquid and not stable at room temperature.


Aneurysmal dilatation of ductus arteriosus during lipo-prostaglandin E1 therapy for diaphragmatic hernia.
We report a case of congenital diaphragmatic hernia in which aneurysmal dilatation of ductus arteriosus developed after lipo-prostaglandin E1 (PGE1) therapy for persistent fetal circulation. After surgery Lipo-PGE1 was used at a dosage of 5 ng/kg per minute from days 2-9 during which aneurysmal dilatation (7 mm in diameter) developed and remained thereafter. Ductus arteriosus ligation was then performed. Lipo-PGE1 may promote ductus arteriosus dilatation in cases of persistent fetal circulation.


Diagnostic and prognostic value of serum miR-99a expression in oral squamous cell carcinoma.
Despite progress in the treatment of oral squamous cell carcinoma (OSCC) over past years, the prognosis for OSCC patients remains dismal. MicroRNA-99a (miR-99a) has been found to involve in the development of many cancer types, but its clinical role in OSCC is unclear. The aim of this study was to explore the clinical implications of serum miR-99a in OSCC. This study detected serum miR-99a levels in 121 OSCC cases and 55 healthy controls by using quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. The data showed that serum miR-99a expression was significantly decreased in OSCC patients compared with normal controls. OSCC patients with low miR-99a expression experienced more frequent poor differentiation and advanced clinical stage. Furthermore, in screening OSCC cases from normal controls, miR-99a could yield a receiver-operating characteristic (ROC) area under the curve (AUC) of 0.911 with 83.6% specificity and 80.2% sensitivity. Notably, patients with high miR-99a expression had longer overall survival and recurrence free survival. Finally, serum miR-99a was identified to be an independent prognostic indicator for OSCC. These results suggested that miR-99a might be a valuable marker for the prediction of early detection and prognosis in OSCC.


Chromosomal instability and transcriptome dynamics in cancer.
Whole transcriptome profiling has long been proposed as a method of identifying cancer-specific gene expression profiles. Indeed, a multitude of these studies have generated vast amounts of expression data for many types of cancer, and most have identified specific gene signatures associated with a given cancer. These studies however, often contradict with each other, and gene lists only rarely overlap, challenging clinical application of cancer gene signatures. To understand this issue, the biological basis of transcriptome dynamics needs to be addressed. Chromosome instability (CIN) is the main contributor to genome heterogeneity and system dynamics, therefore the relationship between CIN, genome heterogeneity, and transcriptome dynamics has important implications for cancer research. In this review, we discuss CIN and its effects on the transcriptome during cancer progression, specifically how stochastic chromosome change results in transcriptome dynamics. This discussion is further applied to metastasis and drug resistance both of which have been linked to multiple diverse molecular mechanisms but are in fact driven by CIN. The diverse molecular mechanisms that drive each process are linked to karyotypic heterogeneity through the evolutionary mechanism of cancer. Karyotypic change and the resultant transcriptome change alter network function within cells increasing the evolutionary potential of the tumor. Future studies must embrace this instability-induced heterogeneity in order to devise new research and treatment modalities that focus on the evolutionary process of cancer rather than the individual genes that are uniquely changed in each tumor. Care is also needed in evaluating results from experimental systems which measure average values of a population.


Separation of human renal renin and pseudorenin by affinity chromatography on hemoglobin-Sepharose-2B.
Human renal renin (EC 18.104.22.168) and pseudorenin were easily separated in a single step by affinity chromatography on hemoglobin-Sepharose-2B. Renin and pseudorenin were monitored by their actions on crude and partially purified hog protein renin substrates at neutral and acidic pH and on synthetic labelled polymeric renin substrate. Under the conditions employed (0.1 M sodium acetate (pH 3.5)/1 M sodium chloride at 4 degrees C) renin does not bind to the affinity adsorbent while pseudorenin is effectively bound and can be eluted only after raising the pH to 6.5. Pseudorenin-free renin prepared by this method is devoid of proteolytic activity toward hemoglobin. The chromatographic behaviour of renal pseudorenin on hemoglobin-Sepharose-2B is similar to that of cathepsin D.


Temporary extracorporeal axillo-iliac vascular prosthesis shunt in open repair of a pararenal aortic aneurysm.
When a long aortic clamp time is expected or when upper body to lower body collateral arteries are sparse, temporary lower body perfusion may be needed to reduce ischemic injury during supraceliac clamping in open repair of pararenal aortic aneurysms. The use of conventional extracorporeal perfusion techniques carry extra risks and is not in the armamentarium of most vascular surgeons. An axillo-femoral or -iliac shunt using a vascular prosthesis does not require the same degree of anticoagulation and causes less activation of blood components. A patient, who had extensive vascular stenotic disease and large bowel ischemia, was operated on for a pararenal aortic aneurysm while the lower body was perfused via a temporary extracorporeal vascular prosthesis axillo-iliac shunt. Copious backbleeding encountered while suturing the proximal anastomosis testified to the efficacy of the temporary shunt. A left hemicolectomy had to be performed for gangrene of the sigmoid colon and he needed 2 days of respiratory support; otherwise the postoperative course was uneventful. In our case more ischemic injury than that observed might have been expected without the temporary bypass but significant backbleeding may have negated some of the beneficial effect of the shunt. A temporary axillo-femoral or -iliac shunt prevents lower limb ischemia and provides an ample amount of collateral blood flow to the torso. It does not need to be buried subcutaneously as previously described. Occlusive balloons should be used where possible to prevent backbleeding and to further increase available collateral blood supply.


