High oxidative stress adversely affects NFκB mediated induction of inducible nitric oxide synthase in human neutrophils: Implications in chronic myeloid leukemia.
Increasing evidence support bimodal action of nitric oxide (NO) both as a promoter and as an impeder of oxygen free radicals in neutrophils (PMNs), however impact of high oxidative stress on NO generation is less explored. In the present study, we comprehensively investigated the effect of high oxidative stress on inducible nitric oxide synthase (iNOS) expression and NO generation in human PMNs. Our findings suggest that PMA or diamide induced oxidative stress in PMNs from healthy volunteers, and high endogenous ROS in PMNs of chronic myeloid leukemia (CML) patients attenuate basal as well as LPS/cytokines induced NO generation and iNOS expression in human PMNs. Mechanistically, we found that under high oxidative stress condition, S-glutathionylation of NFκB (p50 and p65 subunits) severely limits iNOS expression due to its reduced binding to iNOS promoter, which was reversed in presence of DTT. Furthermore, by using pharmacological inhibitors, scavengers and molecular approaches, we identified that enhanced ROS generation via NOX2 and mitochondria, reduced Grx1/2 expression and GSH level associated with NFκB S-glutathionylation in PMNs from CML patients. Altogether data obtained suggest that oxidative status act as an important regulator of NO generation/iNOS expression, and under enhanced oxidative stress condition, NOX2-mtROS-NFκB S-glutathionylation is a feed forward loop, which attenuate NO generation and iNOS expression in human PMNs.


A telehealth intervention for ensuring continuity of care of pediatric obesity during the CoVid-19 lockdown in Italy.
Restriction measures adopted during the Coronavirus Disease-19 pandemic favored unhealthy behaviors. Tele-health offered the opportunity to pursue alternative ways of chronic diseases management. This retrospective study sought to determine the effects of a telehealth counselling intervention during the lockdown to children and adolescents with obesity previously engaged in a family-based secondary care program in an outpatient clinic of South Italy. 117 out of 156 patients participated to the tele-health intervention. Participants underwent videocalls with each component of the multidisciplinary team to receive support in adopting adequate dietary habits and to practice exercise at home. They were included in a closed social group to watch age-adapted tutorials on healthy habits. 75 patients returned to the Center after the end of the lockdown, while only 7 patients who did not participate to the videocalls, took part to the follow-up. Body Mass Index and body composition were assessed in all these patients. BMI z score did not increase in both groups. However, a significant increase of fat mass was observed in the non-participating group (0.046), while the intervention group showed an increase of fat free mass (p < 0.000). Notwithstanding the limited sample size, the telehealth intervention allowed the maintenance of baseline weight status in participants, with an increase of fat-free mass. As the CoViD-19 pandemic moves forward, the increasing adoption of the new technologies may help the continuity of care, even in pediatric obesity treatment.


Behavioral science and nutrition: a new perspective.
Increasing collaboration of nutritionists and behavioral scientists is needed in order to bring about desirable long-term changes in eating patterns. The National Heart, Lung, and Blood Institute's growing interest in this area is described, and recent examples of such collaboration are noted. The two papers which follow--one emanating from the area of social psychology, the other from behavior modification--are introduced.


Induction of neuropeptide Y expression in dorsomedial hypothalamus of diet-induced obese mice.
Alterations of hypothalamic neuropeptide Y(NPY) and melanocortinergic functions in diet-induced obese (DIO) C57BL/6J mice were investigated by in situ hybridization. Compared with controls, the DIO mice displayed a profound induction (approximately 40-fold) of NPY expression in the dorsomedial (DMH) and ventromedial (VMH) hypothalamic nuclei, whereas the level of NPY mRNA in the arcuate nucleus (ARC) was reduced by 44%. The expression of pro-opiomelanocortin (POMC) and agouti-related protein was not significantly altered in the ARC of obese mice. Both excess body weight gain and altered hypothalamic NPY expression were reversible. We propose that the highly induced NPY expression in DMH and/or VMH may be a contributing etiological factor for the development of obesity and leptin resistance in the DIO mice.


Breast Imaging in Pregnancy and Lactation.
All breast disorders found during pregnancy and lactation should be carefully evaluated. Most of them are benign, but it is essential to exclude pregnancy-associated breast cancer (PABC), which is too often diagnosed late. The first-line imaging technique is ultrasound (US), which must be completed by mammography if there is any clinical or US suspicious sign . In lactating patients with PABC , breast magnetic resonance imaging (MRI) can be useful for local assessment.Management depends on the precise analysis and BI-RADS classification of the lesion. During pregnancy and lactation, there is an overlap in imaging: many benign lesions can grow, infarct, become heterogeneous and thus suspicious, and on the other hand, PABC does not always present with typical malignant features. That is why biopsy must be performed if after the clinical and radiological evaluation the doubt persists, i.e. for all BI-RADS 4 and 5 lesions, and for some BI-RADS 3 lesions.


Ranking tributaries for setting remediation priorities in a TMDL context.
The San Joaquin River (SJR) in the Central Valley of California has been designated an impaired waterbody based on its loss of fisheries-related beneficial uses and the river is now subject to regulation under total maximum daily load (TMDL) rules. For impaired waterbodies, numeric standards alone may not be sufficient to establish remediation priorities and priorities must be established by comparing drainages to each other. Data collected as part of regional water quality (WQ) studies in the SJR Valley were not normally distributed, so nonparametric methods based on ranking were used to compare the WQ of individual tributaries and drainages. Normalized rank means (NRMs) were calculated from ranked data and NRMs were mapped to identify priority drainages for WQ improvement activities. NRMs for individual parameters were combined into indexes that are useful for examining the relative importance of different drainages for multiple parameters simultaneously. Indexes were developed for eutrophication and overall WQ. This ranking approach is being proposed as an easily understood, transparent, and scientifically rigorous method to assess the relative WQ impact of individual drainages and set watershed remediation priorities.


Problems after restorative proctocolectomy: assessment and therapy.
Restorative proctocolectomy with ileal pouch-anal anastomosis is the surgical treatment of choice for patients with ulcerative colitis or familial adenomatous polyposis who require colectomy. Although the surgical procedure significantly improves the patients' quality of life, complications are common. Mechanical or structural complications related to surgical techniques as well as chronic pouchitis are common after the procedure. Recent literature has suggested some of those mechanical complications, along with chronic pouchitis, may share similar risk factors, particularly between anastomotic leak or sinus and chronic pouchitis. Those factors include male gender, obesity, weight gain, and Clostridium difficile infection. Mounting clinical evidence suggests that ischemia or excessive fat deposition plays an important role in the development of the surgical procedure-associated mechanical complication as well as chronic antibiotic-refractory pouchitis. Those findings along with the theory of ischemia/fat deposition will shed some light on the pathogenesis of the complex pouch disorders, providing the guidance for the risk stratification, prevention, diagnosis, and management.


Infertility in carriers of two bisatellited marker chromosomes.
Two unrelated sterile patients, a male and a female, with karyotypes characterized by the presence of two supernumerary bisatellited marker chromosomes, were studied with the aid of fluorescence in situ hybridization (FISH). Using alphoid centromeric specific probes, the markers were identified as an idic (15) (pter-q11) and a mar (14). In both cases a single accessory bisatellited marker was present in the karyotype of one of the parents. A possible correlation between the excess of constitutive heterochromatin and meiotic disturbances in the two patients is discussed.


Production and characterization of cytostatic protein factors released from human monocytes during exposure to lipopolysaccharide and muramyl dipeptide.
The effect of activating human monocytes in vitro with lipopolysaccharide (LPS) and muramyl dipeptide (MDP) on the production of cytostatic protein factor(s) (CF) has been investigated, and an antiserum against CF has been raised and tested. Upon incubation for 7 hr with LPS, in vitro differentiated human monocytes released CF. During LPS exposure, the presence of the protein synthesis inhibitor cycloheximide, at concentrations which reduced the overall protein synthesis by 60 and 80%, reduced the amount of CF released by only 20 and 40%, respectively. This indicates that the released CF was to a large extent already present in the monocytes before exposure to LPS. Compared to LPS, MDP induced only modest CF release. However, when lymphokine-activated monocytes were exposed to MDP, an increased CF release was observed. By immunizing a rabbit with CF purified by ion-exchange chromatography, chromatofocusing, and gel filtration, an antiserum was raised which neutralized the cytostatic activity released from monocytes exposed to LPS or lymphokines/LPS in sequence on the fourth day of culture. The cytostatic activity obtained by incubating freshly isolated monocytes with LPS was inhibited by the antiserum to a lesser extent, indicating the presence of other cytotoxins or cytotoxic cellular products in addition to CF in supernatants from freshly isolated monocytes. Various CF preparations were tested for IL-1 activity; no correlation between IL-1 activity and cytostatic activity was observed. Moreover, upon gel filtration the CF and IL-1 activities could be separated from each other and are consequently associated with different proteins.


Demography of the twospotted spider mite, Tetranychus urticae Koch.
A simple life table model was constructed for Tetranychus urticae in which daily survivorship of eggs and motil stages, fecundity, and development time was altered to assess the impact of each parameter on the intrinsic rate of increase. r. Interpretation of the trade-offs focused on management considerations.A second aspect of the study concerned age and stage structure in mite populations including the time path of convergence to a stable age distribution and the effect of changes in birth and death rates on the age profile. The stable stage distributions of 7 tetranychid mite species were computed using 25 separate life tables. In spite of the wide range of r-values induced by different experimental conditions, all of the stage distributions were quite similar averaging roughly 66% eggs, 26% immatures, and 8% adults. Several population studies were cited which reported stage distributions of growing mite populations. The empirical evidence suggested that natural mite populations are often quite near this stable distribution.A practical problem involving the extent to which hormoligosis (insecticide stimulation) affects mite population growth rate was addressed using the life table model and laboratory data from controlled studies. The findings suggested that mite populations treated with insecticide may attain a 1.4- to a 4.2-fold difference in population size relative to an untreated population after 2 generations and over a 1,300-fold potential difference after 10 generations.


