Long-term exposure to outdoor air pollution and the incidence of chronic obstructive pulmonary disease in a national English cohort.
The role of outdoor air pollution in the incidence of chronic obstructive pulmonary disease (COPD) remains unclear. We investigated this question using a large, nationally representative cohort based on primary care records linked to hospital admissions. A cohort of 812 063 patients aged 40-89 years registered with 205 English general practices in 2002 without a COPD diagnosis was followed from 2003 to 2007. First COPD diagnoses recorded either by a general practitioner (GP) or on admission to hospital were identified. Annual average concentrations in 2002 for particulate matter with an aerodynamic diameter <10 µm (PM10) and <2.5 µm (PM2.5), nitrogen dioxide (NO2), ozone and sulfur dioxide (SO2) at 1 km(2) resolution were estimated from emission-based dispersion models. Hazard ratios (HRs) per interquartile range change were estimated from Cox models adjusting for age, sex, smoking, body mass index and area-level deprivation. 16 034 participants (1.92%) received a COPD diagnosis from their GP and 2910 participants (0.35%) were admitted to hospital for COPD. After adjustment, HRs for GP recorded COPD and PM10, PM2.5 and NO2 were close to unity, positive for SO2 (HR=1.07 (95% CI 1.03 to 1.11) per 2.2 µg/m(3)) and negative for ozone (HR=0.94 (0.89 to 1.00) per 3 µg/m(3)). For admissions HRs for PM2.5 and NO2 remained positive (HRs=1.05 (0.98 to 1.13) and 1.06 (0.98 to 1.15) per 1.9 µg/m(3) and 10.7 µg/m(3), respectively). This large population-based cohort study found limited, inconclusive evidence for associations between air pollution and COPD incidence. Further work, utilising improved estimates of air pollution over time and enhanced socioeconomic indicators, is required to clarify the association between air pollution and COPD incidence.


Integrin α5β1 inhibition by ATN-161 reduces neuroinflammation and is neuroprotective in ischemic stroke.
Stroke remains a leading cause of death and disability with limited therapeutic options. Endothelial cell β1 integrin receptors play a direct role in blood-brain barrier (BBB) dysfunction through regulation of tight junction proteins and infiltrating leukocytes, potentially mediated by β1 integrins. Following tandem transient common carotid artery/middle cerebral artery occlusion on wild-type mice, we administered the integrin a5b1 inhibitor, ATN-161, intraperitoneal (IP) injection at 1 mg/kg acutely after reperfusion, on post-stroke day (PSD)1 and PSD2. Systemic changes (heart rate, pulse distension, and body temperature) were determined. Additionally, infarct volume and edema were determined by 2,3-triphenyltetrazolium chloride and magnetic resonance imaging, while neurological changes were evaluated using an 11-point Neuroscore. Brain immunohistochemistry was performed for claudin-5, α5β1, IgG, and CD45 + cells, and quantitative polymerase chain reaction (qPCR) was performed for matrix metalloproteinase-9 (MMP-9), interleukin (IL)-1β, collagen IV, and CXCL12. ATN-161 significantly reduced integrin α5β1 expression in the surrounding peri-infarct region with no systemic changes. Infarct volume, edema, and functional deficit were significantly reduced in ATN-161-treated mice. Furthermore, ATN-161 treatment reduced IgG extravasation into the parenchyma through conserved claudin-5, collagen IV, CXCL12 while reducing MMP-9 transcription. Additionally, IL-1β and CD45 + cells were reduced in the ipsilateral cortex following ATN-161 administration. Collectively, ATN-161 may be a promising novel stroke therapy by reducing post-stroke inflammation and BBB permeability.


