Comparative study of the chondrogenic potential of human bone marrow stromal cells, neonatal chondrocytes and adult chondrocytes.
Cartilage tissue engineering is still a major clinical challenge with optimisation of a suitable source of cells for cartilage repair/regeneration not yet fully addressed. The aims of this study were to compare and contrast the differences in chondrogenic behaviour between human bone marrow stromal cells (HBMSCs), human neonatal and adult chondrocytes to further our understanding of chondroinduction relative to cell maturity and to identify factors that promote chondrogenesis and maintain functional homoeostasis. Cells were cultured in monolayer in either chondrogenic or basal medium, recapitulating procedures used in existing clinical procedures for cell-based therapies. Cell doubling time, morphology and alkaline phosphatase specific activity (ALPSA) were determined at different time points. Expression of chondrogenic markers (SOX9, ACAN and COL2A1) was compared via real time polymerase chain reaction. Amongst the three cell types studied, HBMSCs had the highest ALPSA in basal culture and lowest ALPSA in chondrogenic media. Neonatal chondrocytes were the most proliferative and adult chondrocytes had the lowest ALPSA in basal media. Gene expression analysis revealed a difference in the temporal expression of chondrogenic markers which were up regulated in chondrogenic medium compared to levels in basal medium. Of the three cell types studied, adult chondrocytes offer a more promising cell source for cartilage tissue engineering. This comparative study revealed differences between the microenvironment of all three cell types and provides useful information to inform cell-based therapies for cartilage regeneration.


Sedaghatian congenital lethal metaphyseal chondrodysplasia--observations in a second Iranian family and histopathological studies.
In 1980, Sedaghatian described in two brothers and one sister a neonatally lethal disorder associated with slight rhizomelic limb shortness, mild platyspondyly, and severe metaphyseal dysplasia. Here data are presented on another Iranian infant with the Sedaghatian syndrome who died on day 4 and was found to have histologic evidence of severe epimetaphyseal dysplasia. The occurrence in children of both sexes in one instance, born to normal parents who were first cousins, and currently apparent confinement of the disorder to Iranians suggests that the Sedaghatian syndrome is an autosomal recessive trait with high gene frequency in Iranians. This may be a more complexly pleiotropic syndrome than suggested by the roentgenograms, since one of Sedaghatian's patients also had "microphthalmia, asymmetry of ears, depressed nasal bridge, broad nose, short neck, prominent sternum, and short lower extremities."


Late divergence of survival curves in cancer immunotherapy trials: interpretation and implications.
Late divergence of survival curves of treated patients and controls is commonly seen in successful cancer immunotherapy trials. Although late survival curve divergence may be caused by a delayed action of therapy, it may also be related to early effects of the treatment. We suggest that late survival divergence most often reflects a specific benefit of therapy for patients who suffer from a comparatively slow progression of disease. The occurrence of delayed survival curve divergence has important implications for the statistical analysis of immunotherapy trials. Thus, it leads to non-proportional hazard ratios that make commonly used statistical tests, e.g., the logrank test, suboptimal. It is therefore suggested that the statistical analysis of immunotherapy trials primarily should be based on a test that compares the survival curves at or after a prespecified, fixed, late time point.


Retinal toxicity of intravitreal trastuzumab in a rabbit model: preliminary results of an experimental study.
To evaluate the retinal toxicity of intravitreal trastuzumab in a rabbit model. Fourteen New Zealand albino rabbits, weighing between 2.5 and 3 kg were used for this study. In the first group (n=6), 0.1 mL trastuzumab 10 mg/mL was injected into the vitreous. In the second group (n=6), the same volume of sterile balanced saline solution was injected intravitreally (sham injection). Additionally, 0.1 mL of 2 other concentrations of trastuzumab (7.5 and 5 mg/mL, respectively), was injected into the vitreous of 2 rabbits. Slit-lamp and funduscopic examinations were performed and the animals were observed for 2 weeks for signs of inflammation, infection, and toxicity. An electroretinogram (ERG) was performed at baseline and 14 days after the injection. The animals were killed on day 14 and a histological examination was performed in the enucleated eyes. The clinical examination was unremarkable on either sham or intravitreal injection of trastuzumab. Conversely, the ERG was greatly affected and in 2 cases extinguished 14 days after trastuzumab injection. Consistent with electrophysiological abnormalities of the retina, signs of retinal edema in experimented eyes, suggesting morphologic retinal damage, were observed. In contrast, in the sham injected eyes, the ERG was normal without histopathologic retinal changes. Intravitreal trastuzumab seems to be toxic to the retina in albino rabbits even at a concentration of 5 mg/mL. Further studies are needed to evaluate the safety of intravitreal trastuzumab in models of choroidal neovascularization, as well as to obtain experience concerning the intravitreal toxicity of trastuzumab in primates too and not only in rabbits.


Migraine-associated vertigo: clinical characteristics of Japanese patients and effect of lomerizine, a calcium channel antagonist.
Lomerizine, a calcium channel blocker, may be effective as a treatment for migraine-associated vertigo (MAV). Objective. To determine the clinical characteristics of patients with MAV in Japan and the effectiveness of lomerizine. This was a retrospective chart review carried out in a university hospital of 33 patients who fulfilled the diagnostic criteria for MAV. All patients were initially treated with dietary manipulation. If this therapy was unsuccessful, oral medications, mainly lomerizine, were administered. Medical records were reviewed to find clinical characteristics of patients with MAV and to evaluate the effects of the therapy on vertigo/dizziness symptoms. A marked female predominance was found (23 women, 10 men). The frequency and the duration of vertigo varied across patients. About 60% of the patients had cochlear symptoms during an attack, among which bilateral aural fullness was most frequent. Oto-neurological examination showed abnormalities in 33% of the patients. Overall, 27 of the 33 patients (82%) responded to our therapy. Among the 22 patients who were prescribed lomerizine, 19 patients (87%) showed resolution or significant improvement of the symptoms.


Long-term follow-up of the vascularized iliac bone graft.
We retrospectively studied four patients who were treated with vascularized iliac bone graft for reconstruction of the tibia. The average length of the graft was 9.8 cm. The follow-up period was 11-18 years (average, 14.8 years). Although two of them were osteomyelitis, no recurrence occurred. We also studied four patients who were treated with nonvascularized iliac bone graft for anterior spinal interbody fusion (average, 10.8 years). Cosmetic problem slightly exists because the vascularized iliac bone still showed the original shape, which was prominent from the tibial contour. The vascularized iliac bone marrow showed iso intensity in both T1 and T2 image of the MRI. However, nonvascularized iliac bone graft on the spine showed high intensity in both T1 and T2 imaging. Since the vascularized iliac bone graft does not present fatty degeneration, it shows strong resistance against infection.


Application of the intravenous glucose tolerance test and the minimal model to patients with insulinoma: insulin sensitivity (Si) and glucose effectiveness (Sg) before and after surgical excision.
The unmodified frequently sampled intravenous glucose tolerance test (FSIGT) has not previously been used to assess insulin/glucose kinetics in patients with insulinoma. To measure insulin sensitivity (Si) and glucose effectiveness (Sg) by means of the FSIGT in patients with insulinoma, before and after surgical removal of the tumour. FSIGTs were performed in five patients, before and approximately 3 months post-surgery, and in 11 controls. Si and Sg were estimated using Minimal Model computer analysis of dynamic glucose and insulin data. Si was lower in insulinoma patients before, compared with after surgery (3.37 +/- 0.62 vs. 6.24 +/- 1.09 SE [x10(-4)] min(-1)microU(-1) ml, P < 0.05). Sg was similar in patients pre- and post-surgery (3.0 +/- 0.67 vs. 2.4 +/- 0.6 [x10(-2)] min(-1), NS). Insulin sensitivity improves after excision of an insulinoma. Glucose effectiveness is not influenced by chronic hyperinsulinaemia and hypoglycaemia.


Low power laser irradiation alters gene expression of olfactory ensheathing cells in vitro.
Both photobiomodulation (PBM) and olfactory ensheathing cells (OECs) transplantation improve recovery following spinal cord injury. However, neither the combination of these two therapies nor the effect of light on OECs has been reported. The purpose of this study was to determine the effect of light on OEC activity in vitro. OECs were purified from adult rat olfactory bulbs and exposed to 810 nm light (150 mW; 0, 0.2, or 68 J/cm(2)). After 7-21 days in vitro, cells underwent immunocytochemistry or RNA extraction and RT-PCR. Analysis of immunolabeling revealed a significant decrease in fibronectin expression in the cultures receiving 68 J/cm(2). Analysis of gene expression revealed a significant (P < 0.05) increase in brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), and collagen expression in the 0.2 J/cm(2) group in comparison to the non-irradiated and 68 J/cm(2) groups. OEC proliferation was also found to significantly increase in both light treated groups in comparison to the control group (P < 0.001). These results demonstrate that low and high dosages of PBM alter OEC activity, including upregulation of a number of neurotrophic growth factors and extracellular matrix proteins known to support neurite outgrowth. Therefore, the application of PBM in conjunction with OEC transplantation warrants consideration as a potential combination therapy for spinal cord injury.


Inhibition of DNA topoisomerases I and II, and growth inhibition of human cancer cell lines by a marine microalgal polysaccharide.
We have previously reported purification of an extracellular polysaccharide GA3P, D-galactan sulfate associated with L-(+)-lactic acid, produced by a toxic marine microalga Dinoflagellate Gymnodinium sp. A(3) (GA3), and induction thereby of apoptosis on human myeloid leukemia K562 cells. In the present report, we show that the GA3P is a potent inhibitor of DNA topoisomerase (topo) I and topo II, irrespective of the presence or absence of the lactate group. Dextran sulfate also showed similar level of inhibition of topo I and topo II. We also demonstrated that, unlike camptothecin (CPT) or teniposide (VM-26), the inhibition of topo I or topo II by the polysaccharide does not involve accumulation of DNA-topo I/II cleavable complexes, clearly showing that they are not topo poisons but catalytic inhibitors with dual activity. Furthermore, the polysaccharide, when added to the reaction mixture with CPT or VM-26, inhibited stabilization of cleavable complex induced by the latter compounds. In addition, when added to the reaction mixture after the formation of the cleavable complexes by topo poisons, CPT for topo I and VM-26 for topo II, either GA3P or dextran sulfate diminished the amount of the complexes already accumulated, i.e. reversal of the reaction. These results suggest that the polysaccharides bind to the enzymes with high affinities, and that, as for topo I/II inhibition, the GA3P shares a common mechanism with dextran sulfate. As examined in vitro with a human cancer cell line panel, GA3P exhibited significant cytotoxicity against a variety of cancer cells. These findings show that the polysaccharide GA3P would prove to be a potential anticancer chemotherapeutic agent with dual activity of topo I and topo II catalytic inhibition.