Evaluating the effect of co-contraction in optimization models.
The effect of co-contraction of antagonist muscles on spinal compression force is estimated using Karush-Kuhn-Tucker (K-K-T) multipliers. Co-contraction is modelled as an incremental increase in the lower bounds on the allowable muscle forces in an optimization model formation. The K-K-T multipliers associated with each lower bound provide an estimate of the partial derivate of the optimal objective function value with respect to a change in the lower bound. A model whose objective function is spinal compression force is analyzed to estimate the effect of co-contraction on spinal compression force. While the effect depends on the specific muscle and task under consideration, the marginal effect of co-contraction on spinal compression force can be as high as 5.52 N additional spinal compression force for every additional N of muscle force. Paradoxically, the co-contraction may slightly decrease predicted spinal compression in special circumstances.


Role of STAT3 and NFkappaB signaling in the serum factor-induced apoptosis in AK-5 cells.
AK-5, a rat histiocytoma, is rejected in about 70% of the syngeneic animals when injected subcutaneously. The sera from the tumor rejecting animals possess a potent factor, referred to as serum factor (SF) that induces apoptosis in AK-5 tumor cells. In the present study, we show that treatment with SF or JAK/STAT inhibitors AG490 and Piceatannol induces apoptosis to a similar extent in BC-8 (a single cell clone of AK-5) cells. Our results demonstrate downregulation of a transcription factor, STAT3, as a critical regulator of SF-induced apoptosis in BC-8 cells. SF treatment enhanced the activity of NFkappaB, another transcription factor that regulates both pro- and antiapoptotic genes. The enhanced NFkappaB activity resulted in the elevation of TRAIL and its receptor DR4, both known to induce apoptosis. Activation of death receptors in turn enhances caspase-8 activity and stimulates the downstream pathways regulating BC-8 cell apoptosis. SF induced apoptosis in BC-8 cells mediated through downregulation of STAT3 and elevated NFkappaB activity is abrogated by treatment with MAPK inhibitors-PD98059 and SB203580. Our studies therefore indicate that modulation of MAPK activity plays a central role in SF-induced death signaling pathways in BC-8 cells.


Screening of obstructive sleep apnea (OSA) risk in adolescent population and study of association with craniofacial and upper airway morphology.
Obstructive sleep apnea (OSA) is a common form of sleep-disordered breathing with high prevalence and associated co-morbidities. It still goes largely under-reported due to events occurring in sleep and difficulty in identifying predisposing factors. To perform questionnaire-based screening of OSA-risk in adolescents and study association of OSA-risk with craniofacial and upper airway morphology. Modified STOP-BANG questionnaire was used for screening OSA-risk in adolescent orthodontic patients (10-19 years) in a government dental hospital in India. Patients were categorised into two groups: OSA-risk and non-risk, based on the questionnaire scores, and were subsequently evaluated for craniofacial and upper airway morphology, both on examination and on lateral cephalometric radiographs. Documented a high prevalence of 14% for OSA-risk in adolescent orthodontic patients. The extra-oral and intra-oral parameters found significantly associated with OSA-risk were convex profile [Odd's ratio (OR) - 3.824], steep mandibular plane angle [MPA] (OR- 79.75), Type 3/4 faucial pillars (OR- 11.227), Class II molar relationship (OR - 4.518), ovoid upper arch form (OR - 13.750). In addition, the cephalometric parameters: ANB (p- 0.025), SN-MP (p- 0.007), BA-SN (p- 0.020), PNS-AD1 (p < 0.001), PNS-AD2 (p - 0.001) also showed highly significant association to OSA-risk. The ROC curves demonstrated high sensitivity and specificity for PNS-AD1 (60%,83.3%), PNS-AD2 (73.3%, 70%) and SN-MP (60%,70%), respectively for OSA-risk. The study supported applicability of modified STOP-BANG questionnaire for OSA-risk in Indian adolescents. The parameters [extra-oral, intra-oral, cephalometric and upper airway (PNS-AD1, PNS-AD2, SN-MP)] significantly associated with OSA-risk, were identified.


DRL responding by rats during initial and prolonged alcohol administration.
Daily administration of alcohol did not affect the total response rate of rats on a DRL task although alcohol-treated animals made fewer correct (reinforced) responses than did controls.