Absence of the neutrophil serine protease cathepsin G decreases neutrophil granulocyte infiltration but does not change the severity of acute pancreatitis.
Acute pancreatitis is characterized by an early intracellular protease activation and invasion of leukocytes into the pancreas. Cathepsins constitute a large group of lysosomal enzymes, that have been shown to modulate trypsinogen activation and neutrophil infiltration. Cathepsin G (CTSG) is a neutrophil serine protease of the chymotrypsin C family known to degrade extracellular matrix components and to have regulatory functions in inflammatory disorders. The aim of this study was to investigate the role of CTSG in pancreatitis. Isolated acinar cells were exposed to recombinant CTSG and supramaximal cholezystokinin stimulation. In CTSG-/- mice and corresponding controls acute experimental pancreatitis was induced by serial caerulein injections. Severity was assessed by histology, serum enzyme levels and zymogen activation. Neutrophil infiltration was quantified by chloro-acetate ersterase staining and myeloperoxidase measurement. CTSG was expessed in inflammatory cells but not in pancreatic acinar cells. CTSG had no effect on intra-acinar-cell trypsinogen activation. In CTSG-/- mice a transient decrease of neutrophil infiltration into the pancreas and lungs was found during acute pancreatitis while the disease severity remained largely unchanged. CTSG is involved in pancreatic neutrophil infiltration during pancreatitis, albeit to a lesser degree than the related neutrophil (PMN) elastase. Its absence therefore leaves pancreatitis severity essentially unaffected.


[Primary glomangioma of the liver. A new differential benign liver tumor diagnosis].
Glomus organs are arteriovenous anastomoses which control the thermoregulation of the extremities. Benign tumors of these glomus organs, termed "glomangiomas", are therefore most frequently located in the fingers and toes. Case reports of primary glomangiomas in the respiratory- and gastrointestinal tracts as well as in the genital organs have been published. On the other hand, glomus tumors of the liver have not yet been described. We report the case of a 61-year-old patient with a smooth subcapsular lesion within the liver detected by a routine ultrasound scan. Further diagnostic imaging did not match with one of the common liver tumors. The diagnosis of a glomangioma was finally made by liver biopsy and subsequent histology. A review of the literature revealed a potential transformation of glomangiomas. Since the patient reported on inappetence weight loss and the tumor showed growth tendency, the indication for surgical excision was made. Final histologic investigation revealed no signs of malignancy. The primary glomangioma of the liver is a new differential diagnosis of benign liver tumors. As there is a possibility of malignant degeneration, we propose the decision for surgical removal once there are clinical symptoms and a growth tendency of the lesion.


Effects of an Integrated Palliative Care Pathway: More Proactive GPs, Well Timed, and Less Acute Care: A Clustered, Partially Controlled Before-After Study.
This study presents the design of an integrated, proactive palliative care pathway covering the full care cycle and evaluates its effects using 3 types of outcomes: (1) physician-reported outcomes, (2) outcomes reported by family, and (3) (utilization of) health care outcomes. A clustered, partially controlled before-after study with a multidisciplinary integrated palliative care pathway as its main intervention. after assessment in hospital departments of oncology, and geriatrics, and in 13 primary care facilities, terminally ill patients were proactively included into the pathway. Patients' relatives and patients' general practitioners (GPs) participated in a before/after survey and in interviews and focus groups. A multidisciplinary, integrated palliative care pathway encompassing (among others) early identification of the palliative phase, multidisciplinary consultation and coordination, and continuous monitoring of outcomes. Measures included GP questionnaire: perceived quality of palliative care; questionnaires by family members: FAMCARE, QOD-LTC, EDIZ; and 3 types of health care outcomes: (1) utilization of primary care: consultations, intensive care, communication, palliative home visits, consultations and home visits during weekends and out-of-office-hours, ambulance, admission to hospital; (2) utilization of hospital care: outpatient ward consultations, day care, emergency room visits, inpatient care, (radio) diagnostics, surgical procedures, other therapeutic activities, intensive care unit activities; (3) pharmaceutical care utilization. GPs reported that palliative patients die more often at their preferred place of death, and that they now act more proactively toward palliative patients. Relatives of included, deceased patients reported clinically relevant improved quality of dying, and more timely palliative care. Patients in the pathway received more (intensive) primary care, less unexpected care during out-of-office hours, and more often received hospital care in the form of day care. An integrated palliative care pathway improves a variety of clinical outcomes important to patients, their families, physicians, and the health care system. The integration of palliative care into multidisciplinary, proactive palliative care pathways, is therefore a desirable future development.


Ovarian Brenner tumors: MR imaging characteristics.
This study describes the appearance of Brenner tumors on MR imaging and compares quantitative signal intensity measurements of Brenner tumors with that of other ovarian tumors. A search of pathologic and MR records disclosed patients who had MRIs showing Brenner tumors prior to surgical excision. Patients (21) with other surgically proven ovarian masses were randomly selected for comparison. MR imaging was performed at 1.5 T with phased array multicoils and fast spin echo T2-weighted images. Region-of-interest measurements of signal intensity (SI) were made to calculate signal intensity ratios (SIR = mass SI/muscle SI). Brenner tumors showed significantly lower SIR than other tumors on T2-weighted images (p = 0.004) and similar SIR on T1-weighted images. Brenner tumors show lower signal intensity on T2-weighted images than other non-fibrous ovarian tumors. This lower signal intensity may result from the extensive fibrous content of these tumors.


Aging rice straw reduces the bioavailability of mercury and methylmercury in paddy soil.
Straw amendment is a prevalent agricultural practice worldwide, which can reduce air pollution and improve soil fertility. However, the impact of aging straw amendment on the bioavailability of mercury (Hg) and methylmercury (MeHg) in paddy soil remains unclear. To investigate this, incubation experiments were conducted using the diffusive gradient in thin-film technique. Results showed that amendments of dry-wet aging (DRS), photochemical aging (LRS), and freeze-thaw aging rice straw (FRS) reduced the bioavailable MeHg in paddy soil by 2.2-27.6%, 13.5-69.8%, and 23.5-86.1%, respectively, compared to fresh rice straw (RS) amendment. This result could be due to changes in soil properties such as soil pH and overlying water Fe and Mn as well as microbial abundance (including Clostridiaceae, Firmicutes, and Actinobacteriota). Simultaneously, The LRS and FRS amendments reduced bioavailable Hg in paddy soil by 20.0-40.8% and 17.1-48.6%, respectively, while DRS increased the bioavailable Hg by 15.8-120.0%. This could be attributed to changes in soil oxidation-reduction potential and overlying water SO42- content. Additionally, the results of sand culture experiments showed that the concentrations of Hg uptake by rice seedlings were 97.1-118.2%, 28.1-35.6%, and 198.0-217.1% higher in dissolved organic matter (DOM) derived from DRS, LRS, and FRS than RS, indicating that aging straw leached DOM may promote the Hg bioavailable when straw amendment. This result could be due to lower molecular weight and higher CO functional group content. These results provide new insight into how aging straw amendment affects the bioavailability of Hg and MeHg in paddy soil under different climates.


Action of heparin on mammalian nuclei. I. Differential extraction of histone H1 and cooperative removal of histones from chromatin.
Heparin interacts strongly with the histone component of chromatin, forming heparin-histone complexes which resist dissociation by 0.2 M H2SO4. Heparin treatment of unfractionated histones isolated from nuclei of Chinese hamster cells indicates that the affinities of the histone classes for heparin appear in the order from greatest to least: (H3, H4) greater than (H2A, H2B) greater than H1. However, when isolated nuclei are treated with heparin, H1 is released from the chromatin more readily than the other four histone classes. The release of these four histones (H2A, H2B, H3, and H4) is coordinate and occurs in a highly cooperative manner, as indicated by (1) dependence of the initial kinetics of histone removal upon heparin concentration, (2) analysis of DNA and histones in the fractions obtained from differential sedimentation of heparin-treated nuclei, and (3) analysis of the products from heparin-treated nuclei by equilibrium centrifugation in metrizamide density gradients. The results suggest rapid procedures for using heparin as an agent for studying the accessibility of histones in chromatin of intact nuclei. The relationship of these results to current models of chromatin structure is discussed.


The effect of heterogeneity on optimal regimens in cancer chemotherapy.
Optimal drug regimens for cancer chemotherapy are determined when knowledge is only available on the behaviour of the tumour and the drugs used, over a population of patients. The case of two drugs is investigated where they are equivalent on average. Our calculations indicate that the optimal regimen has both drugs given initially but then sequences the two drugs. Our calculations also indicate that as tumour heterogeneity increases, the benefit to be gained from the optimal regimen can decrease in comparison to reasonable regimens. This has the effect of complicating the calculation of optimal regimens in a clinical setting, and may explain why results in experimental oncology fail to carry over to clinical oncology.


Comparative immunocytochemistry of isolated rat & monkey pancreatic islet cell types.
Data on comparative distribution of the islet cell types in the Indian bonnet monkeys and rats are not available. The aim of the present study was to compare the arrangement of the three islet cell types in the native and in isolated rat and Indian bonnet monkey islets by immunocytochemistry. Rat islets isolated by chopped tissue collagenase digestion method and islets of monkey isolated by intraductal collagenase digestion method were immunostained by streptavidin-biotin peroxidase method. Immunocytochemical staining of the isolated islets in both the species revealed the presence of three different cell types: insulin secreting B cells, glucagon secreting A cells and somatostatin secreting D cells. The arrangement of islet cell types in the rats and monkeys was similar to that of the intact islets of the native pancreas but were arranged in a definite pattern. In rats the A and D cells were peripherally arranged around the centrally located B cells. In monkeys the B cells occupied the majority of the periphery while the A and D cells were found mostly in the centre. The findings of the present study showed that the arrangement of cell types in the islets was not affected by the isolation procedure. The difference in the arrangement of islet cell types in the two species may reflect special functional adaptations.