Mechanism of Anti-Inflammatory Drugs in the Early Treatment of Oral Gingival Mucosa and Soft Tissue Trauma.
Traumatic tissue develops an uncontrolled inflammatory response that causes secondary damage to the injured tissue and other parts of the body. Therefore, preventing wound infection, reducing inflammatory response, and reducing secondary tissue damage are the keys to early treatment of tissue trauma. In the treatment of gingival soft tissue trauma, anti-inflammatory and analgesic drugs are reasonably selected according to the condition, which can effectively reduce inflammation, and they help periodontal tissue regeneration and healing. However, there are few studies on the mechanism of anti-inflammatory drugs in the early treatment of oral gingival mucosal soft tissue trauma, and the specific mechanism is unknown. Therefore, this paper explored the mechanism of anti-inflammatory drugs in the early treatment of oral gingival mucosa and soft tissue trauma through experiments, which provided theoretical support for the clinical treatment of gingival mucosa and soft tissue trauma repair. In this paper, two anti-inflammatory drugs, levofloxacin and metronidazole, were selected to measure their release properties in vitro and in vivo. Then, the white-eared rabbits were treated with gingival wound treatment experiments, and the physiological characteristics, intratissue pressure, tissue partial pressure of oxygen, IL-6 content, and PGE2 content were determined at each postinjury period, and the mechanism of action of anti-inflammatory drugs was determined. Research results have shown that anti-inflammatory drugs can significantly inhibit the content of IL-6 and PGE2 in gingival soft tissue after injury, reduce the local inflammatory response, and accelerate tissue healing.


Adult stem cell transplantation in stroke: its limitations and prospects.
A growing number of studies have demonstrated stem cell-based therapy provides a feasible, realistic approach to the restoration of lost brain function after stroke. Moreover, adult stem cells may provide more appropriate clinical strategies. Leading candidate sources include bone marrow, peripheral blood, adipose tissue, skeletal muscle, and olfactory mucosa, which act as central repositories for multipotent stem cells that can repopulate neural tissues. The medical society is currently enthusiastic concerning the clinical applications of autologous adult stem cells in stroke, based on promising results obtained during experimental studies and initial clinical trials. However, before embracing clinical applications, several essential precautions must be properly addressed. For example, the regenerative potentials of adult stem cells decline with age, and stem cells isolated from aged patients may retain dysfunctional characteristics. Are the natures and amounts of available autologous cells appropriate for therapeutic application in stroke? Do transplanted cells remain functional in the diseased brain, and if so what are the optimal injection routes, cell doses, and timings? Thus, we believe that success in future clinical trials will depend on careful investigation at the experimental level, to allow us to understand not only the practicalities of stem cell use, but also the underlying biological principles involved. Here, we review the advantages and disadvantages of the different adult stem cell sources and discuss the challenges that must be negotiated to achieve transplantation success.


Treatment algorithms in child psychopharmacology research.
Clinical trials in child psychiatry research have increased in complexity. Several factors have contributed to this change, including the need to compare multiple therapies, to re-create clinically relevant situations in research, to standardize treatment approaches, to account for the impact of comorbidity, to respond to the needs of individual patients, and to optimize treatment accordingly. To preserve the clinical and internal validity of the experimental interventions vis-à-vis their increasing complexity, researchers have started developing treatment algorithms. These deductive systems for handling data allow us to standardize and incorporate clinical judgment into study designs through the adoption of a stepwise decision making process. Treatment algorithms are different from treatment guidelines. Guidelines are general recommendations that apply to groups of patients with certain characteristics; they are not fully detailed and are created with the expectation that clinical judgment will be applied in individual cases. Algorithms are patient specific, are intended to capture all the relevant details of the clinical situation, and require minimal clinical judgment for their clinical application; they are designed to minimize the role of clinical judgment in research protocols. The entire multistep algorithm is tested in a clinical trial, not the single steps that constitute the algorithm, so proving the efficacy of an algorithm cannot replace a controlled assessment of the individual treatments embedded in the algorithm. Some characteristics, properties, and limitations of algorithms in child psychiatry and psychopharmacology research are presented along with two examples of algorithms currently used in child and adolescent psychopharmacology. Although treatment algorithms seldom have been used in pediatric psychiatry and psychopharmacology, there are indications that their use will increase in the near future and will allow the standardized introduction of clinical judgment into research design.