Countering neurodegeneration by reducing the activity of the insulin/IGF signaling pathway: current knowledge and future prospects.
Human neurodegenerative maladies share two common key features: a mechanistic link to the accumulation and deposition of aberrantly aggregated proteins and late onset. These similarities among otherwise unrelated disorders suggest that the aging process plays an active role in enabling the emergence of these diseases late in life. Invertebrate-based studies have shown that the manipulation of aging by the reduction of the Insulin/IGF signaling (IIS), a prominent aging regulatory pathway, protects model organisms from neurodegeneration-linked toxic protein aggregation. Recent studies have also indicated that the counter proteotoxic effect of IIS reduction is conserved from worms to mice as reduced IGF-1 signaling protected Alzheimer's-model mice from the disease-like behavioral impairments, pathological phenotypes and premature death typical to these model animals. In this article I review the current knowledge on the protective mechanisms that are suppressed by the IIS and discuss the future therapeutic potential of IIS reduction as a treatment for neurodegenerative disorders.


Improved visualization of fetal hemoglobin-containing cells using Nomarski Optics.
The quantitation of fetal hemoglobin-containing cells is generally accomplished by the acid elution of adult hemoglobin and subsequent identification of cells positively stained for fetal hemoglobin by light microscopy. Disadvantages with this technique include difficulty in recognition of intensity of stained cells. This study describes a modification of the acid elution technique using Nomarski Optics to facilitate recognition of fetal hemoglobin cells. Further, the results of the acid elution technique using Nomarski Optics significantly correlate with results from the standard alkali denaturation technique for quantitating fetal hemoglobin.


Mucosal blood flow in the human nose following local challenge with histamine.
Nasal blood flow was measured using the 133Xe wash-out method in 10 non-allergic subjects and 13 asymptomatic hay fever patients. Determinations were made before and 15 min after challenge with diluent, 0.13 mg, 1.3 mg and 13 mg of histamine/nasal cavity. Nasal symptom scores were recorded. The nasal inspiratory peak flow was determined simultaneously in the hay fever patients. No differences in blood flow or symptom score recordings were found between the normal subjects and allergic patients under basal conditions or after histamine challenge. The nasal blood flow increased after challenge with the highest histamine dose. The increase was 34% (P less than 0.05) from baseline in normals and 47% (P less than 0.05) in allergics. There was a dose-dependent increase in nasal symptom scores following histamine challenge, again with no difference between normal and allergic subjects. The nasal peak flow decreased in a similar manner with a maximum decrease of 74% (P less than 0.001). The present study gives further support to the notion that histamine is not the only mediator involved in vascular reactions during allergic rhinitis.


The role of structural fluctuations and environmental noise in the electron/hole separation kinetics at organic polymer bulk-heterojunction interfaces.
We investigate the electronic dynamics of a model organic photovoltaic (OPV) system consisting of polyphenylene vinylene (PPV) oligomers and a [6,6]-phenyl C61-butyric acid methylester (PCBM) blend using a mixed molecular mechanics/quantum mechanics (MM/QM) approach. Using a heuristic model that connects energy gap fluctuations to the average electronic couplings and decoherence times, we provide an estimate of the state-to-state internal conversion rates within the manifold of the lowest few electronic excitations. We find that the lowest few excited states of a model interface are rapidly mixed by C[double bond, length as m-dash]C bond fluctuations such that the system can sample both intermolecular charge-transfer and charge-separated electronic configurations on a time scale of 20 fs. Our simulations support an emerging picture of carrier generation in OPV systems in which interfacial electronic states can rapidly decay into charge-separated and current producing states via coupling to vibronic degrees of freedom.


To what extent are patients' needs met on oncology units? The phenomenon of care rationing.
Evidence suggests that when resources are not sufficient to provide all the care needed by their patients, nurses are forced to ration their attention between care activities. The aim of this study is to examine care omissions and their causes in oncology units. Participants were recruited from all of the hospitals in the Republic of Cyprus with oncology in-patient units. The data were collected with the MISSCARE questionnaire consisting of demographics, part A related to the elements of missed care and part B asking the reasons why nurses omit care. One hundred and fifty seven registered nurses participated in the study (Response Rate = 91.8%). The mean value for part A of the MISSCARE survey was moderate (2.31 from 4). The elements of care described as frequently or always missed were: turning the patient every 2 h (66.9%); ambulation three times a day or as needed (49.1%); mouth care (61.1%); patient teaching (37.6%); emotional support (32.5%); and attend any interdisciplinary conferences (87.9%). Reported causes included inadequate number of staff, urgent patient situations and unexpected rise in patient volume/unit acuity. Spearman correlations showed that there is a relationship between care rationing and job satisfaction (r = 0.469, p < 0.05), with the less satisfied nurses reporting higher incidences of care omissions. The results of this study may facilitate a better understanding of this phenomenon and its impact on patients and nurses, but more research is needed at an international level so as to create more robust evidence that could support nursing practice.


Selective oxidative dehydrogenation of propane to propene using boron nitride catalysts.
The exothermic oxidative dehydrogenation of propane reaction to generate propene has the potential to be a game-changing technology in the chemical industry. However, even after decades of research, selectivity to propene remains too low to be commercially attractive because of overoxidation of propene to thermodynamically favored CO2 Here, we report that hexagonal boron nitride and boron nitride nanotubes exhibit unique and hitherto unanticipated catalytic properties, resulting in great selectivity to olefins. As an example, at 14% propane conversion, we obtain selectivity of 79% propene and 12% ethene, another desired alkene. Based on catalytic experiments, spectroscopic insights, and ab initio modeling, we put forward a mechanistic hypothesis in which oxygen-terminated armchair boron nitride edges are proposed to be the catalytic active sites.