Studies of the activity of peroxidase-like DNAzyme by modifying 3'- or 5'-end of aptamers.
In the presence of hemin and under appropriate conditions, some modalities of G-quadruplexes can form a peroxidase-like DNAzyme that has been widely used in biology. Structure-function studies on the DNAzyme revealed that its catalytic ability may be dependent on the unimolecular parallel G-quadruplex. In this report, we present the preliminary investigation on the relationship between the structure and function of DNAzymes through a terminal oligo modification in G-quadruplex sequences by adding different lengths of oligo-dT to the 3'- or 5'-end of the aptamers. The results suggested that adding dT(n) to the 5'-end of the DNA sequence of the enzyme improved the ability of hemin to bind with DNA, but the addition of dT(n) to the 3'-end decreased the binding ability of hemin for DNA. The increased stability of the assembled DNAzyme would lead to more favorable binding between the enzyme and substrate (H(2) O(2)), facilitating higher peroxidase activity; on the contrary, with lower stability of the DNAzyme complex, we observed reduced peroxidase activity.


Role of cell adhesion in the specification of pigment cell lineage in embryos of the sea urchin, Hemicentrotus pulcherrimus.
To clarify the role of cell adhesion in the specification of pigment cell lineage in sea urchin embryos, cell contacts were inhibited by Ca2+-free artificial seawater (ASW) treatment, and the number of differentiated pigment cells was examined by the method devised for the present study. Obtained results showed that inhibition of cell contacts during mid-to-late blastula stage greatly affects the number of pigment cells. Treatment with Ca2+-free ASW during 7.5-10.5 h of development drastically decreased the number of pigment cells, indicating that cell adhesion during this period is indispensable for the specification of pigment cell lineage. On the other hand, the number of pigment cells were increased by the treatment during 9.5 12.5 h of development. It was suggested that this increase was caused by excess divisions of the precursor cells, that is, the division schedule of the precursor cells was altered by inhibition of cell contacts at this period. Interestingly, the number of pigment cells was a multiple of four in a majority of embryos in which pigment cells were drastically decreased in number. These findings suggest that the founder blastomeres of the pigment cell lineage are specified during 7-10 h of development, and that these blastomeres divide twice before they differentiate into pigment cells.


Conserved collateral antibiotic susceptibility networks in diverse clinical strains of Escherichia coli.
There is urgent need to develop novel treatment strategies to reduce antimicrobial resistance. Collateral sensitivity (CS), where resistance to one antimicrobial increases susceptibility to other drugs, might enable selection against resistance during treatment. However, the success of this approach would depend on the conservation of CS networks across genetically diverse bacterial strains. Here, we examine CS conservation across diverse Escherichia coli strains isolated from urinary tract infections. We determine collateral susceptibilities of mutants resistant to relevant antimicrobials against 16 antibiotics. Multivariate statistical analyses show that resistance mechanisms, in particular efflux-related mutations, as well as the relative fitness of resistant strains, are principal contributors to collateral responses. Moreover, collateral responses shift the mutant selection window, suggesting that CS-informed therapies may affect evolutionary trajectories of antimicrobial resistance. Our data allow optimism for CS-informed therapy and further suggest that rapid detection of resistance mechanisms is important to accurately predict collateral responses.


Functional Recovery Rate: A Feasible Method for Evaluating and Comparing Rehabilitation Outcomes Between Skilled Nursing Facilities.
The recovery of patients' physical function and the rate at which this occurs are important parameters for evaluating value in post-acute care (PAC). However, no metrics are presently used to compare skilled nursing facilities (SNFs) based on the functional recovery rates (FRRs) for patients in their care. The objectives of this study were to examine whether the average FRR differed significantly among SNFs and to compare the FRR to other measures currently used to assess care quality in SNFs. Retrospective observational study. 3913 patients discharged from hospitals in one health system to one of 10 partner SNFs between January 2017 and September 2019. The FRR-the difference in Activity Measure for Post-Acute Care 6-Clicks basic mobility score from SNF admission to discharge relative to the SNF length of stay (in days)-was the primary outcome. Secondary outcomes included metrics from the SNF Quality Reporting Program (functional recovery alone, discharge to the community, and 30-day hospital readmission). Differences in patients' outcomes between SNFs were tested using multiple regression in order to adjust for patient characteristics. Across the 10 SNFs, the highest adjusted mean FRR was 0.70 [95% confidence interval (CI): 0.55, 0.90] and the lowest was 0.39 (95% CI: 0.33, 0.46) points per day. Two SNFs had an adjusted mean FRR statistically higher, and 2 had an FRR statistically lower, than the sample mean (0.50, 95% CI: 0.48-0.52). SNF rankings varied by metric. Individual SNFs vary in their mean FRR for patients making it a potentially useful measure of value for comparing SNFs. Standardized measurement and reporting of FRR could be beneficial to patients and their families as they consider specific SNFs for necessary post-acute rehabilitation and to hospital systems seeking to identify high-value PAC providers with whom to partner in collaborative care models.


Endocrine diseases in dogs and cats: similarities and differences with endocrine diseases in humans.
Over several millennia, humans have created hundreds of dog and cat breeds by selective breeding, including fixation of mutant genes. The domestic dog is unique in the extent of its variation in height, weight and shape as well as its behavior. It is primarily the relatively long persistence of high levels of growth hormone (GH) release at a young age that accounts for the large body size in giant breeds of dogs. Several of the endocrine diseases of humans are also known to occur as similar entities in dogs and cats. With some variations, this is true for conditions such as diabetes mellitus and the hypofunction syndromes of the thyroid and adrenal cortex. Also, the hyperfunction syndromes of hypercortisolism and hyperparathyroidism in dogs and cats have many similarities with their human counterparts. The exception seems to be Graves' disease. This condition, which is due to production of thyroid-stimulating hormone (TSH)-receptor antibodies, has not been observed in dogs and cats. The very common form of hyperthyroidism in cats is due to toxic adenomas. In the 1980s it was discovered that in dogs exogenous progestins and endogenous progesterone can induce GH excess. This GH excess originates form the mammary gland and may give rise to acromegaly and insulin resistance. GH production by the mammary gland is not unique to the dog. It has become clear that cats and humans also express the GH gene in the mammary gland. There is increasing evidence that this locally produced GH not only plays a role in the morphologic changes of the mammary gland associated with the ovarian cycle and gestation, but that it is also involved in the development of breast cancer. In dogs, induction of mammary GH production by progestin administration allows for treatment of GH deficiency.


High tumour cannabinoid CB1 receptor immunoreactivity negatively impacts disease-specific survival in stage II microsatellite stable colorectal cancer.
There is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB(1) receptor immunoreactive intensity (CB(1)IR intensity) is associated with disease severity and outcome. CB(1)IR was assessed in formalin-fixed, paraffin-embedded specimens collected with a consecutive intent during primary tumour surgical resection from a series of cases diagnosed with colorectal cancer. Tumour centre (n = 483) and invasive front (n = 486) CB(1)IR was scored from 0 (absent) to 3 (intense staining) and the data was analysed as a median split i.e. CB(1)IR <2 and ≥2. In microsatellite stable, but not microsatellite instable tumours (as adjudged on the basis of immunohistochemical determination of four mismatch repair proteins), there was a significant positive association of the tumour grade with the CB(1)IR intensity. The difference between the microsatellite stable and instable tumours for this association of CB(1)IR was related to the CpG island methylation status of the cases. Cox proportional hazards regression analyses indicated a significant contribution of CB(1)IR to disease-specific survival in the microsatellite stable tumours when adjusting for tumour stage. For the cases with stage II microsatellite stable tumours, there was a significant effect of both tumour centre and front CB(1)IR upon disease specific survival. The 5 year probabilities of event-free survival were: 85±5 and 66±8%; tumour interior, 86±4% and 63±8% for the CB(1)IR<2 and CB(1)IR≥2 groups, respectively. The level of CB(1) receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB(1)IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients.


Distribution and axial diffusion of retinol in bleached rod outer segments of frogs (Rana pipiens).
Isolated retinas and rod outer segments from frogs (Rana pipiens) were exposed to light that produced axially uniform total bleaches of rhodopsin. Using fluorescence video microscopy, it was shown that the formation and equilibrium distribution of all-trans-retinol, the final chromophore product of rhodopsin bleaching is axially uniform. This result shows that the rate and amount of oxidoreductase-mediated reduction of all-trans-retinal to all-trans-retinol is not affected by the relative age of the disk membranes to which the enzymes are bound. Therefore previously reported axial differences in regeneration of rhodopsin and recovery of photocurrent after exposure to bright light probably are not due to axial differences in the formation of rhodopsin photoproducts. In addition, measurements on individual rod cells show that there is no significant redistribution of retinol for up to 2 hr following localized partial bleaches of rhodopsin. This raises the perplexing question of how retinol is shuttled between disk membranes and the pigment epithelium during visual pigment regeneration following substantial bleaches.


Auto-immune (lupoid) hepatitis: an entity in the spectrum of chronic active liver disease.
The concept of auto-immune hepatitis as a disease entity evolved from the descriptions of 'chronic active hepatitis' (CAH) in the 1950s. Several types of CAH are distinguished by disease-specific features. The distinctive (but not exclusive) markers for auto-immune CAH include: a negative test for HBsAg; female; Northern European ethnic background; multisystem disease expression; histological CAH with large areas of periportal piecemeal necrosis and plasmacytosis; pronounced hypergammaglobulinaemia; serum auto-antibodies the HLA B8-DR3 phenotype; responsiveness to corticosteroid therapy; and rarity of supervening hepatocellular carcinoma. Much weight is attached to the serological marker auto-antibodies to nuclear or smooth muscle (actin) antigens (ANA, SMA). However, these auto-antibodies do not have an absolute association with auto-immune CAH: the serological reactions are not yet standardized; titres decrease with remission of disease; and other auto-antibodies mark variant forms of auto-immune hepatitis. A more confident acceptance of auto-immune hepatitis as an entity requires detection of a liver-specific antigen, a valid experimental disease model in animals, and a better understanding of immune-mediated damage to liver cells.


Impact of the functional neck dissection in maxillofacial surgical oncology: its role in robotic-based surgery era.
Head and neck cancers demonstrate an increased prevalence worldwide. The main therapeutic approaches are still surgery and radiotherapy, although in selective cases novel targeted therapeutic strategies based on monoclonal antibodies (ie anti-EGFR) are also applied. Concerning maxillofacial surgical oncology, a variety of methods has been developed. Among them the functional neck dissection technique seems to be a reliable and significant surgical approach, especially in removing identified cervical metastatic lymph node(s). In this technical paper, we focused on the method, its modifications adding our experience and also the challenges that arise in the modern robotic-based era regarding head and neck surgery.