Trust in risky messages: the role of prior attitudes.
Risk perception researchers have observed a "negativity bias" for hazard-related information. Messages indicating the presence of risk seem to be trusted more than messages indicating the absence of risk, and risk perceptions seem more affected by negative than positive information. Two experiments were conducted to examine alternative explanations of this finding within the area of food additives. Study 1 (N = 235) extended earlier work by (a) unconfounding message valence (positive or negative) from message extremity (definite or null finding) and (b) exploring the role of prior attitudes. Results suggested that negative/risky messages were indeed trusted more even when extremity was taken into account. However, prior attitudes significantly moderated the effect of message valence on trust. Positive messages were distrusted only by those with negative prior attitudes. Study 2 (N = 252), further explored the role of prior attitudes and extended the work by examining reactions to risky messages about a positively viewed additive--a vitamin. The results again found a moderating effect of prior attitudes on message valence. Participants had greater confidence in messages that were more congruent with their prior attitudes, irrespective of valence. Furthermore, positive messages had a greater impact on risk perception than negative messages. These findings suggest that greater trust in negative messages about hazards may be a product of a "confirmatory" rather than a "negativity" bias.


Benefits of sharing neurophysiology data from the BRAIN Initiative Research Opportunities in Humans Consortium.
Sharing human brain data can yield scientific benefits, but because of various disincentives, only a fraction of these data is currently shared. We profile three successful data-sharing experiences from the NIH BRAIN Initiative Research Opportunities in Humans (ROH) Consortium and demonstrate benefits to data producers and to users.


The role of diabetes mellitus in patients with bloodstream infections.
Since diabetes mellitus predisposes to infection, we evaluated whether diabetes increases the risk of bloodstream infection and worsens its outcome. During a 4-year period 71 diabetic and 252 non-diabetic patients with bloodstream infection were included. Risk factors for death were assessed by univariate and multivariate analysis. Bloodstream infection was more frequent in diabetics than in non-diabetics (25.8/1000 admissions vs. 5.8/1000 admissions, p <0.0001). Urinary tract infection was the predominant source, and Escherichia coli the most frequent microorganism in both groups. Klebsiella pneumoniae was more frequent in diabetics than in non-diabetics (18% vs 5%, p <0.001). Whereas sepsis of unknown origin was more common in diabetics (14% vs. 6%, p <0.05), catheter-related bloodstream infection predominated in non-diabetics (3% vs 10%, p <0.05). Secondary septic foci (p <0.05) and disseminated intravascular coagulation (p <0.05) were more frequent in diabetics. The in-hospital mortality rate was similar in the two groups (18% vs. 14%). Univariate analysis (RR [CI 95%]) in diabetics revealed glycaemia >20 mmol/L (3.9 [1.7-22]), ICU stay (7.1 [2-25]), mechanical ventilation (8.4 [1.2-57]) and chronic renal/hepatic failure (8.2 [1.6-43]) as significant risk factors. Hyperglycaemia (4.3 [3.4-5.2]) and ICU stay (3.3 [1.9-4.9]) remained significant in multivariate analysis. Diabetics had a 4.4-fold higher risk of bloodstream infection, were more prone to sepsis of unknown origin and had more septic complications than non-diabetics. The mortality rate was similar in the two groups.


High-flow nasal cannula oxygen therapy in patients undergoing thoracic surgery: current evidence and practice.
Patients undergoing thoracic surgery are at high risk for pulmonary and extra pulmonary complications, and may develop impairment of gas exchange during surgery and in the postoperative period. This review focuses on the potential benefits of high-flow nasal cannula (HFNC) oxygen therapy in those patients. HFNC oxygen therapy can be used pre, intra and postoperatively. However, evidence for the use of HFNC oxygen therapy is still limited. Most trials investigated the effects of HFNC oxygen therapy in the postoperative period only, with promising beneficial effects. Preoperative HFNC oxygen therapy might be an alternative to conventional techniques, and allows continuous oxygenation during the apneic time of laryngoscopy. In certain patients, thoracic surgery might be performed in awake and nonintubated patients who are breathing spontaneously. Under these conditions, HFNC oxygen therapy might be considered for respiratory support by experienced anesthesiologists. In the postoperative period, HFNC oxygen therapy can prevent escalation of respiratory management and has the potential to reduce the length of hospital stay. Throughout the perioperative period, close monitoring of patients receiving HFNC oxygen therapy is key, and intubation criteria to avoid delayed intubation should be defined a priori to prevent harm. HFNC oxygen therapy is a promising tool in the perioperative care of thoracic surgical patients, when properly set, performed by experienced staff and closely monitored.