COVID-19: Fear, quackery, false representations and the law.
Fear, anxiety and even paranoia can proliferate during a pandemic. Such conditions, even when subclinical, tend to be a product of personal and predispositional factors, as well as shared cultural influences, including religious, literary, film, and gaming, all of which can lead to emotional and less than rational responses. They can render people vulnerable to engage in implausible conspiracy theories about the causes of illness and governmental responses to it. They can also lead people to give credence to simplistic and unscientific misrepresentations about medications and devices which are claimed to prevent, treat or cure disease. In turn such vulnerability creates predatory opportunities for the unscrupulous. This article notes the eruption of quackery during the 1889-1892 Russian Flu and the 1918-1920 Spanish Flu and the emergence during 2020 of spurious claims during the COVID-19 pandemic. It identifies consumer protection strategies and interventions formulated during the 2020 pandemic. Using examples from the United States, Japan, Australia and the United Kingdom, it argues that during a pandemic there is a need for three responses by government to the risks posed by conspiracy theories and false representations: calm, scientifically-based messaging from public health authorities; cease and desist warnings directed toward those making extravagant or inappropriate claims; and the taking of assertive and well publicised legal action against individuals and entities that make false representations in order to protect consumers rendered vulnerable by their emotional responses to the phenomenology of the pandemic.


Near full-length HIV type 1M genomic sequences from Cameroon : Evidence of early diverging under-sampled lineages in the country.
Cameroon is the country in which HIV-1 group M (HIV-1M) likely originated and is today a major hotspot of HIV-1M genetic diversity. It remains unclear, however, whether the highly divergent HIV-1M lineages found in this country arose during the earliest phases of the global HIV-1M epidemic, or whether they arose more recently as a result of recombination events between globally circulating HIV-1M lineages. To differentiate between these two possibilities, we performed phylogenetic analyses of the near full genome sequences of nine newly sequenced divergent HIV-1M isolates and 15 previously identified, apparently unique recombinant forms (URFs) from Cameroon. Although two of the new genome sequences were clearly classifiable within subtype G, the remaining seven were highly divergent and phylogenetically branched either outside of, or very near the bases of clades containing the well characterised globally circulating viral lineages that they were most closely related to. Recombination analyses further revealed that these divergent viruses were likely complex URFs. We show, however that substantial portions (>1 Kb) of three of the new genome sequences and 15 of the previously characterised Cameroonian URFs have apparently been derived from divergent parental viruses that branch phylogenetically near the bases of the major HIV-1M clades. Our analyses indicate the presence in Cameroon of contemporary descendants of numerous early-diverging HIV-1M lineages. Further efforts to sample and sequence viruses from such lineages could be crucial both for retracing the earliest evolutionary steps during the emergence of HIV-1M in humans, and accurately reconstructing the ancestral sequences of the major globally circulating HIV-1M lineages.


Is IL-2 regulated by a serum inhibitor?
Normal murine serum inhibits the proliferation of cloned cytotoxic T lymphocytes driven by pure interleukin 2 (IL-2), indicating that a component of normal murine serum is directly inhibitory to IL-2-dependent proliferation. However, the effect is not specific to such cells, since an IL-2-independent variant cell, and a number of lymphoid tumor cell lines are similarly inhibited. Addition of purified IL-2 does not overcome the inhibition, although its degree is reduced. Fractionation of murine serum showed that there are at least two inhibitory activities, which migrate with globular proteins of molecular weights greater than or equal to 10(6) and 4 X 10(4), respectively, on gel chromatography. Neither of the activities was specific for IL-2-dependent cells. Furthermore, murine IL-2 is stable in murine serum in vitro, although it disappears rapidly from the circulation after intravenous injection. It is therefore unlikely that serum inhibitor of IL-2 is an important immunoregulator in vivo.


High-Risk Histopathologic Features of Retinoblastoma Treated at a Tertiary Hospital in West Java, Indonesia.
To evaluate the histopathological characteristics of clinically advanced retinoblastoma (RB) and its relationship with tumor differentiation. This was a cross-sectional study of primary enucleated group D/E intraocular RB using medical records from 2017 to 2020 in a tertiary referral hospital. Cases with incomplete histopathological results were excluded. Tumors were classified into well, moderately, and poorly differentiated and undifferentiated. High-risk histopathological features were classified as per Thaung and Karaa [Community Eye Health. 2018;31(101):17-3]. This study included 121 patients (129 eyes), of which 32.2% were diagnosed at 25-36 months. High-risk features (HRFs) were found in 100/129 eyes, and of 73 complete histopathological results, the 2 most common HRFs were postlaminar optic nerve invasion and massive choroidal invasion. RB was poorly differentiated in 69.9% and well differentiated in 12.3% of eyes. There was no statistically significant association between any HRFs and tumor differentiation, with age >2 years associated with tumor differentiation (p < 0.05). The frequency of HRFs is 77.5% of primary enucleated eyes, mainly poorly and undifferentiated cells, particularly in children aged >2 years old.