Long-term effects of chronic methamphetamine administration in rhesus monkeys.
Biochemical and neuropathological effects of exposure to a high dose regimen of methamphetamine were evaluated in rhesus monkeys approximately 4 years after the last drug injection. Concentrations of dopamine and serotonin in caudate were below control levels as were concentrations of serotonin in several other brain regions. These changes were more severe in a monkey that was exposed twice to the drug regimen. A decrease in caudate synaptosomal uptake of both neurotransmitters as well as neuropathological changes were evident in that monkey. Although it is possible that partial recovery occurred, these results strongly suggest that methamphetamine-induced neurotoxicity may be permanent.


[Morphometric picture of chronic bronchitis in bronchiectases--morphologic and morphometric changes in the proximal and distal bronchi and bronchioles].
Morphological specific features of proximal and distal bronchi and bronchioles were studied in secondary chronic bronchitis as compared to the primary one basing on the morphometric data. Some specificity was noted in separate forms of secondary bronchitis. Secondary chronic bronchitis is characterized by non-uniform pathological changes in bronchial walls. Wall enlargement, infiltration and sclerosis are more pronounced in secondary chronic bronchitis as compared to the primary one. The relative volume of glands and muscles is less in secondary chronic bronchitis than in the primary one; the Reid index does not differ from the standard in spite of the enlargement of the mucosal inner layer. Atrophic bronchitis is characterized by thinning of mucosal inner layer and decrease in the number of glands. Secondary chronic bronchitis is characterized by narrowing of bronchioles, in contrast to the primary chronic bronchitis where the mean diameter of bronchioles is extended.


Real-world utility of early measurable residual disease assessments by multi-parametric flow cytometry in adult patients with B-lymphoblastic leukemia receiving Hyper-CVAD induction chemotherapy.
Multi-parametric flow cytometry (MFC) has a well-established role in measurable residual disease (MRD) monitoring in patients with B-lymphoblastic leukemia (B-ALL). However, the optimal time-point (TP) for early MRD testing and associated prognostic impact remain undefined in adult B-ALL patients receiving Hyper-CVAD induction chemotherapy. To evaluate the utility of MRD analysis after one cycle (TP1) in comparison to MRD analysis after two cycles (TP2) of induction treatment with Hyper-CVAD chemotherapy, we studied 49 adult B-ALL patients over a 10-year period (2010-2020) who had available bone marrow samples for morphological and MFC MRD assessments at the two separate TPs. Median times to TP1 and TP2 relative to start of treatment were 21 and 45 days, respectively. When censored at transplant, achievement of MRD negativity at TP1 was not associated with a statistically significant improvement in either event-free survival (EFS) (p = .426) or overall survival (OS) (p = .335) when compared to patients with MRD positivity. In contrast, achieving MRD negativity at TP2 was associated with a statistically significant improvement in both EFS (p = ·005) and OS (p = .047) over patients who remained MRD positive. Multivariate analysis demonstrated that KMT2A-rearrangement and MRD positivity at TP2 were the only significant predictors of outcome, correlating with worse EFS and OS. Therefore, in the absence of residual morphologic disease, MRD analysis after one cycle of Hyper-CVAD induction chemotherapy did not provide additional benefit with regard to risk stratification or correlation with survival outcomes when compared to MRD testing after two cycles of Hyper-CVAD in adult B-ALL patients.


Lewis base promoted intramolecular acylcyanation of α-substituted activated alkenes: construction of ketones bearing β-quaternary carbon centers.
A novel phosphine-promoted intramolecular acylcyanation of α-substituted activated alkenes has been developed, which provides a unique access to densely functionalized acyclic ketones bearing β-quaternary carbon centers with a remarkable feature that both α- and β-positions of activated alkene are functionalized.


Novel approach to recurrent cavoatrial renal cell carcinoma.
Renal cell carcinoma (RCC) with cavoatrial extension is a rare and complex problem. Complete resection is difficult but correlates with favorable patient outcomes. We present 2 cases of successful reoperative resections of recurrent RCC in patients with level III-IV cavoatrial involvement. We used a thoracoabdominal approach, peripheral cannulation, and hypothermic circulatory arrest. We advocate this novel approach as a successful means of avoiding a more difficult reoperation.


Parental and Child Self-Efficacy Explaining Food Intake through Self-Regulation: A Dyadic Prospective Study.
According to social cognitive theory and socio-ecological models, self-efficacy and temptation-related self-regulation (the use of distraction or suppression) are modifiable predictors of health behaviors, such as food intake. Yet, there is limited evidence explaining how these factors are interlinked among parent-child dyads. This study investigated indirect effects of parental and child self-efficacy on food intake, via parental and child self-regulation. The prospective study (the baseline [T1] and the 10-month follow-up [T2]) enrolled 924 parent-child dyads (1,848 individuals; 54.3% girls, aged 5-11 years, 88.9% mothers). Dyads were interviewed or completed self-report measures. Path analyses with maximum likelihood estimation were conducted. Child self-efficacy and distraction (T1) mediated between parental self-efficacy (T1) and higher levels of child fruit and vegetable intake (T2). No significant mediating effects of suppression were found, nor indirect effects of parental self-efficacy (T1) on energy-dense food intake (T2). Health promotion interventions aiming at changing fruit and vegetable intake among 5-11-year-old children should target enhancing parental and child self-efficacy that may facilitate the use of self-regulation and, in turn, healthy diet.


Enlarged left atrial volume in hypertrophic cardiomyopathy: a marker for disease severity.
Patients with hypertrophic cardiomyopathy and left atrial (LA) enlargement have increased morbidity and mortality. We analyzed the clinical and echocardiographic factors related to LA enlargement, particularly the degree of left ventricular (LV) hypertrophy and diastolic function. A total of 104 patients with hypertrophic cardiomyopathy (age 53 +/- 15 years, 64% men) were divided into two groups based on the indexed LA volume (LAVI) (mL/m2) measured by echocardiography: group A (or smaller LAVI group, n = 43) was defined as LAVI < or = 34 mL/m2; and group B (or larger LAVI group, n = 61) as LAVI > 34 mL/m2. Detailed clinical and echocardiographic data were obtained. LV wall thickness was measured at 15 sites at 3 levels (base, mid, and apex). Diastolic function was assessed from mitral and pulmonary venous inflow velocities and Doppler tissue imaging. Both groups were similar in terms of sex, functional class (1.6 +/- 0.8 vs 1.5 +/- 0.8, group B vs A, P = .64), and incidence of atrial fibrillation (13% vs 5%, P = .19). However, patients of group B had a significantly higher incidence of serious cardiovascular events (16.4% vs 2.3%, group B vs A, P = .024). Both groups had a similar degree of resting LV outflow tract obstruction (19 +/- 30 vs 12 +/- 13 mm Hg, group B vs A, P = .06). However, those in group B had a higher incidence of at least moderate mitral regurgitation (25% vs 5%, group B vs A, P = .007), more LV hypertrophy at 6 LV nonapical wall segments (P < .05-P < .001), and a higher hypertrophy (Wigle) score (6.2 +/- 2.2 vs 4.5 +/- 2.1, group B vs A, P < .001). In addition, patients of group B had a higher incidence of abnormal diastolic filling (57% vs 28%, group B vs A, P = .003), a higher early diastolic velocity/early diastolic mitral annular velocity (10.2 +/- 4.9 vs 7.5 +/- 2.9, group B vs A, P = .003), and a higher calculated LA pressure (14.8 +/- 6.5 vs 11.1 +/- 3.4 mm Hg, group B vs A, P = .0011). Patients with hypertrophic cardiomyopathy and LA enlargement had more serious cardiovascular events and demonstrated greater LV hypertrophy, more diastolic dysfunction, and higher filling pressures.


Dose-response relationship in the migration inhibition test using peritoneal exudate cells and blood leucocytes of tuberculin sensitive guinea pigs.
A comparison of the direct migration inhibition using peritoneal exudate cells and peripheral blood leucocytes from the same tuberculin sensitive guinea pigs was performed. Three antigen concentrations: 3, 15, and 75 microgram of PPD per ml were used. Both type of cells provided similar results except at early incubation intervals when leucocytes, in the presence of lower doses of the antigen, displayed stronger inhibition than peritoneal cells. Thus, in our study, peripheral blood leucocytes are at least equivalent to peritoneal exudate cells in the migration inhibition test.


Optimization of Ni (II) biosorption from aqueous solution on modified lemon peel.
The valorization of agricultural waste peels as a low-cost biosorbent is a promising approach to water treatment. In this work, the improvement of the adsorption capacity of lemon peel to remove Ni (II) from aqueous effluents was explored using several chemical modifiers: HNO3, HCl, H3PO4, CaCl2, NH3 and NaOH. The surface pretreatment using NaOH was selected as the best option because of the improvement of the maximum adsorption capacity. The maximum adsorption capacity was of 36.74 mg g-1 according to the Langmuir model at optimum conditions (pH = 5, S/L = 5 g L-1, 25 °C). The pseudo-first order model of biosorption kinetics provides the best fit for experimental data. From thermodynamic studies, it was concluded that Ni (II) biosorption by modified lemon peel was endothermic and spontaneous. After five consecutives adsorption-desorption cycles using 0.1 M of HNO3 and H2SO4, a recovery of 90% of Ni (II) was obtained. Regarding characterization of the biosorbent, the surface morphology was studied by Scanning Electron Microscopy while the functional groups responsible for Ni (II) adsorption were evaluated by Fourier transform infrared spectroscopy.


Immunohistochemical localization and quantification of glucose transporters in the mouse brain.
A family of seven facilitative glucose transporters (Glut1-5, 7 and 8) mediates the cellular uptake of glucose. In the brain, Glut2, Glut5 and Glut8 are found at relatively low levels whereas Glut1, Glut3 and Glut4 were reported in abundance in several brain regions. Using immunofluorescence, this study investigated, compared and quantified the localization of the brain major glucose transporters, Glut1, Glut3 and Glut4, in the different cerebral areas of CD1 mice. Most of the staining of Glut1, Glut3 and Glut4 in the mouse brain coincides with observations made in rats. The results confirm the cortical neuropil distribution of Glut3, the prominence of this transporter in the mossy fiber field of the hippocampus and the Glut3 and Glut4 immunostaining of the hippocampal pyramidal cell layer. The present study also reports novel localizations of the transporters such as the presence of Glut3 in neuronal perikarya, Glut4-labeled neurons in the CA3 of the hippocampus and the subiculum. In the cerebellum, Glut3 shows subcellular localization to the base of the Purkinje cell bodies near the axon hillock. Furthermore, an important population of Golgi cells was found to be strongly immunostained for Glut4 in the granular cell layer of the cerebellum. The quantification results suggest that the relative abundance of Glut1 in the frontal and motor cortices coincides well with the high-energy demands of these brain regions. However, the Glut4-selective abundance in cerebral motor areas supports its suggested role in providing the energy needed for the control of the motor activity. The reported neuropil distribution of Glut3 seems to uphold its suggested role in synaptic energy provision and neurotransmitter synthesis. We conclude that the cellular and regional distributions of the glucose transporters in the rodent brain seem to be relevant to their corresponding functions.