Health and nutritional promotion program for patients with dementia (NutriAlz Study): design and baseline data.
There is a lack of data on global weight loss prevention programs for patients with dementia or clear evidence about their impact on a functional level, caregiver burden or the use of healthcare and social resources. NutriAlz is a socio-educative and nutritional intervention program to prevent weight loss and loss of function in dementia patients. A cluster randomized multi-centre study, which will allow the comparison of a group benefiting from the intervention with a control group after a year of monitoring. Patients were recruited from 11 hospitals in the ambulatory diagnostic units and day care centres. The baseline interview include: sociodemographic and socioeconomic variables (age, gender, educational level, marital status); diagnostic, treatments, MMS, a list of comorbid conditions; activities of daily living (ADL, IADL), Zarit Scale, brief-NPI, Cornell scale and nutritional status as measured by the Mini Nutritional Assessment. All participants or their family signed the inform consent form. Total of 946 patients were included, with a mean (+/- SD) of 79 +/- 7.3 year of age; 68,1 % were women; 44,9% lives with their partner, only 3% lives alone; 79.8% had Alzheimer's dementia, 5.25 +/- 3.0 years since symptoms of dementia and 2.8 +/- 2.11 years since diagnosis. Mean MMSE score was 15.4 +/- 6.2; mean weight was 64.4 +/- 12.5 kg; mean BMI was 27.0 +/- 4.5 (with 3% below 19, 5% between 19-21, 10% between 21-23, and 82% above 23). Mean ADL without difficulties was 3.2 +/- 2.1; mean IADL without difficulties was 0.7 +/- 1.6; mean number of symptoms in the NPI was 4.4 +/- 2.59, with severity score of 7.9 +/- 5.9 and distress score of 11.3 +/- 9.0; mean Zarit scale was 27.4 +/- 15.5; mean MNA was 23.2 +/- 3.5 with 5 % as malnourished, 32 % at risk of malnutrition, and 63 % with adequate nutritional status.


Mobile Vaccination Teams for Improving Vaccination Coverage in the Kyrgyz Republic: Results of a National Health System-Strengthening Project during the First Two Years of the COVID-19 Pandemic.
(1) Background: This implementation study reports on the results of the mobile vaccination teams' (MVTs) activities during the first two years of the COVID-19 pandemic in Kyrgyzstan, when other vaccination services were disrupted. (2) Methods: Through a national health system-strengthening project under an order of the Ministry of Health, in 2020, the number of MVTs was increased, focusing on internal immigrant settlements around the cities of Bishkek and Osh and geographically remote areas. MVTs provided free vaccination services. (3) Results: MVTs vaccinated a total of 125,289 and 158,047 children in 2020 and 2021, respectively. The higher contribution of MVTs to vaccination coverage was in children under 5 years of age, with the three top vaccines being IPV (8.9%), MMR (7%), and PCV (6.6%). In 2021, 13,000 children who had not received an IPV vaccination and 8692 children who had not received the Pentavalent vaccine (DPT-HBV-Hib) were reached. The number of cases of vaccine-preventable disease reported in official statistics has reduced over time. (4) Conclusions: MVTs increased vaccination coverage in Kyrgyzstan, in particular in remote regions and migrant settlements, where it accounted for a considerable proportion of the vaccinated. This study adds to previous evidence in the literature of the role of MVTs as a strategy to improve immunization in hard-to-reach populations, particularly children.