Some T-cell leukemia lines express surface markers related to a restricted set of human VH determinants.
Serological studies were carried out to obtain information regarding the relationship of the VH-related determinants expressed by certain permanent in vitro T-cell leukemia lines and corresponding determinants expressed by characterized human serum immunoglobulins. A panel of conventional (goat and rabbit) antisera, produced against various Fab-related fragments of monoclonal human Waldenstrom macroglobulins and polyclonal IgG molecules, bound to certain in vitro T-cell leukemia lines, notably, 70-N2, MT-1, YT4E, and HUT78, as shown by microhemagglutination. Inhibition studies using characterized myeloma proteins to inhibit this agglutination indicated the expression of a restricted VH-related determinant by these T-cell lines. Parallel studies performed using conventional (rabbit) and murine monoclonal/hybridoma antibodies produced against the isolated 68,000-Da VH-related product synthesized by the 70-N2 line showed that the determinant expressed by this molecule was restricted in expression, comprising 2-3% of the normal, polyclonal human Fab pool, and that the determinants found on the other positive T-cell leukemias were cross-reactive rather than identical. The inhibition studies suggest that the determinant resides between residue 22 and the end of the VH region. These results further define the antigenic nature of the VH-related marker found on the surfaces of certain normal and neoplastic T-cell lines.


Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer.
In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1. Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes. Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35). Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings. NCT01345682.


A phase II trial of aclacinomycin-A in advanced squamous cell carcinoma of the head and neck.
Sixteen patients with advanced squamous cell carcinoma of the head and neck were entered into a phase II trial of Aclacinomycin-A (ACM), 100 mg/M2 administered by brief infusion every three weeks. All patients had received prior radiation therapy and prior non-anthracycline containing chemotherapy. No clinically significant disease regression was observed in fourteen patients having adequate trials. The major toxicity was myelosuppression; leukopenia occurred in 93% of patients. Gastro-intestinal toxicity was mild and included two patients with transient liver function test abnormalities. No antitumor activity was observed in this patient population which was heavily pre-treated and had a median Karnofsky performance status of only 60%. The results of other phase II trials of ACM-A have been similarly disappointing suggesting that it is not a clinically useful agent in the treatment of solid tumors.


Hypothetical interpretation of the calcium paradox in renin secretion.
Most renin-positive cells of the preglomerular arteriole are intermediate in morphological appearence between smooth muscle cells and epithelioid cells. Intermediate cells contain, in addition to secretory granules, contractile proteins arranged as a sublemmal network. The paradoxical (inhibitory) role of calcium in renin secretion is explained, on the basis of these findings, by an increased tone of the sublemmal network; this might impair the preexocytotic access of renin granules to the cell membrane.


Overexpression of NADPH-cytochrome P450 reductase is associated with sulfoxaflor resistance and neonicotinoid cross-resistance in Nilaparvata lugens (Stål).
Nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P450 reductase (CPR), a crucial electron-transfer partner of P450 systems, is required for various biological reactions catalyzed by P450 monooxygenase. Our previous study indicated that enhanced P450 enzyme detoxification and CYP6ER1 overexpression contributed to sulfoxaflor resistance in Nilaparvata lugens. However, the association between CPR, sulfoxaflor resistance, and neonicotinoid cross-resistance in N. lugens remains unclear. In this study, the sulfoxaflor-resistant (SFX-SEL) (RR = 254.04-fold), resistance-decline (DESEL) (RR = 18.99-fold), and susceptible unselected (UNSEL) strains of N. lugens with the same genetic background were established. Real-time quantitative polymerase chain reaction (RT-qPCR) revealed that the N. lugens CPR (NlCPR) expression level in the SFX-SEL strain was 6.85-fold and 6.07-fold higher than in UNSEL and DESEL strains, respectively. NlCPR expression was significantly higher in the abdomens of UNSEL, DESEL, and SFX-SEL fourth-instar nymphs than in other tissues (thoraxes, heads, and legs). Additionally, sulfoxaflor stress significantly increased NlCPR mRNA levels in the UNSEL, SFX-SEL and DESEL strains. NlCPR silencing by RNA interference (RNAi) dramatically increased the susceptibility of the UNSEL, DESEL, and SFX-SEL strains to sulfoxaflor, but the recovery of SFX-SEL was more obvious. Furthermore, NlCPR silencing led to a significant recovery in susceptibility to nitenpyram, dinotefuran, clothianidin, and thiamethoxam across all strains (UNSEL, DESEL, and SFX-SEL), with the greatest degree of recovery in the sulfoxaflor-resistant strain (SFX-SEL). Our findings suggest that NlCPR overexpression contributes to sulfoxaflor resistance and neonicotinoid cross-resistance in N. lugens. This will aid in elucidating the significance of CPR in the evolution of P450-mediated metabolic resistance in N. lugens.


"Stunning" of the left atrium after spontaneous conversion of atrial fibrillation to sinus rhythm: demonstration by transesophageal Doppler techniques in a canine model.
This study compared left atrial and left atrial appendage contraction velocities in sinus rhythm before and after a brief period of atrial fibrillation in a canine model. In patients, left atrial appendage contraction velocities measured during sinus rhythm after cardioversion from atrial fibrillation are depressed relative to left atrial appendage emptying velocities measured during atrial fibrillation, suggesting that the left atrial appendage is mechanically "stunned." This phenomenon was studied in a canine model of acute (60 min) pacing-induced atrial fibrillation followed by spontaneous reversion to sinus rhythm using epicardial and transesophageal pulsed wave Doppler. Unique features of the model include: 1) comparison of left atrial function postconversion to baseline sinus rhythm rather than to measurements during atrial fibrillation, 2) control of the duration of atrial fibrillation and 3) elimination of the extraneous influences of direct current shock and antiarrhythmic agents, which may independently depress left atrial function. Hemodynamic conditions (heart rate, mean arterial pressure, cardiac output, mean pulmonary artery pressure, mean right atrial pressure and mean left atrial pressure) at baseline, during 60 min of atrial fibrillation and after reversion to sinus rhythm were constant throughout the study period. Peak left atrial contraction velocities (measured from the transmitral flow velocity profile) were significantly (p < 0.02) reduced to 64+/-22% of baseline values upon spontaneous conversion of atrial fibrillation to sinus rhythm and recovered to basal values by 20 min after resumption of sinus rhythm. Peak left atrial appendage contraction velocities were significantly (p < 0.001) reduced to 49+/-24% of baseline values upon spontaneous conversion of atrial fibrillation to sinus rhythm and recovered to basal values by 40 min after reversion to sinus rhythm. Even brief (60 min) periods of atrial fibrillation in normal canine hearts result in marked depression of global left atrial systolic function and regional left atrial (left atrial appendage) systolic function upon resumption of sinus rhythm. This "mechanical stunning" of left atrial systolic function appears to be more profound and of longer duration for the left atrial appendage compared with the left atrium as a whole, which may predispose the appendage to blood stasis and thrombus formation. Chronic models of atrial fibrillation need to be developed to examine the impact of longer periods of atrial fibrillation upon the magnitude and duration of postconversion left atrial "stunning."


Functional Neuroimaging Test of an Emerging Neurobiological Model of Hoarding Disorder.
Over the past decade, functional neuroimaging studies have found abnormal brain function in several cortical systems when patients with compulsive hoarding behaviors make decisions about personal possessions. The purpose of this study was to use functional magnetic resonance imaging to test a neurobiological model of hoarding disorder (HD) that has begun to emerge from these small studies by confirming HD-related brain dysfunction in previously implicated brain regions in the largest sample of HD patients examined to date. We compared 79 adults diagnosed with DSM-5 HD with 44 non-HD control participants using a functional magnetic resonance imaging task of decision making to acquire or discard material possessions and on a control task involving semantic processing. HD brain activation profiles prominently featured insular and anterior cingulate cortex overengagement during possession-related choices that were not seen in non-HD brain activation profiles and also correlated with hoarders' clutter and difficulty discarding. Although HD patients overengaged the insula when deciding to discard, relative to when performing the non-decision making task contrast, the HD insula also was generally blunted. This study links the defining behavioral symptoms of HD to localized brain dysfunction within cingulo-opercular brain systems and firmly establishes the context-dependent importance of this network dysfunction in HD. The relevance of dysfunction in these brain regions is highlighted by a failure to replicate HD-related abnormalities in other brain regions implicated in prior HD functional magnetic resonance imaging studies. This study also raises the novel possibility that HD may involve abnormality in the inferior frontal cortex engaged for executive control over semantic processing.


Natalizumab is associated with early improvement of working ability in relapsing-remitting multiple sclerosis patients: WANT observational study results.
The Work Ability in Natalizumab-Treated MS Patients (WANT) study assessed work ability, quality of life, and cognitive processing speed during natalizumab treatment. WANT was a 1-year, prospective, multicenter observational study conducted in Italy. Inclusion criteria included relapsing-remitting multiple sclerosis (MS), natalizumab treatment, full-time worker status, and loss of working hours due to MS as measured by the Work Productivity and Activity Impairment Questionnaire for MS (WPAI:MS). The primary endpoint was change in WPAI:MS domain scores after 1 year on natalizumab. Secondary endpoints included change in annualized relapse rate (ARR), Multiple Sclerosis Impact Scale (MSIS-29) score, and Symbol Digit Modalities Test (SDMT) score. At enrollment, the 91 patients had a mean age of 38.3 (standard deviation [SD], 9.0) years and a mean ARR of 1.5 (SD, 0.8). After 1 year, improvements were observed in all WPAI:MS domains, with significant reductions in Absenteeism (-4.2 [SD, 26.0], p = 0.0190) and Work Productivity Loss (-7.2 [SD, 28.6]; p = 0.0456). These changes were accompanied by a low ARR (0.1), and 87.9% of patients were relapse free. Significant improvement was observed in MSIS-29 physical and psychological domains (reductions of 2.8 [SD, 11.6; p = 0.0295] and 6.3 [SD, 15.6; p = 0.0007], respectively) and SDMT score (increase of 2.4 [SD, 7.9; p = 0.0006]). Adverse events were reported in 32 of 104 patients (30.8%). The reductions in Absenteeism and Work Productivity Loss and the improved physical and psychological functioning reported after 1 year of natalizumab treatment in real-world settings extend our understanding of natalizumab's effects on patient-centric and health economics outcomes.


Evaluation of the efficacy of interdental cleaning devices. How to design a clinical study.
A review of the literature was made, focusing on experimental designs used in clinical studies for assessment of the efficacy of interdental cleaning aids with regard to plaque removal and the prevention of caries and gingivitis. After careful consideration of the pros and cons of published procedures, an experimental design for such studies is proposed.