Diterpene alkaloids and diterpenes from Spiraea japonica and their anti-tobacco mosaic virus activity.
Five new naturally occurring natural products, including two atisine-type diterpene alkaloids (1 and 2), two atisane-type diterpenes (3 and 4), and a new natural product spiramine C2 (5), along with nine known ones (6-14), were isolated from the ethanolic extracts of the whole plant of Spiraea japonica var. acuminata Franch. Their structures were elucidated by extensive spectroscopic analysis. The anti-tobacco mosaic virus (TMV) activities of all the compounds were evaluated by the conventional half-leaf method. Six compounds (2, 3, 6, 7, 11, and 12) exhibited moderate activities at 100 μg/mL with inhibition rates in the range of 69.4-92.9%, which were higher than that of the positive control, ningnanmycin. Their preliminary structure-activity relationships were also discussed.


Evolution of cell types and T-cell subsets in the spleens of Mycobacterium bovis BCG-resistant and M. bovis BCG-susceptible strains of mice after infection with M. bovis BCG.
In mice, the early host response to intravenous infection with small doses of dispersed Mycobacterium bovis BCG is controlled by the Bcg gene. After infection with a low dose of M. bovis BCG, Lyt-1+ cells were generated in the spleens of BCG-susceptible mice (Bcgs) in parallel with an increase in the proportion of phagocytic cells. Very few changes occurred in the splenic cell types of BCG-resistant mice (Bcgr).


Sexual Harassment at the Workplace is Still a Hindrance among Midwives and Nurses Working in Northwestern Ethiopia Referral Hospitals: A Multicenter Cross-Sectional Study.
Sexual harassment in the workplace is still the tip of the iceberg among front-line health workers, resulting in a high turnover of professionals, job dissatisfaction, absenteeism, and disharmonized health-care delivery. Research on the magnitude of workplace sexual harassment and factors associated with the workplace among nurses and midwives in Ethiopia is lacking. The study aimed to assess the magnitude and its associated factors among nurses and midwives working in northwestern Ethiopia referral hospitals. This multicenter hospital-based cross-sectional study was conducted from April 11 to May 15, 2021 in northwestern Ethiopia referral hospitals. A self-administered structured questionnaire was used to collect data. Data were entered into EPI info 126.96.36.199 and analyzed using SPSS version 25. Binary logistic regression was utilized to identify factors associated with sexual harassment, and associations were deemed significant at P<0.05. As the findings show, sexual harassment prevalence in the workplace among female nurses and midwives was found to be 17.4% (95% CI 14.5%-19.5%). Many nurses and midwives who had experienced sexual harassment were harassed by patients' families - 43.2%. Factors associated with sexual harassment in the workplace were being unmarried (AOR 4, 95% CI 2.3-12.6), work experience of less than 5 years (AOR 5, 95% CI 1.2-19), and participant age of 18-25 (AOR 7.2, 95% CI 5.9-17) years, all strongly associated with the outcome variable. Sexual harassment among midwives and nurses employed in northwestern Ethiopia referral hospitals is not tolerable, as indicated in these findings. The government should address this by amending and reforming policies and strategies to obviate this problem.


Elastic tissue changes in skin following PUVA therapy.
Treatment of psoriasis with psoralens and high-intensity long-wave ultraviolet light (PUVA) produces changes in the ultrastructure of elastic tissue in skin. Early alterations consist of a loss of elastin followed by a breakdown of the microfibrils and subsequent fragmentation of the elastic fiber. Tissue examined 15 months after treatment was stopped still showed marked ultrastructural changes in the elastic fibers.


Variations in the Processing of DNA Double-Strand Breaks Along 60-MeV Therapeutic Proton Beams.
To investigate the variations in induction and repair of DNA damage along the proton path, after a previous report on the increasing biological effectiveness along clinically modulated 60-MeV proton beams. Human skin fibroblast (AG01522) cells were irradiated along a monoenergetic and a modulated spread-out Bragg peak (SOBP) proton beam used for treating ocular melanoma at the Douglas Cyclotron, Clatterbridge Centre for Oncology, Wirral, Liverpool, United Kingdom. The DNA damage response was studied using the 53BP1 foci formation assay. The linear energy transfer (LET) dependence was studied by irradiating the cells at depths corresponding to entrance, proximal, middle, and distal positions of SOBP and the entrance and peak position for the pristine beam. A significant amount of persistent foci was observed at the distal end of the SOBP, suggesting complex residual DNA double-strand break damage induction corresponding to the highest LET values achievable by modulated proton beams. Unlike the directly irradiated, medium-sharing bystander cells did not show any significant increase in residual foci. The DNA damage response along the proton beam path was similar to the response of X rays, confirming the low-LET quality of the proton exposure. However, at the distal end of SOBP our data indicate an increased complexity of DNA lesions and slower repair kinetics. A lack of significant induction of 53BP1 foci in the bystander cells suggests a minor role of cell signaling for DNA damage under these conditions.


Biosorption of the metal-complex dye Acid Black 172 by live and heat-treated biomass of Pseudomonas sp. strain DY1: kinetics and sorption mechanisms.
The ability of Pseudomonas sp. strain DY1 to adsorb Acid Black 172 was studied to determine the kinetics and mechanisms involved in biosorption of the dye. Kinetic data for adsorption fit a pseudo-second-order model. Increased initial dye concentration could significantly enhance the amount of dye adsorbed by heat-treated biomass in which the maximum amount of dye adsorbed was as high as 2.98 mmol/g biomass, whereas it had no significant influence on dye sorption by live biomass. As treated temperature increased, the biomass showed gradual increase of dye sorption ability. Experiments using potentiometric titration and Fourier transform infrared spectroscopy (FTIR) indicated that amine groups (NH2) played a prominent role in biosorption of Acid Black 172. Scanning electron microscopy (SEM), atomic force microscopy (AFM) and transmission electron microscopy (TEM) analysis indicated that heat treatment of the biomass increased the permeability of the cell walls and denatured the intracellular proteins. The results of biosorption experiments by different cell components confirmed that intracellular proteins contributed to the increased biosorption of Acid Black 172 by heat-treated biomass. The data suggest that biomass produced by this strain may have application for removal of metal-complex dyes from wastewater streams generated from the dye products industry.


Protein-bound tyrosine oxidation, nitration and chlorination by-products assessed by ultraperformance liquid chromatography coupled to tandem mass spectrometry.
Free radicals cause alterations in cellular protein structure and function. Oxidized, nitrated, and chlorinated modifications of aromatic amino acids including phenylalanine and tyrosine are reliable biomarkers of oxidative stress and inflammation in clinical conditions. To develop, validate and apply a rapid method for the quantification of known hallmarks of tyrosine oxidation, nitration and chlorination in plasma and tissue proteins providing a snapshot of the oxidative stress and inflammatory status of the organism and of target organs respectively. The extraction and clean up procedure entailed protein precipitation, followed by protein re-suspension and enzymatic digestion with pronase. An Ultra Performance Liquid Chromatography-tandem Mass Spectrometry (UPLC-MS/MS) method was developed to quantify protein released ortho-tyrosine (o-Tyr), meta-tyrosine (m-Tyr), 3-nitrotyrosine (3NO2-Tyr) and 3-chlorotyrosine (3Cl-Tyr) as well as native phenylalanine (Phe) and tyrosine (p-Tyr) in plasma and tissue from a validated hypoxic newborn piglet experimental model. In plasma there was a significant increase in the 3NO2-Tyr/p-Tyr ratio. On the other hand m-Tyr/Phe and 3Cl-Tyr/p-Tyr ratios were significantly increased in liver of hypoxic compared with normoxic animals. Although no significant differences were found in brain tissue, a clear tendency to increased ratios was observed under hypoxic conditions. UPLC-MS/MS has proven suitable for the analysis of plasma and tissue samples from newborn piglets. The analysis of biomarkers of protein oxidation, nitration and chlorination will be applied in future studies aiming to provide a deeper insight into the mechanisms of oxidation-derived protein modification caused during neonatal asphyxia and resuscitation.


[Study of the gene expression pattern in the Kkay mouse with type 2 diabetes by genomic-scale gene expression analysis].
To study the genes differentially expressed in the liver of Kkay diabetic and normal mice by genomic-scale gene expression analysis. cDNA microarray chips containing 8,192 cDNAs were used to explore the gene expression pattern of Kkay mouse liver. One hundred and fifty-four genes were screened out, including 68 complete cDNAs and expressed sequence tags, and among them 40 genes were up-regulated and 114 genes were down-regulated respectively. Most of the gene expression analysis results were consistent with previous study, and the gene expression pattern of Kkay mouse based on cDNA microarray could be used for high-throughout screening out the genes associated with type 2 diabetes.


[Cardiac resynchronization therapy: mortality, rehospitalization, and procedure-related complications. A three-year single-center observational study within the Italian Health System].
The aim of this study was to evaluate whether the benefit of cardiac resynchronization therapy with an implantable defibrillator (CRT-D) may differ among classes of indications to device therapy. All-cause mortality, first hospitalization for non-fatal heart failure, stable improvement of NYHA functional class (responders), and implant-related complications were evaluated retrospectively in 103 patients selected among those (n = 133) who received consecutively CRT-D between 2006 and 2009. Patients were divided into three groups: group IA (n = 65) included patients receiving CRT-D for a class IA indication; group IIa (n = 26) included patients with atrial fibrillation and QRS ≥ 130 ms receiving CRT-D for a class IA indication; nonconventional group (NC) (n = 12) included patients with an indication to defibrillator implantation extended to CRT-D because of NYHA class III-IV and echocardiographic evidence of electromechanical dyssynchrony. Echocardiographic examination was performed in all patients to identify wall target for left-side lead placement. Group IIa patients were slightly older than group IA patients (p<0.05); gender distribution, left ventricular ejection fraction at implantation, ischemic etiology, and heart failure treatment were comparable among groups (all p>0.5), except for a higher digitalis use in group IIa patients (p<0.05). In a mean observation period of 3 years (up to December 2010), the rates of fatal events (IA: 22%, IIa: 23%, NC: 20%), rehospitalization for worsening heart failure (IA: 30%, IIa: 33%, NC: 22%), clinical responders (IA: 78%, IIa: 78%, NC: 78%), implant-related complications requiring reintervention (IA: 15%, IIa: 19%, NC: 25%), including pocket or catheter infections (IA: 5%, IIa: 11%, NC: 8%) were comparable among groups (all p>0.5). In the "real world", the benefit of CRT-D in advanced heart failure patients might be comparable among class IA, IIa or NC indication.