Serum IgG antibodies to peptidylarginine deiminase 4 predict radiographic progression in patients with rheumatoid arthritis treated with tumour necrosis factor-alpha blocking agents.
Peptidylarginine deiminase 4 (PAD4) may generate epitopes targeted by anticitrullinated protein antibodies in rheumatoid arthritis (RA). A subset of patients with RA has serum autoantibodies to human recombinant PAD4 (hPAD4). Here, we assessed whether anti-hPAD4 status in RA predicted disease outcome after antitumour necrosis factor (anti-TNF)-alpha therapy. We analysed RA sera obtained at baseline (n = 40) and after 1 year on anti-TNF-alpha therapy (n = 33) for anti-hPAD4 IgG. Association analyses between baseline anti-hPAD status and disease progression were performed. We found that 17 of 40 patients (42.5%) were serum anti-hPAD4 positive at baseline, and the anti-hPAD4 IgG levels were stable over 1 year on anti-TNF-alpha therapy. At baseline, there were indications that anti-hPAD4 positive patients had more severe disease than the negative patients. After 1 year on anti-TNF-alpha therapy, the anti-hPAD4 positive patients displayed a persistently elevated disease activity score using 28 joint counts score and increased progression in the van der Heijde-modified Sharp erosion score. Accordingly, more anti-hPAD4 positive than negative patients presented an increase in van der Heijde-modified Sharp erosion scores >0 over 1 year. Anti-hPAD4 IgG can be detected in a subset of RA sera and the levels are stable after initiation of anti-TNF-alpha therapy. Serum anti-hPAD4 may predict persistent disease activity and radiographic progression in patients with RA receiving anti-TNF-alpha therapy.


Please empathize! Instructions to empathise strengthen response facilitation after pain observation.
Recent research has shown that observing others in pain leads to a general facilitation of reaction times. The current study sheds further light on the relationship between pain observation and reaction time by exploring how bottom-up processes, in the form of perceived pain intensity, and top-down processes, in the form of explicit instructions to empathise, influence response facilitation after pain observation. Participants watched videos of a hand getting pierced by a needle or touched by a Q-tip. To manipulate bottom-up information, participants saw videos depicting either deep or shallow insertion of the needle. To investigate potential top-down modulation, half the participants were explicitly requested to empathise with the person in the video, while the other half were told to simply watch and attend to the video. Results from two experiments corroborate previous results showing response facilitation after pain observation. Critically, experiment 2 provides robust evidence that explicit instructions to empathise with a person in pain strengthen response facilitation. We discuss these results considering social cognitive neuroscience and experimental psychology studies of empathy and pain observation.


Cytochrome P450 7A1 cholesterol 7alpha-hydroxylation: individual reaction steps in the catalytic cycle and rate-limiting ferric iron reduction.
Cytochrome P450 (P450) 7A1 is well known as the cholesterol 7α-hydroxylase, the first enzyme involved in bile acid synthesis from cholesterol. The human enzyme has been reported to have the highest catalytic activity of any mammalian P450. Analyses of individual steps of cholesterol 7α-hydroxylation reaction revealed several characteristics of this reaction: (i) two-step binding of cholesterol to ferric P450, with an apparent K(d) of 0.51 μM, (ii) a rapid reduction rate in the presence of cholesterol (∼10 s(-1) for the fast phase), (iii) rapid formation of a ferrous P450-cholesterol-O(2) complex (29 s(-1)), (iv) the lack of a non-competitive kinetic deuterium isotope effect, (v) the lack of a kinetic burst, and (vi) the lack of a deuterium isotope effect when the reaction was initiated with the ferrous P450-cholesterol complex. A minimum kinetic model was developed and is consistent with all of the observed phenomena and the rates of cholesterol 7α-hydroxylation and H(2)O and H(2)O(2) formation. The results indicate that the first electron transfer step, although rapid, becomes rate-limiting in the overall P450 7A1 reaction. This is a different phenomenon compared with other P450s that have much lower rates of catalysis, attributed to the much more efficient substrate oxidation steps in this reaction.