A website dedicated to ionizing radiation metrology.
In order to disseminate information about decay data and their evaluation, as well as other topics in the field of ionizing radiation, the Bureau National de Métrologie-Laboratoire National Henri Becquerel (BNM-LNHB) has published a website. Most of the web pages are concerned with the international working groups in which the BNM-LNHB takes part. In particular, a library of uranium and plutonium spectra is now available, as well as the results of evaluation of decay data of nuclides of special interest.


Habituation of sympathetic-adrenal medullary responses following exposure to chronic intermittent stress.
Two experiments examined sympathetic-adrenal medullary responses of laboratory rats after exposure to a brief period of stressful stimulation daily for 26 consecutive days. In the first experiment, rats were exposed to restraint stress for 30 minutes per day and in the second experiment, rats were exposed to inescapable footshock for 10 minutes per day. For each experiment, handled controls were stressed acutely to provide a basis for comparison with chronically stressed animals. In both experiments, chronically stressed rats gained less weight than controls. Basal plasma levels of norepinephrine (NE) and epinephrine (EPI) were similar in control and chronically stressed rats. However, there was a substantial attenuation of the plasma catecholamine response to the 27th episode of restraint or footshock compared to acutely stressed controls. These findings indicate that sympathetic-adrenal medullary responses are dampened considerably in animals exposed to a highly predictable regimen of chronic intermittent stress.


Long-term results of cementless femoral reconstruction following intertrochanteric osteotomy.
The objective of this retrospective cohort study was to assess the long-term outcome of cementless femoral reconstruction in patients with previous intertrochanteric osteotomy (ITO). We evaluated the clinical and radiographic results of a consecutive series of 45 patients (48 hips, mean age 50 years) who had undergone conversion hip replacement following ITO with a cementless, grit-blasted, double-tapered femoral component. Clinical outcome was determined using the Harris hip score. Stem survival for different end points was assessed using Kaplan-Meier survivorship analysis. At a mean follow-up of 20 (range, 16-24) years, 11 patients (12 hips) had died, and no patient was lost to follow-up. Six patients (six hips) underwent femoral revision, two for infection, three for aseptic loosening and one for periprosthetic fracture. Mean Harris hip score at final follow-up was 78 points (range, 23-100 points). Stem survival for all revisions was 89% (95%CI, 75-95) at 20 years, and survival for aseptic loosening was 93% (95%CI, 80-98). The long-term results with this type of cementless femoral component in patients with previous intertrochanteric osteotomy are encouraging and compare well to those achieved in patients with normal femoral anatomy.


Clinical trials of bivalent A/New Jersey/76-A/Victoria/75 influenza vaccines in high-risk children.
Various doses of two whole-virus and one split-product bivalent influenza A/New Jersey/76-A/Victoria/75 vaccines were administered to 253 children aged six to 18 years. There were no statistically significant differences in either reactivity or humoral antibody response among the 167 children in seven chronic disease categories and 86 healthy children. The whole-virus vaccines were associated with unacceptably high rates of reaction when given in sufficiently antigenic initial doses but were relatively nonreactive when used for booster immunization. Split-product vaccines were no more reactive than placebo. All vaccine preparations induced adequate seroconversion rates and protective titers of antibody to A/Victoria virus after one dose and to A/New Jersey virus after two doses.


Characterization of monoclonal antibodies against ovine Sarcocystis spp. antigens by immunoblotting and immuno-electron microscopy.
Six monoclonal antibodies were raised in mice against purified cytozoite extracts of Sarcocystis gigantea and S. tenella from sheep. Each monoclonal antibody was evaluated for specificity by enzyme immunoassay, immunoblotting and immuno-electron microscopy using homologous and heterologous antigenic preparations. All six monoclonal antibodies exhibited good species-specificity when reacted against crude soluble cystozoite antigens in enzyme immunoassays. However, only two monoclonal antibodies (IgM and IgG2a) exhibited reactivity in Western blots against specific protein bands. Both reacted against S. gigantea antigens of 100,000, 43,000 and 39,000 molecular weight. Neither monoclonal antibody reacted against the heterologous species S. tenella. Ultrastructural studies performed with colloidal-gold conjugated antisera revealed that both monoclonal antibodies reacted against antigens located around micronemes and amylopectin granules in S. gigantea cystozoites. Another monoclonal antibody (IgGI) reacted only against microneme determinants in S. tenella cystozoites. In contrast, polyclonal sheep and rabbit immune sera cross-reacted against a wide range of cystozoite antigens.