Epstein-Barr virus-targeted therapy in nasopharyngeal carcinoma.
Despite successful primary treatment of nasopharyngeal carcinoma (NPC), the incidence of distant metastasis remains 25-34 %. Treatment options are limited, and survival is poor. Intratumoural Epstein-Barr virus (EBV) was used as treatment target. In NPC, EBV is present in a latent state, expressing only few non-immunogenic viral products. Gemcitabine and valproic acid can trigger EBV to the lytic state, wherein viral kinases are expressed, making EBV-positive tumour cells susceptible for antiviral therapy with, i.e. valganciclovir, and inducing an EBV-specific immune response. This drug combination was applied in eight patients with EBV-positive NPC, refractory to conventional treatment. The primary endpoints were safety, tolerability and clinical response. Secondary endpoint was to get proof of concept based on biomarkers, i.e. pharmacokinetics, EBV-DNA load in whole blood and nasopharyngeal brushes, EBV-RNA profiling for proof of lytic induction, EBV-IgG and EBV-IgA levels and diversity and EBV-specific T cell response. The best observed clinical response was partial in two patients (25 %) and stable disease in three patients (37.5 %). The median survival was 9 months (95 % confidence interval 7-17 months). Effective dose levels were reached. Peaking of EBV-DNA loads in blood and brush proved the biological effect on EBV during most treatment cycles. In one patient, RNA profiling confirmed lytic EBV induction. EBV-IgG and EBV-IgA antibody levels were already high before treatment and did not change during treatment. No changes in EBV-specific T cell response were detected. The treatment was safe with manageable side effects, clinical response was observed, and viral activation corroborated.


New cinnamic - N-benzylpiperidine and cinnamic - N,N-dibenzyl(N-methyl)amine hybrids as Alzheimer-directed multitarget drugs with antioxidant, cholinergic, neuroprotective and neurogenic properties.
Here we describe new families of multi-target directed ligands obtained by linking antioxidant cinnamic-related structures with N-benzylpiperidine (NBP) or N,N-dibenzyl(N-methyl)amine (DBMA) fragments. Resulting hybrids, in addition to their antioxidant and neuroprotective properties against mitochondrial oxidative stress, are active at relevant molecular targets in Alzheimer's disease, such as cholinesterases (hAChE and hBuChE) and monoamine oxidases (hMAO-A and hMAO-B). Hybrids derived from umbellic - NBP (8), caffeic - NBP (9), and ferulic - DBMA (12) displayed balanced biological profiles, with IC50s in the low-micromolar and submicromolar range for hChEs and hMAOs, and an antioxidant potency comparable to vitamin E. Moreover, the caffeic - NBP hybrid 9 is able to improve the differentiation of adult SGZ-derived neural stem cells into a neuronal phenotype in vitro.


Resonance assignment of DVU2108 that is part of the Orange Protein complex in Desulfovibrio vulgaris Hildenborough.
We report the 94 % assignment of DVU2108, a protein belonging to the Orange Protein family, that in Desulfovibrio vulgaris Hildenborough forms a protein complex named the Orange Protein complex. This complex has been shown to be implicated in the cell division of this organism. DVU2108 is a conserved protein in anaerobic microorganisms and in Desulfovibrio gigas the homologous protein was isolated with a novel Mo-Cu cluster non-covalently attached to the polypeptide chain. However, the heterologously produced DVU2108 did not contain any bound metal. These assignments provide the means to characterize the interaction of DVU2108 with the proteins that form the Orange Protein complex using NMR methods.


Interleukin-23 orchestrates mucosal responses to Salmonella enterica serotype Typhimurium in the intestine.
Salmonella enterica serotype Typhimurium causes an acute inflammatory reaction in the ceca of streptomycin-pretreated mice that involves T-cell-dependent induction of gamma interferon (IFN-gamma), interleukin-22 (IL-22), and IL-17 expression (genes Ifn-gamma, Il-22, and Il-17, respectively). We investigated here the role of IL-23 in initiating these inflammatory responses using the streptomycin-pretreated mouse model. Compared to wild-type mice, the expression of IL-17 was abrogated, IL-22 expression was markedly reduced, but IFN-gamma expression was normal in the ceca of IL-23p19-deficient mice during serotype Typhimurium infection. IL-23p19-deficient mice also exhibited a markedly reduced expression of regenerating islet-derived 3 gamma, keratinocyte-derived cytokine, and reduced neutrophil recruitment into the cecal mucosa during infection. Analysis of CD3(+) lymphocytes in the intestinal mucosa by flow cytometry revealed that alphabeta T cells were the predominant cell type expressing the IL-23 receptor in naive mice. However, a marked increase in the number of IL-23 receptor-expressing gammadelta T cells was observed in the lamina propria during serotype Typhimurium infection. Compared to wild-type mice, gammadelta T-cell-receptor-deficient mice exhibited blunted expression of IL-17 during serotype Typhimurium infection, while IFN-gamma expression was normal. These data suggested that gammadelta T cells are a significant source, but not the sole source, of IL-17 in the acutely inflamed cecal mucosa of mice. Collectively, our results point to IL-23 as an important player in initiating a T-cell-dependent amplification of inflammatory responses in the intestinal mucosa during serotype Typhimurium infection.


Histone H3K9 demethylase JMJD2B induces hepatic steatosis through upregulation of PPARγ2.
Understanding the epigenetic mechanisms underlying the progression of hepatic steatosis is important for identifying new therapeutic targets against nonalcoholic fatty liver disease (NAFLD). We investigated the functional role of histone demethylase JMJD2B in the pathologic regulation of hepatic steatosis. JMJD2B expression was markedly increased in HepG2 cells treated with palmitate and oleate or liver X receptor agonist T09013178 and in the liver of high-fat diet (HFD)-induced obese mice. Overexpression of JMJD2B using adenovirus in HepG2 cells stimulated the expression of peroxisome proliferator-activated receptor γ2 (PPARγ2) and its steatosis target genes associated with fatty acid uptake and lipid droplet formation, resulting in increased intracellular triglyceride (TG) accumulation. Conversely, knocking down JMJD2B using siRNA reversed JMJD2B-mediated effects in HepG2 cells. The JMJD2B-dependent upregulation of PPARγ2 was associated with the removal of di- and trimethylation of histone H3 lysine 9 on the promoter of PPARγ2. Furthermore, exogeneous expression of JMJD2B using adenovirus in mice resulted in hepatic steatosis when fed a HFD, which was accompanied with increased expression of hepatic PPARγ2 and its steatosis target genes. Together, our results provide novel insights into the pivotal role of JMJD2B in the development of hepatic steatosis through upregulation of PPARγ2 and steatosis target genes.


Sharpened cortical tuning and enhanced cortico-cortical communication contribute to the long-term neural mechanisms of visual motion perceptual learning.
Much has been debated about whether the neural plasticity mediating perceptual learning takes place at the sensory or decision-making stage in the brain. To investigate this, we trained human subjects in a visual motion direction discrimination task. Behavioral performance and BOLD signals were measured before, immediately after, and two weeks after training. Parallel to subjects' long-lasting behavioral improvement, the neural selectivity in V3A and the effective connectivity from V3A to IPS (intraparietal sulcus, a motion decision-making area) exhibited a persistent increase for the trained direction. Moreover, the improvement was well explained by a linear combination of the selectivity and connectivity increases. These findings suggest that the long-term neural mechanisms of motion perceptual learning are implemented by sharpening cortical tuning to trained stimuli at the sensory processing stage, as well as by optimizing the connections between sensory and decision-making areas in the brain.


Antibody to poly(ADP-ribose) is an indicator of obstetric complications in pregnant patients with systemic lupus erythematosus.
Anti-poly(ADP-ribose) antibodies were measured by an enzyme-linked immunosorbent assay (ELISA) in 6 pregnant women with systemic lupus erythematosus (SLE), 11 normal pregnant women and 6 randomly selected female SLE patients. Four pregnant SLE patients who had either an abortion after 13 weeks of gestation or a premature delivery showed very high titers of anti-poly(ADP-ribose) antibodies in week 8 of pregnancy. However, the titers of anti-poly(ADP-ribose) antibodies of all the normal pregnant women were similar to those of non-pregnant female SLE patients, being slightly higher than those of normal non-pregnant women. The isotype of anti-poly(ADP-ribose) antibodies in pregnant SLE patients was IgG, which did not crossreact with either DNA or cardiolipin. The number of pregnant SLE patients tested was small, but the coincidence of abortion with high titers of anti-poly (ADP-ribose) antibody was very close. Therefore, a high titer of anti-poly(ADP-ribose) antibody in pregnant SLE patients seems useful as an indicator of abortion or fetal distress.


Water quality assessment and pollution threat to safe water supply for three river basins in Malaysia.
Pollution in raw water poses increasing threats to safe water supply in many developing countries. Therefore, a comprehensive water quality assessment is essential to provide various stakeholders the information to deal with this problem. This study applies chemometrics to interpret a recent 10-year water quality data from three major river basins (Selangor River basin, Langat River basin, and Klang River basin) frequented by water supply disruptions in Selangor, Malaysia. We present the application of selected chemometrics approaches, namely agglomerative hierarchical cluster analysis, principal component analysis, factor analysis and Man-Kendall trend analysis. The results showed three spatial groups of monitoring stations with similar land use practices and pollution characteristics. Besides spatial differences, periodic variations were observed when similar pollutants exhibited different pollution loads during rainy and dry periods. We found that nitrogen species, total suspended solids, and dissolved solids represented the major pollution loads in the studied basins. The results further confirmed a significant increasing trend in ammonia pollution. Our study demonstrates how ammonia pollutant is likely to pose a threat to water supply and highlights the vulnerability of Selangor's water resource system to water pollution. The results of this study could facilitate decision making towards more holistic strategies, specifically, incorporating ammonia treatment facilities into the conventional water treatment plant will help achieve smooth water supply operations.


[Relationships between dental calcification stages and cervical vertebral bone ages among children and adolescents in Chengdu].
To investigate the relationship between the stages of calcification of various teeth and cervical vertebral bone ages among children and adolescents in Chengdu. The study subjects consist of 256 children and adolescents in Chengdu with age ranging from 10 to 16 years. All panoramic radiographs and cephalometric radiographs were obtained. The relationship with the stages of chronological ages, calcification of various teeth and cervical vertebral bone ages were analyzed. The Spearman rank correlation coefficient revealed highly significant relationships between cervical vertebral bone ages and chronological ages (r = 0.726, P < 0.01). Dental ages and chronological ages had medium relationship (r = 0.629, P < 0.01), also dental ages and cervical vertebral bone ages medium relationship (r = 0.668, P < 0.01). Cervical vertebral bone ages, chronological ages and dental calcification stages have correlation among children and adolescents in Chengdu. The cervical vertebral bone ages have high connection with chronological ages. Cervical vertebral bone age might be a better indicator in judging growth and development of children and adolescents during orthodontic treatment.