Chronic hepatitis C in patients with normal or near normal alanine aminotransferase levels: the role of interferon alpha 2b therapy.
Interferon is the only approved therapy for chronic hepatitis occurring as a consequence of an infection with the hepatitis C virus. Because interferon is expensive, has a large number of untoward effects and its efficacy is not guaranteed, many physicians limit their use of this therapy to those with histologically advanced but not end-stage cirrhotic disease. Moreover, most cases are biopsied only after 6 months or more of abnormal alanine aminotransferase levels have been documented. The rationale for this approach to patients with hepatitis C virus infection has not been demonstrated. In the present study, a total of 37 patients with alanine aminotransferase levels < 1.5 upper limits of normal (59 IU/l or less) who were HCV-RNA positive by reverse transcriptase polymerase chain reaction, were selected for interferon treatment, having been identified as having hepatitis C virus disease as the result of a screening Ab-HCV test confirmed with a positive radio immune blotting assay. Once identified, each subject underwent a percutaneous liver biopsy and was tested for the presence of HBsAg, Ab-HBs and HBV-DNA. All liver biopsies were read and graded according to the criteria of Knodell et al. Each subject was treated with interferon a2b at a dose of 5 MU administered daily until a response was achieved (a minimum period of 6 months) or until a full year had elapsed. A response was defined as HCV-RNA negativity in serum on three consecutive monthly determinations. The study population consisted of 21 males and 16 females ranging in age from 17 to 72 years (mean 46.7 +/- 2.2 years). Their mean serum alanine aminotransferase level at the initiation of therapy was 37.5 +/- 2.1 IU/l with a range of 10-59 (normal values being 40 IU/l or less). 54% of the subjects were presumed to have acquired their hepatitis C virus infection as a result of a blood transfusion; 32% as a result of prior intravenous drug abuse; and 13% had no identifiable risk factor for hepatitis C virus. Despite having normal or near normal serum alanine aminotransferase levels, 9 subjects had chronic persistent hepatitis, 13 had chronic active hepatitis and 15 had chronic active hepatitis + cirrhosis documented by histopathologic assessment of their liver biopsies. An interferon response was achieved in 5/9 with chronic persistent hepatitis, 11/13 with chronic active hepatitis and 8/15 with chronic active hepatitis + cirrhosis for an overall response rate of 65%. This study has demonstrated that individuals who: 1) are hepatitis C virus positive with serum alanine aminotransferase levels < 1.5 x upper limits of normal can have histologically advanced liver disease; 2) can respond to interferon therapy defined as clearance of detectable HCV-RNA in serum; and, 3) should be considered for interferon treatment.


Acute response of airway muscle to extreme temperature includes disruption of actin-myosin interaction.
Despite the emerging use of bronchial thermoplasty in asthma therapy, the response of airway smooth muscle (ASM) to extreme temperatures is unknown. We investigated the immediate effects of exposing ASM to supraphysiologic temperatures. Isometric contractions were studied in bovine ASM before and after exposure to various thermal loads and/or pharmacologic interventions. Actin-myosin interactions were investigated using a standard in vitro motility assay. We found steep thermal sensitivity for isometric contractions evoked by acetylcholine, with threshold and complete inhibition at less than 50°C and greater than 55°C, respectively. Contractile responses to serotonin or KCl were similarly affected, whereas isometric relaxations evoked by the nitric oxide donor S-nitrosyl-N-acetylpenicillamine or the β-agonist isoproterenol were unaffected. This thermal sensitivity developed within 15 minutes, but did not evolve further over the course of several days (such a rapid time-course rules out heat shock proteins, apoptosis, autophagy, and necrosis). Although heat-sensitive transient receptor potential (TRPV2) channels and the calmodulin-dependent (Cam) kinase-II-induced inactivation of myosin light chain kinase are both acutely thermally sensitive, with a temperature producing half-maximal effect (T(1/2)) of 52.5°C, the phenomenon we describe was not prevented by blockers of TRPV2 channels (e.g., ruthenium red, gadolinium, zero-Ca(2+) or zero-Na(+)/zero-Ca(2+) media, and cromakalim) or of Cam kinase-II (e.g., W7, trifluoperazine, and KN-93). However, direct measurements of actin-myosin interactions showed the same steep thermal profile. The functional changes preceded any histologic evidence of necrosis or apoptosis. We conclude that extreme temperatures (such as those used in bronchial thermoplasty) directly disrupt actin-myosin interactions, likely through a denaturation of the motor protein, leading to an immediate loss of ASM cell function.


When passion leads to problematic outcomes: a look at gambling.
Vallerand et al. (2003) have proposed that individuals can have two distinct types of passion toward an activity. Harmonious passion, an internal force leading one to choose to engage in the activity, is proposed to be associated with positive consequences. Obsessive passion, an internal pressure forcing one to engage in an activity, is posited to be associated with negative consequences. The present study sought to determine the role of the two types of passion in various cognitive and affective states associated with dependence and problems with gambling. Participants (n = 412) were recruited at the Montréal Casino and given a questionnaire measuring passion toward gambling, as well as consequences associated with dependence and problem gambling. Results showed that obsessive passion for gambling predicted poorer vitality and concentration in daily tasks, as well as increased rumination, anxiety, negative mood, guilt, and problem gambling. These relations were not found for harmonious passion for gambling. Results are discussed in light of the motivational approach to passion (Vallerand et al., 2003).