Serum interleukin-18 levels in patients with Behçet's disease. Is its expression associated with disease activity or clinical presentations?
Interleukin (IL)-18 is a proinflammatory cytokine which plays a crucial role in T helper (Th)1 type immune response. The aim of this study is to investigate the relationship of serum levels of IL-18 with disease activity and clinical presentations in patients with Behcet's disease (BD). Sixty patients with BD and 20 healthy controls were included in the study. Patients were grouped as having active or inactive disease according to the Leeds activity score. They were also separated as a systemic involvement or mucocutaneous symptoms only. Patients with systemic involvement were further grouped according to the presence of ocular, articular and vascular involvement. IL-18 levels were significantly higher in all patient subgroups as compared to healthy controls and found to be correlated with the activity score in patients having active disease. In conclusion, this cytokine participates in the pathogenesis of BD and its levels are correlated with the disease activity. Detection of increased levels of IL-18 in patients with inactive disease implies that Th1 activation and subclinical inflammation persist during the inactive period of the disease.


Anatomical sciences in the allopathic medical school curriculum in the United States between 1967-2001.
The present article surveys the changes in the time allocated for the four disciplines in the anatomical sciences in the medical curricula of allopathic medical schools in the United States from 1967-2001. The results indicate that there was a great reduction in the laboratory portions, but not in the lecture portions of Gross Anatomy, Histology, Neuroanatomy, and Embryology. The greatest time reduction overall for the disciplines occurred between 1967-1973 (502 to 387 hr), followed by the time reduction between 1982-1995 (380 to 329 hr).


Dimerization of sumatriptan as an efficient way to design a potent, centrally and orally active 5-HT1B agonist.
A new bivalent ligand of formula 3 which results from the covalent coupling of two sumatriptan molecules with a p-xylyl spacer at the level of the sulfonamide nitrogen has been prepared and evaluated as a 5-HT1B/1D receptors agonist. In vitro experiments at 5-HT1B human cloned receptors (Ki = 0.64 nM; EC50 = 0.58 nM) and at the level of the contraction of the New Zealand white rabbit saphenous vein (pD2 = 6.6) demonstrate the superior potency of dimer 3 as a 5-HT1B receptor agonist when compared to sumatriptan or zolmitriptan. Interestingly enough, the new bivalent agonist 3 was found to induce hypothermia in the guineapig upon oral administration suggesting good oral activity and access to the brain.


Evidence for a central muscarinic action by 1-(2-methyl-3-hydroxy-5-hydroxymethyl-4-pyridyl)-6,7-dihydroxy-1,2, 3,4-tetrahydroisoquinoline in regulating blood pressure in the anesthetized dog.
Anesthetized dogs injected with 1-(2-methyl-3-hydroxy-5-hydroxymethyl-4-pyridyl)-6,7-dihydroxy-1,2, 3,4-tetrahydroisoquinoline (PTIQ) into the common carotid artery, showed an immediate fall in blood pressure, whereas injection into the femoral vein produced a fall in blood pressure after a lapse of approximately 8 sec. Anesthetized dogs pretreated with atropine showed a decrease in mean blood pressure of 22% of control (PTIQ alone) after PTIQ was injected. In contrast, dogs pretreated with methylatropine showed a decrease of 41% of control after PTIQ was injected. Our data suggest that PTIQ may act centrally and peripherally by activation of muscarinic receptors.


Photoimmunotherapy of hepatocellular carcinoma-targeting Glypican-3 combined with nanosized albumin-bound paclitaxel.
Effectiveness of Glypican-3 (GPC3)-targeted photoimmunotherapy (PIT) combined with the nanoparticle albumin-bound paclitaxel (nab-paclitaxel) for hepatocellular carcinoma was evaluated. GPC3 expressing A431/G1 cells were incubated with a phthalocyanine-derivative, IRDye700DX (IR700), conjugated to an anti-GPC3 antibody, IR700-YP7 and exposed to near-infrared light. Therapeutic experiments combining GPC3-targeted PIT with nab-paclitaxel were performed in A431/G1 tumor-bearing mice. IR700-YP7 bound to A431/G1 cells and induced rapid target-specific necrotic cell death by near-infrared light exposure in vitro. IR700-YP7 accumulated in A431/G1 tumors. Tumor growth was inhibited by PIT compared with nontreated control. Additionally, PIT dramatically increased nab-paclitaxel delivery and enhanced the therapeutic effect. PIT targeting GPC3 combined with nab-paclitaxel is a promising method for treating hepatocellular carcinoma.