Zenker Diverticulum: A Potential Pitfall in Thyroid Ultrasound Evaluation: A Case Report and Systematic Review of Literature.
Zenker Diverticulum (ZD) can sometimes be misinterpreted as a thyroid nodule both at clinical evaluation and at Ultrasound (US). We reported the case of a 46-years-old woman complaining of a lump in the anterior left aspect of the neck. Following clinical examination and US evaluation, a thyroid nodule was initially diagnosed and the patient was referred to our institution to be submitted to a fine-needle aspiration cytology. Management and Outcome: A ZD was suspected by US and diagnosed by gastrografin esophagram, thus an endoscopic diverticulotomy was requested. A correct US evaluation can be crucial for the appropriate management of a neck mass.


AML bearing the translocation t(11;17)(q23;q21): involvement of MLL and a region close to RARA, with no differentiation response to retinoic acid.
We describe a case of acute myeloid leukemia (AML) bearing the translocation t(11;17)(q23;q21). The morphological phenotype represented a monoblastic leukemia, AML French-American-British (FAB) M5a. Further analysis of the translocation revealed an involvement of the mixed-lineage leukemia (MLL) gene and a region closely proximal to the retinoic acid (RA) receptor alpha (RARA) gene. AMLs involving both a rearranged MLL and the 17q21 region, in which the RARA gene is located, have only been described in some individual cases. The functional role of this translocation is still unknown. Rearrangements of the MLL (11q23) gene in AML are usually related to the morphological phenotype FAB M5. In general, they are associated with an adverse prognosis. In acute promyelocytic leukemia, the translocation (15;17)(q22;q11-21) involving the RARA leads to a maturation arrest that can be overcome by RA, often inducing remission. In other forms of AML, however, the effects of RA are limited and diverse. To study whether RA might have a therapeutical potential in our case, we performed an in vitro analysis of RA effects on AML cells. We found that RA leads to enhanced cell death and up-regulation of CD38 and CD117. However, no hints of RA-induced in vitro differentiation were visible. Our data indicate that in AML cells bearing the t(11;17)(q23;q21), a differentiation arrest that is overcome by RA is not present. On the contrary, RA induces alterations in cellular regulation that are similar to the RA-induced changes observed in early hematogenic progenitors; thus, a possible therapeutical benefit of RA in such cases remains open.


Diabetes in an emergency context: the Malian case study.
The World Health Organization proposes 6 building blocks for health systems. These are vulnerable to challenges in many contexts. Findings from a 2004 assessment of the health system in Mali for diabetes care found many barriers were present for the management and care of this condition. Following this assessment different projects to strengthen the healthcare system for people living with diabetes were undertaken by a local NGO, Santé Diabète. In March 2012, following a Coup in Bamako, the northern part of Mali was occupied and cut-off from the rest of the country. This had a major impact on the health system throughout the country. Due to the lack of response by humanitarian actors, Santé Diabète in close collaboration with other local stakeholders developed a humanitarian response for patients with diabetes. This response included evacuation of children with Type 1 diabetes from northern regions to Bamako; supplies of medicines and tools for management of diabetes; and support to people with diabetes who moved from the north to the south of the country. It has been argued that diabetes is a good tracer for health systems and based on Santé Diabète's experience in Mali, diabetes could also be used as a tracer in the context of emergencies. One lesson from this experience is that although people with diabetes should be included as a vulnerable part of the population they are not considered as such. Also within a complex emergency different "diabetes populations" may exist with different needs requiring tailored responses, such as internally displaced people versus those still in conflict areas. From Santé Diabète's perspective, the challenge was changing the ways it operated from a development NGO to an emergency NGO. In this role it could rely on its knowledge of the local situation and its function as part of the post-conflict situation. The lessons learnt from this experience by Santé Diabète in Mali may be useful for other NGOs and the humanitarian response in general in addressing the challenge of managing non communicable diseases and diabetes in conflict and disaster situations in countries with weak health systems.


Characteristics of infant mortality in the RSA 1929-1983. Part I. Components of the white and coloured infant mortality rate.
Secular trends in white and coloured neonatal, post-neonatal and infant mortality rates are presented for the period 1929-1983. More detailed information is given for deaths in the first month of life. During this 54-year period the infant mortality rate for whites has declined from 64.2/1,000 to 13.5/1,000, whereas the rate for coloureds fell from 158.8 (1938) to 55.0/1,000. The greater part of the latter decline occurred after 1970. Since 1945 the neonatal mortality rate (NMR) for whites has exceeded the post-neonatal mortality rate (PNMR) but among coloureds the PNMR still exceeds the NMR.


Systematic Reviews and Meta-analyses of the Procedure-specific Risks of Thrombosis and Bleeding in General Abdominal, Colorectal, Upper-Gastrointestinal and Hepatopancreatobiliary Surgery.
To provide procedure-specific estimates of symptomatic venous thromboembolism (VTE) and major bleeding following abdominal surgery. Use of pharmacological thromboprophylaxis represents a trade-off that depends on VTE and bleeding risks that vary between procedures; their magnitude remains uncertain. We identified observational studies reporting procedure-specific risks of symptomatic VTE or major bleeding after abdominal surgery; adjusted the reported estimates for thromboprophylaxis and length of follow-up; and estimated cumulative incidence at 4 weeks post-surgery, stratified by VTE risk groups; and rated evidence certainty. After eligibility screening, 285 studies (8,048,635 patients) reporting on 40 general abdominal, 36 colorectal, 15 upper-gastrointestinal, and 24 hepatopancreatobiliary surgery procedures proved eligible. Evidence certainty proved generally moderate or low for VTE and low or very low for bleeding requiring reintervention. The risk of VTE varied substantially between procedures: in general abdominal surgery from a median of <0.1% in laparoscopic cholecystectomy to a median of 3.7% in open small bowel resection; in colorectal from 0.3% in minimally-invasive sigmoid colectomy to 10.0% in emergency open total proctocolectomy; and in upper-gastrointestinal/hepatopancreatobiliary from 0.2% in laparoscopic sleeve gastrectomy to 6.8% in open distal pancreatectomy for cancer. VTE thromboprophylaxis provides net benefit through VTE reduction with small increase in bleeding in some procedures (e.g., open colectomy, open pancreaticoduodenectomy), whereas the opposite is true in others (e.g., laparoscopic cholecystectomy, elective groin hernia repairs). In many procedures, thromboembolism and bleeding risks are similar, and decisions depend on individual risk prediction and values and preferences regarding VTE and bleeding.


[Study on the association of ABCA1 gene common variants with the risk of coronary atherosclerotic heart disease].
To investigate the association of R219K and M883I polymorphisms of ATP binding cassette transporter 1 gene with lipid metabolism and the susceptibility to coronary atherosclerotic heart disease in Chinese population. Genotypes were determined by PCR-restriction fragment length polymorphism and Primer introduced restriction analysis-PCR techniques, respectively, in 248 unrelated CHD-free controls and 224 CHD cases. Smoking, high blood pressure and high serum glucose were independent risk factors for CHD. Multivariate logistic regression analysis revealed that individuals carrying at least one 219K variant allele (RK + KK genotypes) had a significantly decreased risk for CHD (adjusted OR = 0.41; 95% CI = 0.27-0.61) compared with the wild-type genotype (219RR) and only 883II homozygotes displayed a decreased risk for CHD (adjusted OR = 0.54; 95% CI = 0.26-1.11) compared with 883MM and 883MI genotypes. Furthermore, compared with individuals with both wild genotypes (219 RR and 883 MM or 883 MI) other individuals with all other assembly genotypes had a significantly decreased risk (adjusted OR = 0.39, 95% CI = 0.26-0.60). Plasma HDL-C in 219K allele carriers were markedly higher than those in 219 K non-carriers in controls (P = 0.037). The ABCA1 R219K polymorphism may be involved in the variability of serum HDL-C and the susceptibility to coronary artery disease.


Coordination of divalent metal cation to amide group to form adduct ion in FAB mass spectrometry: implication of Zn2+ in enzymatic hydrolysis of amide bond.
The structures of complexes between amides and metal ions were examined by FAB mass spectrometry and collision-induced dissociation (CID). Zn2+ was coordinated by the amide carbonyl oxygen atom of N-tetradecylacetamide (1). In contrast, Ca2+ and Mg2+ were coordinated by the amide group of 1 in both the keto and enol forms. The catalytic role of Zn2+ at the active site of the hydrolases might partly be explained by the effective attack of Zn2+ on carbonyl oxygen atom of the scissile amide group.


Relationship of planter pressure and glycemic control in type 2 diabetic patients with and without neuropathy.
Foot disease is a common complication of type 2 diabetes that can have tragic consequences. Abnormal plantar pressures are considered to play a major role in the pathologies of neuropathic ulcers in the diabetic foot. To examine Relationship of Planter Pressure and Glycemic Control in Type 2 Diabetic Patients with and without Neuropathy. The study was conducted on 50 type 2 diabetic patients and 30 healthy volunteers. BMI calculation, disease duration, Hemoglobin A1c and presence of neuropathy (by history, foot examination and DN4 questionnaire) were recorded. Plantar pressure was recorded for all patients using the Mat-scan (Tekscan, Inc.vers. 6.34 Boston USA) in static conditions (standing) and dynamic conditions (taking a step on the Mat-scan). Plantar pressures (kPa) were determined at the five metatarsal areas, mid foot area, medial and lateral heel areas and medial three toes. Static and dynamic plantar pressures in both right and left feet were significantly higher in diabetic with neuropathy group than in control group in measured areas (P<0.05). Static and dynamic pressures in right and left feet were significantly higher in diabetic with neuropathy group than in diabetic without neuropathy group in measured areas (P<0.05). On comparison between controls and diabetic without neuropathy group there was a significant difference in plantar pressures especially in metatarsal areas (P<0.05). No significant correlations were present between the studied variables age, disease duration, BMI and HbA1c and plantar pressures in all studied areas. Persons with diabetic neuropathy have elevated peak plantar pressure (PPP) compared to patients without neuropathy and control group. HbA1c% as a surrogate for glycemic control had no direct impact on peak planter pressure, yet it indirectly impacts neuropathy evolution through out disease duration eventually leading to the drastic planter pressure and gait biomechanics changes.