[Resection of bronchial carcinoma combined with lung volume reduction].
Lung volume reduction (LVRO) combined with simultaneous resection of bronchial carcinoma ignores the well known principles of functional operability. In case of 6 patients with LVRO and resection of the lung because of a non-small-cell lung cancer (NSCLC) stage I (4 x), stage II (1 x) and stage IIIa (1 x) located in the emphysematous lung parenchyma lobectomy was done four times and extraanatomical resection twice. Because of a gangrene the resection of middle lobe was necessary in case of one patient. There were no other perioperative complications. 6 months after the operation 5 patients noticed decreased dyspnea. The survival rate after 2 years was 66 %, after 3 years 34 %. 1 patient is still alive after 56 months. Cause of death was in every case progress of tumour. Due to the principles of oncologic surgery lung resection will be functional tolerated if the cancer is located in the area of bullous lung destruction; in singular cases lung resection will improve the cardiorespiratory status at least temporary. In case of extraanatomic or segmental resections there is a low rate of morbidity and lethality but a high incidence of recurrence of carcinoma. The short- and medium- term functional results seem to be encouraging. Limiting factor for carrying out extensive resections is the tumour infiltration of non emphysematous lung parenchyma. There is no doubt that simultaneous resection will be reserved for a group of highly selected patients.


Inflammatory response elicited by Ureaplasma parvum colonization in human cervical epithelial, stromal, and immune cells.
Ureaplasma parvum is a commensal bacterium in the female reproductive tract but has been associated with pregnancy complications such as preterm prelabor rupture of membranes and preterm birth (PTB). However, the pathologic effects of U. parvum in the cervix, which prevents ascending infections during pregnancy, are still poorly understood. To determine the impact of U. parvum on the cervix, ectocervical (ecto) and endocervical (endo) epithelial and stromal cells were incubated with U. parvum. Macrophages were also tested as a proxy for cervical macrophages to determine the antigenicity of U. parvum. The effects of U. parvum, including influence on cell cycle and cell death, antimicrobial peptide (AMP) production, epithelial-to-mesenchymal transition (EMT), and inflammatory cytokine levels, were assessed. U. parvum colonized cervical epithelial and stromal cells 4 h post-infection. Like uninfected control, U. parvum neither inhibited cell cycle progression and nor caused cell death in cervical epithelial and stromal cells. U. parvum increased the production of the AMPs cathelicidin and human β-defensin 3 and exhibited weak signs of EMT evidenced by decreased cytokeratin 18 and increased vimentin expression in cervical epithelial cells. U. parvum induced a proinflammatory environment (cytokines) and increased MMP-9 in cervical epithelial cells but promoted pro- and anti-inflammatory response in cervical stromal cells and macrophages. U. parvum may colonize the cervical epithelial layer, but induction of AMPs and anti-inflammatory response may protect the cervix and may prevent ascending infections that can cause PTB. These findings suggest that U. parvum is a weak inducer of inflammation in the cervix.


Investigation of the relationship between chronic montelukast treatment, asthma and depression-like behavior in mice.
In 2008, the Food and Drug Administration of the US issued a warning about the neuropsychiatric side effects of montelukast. Previous clinical studies on montelukast have reported conflicting results and, to the best of our knowledge, no experimental studies concerning these side effects had been conducted. In the current study, the effect of montelukast on depression-like behavior in an ovalbumin (OVA)-induced mouse model was investigated. A total of 3 OVA challenges were applied at 2 week intervals for the persistence of asthma. Depression-like behavior was assessed using forced swim tests following each challenge and locomotor activities were evaluated using open field tests. At the end of the current study, plasma montelukast concentrations were measured and the development of asthma and effect of montelukast treatment were histopathologically examined. Inflammation scores that were increased in the OVA mice following all challenges were indicated to be reduced by montelukast treatment. The immobility time of mice increased beginning with the first challenge and this was also reduced by montelukast treatment. Montelukast administration to the control mice did not alter immobility times. Moreover, motor activity of the OVA and montelukast-treated mice were not altered. The results indicated there was no association between chronic montelukast treatment and depression. Furthermore, the chronic administration of montelukast to non-asthmatic mice did not increase immobility. However, depressive behavior increased at all time points in the OVA mice. These results indicated that chronic montelukast treatment is not associated with depression-like behavior and confirmed the association between asthma and depression. Further studies are required to provide an improved understanding of the neuropsychiatric side effects of montelukast.