Metabolism of pentachlorophenol in vivo and in vitro.
Pentachlorophenol has earlier been shown to be metabolized in mammals to tetrachloro-p-hydroquinone. The metabolite possesses pronounced inhibitory activity on bacterial beta-glucuronidase but not on beta-glucuronidase from liver. Indirect evidence for the occurrence of both pentachlorophenol and tetrachloro-p-hydroquinone as conjugates with glucuronic acid in the urine from pentachlorophenol-treated rats is now presented. Bovine liver beta-glucuronidase has been utlizied to split the conjugates present. The in vivo metabolism of pentachlorophenol has also been studied in rats treated with phenobarbital and beta-diethylaminoethylidiphenyl propylacetate (SKF 525-A). In vitro metabolism has been studied using liver microsomes from rats pretreated with pehnobarbital. Quantitative analysis of the compounds occurring in extracts of urine or extracts from the microsomal incubates was performed by means of mass fragmentography. Pretreatment with phenobarbital increased the metabolism of pentachlorophenol to tetrachloro-p-hydroquinone both in vivo and in vitro. SKF 525-A, however, inhibited the metabolism in vitro but enhanced the metabolism in vivo when given less frequently than every 6th h. Dechlorination of pentachlorophenol is mediated by microsomal enzymes that can be induced by phenobarbital. SKF 525-A does not inhibit the dechlorination in vivo but does so in vitro.


Engineered Escherichia coli with periplasmic carbonic anhydrase as a biocatalyst for CO2 sequestration.
Carbonic anhydrase is an enzyme that reversibly catalyzes the hydration of carbon dioxide (CO2). It has been suggested recently that this remarkably fast enzyme can be used for sequestration of CO2, a major greenhouse gas, making this a promising alternative for chemical CO2 mitigation. To promote the economical use of enzymes, we engineered the carbonic anhydrase from Neisseria gonorrhoeae (ngCA) in the periplasm of Escherichia coli, thereby creating a bacterial whole-cell catalyst. We then investigated the application of this system to CO2 sequestration by mineral carbonation, a process with the potential to store large quantities of CO2. ngCA was highly expressed in the periplasm of E. coli in a soluble form, and the recombinant bacterial cell displayed the distinct ability to hydrate CO2 compared with its cytoplasmic ngCA counterpart and previously reported whole-cell CA systems. The expression of ngCA in the periplasm of E. coli greatly accelerated the rate of calcium carbonate (CaCO3) formation and exerted a striking impact on the maximal amount of CaCO3 produced under conditions of relatively low pH. It was also shown that the thermal stability of the periplasmic enzyme was significantly improved. These results demonstrate that the engineered bacterial cell with periplasmic ngCA can successfully serve as an efficient biocatalyst for CO2 sequestration.


Morphologic appearance of peripheral blood cells from Zovawk pigs (Sus scrofa domesticus) visualized by transmission electron microscopy.
Ultrastructural information regarding the peripheral blood cells of local (Zovawk) pigs from Mizoram, India, is not available in the scientific literature. The present study was designed to reveal the fine structural details of the blood cells from these local pigs using a transmission electron microscope (TEM). Blood samples were collected from 12 healthy Zovawk pigs of either sex and processed according to a standard protocol. Processed blood samples were then sent to the All India Institute of Medical Sciences, New Delhi, for further processing and imaging under TEM. Different types of blood cells were viewed under TEM, and different characteristics of these cells were assessed. In the present study, erythrocytes are elongated, biconcave, and nucleated without cytoplasmic organelles. Neutrophils are round with 2-5 lobed nuclei surrounded by cytoplasm with an indistinct bilayered nuclear membrane. The cytoplasm is packed with membrane bound round, oval, and elongated cytoplasmic granules. Eosinophils are round to oval with 2-3 lobed nuclei with distinct nuclear membranes. Basophils are spherical and contained small, medium, and large electron-dense granules. Lymphocytes are small, medium, and large and contained all cellular components. Monocytes are irregularly spherical with slight nuclear indentations. The platelets are elongated, oval, or rounded, with a few pseudopods at the cell surface. From the present study, we can conclude that the ultrastructural morphology of blood cells from Zovawk pigs resembles those of other domestic animals. However, a few differences have been observed.


Dopamine-induced changes in renal blood flow in normals and in patients with renal dysfunction.
Despite their controversial effect, "renal" doses of dopamine (3-5 microg kg(-1) min(-1)) are often used in intensive care units to preserve renal function and to improve final outcome. To assess the effects of different doses of dopamine on renal blood flow in patients with normal renal function and in patients with renal dysfunction. In 17 patients with normal renal function and in 12 patients with moderate renal dysfunction, mean arterial pressure (MAP), heart rate (HR), and average peak renal flow velocities (FlowWire APV) were continuously recorded at baseline and during IV administration of increasing dopamine doses (3, 5, 10, 20, and 30 microg kg(-1) min(-1)). MAP and HR did not change during infusion of 3-5 microg kg(-1) min(-1) but increased to the same extent in both groups during infusion of >10 microg kg(-1) min(-1). Baseline APV was similar in both groups. Infusion of 3-5 mug . kg(-1) . min(-1) induced a significant change in APV only in patients with normal renal function. In patients with renal dysfunction, APV increased only during infusion of >10 microg kg(-1) min(-1) in parallel with MAP and HR. "Renal" doses of dopamine increase renal blood flow in normals but not in patients with moderate renal dysfunction.


Novel therapeutic applications of nitric oxide donors in cancer: roles in chemo- and immunosensitization to apoptosis and inhibition of metastases.
The treatment of primary tumors results in an initial response to approved conventional therapeutics. However, recurrences and malignancies develop as a result of tumors' acquisition of anti-apoptotic mechanisms of resistance. Hence, there is an urgent need of novel therapeutics that can reverse resistance. One approach of interest is the inhibition of cell survival and anti-apoptotic pathways by sensitizing agents that can render resistant tumor cells sensitive to respond to various cytotoxic therapies. We have found that nitric oxide donors, similar to DETANONOate, inhibit cell survival anti-apoptotic pathways, such as the constitutively activated NF-kappaB and sensitize drug-resistant tumor cells to apoptosis by both chemotherapy and immunotherapy. Sensitization by DETANONOate was shown to inhibit the transcription repressor Yin Yang1 (YY1) shown to regulate resistance to both Fas ligand and TRAIL. In addition, DETANONOate-induced inhibition of NF-kappaB results downstream in the inhibition of several anti-apoptotic gene products, thus facilitating the activation of the apoptotic pathways with both chemotherapy and immunotherapy. In addition, DETANONOate induces the expression of the metastatic tumor suppressor gene product, Raf-1 Kinase Inhibitor Protein (RKIP), which inhibits the survival pathways induced by NF-kappaB and Raf-1/MEK which also contributes to the sensitizing activity. This indicates a novel finding that RKIP may also play an important role in the prevention of metastasis. Inhibition of NF-kappaB activation by DETANONOate results downstream in the inhibition of the RKIP transcription repressor Snail, resulting in upregulation of RKIP. Inhibition of Snail results in downstream inhibition of the metastatic cascade initiated by the epithelial-mesenchymal transition (EMT). Thus, nitric oxide donors have the dual functions of both sensitizing tumor cells to chemotherapy and immunotherapy and are also involved in the regulation and inhibition of metastasis.


Renal, hepatic, pulmonary and adrenal tumors induced by prenatal inorganic arsenic followed by dimethylarsinic acid in adulthood in CD1 mice.
Inorganic arsenic, an early life carcinogen in humans and mice, can initiate lesions promotable by other agents in later life. The biomethylation product of arsenic, dimethylarsinic acid (DMA), is a multi-site tumor promoter. Thus, pregnant CD1 mice were given drinking water (0 ppm or 85 ppm arsenic) from gestation day 8 to 18 and after weaning male offspring received DMA (0 ppm or 200 ppm; drinking water) for up to 2 years. No renal tumors occurred in controls or DMA alone treated mice while gestational arsenic exposure plus later DMA induced a significant renal tumor incidence of 17% (primarily renal cell carcinoma). Arsenic plus DMA or arsenic alone also increased renal hyperplasia over control but DMA alone did not. Arsenic alone, DMA alone and arsenic plus DMA all induced urinary bladder hyperplasia (33-35%) versus control (2%). Compared to control (6%), arsenic alone tripled hepatocellular carcinoma (20%), and arsenic plus DMA doubled this rate again (43%), but DMA alone had no effect. DMA alone, arsenic alone, and arsenic plus DMA increased lung adenocarcinomas and adrenal adenomas versus control. Overall, DMA in adulthood promoted tumors/lesions initiated by prenatal arsenic in the kidney and liver, but acted independently in the urinary bladder, lung and adrenal.


Inhibition of tissue prostaglandin synthesis during third molar surgery: use of preoperative fenbufen.
Preoperative administration of a non-steroidal anti-inflammatory drug (fenbufen) reduced immediate postoperative pain in a group of 38 patients undergoing removal of mandibular third molars, compared to placebo. However, overall pain experience and morbidity were not significantly improved suggesting that there was no clinical benefit derived from interference with tissue prostaglandin synthesis at the time of surgery.


The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis.
Interferon (IFN) signature has been reported in definite systemic sclerosis (SSc) but it has not been characterised in early SSc (EaSSc). We aim at characterising IFN type I signature in SSc before overt skin fibrosis develops. The expression of 11 IFN type I inducible genes was tested in whole-blood samples from 30 healthy controls (HCs), 12 subjects with primary Raynaud's phenomenon (RP), 19 patients with EaSSc, 7 patients with definite SSc without cutaneous fibrosis, 21 limited cutaneous SSc and 10 diffuse cutaneous SSc subjects. The correlation between IFN activity in monocytes, B cell activating factor (BAFF) mRNA expression and type III procollagen N-terminal propeptide (PIIINP) serum levels was tested. In all the SSc groups, higher IFN scores were observed compared with HC. An IFN score ≥7.09 discriminated HCs from patients with SSc (sensitivity=0.7, specificity=0.88, area under receiving operating characteristic (AUROC)=0.82); the prevalence of an elevated IFN score was: HC=3.3%; RP=33.3%, EaSSc=78.9%, definite SSc=100%, limited cutaneous SSc=42.9%, diffuse cutaneous SSc=70.0%. In monocytes an IFN score ≥4.12 distinguished HCs from patients with fibrotic SSc (sensitivity=0.62, specificity=0.85, AUROC=0.76). Compared with IFN-negative subjects, IFN-positive subjects had higher monocyte BAFF mRNA levels (19.7±5.2 vs 15.20±4.0, p=2.1×10(-5)) and serum PIIINP levels (median=6.0 (IQR 5.4-8.9) vs median=3.9 (IQR 3.3-4.7), p=0.0004). An IFN type I signature is observed in patients with SSc from the earliest phases of the disease, even before overt skin fibrosis. The presence of IFN type I signature in monocytes is correlated with BAFF mRNA expression and serum PIIINP levels, supporting a contribution in the pathogenesis and progression of SSc.