Racial and Ethnic Disparities in Pediatric Musculoskeletal Care.
This article provides a review of recent published research studying racial, ethnic, and socioeconomic disparities in pediatric musculoskeletal care. Disparities in pediatric musculoskeletal care are demonstrated in two general realms: access to care and health outcomes. Though initiatives have been proposed or enacted to address disparities, underrepresented minorities and patients from lower socioeconomic statuses continue to face barriers across the spectrum of orthopedic care and poorer ultimate outcomes after both non-operative and operative management. Minority pediatric patients and those from lower socioeconomic statuses experience delays across the spectrum of orthopedic care for both urgent and non-urgent conditions. They wait longer between injury date and initial orthopedic evaluation, longer to receipt of diagnostic imaging, and longer to ultimate treatment than their counterparts. When finally able to obtain musculoskeletal care and treatment, they are at higher risk of poor in-hospital outcomes and inpatient complications, worse patient reported outcomes, and suboptimal pain management. In the outpatient setting, they receive less physical therapy and follow-up clinic visits, resulting in greater stiffness and strength deficits, and are ultimately less likely to meet return to sport criteria.


PRMT6 functionally associates with PRMT5 to promote colorectal cancer progression through epigenetically repressing the expression of CDKN2B and CCNG1.
Protein arginine methyltransferase 6 (PRMT6) is a type I arginine methyltransferase that asymmetrically dimethylates histone H3 arginine 2 (H3R2me2a). However, the biological roles and underlying molecular mechanisms of PRMT6 in colorectal cancer (CRC) remain unclear. PRMT6 expression in CRC tissue was examined using immunohistochemistry. The effect of PRMT6 on CRC cells was investigated in vitro and in vivo. Mass spectrometry, co-immunoprecipitation and GST pulldown assays were performed to identify interaction partners of PRMT6. RNA-seq, chromatin immunoprecipitation, Western blot and qRT-PCR assays were used to investigate the mechanism of PRMT6 in gene regulation. PRMT6 is significantly upregulated in CRC tissues and facilitates cell proliferation of CRC cells in vitro and in vivo. Through RNA-seq analysis, CDKN2B (p15INK4b) and CCNG1 were identified as new transcriptional targets of PRMT6. PRMT6-dependent H3R2me2a mark was predominantly deposited at the promoters of CDKN2B and CCNG1 in CRC cells. Furthermore, PRMT5 was firstly characterized as an interaction partner of PRMT6. Notably, H3R2me2a coincides with PRMT5-mediated H4R3me2s and H3R8me2s marks at the promoters of CDKN2B and CCNG1 genes, thus leading to transcriptional repression of these genes. PRMT6 functionally associates with PRMT5 to promote CRC progression through epigenetically repressing the expression of CDKN2B and CCNG1. These insights raise the possibility that combinational intervention of PRMT6 and PRMT5 may be a promising strategy for CRC therapy.


Molecular evaluation of the SRY gene for gonads of patients with mixed gonadal dysgenesis.
To determine whether the SRY gene is present in the gonads of patients with mixed gonadal dysgenesis (MGD). Molecular analysis was performed in three patients with MGD. Polymerase chain reactions were used to test for the presence of the SRY gene in the peripheral lymphocytes, testes and streak gonads. Chromosome analysis revealed 45,XO/46,XY in two patients, and 46,XY in the third patient. In the peripheral lymphocytes and testicular tissue, the SRY sequences were positive in all cases. However, the SRY sequence was detected in the streak gonad in only two of the three patients. It is interesting that we identified both SRY-positive and SRY-negative streak gonads. Although the SRY gene has a very important role in testicular differentiation, genes other than the SRY gene might also influence the development of the indifferent gonad in MGD.


The Role of Body Mass Index in Triple Negative Breast Cancer.
Triple-negative breast cancer (TNBC) has none of the targeted treatment choices due to its distinct biological property, making this subtype a unique disease. In this study, we evaluated the impact of obesity on clinical outcomes of TNBC. The data of breast cancer patients admitted to our department were collected. TNBC was defined as lack of estrogen receptor (ER), progesterone receptor (PR) and HER-2. The body mass index (BMI) of 112 TNBC patients was calculated with weight at the time of diagnosis and height. The patients were classified into groups with a BMI of < 25 (normal/underweight), 25-29.9 (overweight) or ≥ 30 (obese). After a mean follow-up of 23.2 ± 15.5 months, there were 12 recurrences (10.71%) and 6 deaths (5.35%). Disease-free survival (DFS) and overall survival (OS) were assessed. The survival analyses of all the patients did not demonstrate any differences in OS or DFS in obese as compared to non-obese patients. However, we showed that obesity was associated with a poorer OS for postmenopausal TNBC patients (p < 0.05). Obesity is related to a poorer OS in postmenopausal TNBC patients. Due to the heterogeneous disease profile of TNBC, larger randomized studies will be needed to clarify the exact role of obesity in TNBC.


RNF38 encodes a nuclear ubiquitin protein ligase that modifies p53.
The RNF38 gene encodes a RING finger protein of unknown function. Here we demonstrate that RNF38 is a functional ubiquitin protein ligase (E3). We show that RNF38 isoform 1 is localized to the nucleus by a bipartite nuclear localization sequence (NLS). We confirm that RNF38 is a binding partner of p53 and demonstrate that RNF38 can ubiquitinate p53 in vitro and in vivo. Finally, we show that overexpression of RNF38 in HEK293T cells results in relocalization of p53 to discrete foci associated with PML nuclear bodies. These results suggest RNF38 is an E3 ubiquitin ligase that may play a role in regulating p53.


Comparative studies of the physical state of the lipid phase of normal and hypercholesterolemic very low density lipoprotein.
Very low density lipoproteins (VLDL) were prepared from the serum of rabbits at various stages of hypercholesterolemia (95--1665 mg cholesterol/100 ml of serum). The most notable chemical change in hypercholesterolemic (hc) VLDL was the greatly increased content of cholesteryl esters and the greatly decreased content of triglycerides, compared to normal (n) VLDL. Structurally, the lipid region of n VLDL possessed a much lower microviscosity than did hc VLDL, when analyzed by fluorescence polarization and pyrene eximer methods. The microviscosity of the redispersed n VLDL lipid extract was considerably greater than the observed in n VLDL; but less than that of hc VLDL. Incorporation of pyrene into the lipid region of n VLDL and hc VLDL allowed assessment of various properties of the surface and hydrocarbon regions of these lipoproteins. Only slight differences were found in the pyrene monomer 3 : 1 fluorescence emission peak ratios, and in the rate constant for quenching of pyrene by O2. However, the quenching rate constant of pyrene by I- and iodoheptane were different for each lipoprotein.


[Measurement of bronchoconstrictive eicosanoids in chronic obstructive pulmonary disease].
The aim of the study was the evaluation of the concentration of 9α11β prostaglandin F(2) - a stable metabolite of prostaglandin D(2) (PGD(2)) and leukotriene E(4) (LTE(4)) in stable and exacerbated COPD patients. 29 COPD patients aged 73 ± 8.34, mean FEV1 = 48.64 ± 15.75% of predictive value and 29 healthy controls aged 57.48 ± 10.86, mean FEV1 = 97.17 ± 13.81% of predictive value participated in this study. Samples of urine and blood were taken from COPD patients during exacerbation and in stable state of the disease; LTE(4) was determined in urine using commercial enzyme immunoassay (EIA) and 9α11β prostaglandin F(2) (9α11βPGF(2)) - stable metabolite of PGD(2) was evaluated in blood and urine using GC/MS. LTE(4) concentration in urine (677.15 vs. 436.4 pg/mg of creatinine; p = 0.035) and 9α11βPGF(2) in blood serum (5.35 vs. 3.07 pg/ml; p = 0.007) were significantly higher in exacerbated COPD patients than in control group. There was no difference in LTE(4) level in urine and 9α11βPGF2 in blood serum between exacerbated and stable COPD. The urinary 9α11βPGF(2) concentration did not differ between all studied groups. We found a positive correlation between smoking history and the urine LTE(4) level (r = 0.395; p = 0.002) as well as blood 9α11βPGF(2) concentration (r = 0.603; p = 0.001) in COPD patients. 9α11βPGF(2) and LTE(4) level in urine did not differ between the stable COPD group and the control group. We also did not find any difference between LTE4 level in urine and 9α11βPGF(2) in blood and urine between exacerbated and stable COPD. Finally, LTE(4) concentration in urine and 9α11βPGF(2) in blood occurred to be significantly higher in exacerbated COPD patients than in control group.


Identification of common lipooligosaccharide types in isolates from patients with otitis media by monoclonal antibodies against nontypeable Haemophilus influenzae 9274.
Twenty-one murine monoclonal antibodies (MAbs) were induced by nontypeable Haemophilus influenzae (NTHi) 9274. Nineteen MAbs were specific for the lipooligosaccharide (LOS) as determined by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. When the MAbs were assayed with five LOS prototype strains by ELISA, all bound to strain 3198 LOS (type III), while six of the MAbs were also reactive with LOSs from strain 1479 (type I), 5657 (type IV), or 7502 (type V). Ten MAbs had complement-mediated bactericidal activity, and three MAbs were opsonophagocytic against the homologous strain. Five LOS MAbs with different specificities were used to analyze 155 NTHi clinical isolates from the United States and from Japan. These isolates were classified into nine groups by ELISA. Only four isolates (2.6%) were not recognized by any of the five MAbs. Most of the isolates (91.6%) were in four groups which bound three of the five MAbs. One of three MAbs, 6347C11, had strong activity against the homologous strain and was also bactericidal to 45 clinical isolates (29%) which belonged to the four common patterns (25 belonged to pattern 1). These data indicate that these MAbs can be used for LOS typing in which almost all NTHi strains can be typed according to the LOS antigenicity. Among NTHi, at least one conserved LOS epitope which is a target of bactericidal antibodies exists. We conclude that strain 9274 LOS, which is the target for bactericidal antibodies, is a candidate for LOS-based NTHi vaccines.