Epigenetic loci for blood pressure are associated with hypertensive target organ damage in older African Americans from the genetic epidemiology network of Arteriopathy (GENOA) study.
Hypertension is a major modifiable risk factor for arteriosclerosis that can lead to target organ damage (TOD) of heart, kidneys, and peripheral arteries. A recent epigenome-wide association study for blood pressure (BP) identified 13 CpG sites, but it is not known whether DNA methylation at these sites is also associated with TOD. In 1218 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study, a cohort of hypertensive sibships, we evaluated the associations between methylation at these 13 CpG sites measured in peripheral blood leukocytes and five TOD traits assessed approximately 5 years later. Ten significant associations were found after adjustment for age, sex, blood cell counts, time difference between CpG and TOD measurement, and 10 genetic principal components (FDR q < 0.1): two with estimated glomerular filtration rate (eGFR, cg06690548, cg10601624), six with urinary albumin-to-creatinine ratio (UACR, cg16246545, cg14476101, cg19693031, cg06690548, cg00574958, cg22304262), and two with left ventricular mass indexed to height (LVMI, cg19693031, cg00574958). All associations with eGFR and four associations with UACR remained significant after further adjustment for body mass index (BMI), smoking status, and diabetes. We also found significant interactions between cg06690548 and BMI on UACR, and between 3 CpG sites (cg19693031, cg14476101, and cg06690548) and diabetes on UACR (FDR q < 0.1). Mediation analysis showed that 4.7% to 38.1% of the relationship between two CpG sites (cg19693031 and cg00574958) and two TOD measures (UACR and LVMI) was mediated by blood pressure (Bonferroni-corrected P < 0.05). Mendelian randomization analysis suggests that methylation at two sites (cg16246545 and cg14476101) in PHGDH may causally influence UACR. In conclusion, we found compelling evidence for associations between arteriosclerotic traits of kidney and heart and previously identified blood pressure-associated DNA methylation sites. This study may lend insight into the role of DNA methylation in pathological mechanisms underlying target organ damage from hypertension.


Regional mapping of human genes for hexosaminidase B and diphtheria toxin sensitivity on chromosome 5 using mouse X human hybrid cells.
Mouse 3T3 (TK-) cells were fused to human leukocytes containing a balanced translocation [ins(3;5) (q27;q13q15)] in which part of the long arm of a chromosome 5 has been inserted into the long arm of a chromosome 3. Two independent, primary hybrid clones (XVI-10C;XVI-18A) retained the deleted chromosome 5 [del(5) (q13q15)] translocation product and were informative for regional mapping on chromosome 5 of genes involved in expression of hexosaminidase B (HEXB) and diphtheria toxin sensitivity (DTS). Both XVI-10C and XVI-18A clones were sensitive to diphtheria toxin. Toxin-resistant derivatives of these clones (XVI-10C DTR; XVI-18A DTR) were analyzed for chromosome content and expression of Hex B activity, as were XVI-10C and XVI-18A cells which had not been exposed to diphtheria toxin. The results of this study provide evidence for localization of DTS to region 5q15 leads to 5 qter on the long arm of chromosome 5, and localization of HEXB to region 5pter leads to 5q13.


Characterization of the EP-receptor mediating dilatation and potentiation of inflammation in rabbit skin.
The interactions of bradykinin (BK) and FMLP (a leukocyte-dependent mediator of inflammation) with thirteen prostaglandin E analogs have been investigated in a rabbit skin model of inflammation. The PGE analogs were chosen with a view to defining the EP-receptor subtypes involved. Five analogs, PGE2, misoprostol, 16,16-dimethyl PGE2, nocloprost, and enisoprost, were potent vasodilators (133Xe clearance method) and potent potentiators of both BK and FMLP exudation ([125I]albumin method). A further four analogs, butaprost, 11-deoxy PGE1, mexiprostil, and AH 13205, were weaker vasodilators and weaker potentiators of exudation. The remaining four analogs, 11-deoxy PGE2-1-alcohol, MB 28767, sulprostone, and GR 63779X did not induce vasodilatation and did not potentiate FMLP exudation. However, the latter three prostanoids (which are all potent and moderately selective EP3 agonists) produced a modest potentiation of BK exudation at low doses (1 and 10 ng), with no greater effect at higher doses (100 and 1000 ng). Statistical correlation of vasodilator responses with potentiation of FMLP exudation responses was highly significant. A similar correlation for vasodilation/BK exudation, although statistically significant, was not as convincing. The analyses suggested that vasodilatation is a major mechanism of PGE-induced potentiation of plasma exudation and that an EP2-receptor subtype is involved. However, the possibility of a second non-dilator mechanism could not be ruled out.


[Plasma renin activity in hypertensive patients under basal conditions and in various postures: preliminary data].
We have studied PRA levels in 10 healthy subjects compared with 10 patients affected with essential hypertension (with low PRA) on venous blood samples collected after 8 hours of rest and after 15-20 minutes of slow plain walk. Contemporarely we have taken up arterious pression levels in each class of subjects of these studies. No significant differences of PRA are demonstrable in healthy subjects and in patients affected with essential hypertension. Postural changes in hypertension produces significant rise of PRA, not related to arterial pressure.


Mandibular first molar having an unusual mesial root canal morphology with contradictory cone-beam computed tomography findings: a case report.
The objective of this article is to highlight the importance of having a thorough knowledge about the root canal anatomy and the possibility of misleading findings in the cone-beam computed tomography (CBCT) images. This case report presents the endodontic management of a right mandibular first molar with 2 roots and 2 canals. A CBCT imaging was performed to ascertain this rare root canal anatomy. The clinical and radiographic diagnosis of the existence of a single root canal within the mesial root of mandibular first molar did not correlate with the CBCT findings. The confirmative diagnosis should be based on cognitive deduction of the clinical picture and intelligent interpretation of radiologic information.