Comparison of Direct and Indirect Laryngoscopes in Vomitus and Hematemesis Settings: A Randomized Simulation Trial.
Videolaryngoscopes may not be useful in the presence of hematemesis or vomitus. We compared the utility of the Macintosh laryngoscope (McL), which is a direct laryngoscope, with that of the Pentax-AWS Airwayscope (AWS) and McGRATH MAC (McGRATH), which are videolaryngoscopes, in simulated hematemesis and vomitus settings. Seventeen anesthesiologists with more than 1 year of experience performed tracheal intubation on an adult manikin using McL, AWS, and McGRATH under normal, hematemesis, and vomitus simulations. In the normal setting, the intubation success rate was 100% for all three laryngoscopes. In the hematemesis settings, the intubation success rate differed significantly among the three laryngoscopes (P = 0.021). In the vomitus settings, all participants succeeded in tracheal intubation with McL or McGRATH, while five failed in the AWS trial with significant difference (P = 0.003). The intubation time did not significantly differ in normal settings, while it was significantly longer in the AWS trial compared to McL or McGRATH trial in the hematemesis or vomitus settings (P < 0.001, compared to McL or McGRATH in both settings). The performance of McGRATH and McL can be superior to that of AWS for tracheal intubation in vomitus and hematemesis settings in adults.


A case of intrapulmonary lymphangioma surrounded by pulmonary hilar structures.
A 53-year-old man was referred to our hospital for examination of a nodule in the right hilar region observed on a chest roentgenogram. Computed tomography and magnetic resonance imaging revealed a 34 × 32-mm multilocular cystic mass with partial calcification adjacent to the hilar structures in the right upper lung lobe. The mass was resected using video-assisted thoracoscopic surgery and identified as pulmonary cystic lymphangioma through postoperative histopathological analysis. Intrapulmonary lymphangioma is an uncommon benign tumor, with only few reports of surgically resected cases. We describe our surgical findings and recommend surgical resection where possible for suspected intrapulmonary lymphangioma.


Long-term hypothermia reduces infarct volume in aged rats after focal ischemia.
In aged humans, stroke is a major cause of disability for which no neuroprotective measures are available. A viable alternative to conventional drug-based neuroprotective therapies is brain/body cooling, or hypothermia. In animal studies of focal ischemia, short-term hypothermia consistently reduces infarct size. Nevertheless, efficient neuroprotection requires long-term, regulated lowering of whole body temperature. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 17-month-old male Sprague-Dawley rats. After stroke, the aged rats were exposed for 2 days to a mixture of air and a mild inhibitor of oxidative phosphorylation, hydrogen sulfide (H(2)S), which resulted in sustained, deep hypothermia (30.8+/-0.7 degrees C). Long-term hypothermia led to a 50% reduction in infarct size with a concomitant reduction in the number of phagocytic cells. At the transcription level, hypothermia caused a reduction in the mRNA coding for caspase 12, NF-kappa B and grp78 in the peri-infarcted region, suggesting an overall decrease in the transcriptional activity related to inflammation and apoptosis. Behaviorally, hypothermia was associated with better performance on tests that require complex sensorimotor skills, in the absence of obvious neurological deficits or physiological side effects, in aged rats. Prolonged, H(2)S-induced hypothermia is a simple and efficacious method to limit the damage inflicted by stroke in aged rats.


Gastric outlet obstruction secondary to post cholecystectomy biloma: case report and review of the literature.
Postcholecystectomy bilomas are relatively uncommon with a reported incidence of about 2.5%, and most often present with right upper quadrant pain and fever within seven days of the operation. There are a number of approaches to the treatment of this uncommon lesion. The authors report a case of a cholecystectomy performed in a 35-year-old female which resulted in a biloma, presenting 11 days postoperatively with gastric outlet obstruction. The literature is reviewed to suggest the optimal management and treatment plans for this complication. This patient was successfully managed with radiologic intervention for the treatment of a biloma and resulting gastric outlet obstruction after open cholecystectomy. Although uncommon, bilomas may present in an unusual manner such as with gastric outlet obstruction. As with early bilomas, they may be treated successfully with interventional radiologic techniques.


Rosalydia, a new genus of Neocoelidiinae (Hemiptera: Cicadellidae) from Brazilian Amazon, with description of three new species.
A new neocoelidiine leafhopper genus from the Brazilian Amazon, Rosalydia gen. nov., is described based on three new species: R. alvarengai gen. et sp. nov. from the state of Mato Grosso, R. inpa gen. et sp. nov. and R. xavieri gen. et sp. nov. from the state of Amazonas. An identification key to species of Rosalydia gen. nov. is provided.


Extrapineal melatonin and exogenous serotonin in seasonal affective disorder.
Visible light inhibits the binding of melatonin and serotonin to cultured human peripheral blood mononuclear leukocytes (PBMLs) in winter. The decreased binding switches the metabolism in PBMLs towards serotonin synthesis, resulting in the reduced production of melatonin. The ingestion of L-tryptophan during the day is hypothesized to increase the levels of melatonin, released from the gastrointestinal tract, in patients with winter seasonal affective disorder (SAD). Due to the relative shortage of light, coincident with a predisposed metabolic error, there would be no switch towards serotonin synthesis among winter SAD patients in winter. The rate of serotonin synthesis could thus remain inadequately low to maintain optimal mood in winter SAD patients.


Optimized Scansystem platelet kit for bacterial detection with enhanced sensitivity: detection within 24 h after spiking.
The prevention and detection of bacterial contamination of platelet concentrates remains a major challenge for transfusion medicine. To be suitable for blood-transfusion services, the contamination detection method must be highly sensitive, easy to perform and preferably of low cost. In this spiking study, we evaluated the new optimized Scansystem Platelet Kit detection method for use on apheresis platelets. Apheresis platelet concentrates (APCs) were individually spiked with 10 colony-forming units (CFU)/ml of one of 10 different strains of bacteria. The spiked APCs were analysed at specific time-points during incubation by using the optimized Scansystem Platelet Kit. Bacterial enumeration was performed by plating onto blood agar. All the bacterial strains tested were detected by using the optimized Scansystem Platelet Kit when sampled 24 h after spiking. Compared to the Scansystem standard kit, sensitivity was increased to < 50 CFU/ml. The identity of the spiked bacteria was confirmed by Gram staining and DNA fingerprinting. The optimized Scansystem Platelet Kit was able to reliably detect, within 70 min, 10 transfusion-relevant bacterial species in APCs when a sample volume was taken 24 h after spiking. This is the first study carried out by using the optimized Scansystem bacterial detection that was found to have an enhanced sensitivity compared to the standard kit.


Atrial Fibrillation Better Care Pathway Adherent Care Improves Outcomes in Chinese Patients With Atrial Fibrillation.
Atrial fibrillation (AF) is a complex disease associated with comorbidities and adverse outcomes. The Atrial fibrillation Better Care (ABC) pathway has been proposed to streamline the integrated and holistic approach to AF care. This study sought to evaluate patients' characteristics, incidence of adverse events, and impact on outcomes with ABC pathway-adherent management. The study included consecutive AF patients enrolled in the nationwide, ChioTEAF registry (44 centers, 20 Chinese provinces from October 2014 to December 2018), with available data to evaluate the ABC criteria and on the 1-year follow-up. A total of 3,520 patients (mean age 73.1 ± 10.4 years, 43% female) were included, of which 1,448 (41.1%) were managed as ABC pathway adherent. The latter were younger and had comparable CHA2DS2-VASc and lower HAS-BLED (mean 71.7 ± 10.3 years of age vs 74.1 ± 10.4 years of age; P < 0.01; 3.54 ± 1.60 vs 3.44 ± 1.70; P = 0.10; and 1.95 ± 1.10 vs 2.12 ± 1.20; P < 0.01, respectively) scores compared with ABC-nonadherent patients. At 1-year follow-up, patients managed adherent to the ABC pathway had a lower incidence of the primary composite outcome of all-cause death or any thromboembolic event (1.5% vs 3.6%; P < 0.01) as compared with ABC-nonadherent patients. On multivariate analysis, ABC pathway-adherent care was independently associated with a lower risk of the composite endpoint (OR: 0.51; 95% CI: 0.31-0.84). Adherence to the ABC pathway for integrated care in a contemporary nationwide cohort of Chinese AF patients was suboptimal. Clinical management adherent to the ABC pathway was associated with better outcomes.


Age and gender dependent alterations in the activities of glutathione related enzymes in healthy subjects.
Oxidative stress as a result of increased free radical production is implicated in the pathogenesis of several diseases. Specific antioxidant enzymes have a crucial role in the prevention of these deleterious effects. Since the activities of these enzymes differ significantly in different populations and seem to be affected by various environmental factors, in this study we aimed to determine the reference values of glutathione related antioxidant enzyme activities in the erythrocytes of healthy subjects and to investigate the possible variations as a function of age and gender in a healthy Turkish Mediterranean population. 130 healthy subjects (12-90 yr, 82 females, 48 males) were divided into six different age groups. Erythrocyte glutathione peroxidase (GSH-PX), glutathione reductase (GR) and glutathione-s-transferase (GST) activities were measured on a Hitachi 704 autoanalyser by the modification of previously described manual UV spectrophotometric methods. No significant differences were observed in erythrocyte GSH-PX, GR and GST activities between different age groups. Overall, GST activities were significantly higher in females compared with males (8.08 +/- 1.39, 6.88 +/- 1.51 U/g Hb respectively, mean +/- SD, p < 0.001). A significant positive correlation between GSH-PX and GR activities was observed (r = 0.49, p < 0.001). The results of this study suggested that the activities of GSH-PX, GR and GST did not depend. GST activities overall were higher in females. The reference values that we obtained were different than the previous reports. This situation implies that each population should determine its own reference values and should investigate the influence of environmental factors and life style habits on the activities of these enzymes that constitute a major part of the antioxidant defense system in the human organism.