Entropic repulsion of cholesterol-containing layers counteracts bioadhesion.
Control of adhesion is a striking feature of living matter that is of particular interest regarding technological translation1-3. We discovered that entropic repulsion caused by interfacial orientational fluctuations of cholesterol layers restricts protein adsorption and bacterial adhesion. Moreover, we found that intrinsically adhesive wax ester layers become similarly antibioadhesive when containing small quantities (under 10 wt%) of cholesterol. Wetting, adsorption and adhesion experiments, as well as atomistic simulations, showed that repulsive characteristics depend on the specific molecular structure of cholesterol that encodes a finely balanced fluctuating reorientation at the interface of unconstrained supramolecular assemblies: layers of cholesterol analogues differing only in minute molecular variations showed markedly different interfacial mobility and no antiadhesive effects. Also, orientationally fixed cholesterol layers did not resist bioadhesion. Our insights provide a conceptually new physicochemical perspective on biointerfaces and may guide future material design in regulation of adhesion.


Clinical impact of endoscopic papillectomy for benign-malignant borderline lesions of the major duodenal papilla.
The present study retrospectively analyzed the clinical impact of endoscopic papillectomy on the selection of a treatment strategy for patients with benign-malignant borderline lesions of the major duodenal papilla. Between November 1995 and July 2009, 28 patients were selected for endoscopic papillectomy. The clinical impact of endoscopic papillectomy was assessed. Snare resection was performed in a radical fashion. An endoscopic papillectomy was technically feasible in all patients. En bloc excision was achieved in 22 cases (79%). The final histopathological diagnoses of the endoscopic specimen were 17 adenoma (61%), 7 carcinoma in adenoma (25%), and 4 adenocarcinoma (14%). Two out of the four adenocarcinoma cases were referred for surgery. The other two patients with negative margins have not experienced recurrences during the follow-up period. A residual tumor was detected in 1 out of 17 cases (6%) of adenoma and 2 out of 7 cases (29%) of carcinoma in adenoma. Endoscopic papillectomy is therefore considered to be an effective treatment for patients with a benign-malignant borderline lesion of the major duodenal papilla. This method also has an important clinical impact because it provides an accurate diagnosis, aids in the selection of an appropriate treatment strategy, and reduces unnecessary surgery.


Activation of Scapular and Lumbopelvic Muscles During Core Exercises Executed on a Whole-Body Wobble Board.
Previous studies highlighted that exercises executed on unstable surfaces can yield important benefits to the function of the core musculature in rehabilitation settings, general conditioning settings, and athletic training when properly introduced within a periodized training schedule. No previous study has analyzed core-stability exercises executed in lying, quadruped, plank, and bridge positions on a whole-body wobble board (WWB) specifically designed to accommodate the exerciser's entire body and promote whole-body instability. We have designed a WWB allowed to roll in a plane perpendicular to its longitudinal axis to promote proactive and reactive activation of the core muscles with a transverse or diagonal line of action, which provides trunk and pelvic stability with low spine compression forces. To determine the effect of the use of this newly designed WWB by assessing differences in core-muscle activity during core-stability exercises performed on the ground, in a stable condition, and on the WWB. Controlled laboratory study. Research laboratory. Eighteen participants recruited from fitness centers. The electromyographic (EMG) activity of lumbopelvic and scapular muscles has been recorded during core-stability exercises executed on the WWB (unstable condition) and on ground (stable condition). Mean and peak EMG activity were compared between stable and unstable condition with paired t tests or Wilcoxon signed-rank tests. Overall, exercises performed on the WWB yielded significantly higher EMG activity in the serratus anterior and anterolateral abdominal muscles compared with the same exercises executed on the ground. Conversely, for the bird dog exercise, lower-back muscle activity was significantly higher on the ground. Compared with the ground, core-stability exercises executed on WWB constitute a simple and effective strategy to increase the activity level of the core muscles that control transverse-plane lumbopelvic and trunk stability, avoiding the use of external overload.


Antithrombotic therapy for stroke in young adults.
Stroke in young adults is a markedly heterogeneous disease, and remains an understudied phenomenon. While advances are being made in our understanding of the pathophysiology of its underlying conditions, treatment concerns are controversial, and clinical trials are sorely lacking. This review presents an overview of some of the relevant management issues in hypercoagulable states, migraine, patent foramen ovale, vascular dissection and venous sinus thrombosis.


Linking producers' and consumers' perceptions in the valorisation of non-timber forest products: An analysis of Ogiek forest honey.
This work aims to present a multidisciplinary approach that combines methodologies from economic anthropology and sensory science to valorise non-timber forest products; this is performed by using Kenyan forest honey as a case study to foster a positive alignment between producers and consumers living in the target market. Firstly, ethnographic research was carried out in Kenya to analyse the core competences of the forest honey producers (n = 20) and to select honey samples for the sensory evaluation. Secondly, a consumer test was performed in Italy to investigate the perception of the sensory properties by using a rate-all-that-apply test and its hedonic responses for six forest honeys by subjects living in Italy (n = 50). Based on the producers' perceptions of the definition of the harvesting area and the floral origin of the honeys, an indigenous classification was outlined. The key core competences of the producers centred around the traditional method of production. The harvesting area was determinant in the preference of the interviewees, being forest honeys produced from the nectar of indigenous melliferous species, from which originate the most appreciated products. Similarly, results from the consumer test showed that harvesting area and the floral origin influenced the hedonic response. Moreover, the drivers of liking (e.g. intense colour, clear appearance, smoked flavour) and disliking (e.g., granularity, opaque appearance) were identified. The paper suggests a development trajectory that promotes the commercial potential of local production but preserves the heritage thereof. The approach is potentially applicable to all marginalised food products and facilitates a promising prospective for sustainable development.


Determinants of the onset of continuous air breathing at birth.
We used mechanical ventilation of the fetal lungs in utero on 11 fetal lambs at 140-145 days gestation to alter fetal blood gases and thus separate the influences of PaO2 and PaCO2 on extrauterine breathing after cord clamping. The fetus was delivered either into a 40 degrees C saline bath or onto a cold table. Mechanical ventilation was stopped 2 min after delivery and the time to onset of continuous air breathing was observed. Also two fetuses were ventilated in utero 5 or more days after chronic instrumentation at 127 days gestation; in these animals the time to onset of breathing (diaphragm EMG) was recorded after stopping the ventilator and occluding the cord. We conclude: (a) hypercapnia is a stimulus to breathing even in hyperoxia and at 40 degrees C; (b) hypocapnia delays the start of extrauterine breathing in hyperoxia at 40 degrees C; (c) hypoxia inhibits breathing in the absence of hypercapnia or cold; (d) cold overrides the effects of hypocapnia in normoxia or moderate hypoxia.


Chromosome analyses of children after ecological lead exposure.
In the present work chromosome analysis was performed in a group of 30 children living in a town with a lead plant. Due to the emission of the smelter the individual lead uptake through food, drinking water and inhalation was increased. They were selected out of 1600 children whose blood lead level, delta-aminolevulinic acid dehydratase activity in the erythrocytes and erythrocyte porphyrine level was measured. In the investigated group of children the values of these parameters showed to be indicative for a significant lead exposure. A total of 10,000 cells was scored after 48 h culture time. Despite a significantly increased lead load as compared with two groups of 10 children from a suburb and the isle of Helgoland there was neither evidence for a higher number of cells with structural chromosome aberrations, nor for an increased aberration yield.


Hazard report. Reducing the risk of burns from surgical light sources.
Surgical light sources can heat instruments enough to burn patients and can even start small fires in the operating room. Hospitals can reduce this risk by educating clinicians on the proper use of these devices and by purchasing models that incorporate certain safety features.


Analysis of transcriptional regulation of human breast aromatase by in vitro and in vivo studies.
Aromatase mRNA in normal breast tissues is mainly transcribed from exon 1b (I.4) of the gene. However, in breast cancer tissues, it is often transcribed from exon 1c/1d (I.3/PII). Such a switching from exon 1b to exon 1c/1d has often found concomitantly with elevated levels of aromatase mRNA. To elucidate the molecular mechanism of a switching of multiple exons 1 and enhanced expression of aromatase in the breast tissues, we identified essential elements responsible for transcription from exon 1b. Gel shift assays indicated that there are two essential elements for transcription from exon 1b between -300 and -500 bp in the promoter region. The two unique elements have homologous consensus DNA sequences, and competed for binding of the specific nuclear protein with each other. We next generated transgenic mouse expressing a reporter gene controlled by multiple promoters in the human aromatase gene. The mouse gave tissue-specific expression of the reporter gene and tissue-specific utilization of the alternative promoter regions. These results show that this transgenic mouse is a good model animal for the study of tissue-specific regulation of human aromatase gene.


A novel mutation in RNF216 gene in a Turkish case with Gordon Holmes syndrome.
Gordon Holmes syndrome (GHS) is a rare autosomal recessive disorder characterized by hypogonadotropic hypogonadism, cognitive decline, and cerebellar ataxia. Mutations in the Ring Finger Protein 216 (RNF216) gene have been known to be associated with GHS therewithal RNF216 mutations have been detected in cases with Huntington-like disease, 4H syndrome (hypodontia, hypomyelination, ataxia and hypogonadotropic hypogonadism), and congenital hypogonadotropic hypogonadism. Here we report a novel homozygous frameshift mutation in RNF216 gene c.1860_1861dupCT (p.Cys621SerfsTer56) in a patient with hypogonadotropic hypogonadism, ataxia, and cognitive decline diagnosed with GHS also co-occurrence of parkinsonism and dystonia which was not reported before. We report an extremely rare case of GHS. The core features of GHS are well defined, but genotype-phenotype correlations are still limited. To understand the pathophysiology of different phenotypes, the type and localization of novel mutations need to be defined, and the effect of these different variants on clinical features needs to be determined. Further studies should explain the factors of phenotypic variability present in GHS patients with RNF216 mutations.