Use of statistical tools to evaluate the reductive dechlorination of high levels of TCE in microcosm studies.
A large, multi-laboratory microcosm study was performed to select amendments for supporting reductive dechlorination of high levels of trichloroethylene (TCE) found at an industrial site in the United Kingdom (UK) containing dense non-aqueous phase liquid (DNAPL) TCE. The study was designed as a fractional factorial experiment involving 177 bottles distributed between four industrial laboratories and was used to assess the impact of six electron donors, bioaugmentation, addition of supplemental nutrients, and two TCE levels (0.57 and 1.90 mM or 75 and 250 mg/L in the aqueous phase) on TCE dechlorination. Performance was assessed based on the concentration changes of TCE and reductive dechlorination degradation products. The chemical data was evaluated using analysis of variance (ANOVA) and survival analysis techniques to determine both main effects and important interactions for all the experimental variables during the 203-day study. The statistically based design and analysis provided powerful tools that aided decision-making for field application of this technology. The analysis showed that emulsified vegetable oil (EVO), lactate, and methanol were the most effective electron donors, promoting rapid and complete dechlorination of TCE to ethene. Bioaugmentation and nutrient addition also had a statistically significant positive impact on TCE dechlorination. In addition, the microbial community was measured using phospholipid fatty acid analysis (PLFA) for quantification of total biomass and characterization of the community structure and quantitative polymerase chain reaction (qPCR) for enumeration of Dehalococcoides organisms (Dhc) and the vinyl chloride reductase (vcrA) gene. The highest increase in levels of total biomass and Dhc was observed in the EVO microcosms, which correlated well with the dechlorination results.


Acinetobacter septicemia: a threat to neonates? Special aspects in a neonatal intensive care unit.
Acinetobacter is one of the organisms responsible for nosocomial infections in intensive care, neurosurgery, burn and hemodialysis units. There are only a few reports on Acinetobacter infections in neonatal intensive care units. Over a 31 month period, nine cases of Acinetobacter sepsis occurred in our unit, with four deaths. There was a cluster of four cases within 3 days. In this study the English literature on this pathogen is reviewed and it is suggested that Acinetobacter should be added to the list of organisms causing severe nosocomial infection in neonatal intensive care units.


[Effect of Inhibiting NGAL Gene Expression on A549 Lung Cancer Cell Migration and Invasion].
To detect the expression of neutrophil gelatinase-assoeiated lipocalin (NGAL) in the different differentiations of lung cancer tissues and to study the mechanism of invasion of A549 cells affected by NGAL. The expression of NGAL was detected by immunochemistry in lung cancer tissue and the tissue around edge of the cancer. The effect of NGAL expression on A549 cells was observed by using qRT-PCR and Western blot. The abilities of invasion and metastasis were evaluated by transwell invasion and migration assay, and cell scratch assay in vitro. The protein expression of E-cadherin, Vimentin was measured by immunofluoresence and Western blot. The positive expression rate of NGAL was 76.32% (58/76) in the lung cancer, 13.3% (4/30) in adjacent tissue by immunochemistry. NGAL expression levels in the lung cancer tissues were significantly higher than that in adjacent tissues. The rate of migration and invasion in NGAL-siRNA group was 60.4% ± 6.4% compared to 50.5% ± 4.4% in the control group, there was a significant difference (P < 0.05). Vimentin was suppressed, and E-cadherin was upregulated when NGAL was inhibited. MMP-2 and MMP-9 decreased when NGAL was knocked down. The expression level of NGAL is highly expressed in lung cancer. NGAL may be one of important indicators involved in lung cancer infiltrated and transferred. NGAL might be one of potential targets for lung cancer treatment.


Chemical substitutions in the selectivity filter of potassium channels do not rule out constricted-like conformations for C-type inactivation.
In many K+ channels, prolonged activating stimuli lead to a time-dependent reduction in ion conduction, a phenomenon known as C-type inactivation. X-ray structures of the KcsA channel suggest that this inactivated state corresponds to a "constricted" conformation of the selectivity filter. However, the functional significance of the constricted conformation has become a matter of debate. Functional and structural studies based on chemically modified semisynthetic KcsA channels along the selectivity filter led to the conclusion that the constricted conformation does not correspond to the C-type inactivated state. The main results supporting this view include the observation that C-type inactivation is not suppressed by a substitution of D-alanine at Gly77, even though this modification is believed to lock the selectivity filter into its conductive conformation, whereas it is suppressed following amide-to-ester backbone substitutions at Gly77 and Tyr78, even though these structure-conserving modifications are not believed to prevent the selectivity filter from adopting the constricted conformation. However, several untested assumptions about the structural and functional impact of these chemical modifications underlie these arguments. To make progress, molecular dynamics simulations based on atomic models of the KcsA channel were performed. The computational results support the notion that the constricted conformation of the selectivity filter corresponds to the functional C-type inactivated state of the KcsA. Importantly, MD simulations reveal that the semisynthetic KcsAD-ala77 channel can adopt an asymmetrical constricted-like nonconductive conformation and that the amide-to-ester backbone substitutions at Gly77 and Tyr78 perturb the hydrogen bonding involving the buried water molecules stabilizing the constricted conformation.