Detection of cow hind-leg activity during milking by using a 3-dimensional accelerometer attached to the milking cluster.
Hind-leg activity in dairy cows during milking is considered an indicator of a stressful situation or discomfort. Automatic detection of cow hind-leg activity during milking could be used to monitor deficiencies at the cow, milking machine, or human level. We assumed that the milking cluster follows cow hind-leg movements during milking. Therefore, the aim of our study was to estimate the ability of a 3-dimensional (3D) accelerometer attached to the claw's hook of the milking cluster to indirectly measure cow hind-leg activity during milking. The behavior of 45 dairy cows during 1 morning and 1 evening milking in a 2 × 3 auto tandem milking parlor was monitored by using direct visual observations and a 3D accelerometer attached directly to the hook of each milking claw. We recorded when hind-leg foot-lifting or stepping (undifferentiated) and kicking behaviors occurred. Detected activities were obtained after applying a standard deviation filter (over a sliding window of 1 s) on the x (left/right lateral) acceleration axis only. We set the detection threshold at 0.13 g (i.e., 1.27 m·s-2), based on the visual evaluation of 10 "reference" graphs (from 5 randomly chosen cows). Periods of activity were created for each observed or detected activity (and for consecutive activities that were less than 3 s apart) to take into account the milking cluster's rocking motion resulting from a single movement. Observed and detected periods of activity were considered matching when they occurred simultaneously (with a 2-s delay acceptance in the visual observations). In total, 472 periods of hind-leg activity were observed. The detection of hind-leg activity by using a 3D accelerometer attached to the milking cluster was found to have 69% sensitivity, 99% specificity, 75% positive predictive value, 98% negative predictive value, and an overall accuracy of 97%. On average, cows were observed being active 0.94 times per minute and being detected active 0.86 times per minute. The observed and detected periods of activity were found to be correlated (r = 0.657). Therefore, the use of a 3D accelerometer attached to the milking cluster seems promising for reliably estimating cow hind-leg activity during milking. Nevertheless, further investigations are necessary to clarify whether other factors can cause variations in milking cluster movements, regardless of cow hind-leg activity, and to generalize our method to better identify deficiencies in cow-machine-human interactions.


Intensive blood pressure control after endovascular thrombectomy for acute ischaemic stroke (ENCHANTED2/MT): a multicentre, open-label, blinded-endpoint, randomised controlled trial.
The optimum systolic blood pressure after endovascular thrombectomy for acute ischaemic stroke is uncertain. We aimed to compare the safety and efficacy of blood pressure lowering treatment according to more intensive versus less intensive treatment targets in patients with elevated blood pressure after reperfusion with endovascular treatment. We conducted an open-label, blinded-endpoint, randomised controlled trial at 44 tertiary-level hospitals in China. Eligible patients (aged ≥18 years) had persistently elevated systolic blood pressure (≥140 mm Hg for >10 min) following successful reperfusion with endovascular thrombectomy for acute ischaemic stroke from any intracranial large-vessel occlusion. Patients were randomly assigned (1:1, by a central, web-based program with a minimisation algorithm) to more intensive treatment (systolic blood pressure target <120 mm Hg) or less intensive treatment (target 140-180 mm Hg) to be achieved within 1 h and sustained for 72 h. The primary efficacy outcome was functional recovery, assessed according to the distribution in scores on the modified Rankin scale (range 0 [no symptoms] to 6 [death]) at 90 days. Analyses were done according to the modified intention-to-treat principle. Efficacy analyses were performed with proportional odds logistic regression with adjustment for treatment allocation as a fixed effect, site as a random effect, and baseline prognostic factors, and included all randomly assigned patients who provided consent and had available data for the primary outcome. The safety analysis included all randomly assigned patients. The treatment effects were expressed as odds ratios (ORs). This trial is registered at ClinicalTrials.gov, NCT04140110, and the Chinese Clinical Trial Registry, 1900027785; recruitment has stopped at all participating centres. Between July 20, 2020, and March 7, 2022, 821 patients were randomly assigned. The trial was stopped after review of the outcome data on June 22, 2022, due to persistent efficacy and safety concerns. 407 participants were assigned to the more intensive treatment group and 409 to the less intensive treatment group, of whom 404 patients in the more intensive treatment group and 406 patients in the less intensive treatment group had primary outcome data available. The likelihood of poor functional outcome was greater in the more intensive treatment group than the less intensive treatment group (common OR 1·37 [95% CI 1·07-1·76]). Compared with the less intensive treatment group, the more intensive treatment group had more early neurological deterioration (common OR 1·53 [95% 1·18-1·97]) and major disability at 90 days (OR 2·07 [95% CI 1·47-2·93]) but there were no significant differences in symptomatic intracerebral haemorrhage. There were no significant differences in serious adverse events or mortality between groups. Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischaemic stroke due to intracranial large-vessel occlusion. The Shanghai Hospital Development Center; National Health and Medical Research Council of Australia; Medical Research Futures Fund of Australia; China Stroke Prevention; Shanghai Changhai Hospital, Science and Technology Commission of Shanghai Municipality; Takeda China; Hasten Biopharmaceutic; Genesis Medtech; Penumbra.


The Effect of Environmental Temperature on Glucose and Insulin After an Oral Glucose Tolerance Test in Healthy Young Men.
The purpose of this study was to compare glucose and insulin responses during an oral glucose tolerance test (OGTT) in cold (C), neutral (N), and hot (H) environments. Eleven males completed three 4-hour climate-controlled OGTT trials (C, 7.2°C; N, 22°C; and H, 43°C). Participants remained semireclined for 60 minutes before ingesting a 1.8 g/kg glucose beverage. Skin and rectal core temperatures were continuously monitored. Blood was collected just before glucose ingestion (time 0) and at 15, 30, 60, 90, 120, and 180 minutes, and analyzed for serum glucose, insulin, hematocrit, and hemoglobin. Expired gases were collected upon entering the chamber (-60 minutes), before glucose ingestion (0 minutes), and at 60, 120, and 180 minutes to determine V(O2) and respiratory exchange ratio. Rectal core temperature was greater in the H condition compared with both C and N (P < .001). Rectal core temperature was not different between C and N, whereas skin temperature was different across all trials (H greater than N greater than C). The V(O2) was greater in C than in both H and N during all time points. Carbohydrate oxidation was greater in C compared with H and N (P < 0.001). Glucose was higher during H compared with C and N (P ≤ 0.002). Glucose was elevated in C compared with N. Insulin was higher in H compared with C (P = 0.009). Area under the curve for serum glucose was greater in H compared with C and N (P ≤ 0.001); however, there was no significant difference in area under the curve for insulin. These data indicate that after an OGTT, glucose and insulin are elevated in a hot environment.


Precise Control of Molecular Self-Diffusion in Isoreticular and Multivariate Metal-Organic Frameworks.
Understanding the factors that affect self-diffusion in isoreticular and multivariate (MTV) MOFs is key to their application in drug delivery, separations, and heterogeneous catalysis. Here, we measure the apparent self-diffusion of solvents saturated within the pores of large single crystals of MOF-5, IRMOF-3 (amino-functionalized MOF-5), and 17 MTV-MOF-5/IRMOF-3 materials at various mole fractions. We find that the apparent self-diffusion coefficient of N,N-dimethylformamide (DMF) may be tuned linearly between the diffusion coefficients of MOF-5 and IRMOF-3 as a function of the linker mole fraction. We compare a series of solvents at saturation in MOF-5 and IRMOF-3 to elucidate the mechanism by which the linker amino groups tune molecular diffusion. The ratio of the self-diffusion coefficients for solvents in MOF-5 to those in IRMOF-3 is similar across all solvents tested, regardless of solvent polarity. We conclude that average pore aperture, not solvent-linker chemical interactions, is the primary factor responsible for the different diffusion dynamics upon introduction of an amino group to the linker.


Anatomical Study and Clinical Observation of Retro-orbicularis Oculi Fat (ROOF).
To study the anatomical location of retro-orbicularis oculi fat (ROOF) in the upper eyelid and to investigate how ROOF affects the appearance of the upper eyelid. Twenty-eight Chinese hemifacial cadaver specimens were used (14 male cadavers; age range 52-82 years). In 28 hemifaces, the eyelids were dissected from the superficial to deep layers, and the appearance, location, extent, and surrounding tissue of ROOF were observed. Additionally, we observed the relationship between the upper eyelid morphology and ROOF of the upper eyelid in surgical patients who were treated in the plastic surgery department of Tongji Hospital affiliated with Huazhong University of Science and Technology in 2018. ROOF is a type of fascia adipose tissue that is located in a fat compartment between the muscles (the orbicularis oculi and frontalis muscles) and the orbital septum/frontalis fascia. In patients with hypertrophic ROOF, the upper eyelid appears as a heavy eyelid and as a drooping eyelid. And in patients with atrophic ROOF, the upper eyelid appears as a sunken eyelid. ROOF is located in the fat compartment between the orbicularis muscle and the orbital septum/frontalis fascia. ROOF covers the entire upper eyelid and appears thinner medially and thicker laterally. It is continuous with the fat under the frontalis muscle and affects the appearance of the upper eyelid. It represents an important factor in upper eyelid surgery. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.


The morbidity of transperineal template-guided prostate mapping biopsy.
To evaluate the effect of transperineal template-guided prostate mapping biopsy (TTMB) on urinary, bowel and erectile function. In all, 129 men had TTMB; a median of 56 biopsy cores were obtained per patient. Tamsulosin (0.8 mg daily) was initiated 2 days before TTMB and continued for 2 weeks. The International Prostate Symptom Score (IPSS), Rectal Function Assessment Score (R-FAS), International Index of Erectile Function (IIEF)-6 and the postvoid residual volume (PVR) were assessed at baseline and after 30 days, except for the IPSS, which was also assessed at 7 days. Several variables were evaluated as predictors of TTMB-induced morbidity. The mean patient age was 64.7 years with a mean prostate volume of 74.3 mL; 60 men (46.5%) were diagnosed with prostate cancer. After TTMB, 39.4%, 7.1% and 1.6% of patients remained catheter-dependent at 0, 3 and 6 days. The median catheter-dependency was 0, 1, 2 and 3 days for prostate volumes of <60, 60-90, 90-120 and >120 mL, respectively. No patient remained catheter- dependent for >12 days or required a transurethral resection secondary to TTMB. The mean IPSS before TTMB was 10.4, and was 4.6 and 3.8 at 7 and 30 days. At baseline and 30 days the mean PVR was 35 and 40 mL, and the median R-FAS and IIEF scores for patients potent before TTMB were 2.0 and 2.2, and 27.0 and 26.0, respectively. TTMB is a promising procedure for diagnosing prostate cancer. TTMB-related morbidity differs from that of standard TRUS biopsy primarily in the incidence of temporary urinary retention, and is comparable in terms of urinary, bowel and erectile function.


Highly sensitive detection of epidermal growth factor receptor in lung cancer cells by aptamer-based target-/probe-mediated cyclic signal amplification.
We develop an antibody-free fluorescence method for the epidermal growth factor receptor (EGFR) assay using aptamer-based target-/probe-mediated cyclic signal amplification. The method is highly sensitive with a detection limit of 0.16 fM, and it can be applied to detect EGFR in lung cancer cells, holding great potential in clinical diagnosis.