A liquid drop RC filter apparatus for detection.
A new analytical detector based on a liquid drop resistor-capacitor (RC) filter is described, in which transformed gain vs. frequency curves are used to analyze compounds. This detector can be used to detect either charged or neutral species (that are dielectrically different) which are dissolved in a liquid (e.g., water, alcohol, solvent mixtures, etc.). This device was fabricated by modifying an electrowetting on dielectric (EWOD)-based experimental setup. When a liquid drop is placed on a dielectric surface, the system acts as a RC filter. At a given frequency, gain is a function of conductivity, surface tension, dielectric constant, double-layer thickness of the solid-liquid drop interface, as well as the applied voltage. Since different liquids and solutions have different physical properties, each liquid/solution has a unique curve (peak) in gain vs. frequency plot. This is the basic principle behind the detector. Different amounts of zinc chloride dissolved in water, benzalkonium chloride in water, 1-methylimidazole in water, cetyltrimethyl-ammonium chloride (CTAC) in water, and CTAC dissolved in ethylene glycol solutions were tested with the detector as proof of principle. The device can be used as a stand-alone detector or can easily be coupled with droplet based microfluidic lab-on-a-chip systems such as EWOD-based microfluidic chips.


Defining the invasive phenotype of proximal gastric cancer cells.
Adenocarcinoma of the proximal stomach is now the most rapidly rising cancer among men in the United States. The development of metastases is the major cause of morbidity and mortality for this aggressive disease. The mechanisms by which tumor cells invade the basement membrane are unknown for this disease. We have identified and established 5 invasive and noninvasive adenocarcinoma cell lines arising from the proximal stomach, which can be used to examine the mechanisms involved in tumor cell invasion. The expression of factors associated with tumor cell attachment, proteolysis, and inhibition of proteolysis was determined by reverse transcription of mRNA to cDNA and subsequent amplification by the polymerase chain reaction. In addition, cells were examined for morphologic changes by scanning electron microscopy. Invasive proximal gastric cancer cells express the 72-kD form of collagenase type IV, whereas the noninvasive cells do not. Other factors examined (including the laminin receptor, cathepsin B, cathepsin L, urokinase-type plasminogen activator, and tissue inhibitor metalloproteinases) are expressed by both invasive and noninvasive gastric cancer cells, whereas collagenase type IV 92-kD form is not expressed by any of the cells examined. In addition, scanning electron microscopy revealed that all the invasive cell lines exhibit long cytoplasmic extensions. The noninvasive cells express short cytoplasmic projections and are rounder than the invasive proximal gastric cancer cell lines. There are distinct phenotypic differences between invasive and noninvasive proximal gastric cancer cell lines both at the level of expression of mRNA for collagenase Type IV 72-kD and at the level of scanning electron microscopy with the expression of cytoplasmic projections. Clinical outcome may be associated with these phenotypic differences.


Clinical signs and symptoms of diaper dermatitis in newborns, infants, and young children: A scoping review.
Diaper dermatitis (DD) is a significant problem in the care of newborns, infants, and young children and good recognition of signs and symptoms optimises timely treatment. There is also a need for a standardised set of related descriptors to enable communication between health care providers about diagnosis and treatment. The study aimed to review the literature for descriptive words to define the clinical signs, symptoms, and characteristics, including anatomical locations and assessment scales or tools, in the newborn, infants and young children population who have been diagnosed with DD. A systematic review process utilising PRISMA guidelines [1] was conducted using advanced search techniques to analyse the terms from the database thesauri and keywords. Data bases including Ovid MEDLINE® and Epub Ahead of Print, in-Process & Other Non-Indexed Citations, Daily and Versions® were searched from 1946 to March 18, 2021. Cochrane Handbook Searching for and selecting studies were used as a guide and as best practice to conduct the search. Of the 551 publications originally identified, 55 full text publications were examined and 21 met the inclusion criteria. The wide range of descriptors used in the literature for DD supports the need for a clearer approach to report the signs and symptoms, and the severity, of DD. These findings point to gaps in the literature, both in recording signs and symptoms of DD and features such as wetness, infection, anatomical location, severity and pain in newborns, infants, and young children. There is a need to develop a robust methodological tool to bridge the gap and link a common terminology on signs and symptoms to support diagnosis of the severity of DD.


Low Circulating Levels of miR-451a in Girls with Polycystic Ovary Syndrome: Different Effects of Randomized Treatments.
Polycystic ovary syndrome (PCOS) is a prevalent disorder in adolescent girls, purportedly driven by hepato-visceral fat excess, and often followed by subfertility and type 2 diabetes. We studied the baseline microRNA (miRNA) profile of girls with PCOS, and the effects of a randomized treatment with an oral contraceptive (OC) or with spironolactone-pioglitazone-metformin (SPIOMET, aiming at loss of hepato-visceral fat excess) for 1 year. The miRNA profile was assessed by RNA sequencing in girls with PCOS who had participated in a randomized, open-label, single-center, pilot study (n = 31; age 15.7 years, body mass index (BMI) 23.1 kg/m2). Healthy age- and BMI-matched girls (n = 13) served as controls. Differentially expressed miRNAs were validated by RT-qPCR in the entire study population. Post-treatment ovulation rates were assessed by salivary progesterone in PCOS girls. Endocrinology Department, University Hospital. Girls with PCOS, compared with controls, had markedly reduced concentrations of circulating miR-451a, miR-652-3p, miR-106b-5p, and miR-206; pathway enrichment analysis showed that these miRNAs target genes involved in energy homeostasis and cell cycle control. In the present study, miR-451a could diagnose PCOS with 100% sensitivity and 100% specificity. SPIOMET (but not OC) was accompanied by on-treatment normalization of the miRNA profile in girls with PCOS; miR-451a concentrations after 1 year on OC or SPIOMET treatment associated closely (r = 0.66; P < .0001) with post-treatment ovulation rates. SPIOMET treatment for 1 year normalizes the miRNA profile of girls with PCOS. Circulating miR-451a may become a biomarker to guide the diagnosis and treatment of PCOS in adolescence.


[Borderline personality disorder associated with psychotic symptoms and parietal lobe abnormalities].
We explore a case of a forensic patient with severe personality disorder, borderline type, and additional psychotic symptoms. Furthermore, she showed parietal lobe abnormalities. We describe a case report and the relevant theoretical deliberations. Attempts to categorize patients with severe borderline personality disorder and psychotic symptoms have been made since the beginning of the 20th century. We show that in our patient neuroimaging such as SPECT scan can prove parietal lobe abnormalities. We describe possible links between these findings and her symptoms.


A quantitative model to ensure capacity sufficient for timely access to care in a remote patient monitoring program.
Algorithm-enabled remote patient monitoring (RPM) programs pose novel operational challenges. For clinics developing and deploying such programs, no standardized model is available to ensure capacity sufficient for timely access to care. We developed a flexible model and interactive dashboard of capacity planning for whole-population RPM-based care for T1D. Data were gathered from a weekly RPM program for 277 paediatric patients with T1D at a paediatric academic medical centre. Through the analysis of 2 years of observational operational data and iterative interviews with the care team, we identified the primary operational, population, and workforce metrics that drive demand for care providers. Based on these metrics, an interactive model was designed to facilitate capacity planning and deployed as a dashboard. The primary population-level drivers of demand are the number of patients in the program, the rate at which patients enrol and graduate from the program, and the average frequency at which patients require a review of their data. The primary modifiable clinic-level drivers of capacity are the number of care providers, the time required to review patient data and contact a patient, and the number of hours each provider allocates to the program each week. At the institution studied, the model identified a variety of practical operational approaches to better match the demand for patient care. We designed a generalizable, systematic model for capacity planning for a paediatric endocrinology clinic providing RPM for T1D. We deployed this model as an interactive dashboard and used it to facilitate expansion of a novel care program (4 T Study) for newly diagnosed patients with T1D. This model may facilitate the systematic design of RPM-based care programs.


Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation.
The delicate visual axis that makes precise vision possible is highly vulnerable to the destructive potential of immunogenic inflammation. Immune privilege of the eye is the experimental expression of the way in which evolution has coped with the countermanding threats to vision of ocular infections and ocular immunity and inflammation. Ocular immune privilege has five primary features that account for its existence: blood:ocular barriers, absent lymphatic drainage pathways, soluble immunomodulatory factors in aqueous humor, immunomodulatory ligands on the surface of ocular parenchymal cells, and indigenous, tolerance-promoting antigen-presenting cells (APCs). Three manifestations of ocular immune privilege that have received the most extensive study are the intraocular microenvironment, which is selectively anti-inflammatory and immunosuppressive; the prolonged acceptance of solid tissue and tumor allografts in the anterior chamber; and the induction of systemic tolerance to eye-derived antigens. Anterior chamber-associated immune deviation is known to arise when indigenous, ocular APCs capture eye-derived antigens and deliver them to the spleen where multicellular clusters of these cells, natural killer T cells, marginal zone B cells, and gammadelta T cells create an antigen-presentation environment that leads to CD4(+) and CD8(+) alpha/beta T cells, which as regulators, suppress induction and expression of T helper cell type 1 (Th1) and Th2 immune expression systems. The ways the eye influences local and systemic immune responses to ocular antigens and pathogens carry risks to and benefits for mammalian organisms. As loss of sight is a powerful, negative-selecting force, the benefits of ocular immune privilege outweigh the risks.


Toxicity of butylated hydroxytoluene in mouse following oral administration.
Male Swiss--Webster mice were given 400 mg/kg of butylated hydroxytoluene ([methyl-14C]toluene) by stomach tube. Radioactivity was measured in plasma, lung, liver and kidney from 0.5 h to 10 days later. Radioactivity associated with butylated hydroxytoluene (BHT) or its metabolites was highest in plasma and all tissues examined between 1 and 12 h after administration. After 24 h, less than 1% of the administered dose remained in the lung, kidney or liver. One day after BHT, DNA synthesis in lung increased and, on days 3, 4 and 5, was 6--8 times as high as in controls. DNA content of the lungs almost doubled. Synthesis and net increase of pulmonary DNA were dose-dependent. If BHT was given orally following injection of one single dose of urethane, adenoma formation in lung was enhanced. It is concluded that BHT, given by stomach tube and in doses higher than 100 mg/kg, produces extensive cell proliferation in mouse lung and acts as a promoting agent in adenoma development.