The noradrenergic pain regulation system: a potential target for pain therapy.
Noradrenaline, through action on α₁- and α₂-adrenoceptors, is involved in intrinsic control of pain. Peripheral noradrenaline that is mainly released by the sympathetic nervous system has little influence on healthy tissues, whereas in injured or inflamed tissues it has varying effects, including aggravation of pain in neuropathy. The peripheral pronociceptive effect has been associated with injury-induced expression of novel noradrenergic receptors, sprouting of sympathetic nerve fibers, and pronociceptive changes in the ion channel properties on primary afferent nociceptors, whereas an interaction with the immune system may contribute to peripheral antinociceptive effect of noradrenaline. In the spinal dorsal horn, noradrenaline released from descending pathways originating in the pontine A5-A7 cell groups attenuates pain by inhibitory action on α(2A)-adrenoceptors on central terminals of primary afferent nociceptors (presynaptic inhibition), by direct α₂-adrenergic action on spinal pain-relay neurons (postsynaptic inhibition), and by α₁-adrenergic activation of inhibitory interneurons. Moreover, α(2C)-adrenoceptors on axon terminals of excitatory interneurons might contribute to spinal control of pain. At supraspinal levels, the effect of noradrenergic system on pain has varied depending on many factors such as the type of the adrenoceptor, pathophysiological condition, and the brain area. In general, the baseline pain sensitivity is only little influenced by the noradrenergic system, whereas in injured conditions the noradrenergic system contributes to feedback inhibition of pain. The central as well as the peripheral noradrenergic system is subject to various plastic changes following injury or inflammation that influence its antinociceptive efficiency. α₂-Adrenoceptor agonists have proven effective in treating various pain conditions.


A new sampling method for spleen stiffness measurement based on quantitative acoustic radiation force impulse elastography for noninvasive assessment of esophageal varices in newly diagnosed HCV-related cirrhosis.
In our study, we evaluated the feasibility of a new sampling method for splenic stiffness (SS) measurement by Quantitative Acoustic Radiation Force Impulse Elastography (Virtual Touch Tissue Quantification (VTTQ)).We measured SS in 54 patients with HCV-related cirrhosis of whom 28 with esophageal varices (EV), 27 with Chronic Hepatitis C (CHC) F1-F3, and 63 healthy controls. VTTQ-SS was significantly higher among cirrhotic patients with EV (3.37 m/s) in comparison with controls (2.19 m/s, P<0.001), CHC patients (2.37 m/s, P<0.001), and cirrhotic patients without EV (2.7 m/s, P<0.001). Moreover, VTTQ-SS was significantly higher among cirrhotic patients without EV in comparison with both controls (P<0.001) and CHC patients (P<0.01). The optimal VTTQ-SS cut-off value for predicting EV was 3.1 m/s (AUROC=0.96, sensitivity 96.4%, specificity 88.5%, positive predictive value 90%, negative predictive value 96%, positive likelihood ratio 8.36, and negative likelihood ratio 0.04). In conclusion, VTTQ-SS is a promising noninvasive and reliable diagnostic tool to screen cirrhotic patients for EV and reduce the need for upper gastrointestinal endoscopy. By using our cut-off value of 3.1 m/s, we would avoid endoscopy in around 45% of cirrhotic subjects, with significant time and cost savings.


Experimental hyperthyroidism in rats suppresses in vitro prostaglandin metabolism in lung and kidney.
Metabolism of prostaglandin (PG) F2alpha and PGE2 was depressed 40--62% in 100,000 g cytoplasmic supernatants of lungs and kidneys prepared from rats made hyperthyroid by 18 daily L(-) thyroxine injections (200microgram, s--c). These hyperthyroid rats had elevated serum thyroxine levels, cardiac hypertrophy and thyroid atrophy. There were no differences in soluble protein concentrations, NAD+ utilisation by endogenous enzymes and substrates, or in the NAD+ dependence of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) between the supernatants prepared from hyperthyroid rats and saline-injected controls. Thyroxine did not inhibit PG metabolism in vitro up to 260 micrometer. These results suggest that thyroxine specifically decreases intracellular levels of PG-metabolising enzymes, especially of the rate-limiting 15-PGDH. Metabolism of PGF2alpha and PGE2 by 15-PGDH was faster in smaller rats and declined with increasing animal weight. These studies imply that some of the clinical features of hyperthyroidism in man might be caused by deficiencies in PG metabolism.


Host resistance to pulmonary Mycobacterium tuberculosis infection requires CD153 expression.
Mycobacterium tuberculosis infection (Mtb) is the leading cause of death due to a single infectious agent and is among the top ten causes of all human deaths worldwide1. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFNγ production is the primary mechanism of CD4 T-cell-mediated protection2,3. However, IFNγ responses do not correlate with host protection, and several reports demonstrate that additional anti-tuberculosis CD4 T-cell effector functions remain unaccounted for4-8. Here we show that the tumour-necrosis factor (TNF) superfamily molecule CD153 (encoded by the gene Tnfsf8) is required for control of pulmonary Mtb infection by CD4 T cells. In Mtb-infected mice, CD153 expression is highest on Mtb-specific T helper 1 (TH1) cells in the lung tissue parenchyma, but its induction does not require TH1 cell polarization. CD153-deficient mice develop high pulmonary bacterial loads and succumb early to Mtb infection. Reconstitution of T-cell-deficient hosts with either Tnfsf8-/- or Ifng-/- CD4 T cells alone fails to rescue mice from early mortality, but reconstitution with a mixture of Tnfsf8-/- and Ifng-/- CD4 T cells provides similar protection as wild-type T cells. In Mtb-infected non-human primates, CD153 expression is much higher on Ag-specific CD4 T cells in the airways compared to blood, and the frequency of Mtb-specific CD153-expressing CD4 T cells inversely correlates with bacterial loads in granulomas. In Mtb-infected humans, CD153 defines a subset of highly polyfunctional Mtb-specific CD4 T cells that are much more abundant in individuals with controlled latent Mtb infection compared to those with active tuberculosis. In all three species, Mtb-specific CD8 T cells did not upregulate CD153 following peptide stimulation. Thus, CD153 is a major immune mediator of host protection against pulmonary Mtb infection and CD4 T cells are one important source of this molecule.


Association of DRD2 gene variant with schizophrenia.
Schizophrenia is a complex multifactorial disorder for which the pathobiology still remains elusive. Dysfunction of the dopamine D2 receptor signaling has been associated with the illness, but numerous studies provide confounding results. This study investigates the association of synonymous polymorphisms (His313 and Pro319) in the dopamine D2 receptor gene with schizophrenia using a case-control approach, with 101 cases and 145 controls. Our results demonstrated that genotype distribution for the His313 polymorphism was significantly different between schizophrenia patients and control subjects (p=0.0012), while the Pro319 polymorphism did not show any association with the disease. The results suggest that the synonymous SNP His313 in DRD2 may be associated with the illness. However, there is a need for further replication studies with larger sample sets.


Dark-lumen MR colonography with fecal tagging: a comparison of water enema and air methods of colonic distension for detecting colonic neoplasms.
The purpose was to evaluate MR colonography (MRC) with barium fecal tagging in detecting colorectal pathology and to determine how air-based and water-based colonic distension influences MRC. We studied 83 patients with high risk of colonic neoplasms. All received oral barium sulfate for colonic preparation before unenhanced and enhanced T1-weighted gradient-echo MRC using either water (n=54) or air (n=29) for colonic distension. Fecal tagging, distension, and artifacts were recorded. All patients underwent conventional colonoscopy within 2 weeks of MRC; the techniques were compared for detection of malignant neoplasms and polyps >or=1 cm, 6-9 mm, and <or=5 mm. Fecal tagging was "good" in 76% of the colonic segments in water-distended patients and 46% of air-distended patients. The degree of distension was "good" in 90.7% of water-distended patients and 44% of air-distended patients. Severe artifacts were present in 15% air-distended patients and 0.3% of water-distended patients. Both water-distended and air-distended MRC detected all malignant neoplasms and polyps >or=1 cm, but more air-distended MRC were excluded for poor quality. MRC with fecal tagging is useful for detecting lesions >or=1 cm. Air distension was inferior to water distension in most aspects. Water-based colonic distension should be used for barium-tagging MRC.


Treatment of advanced bladder cancer with cis-diamminedichloroplatinum (II NSC 119875): a pilot study.
A pilot study was done using 19 patients with bladder cancer to test the efficacy of cis-diamminedichloroplatinum as a single agent to treat transitional cell carcinoma. Fourteen patients had stage D lesions, 3 patients had stage C and 2 patients had stage B tumors. The patients received 1 mg./kg. cis-diamminedichloroplatinum mixed with 2,000 cc dextrose 5 per cent in one-third normal saline solution, 37.5 gm. mannitol and 40 mEq. potassium chloride. The mixture was given in a slow infusion lasting 6 to 8 hours every week for the first 6 weeks and every 3 weeks thereafter. In the patients with stage D disease 1 complete clinical remission, 7 partial clinical remissions, 1 minimal objective response and 1 subjective response were observed. Four patients did not respond to the treatment. In the 3 stage C patients no response to the drug was observed. In the stage B patients 1 partial remission and 1 minimal objective response were seen. A total objective response (complete remission and partial remission) was seen in 9 of the 19 patients (47 per cent). The duration of the responses varied from 2 to 10 months, with an average of 4.8 months. These promising results seem to indicate the high degree of effectiveness of cis-diamminedichloroplatinum against transitional cell carcinoma of the bladder.


[Genetic, molecular, and humoral endocycle-regulating mechanisms].
The review presents data on the molecular genetic mechanisms controlling endoreduplication. The issues concerning the activity of the main cycle cell regulators, such as cyclins, cyclin-dependent kinases, and their inhibitors, under conditions of a modified cell cycle of polytene cells are considered. Specific features of regulation at the replication origin points and the role of hormones and phytohormones in the ontogenetic control of endoreduplication are analyzed.


Polycyclic aromatic compounds as anticancer agents: synthesis and biological evaluation of some chrysene derivatives.
Synthesis and biological evaluation of new chrysene derivatives aimed at the development of anticancer agents were carried out.


Temporal filtering enhances direction discrimination in random-dot patterns.
In conventional presentations of random-dot kinematograms, two frames of random dots are presented in temporal sequence, separated by a blank inter-stimulus interval, and a coherent offset in spatial position is added to dots in one frame relative to dots in the other frame. Direction discrimination performance is limited temporally to inter-stimulus intervals below about 100 msec (Tmax). Experiments are described in which temporal smoothing was applied to the onset and offset of each frame in the kinematogram. Tmax was found to increase in proportion with the time constant of the temporal smoothing function. An explanation based on contrast-dependent responses in simple motion detectors cannot accommodate the results. Instead, the increase in Tmax with temporal smoothing, and analogous increase in spatial limit (Dmax) with spatial blurring, can be related to the spatiotemporal frequency content of the stimulus. Random-dot kinematograms can be viewed as continuously drifting patterns that have been discretely sampled at regular spatiotemporal intervals. Sampling introduces artefacts (alias signals), which become more intrusive as sampling rate declines (i.e. inter-stimulus interval or spatial displacement increases) and consequently limit discrimination performance. Temporal smoothing or spatial blurring extends performance because it removes alias signals generated by high spatiotemporal frequencies in the pattern. Computational modelling to estimate the Fourier energy available in random-dot kinematograms confirmed that the sampling account can predict the proportional increase in Tmax and Dmax limits as filter time or space constant increases.