Perioperative hyperglycemia: effect on outcome after infant congenital heart surgery.
Studies demonstrate that cardiopulmonary bypass (CPB) causes intraoperative and postoperative hyperglycemia. Hyperglycemia has been associated with morbidity and mortality after infant cardiac surgery. We studied the effects on early postoperative outcomes of glucose (GLU) changes during and after pediatric cardiac surgery. The records of 144 infants less than 10 kg who underwent CPB for a variety of congenital cardiac procedures were reviewed. The GLU values (at multiple intervals during and after surgery), age, weight, CPB time, ultrafiltration volume, and risk adjustment for congenital heart surgery (RACHS-1) score were recorded. Univariate and multivariate linear and binary logistic regression were used to examine the dependence of the composite outcome mortality or postoperative infection, the mechanical ventilation time (VENT time), and the length of stay (LOS), on these variables. The RACHS-1 score was the only significant predictor of the composite variable "mortality or infection" (p = 0.008). Glucose at any time was not a significant factor predicting this outcome. Lower pre-CPB GLU, younger age, and higher RACHS-1 score were significant predictors of greater LOS and VENT time. In this study, post-CPB and postoperative hyperglycemia were not risk factors for postoperative morbidity and mortality after infant cardiac surgery.


Downscaling pollen-transport networks to the level of individuals.
Most plant-pollinator network studies are conducted at species level, whereas little is known about network patterns at the individual level. In fact, nodes in traditional species-based interaction networks are aggregates of individuals establishing the actual links observed in nature. Thus, emergent properties of interaction networks might be the result of mechanisms acting at the individual level. Pollen loads carried by insect flower visitors from two mountain communities were studied to construct pollen-transport networks. For the first time, these community-wide pollen-transport networks were downscaled from species-species (sp-sp) to individuals-species (i-sp) in order to explore specialization, network patterns and niche variation at both interacting levels. We used a null model approach to account for network size differences inherent to the downscaling process. Specifically, our objectives were (i) to investigate whether network structure changes with downscaling, (ii) to evaluate the incidence and magnitude of individual specialization in pollen use and (iii) to identify potential ecological factors influencing the observed degree of individual specialization. Network downscaling revealed a high specialization of pollinator individuals, which was masked and unexplored in sp-sp networks. The average number of interactions per node, connectance, interaction diversity and degree of nestedness decreased in i-sp networks, because generalized pollinator species were composed of specialized and idiosyncratic conspecific individuals. An analysis with 21 pollinator species representative of two communities showed that mean individual pollen resource niche was only c. 46% of the total species niche. The degree of individual specialization was associated with inter- and intraspecific overlap in pollen use, and it was higher for abundant than for rare species. Such niche heterogeneity depends on individual differences in foraging behaviour and likely has implications for community dynamics and species stability. Our findings highlight the importance of taking interindividual variation into account when studying higher-order structures such as interaction networks. We argue that exploring individual-based networks will improve our understanding of species-based networks and will enhance the link between network analysis, foraging theory and evolutionary biology.


Evaluation of a self-awareness education session for youth education with type 1 diabetes.
This research sought to determine if a one-hour education session about self-awareness had any short-or long-term impact on young participants with Type 1 diabetes. The study was conducted within Hernandez' (1991) theory of integration. Twenty-nine adolescents and young adults participated in the intervention, which was operationalized through the collaborative alliance educational method. The intervention consisted of viewing a videotape on self-awareness and participating in discussion of cues of low, high, and normal blood glucose as well as the situations that cause these. Questionnaires were completed pre-education, immediately following education, and 12 months later. The number of cues identified for all levels of blood glucose was significantly increased by the intervention. Many of the body cues identified by participants were different than those typically presented in diabetes education materials and programs. Participants identified issues regarding changes in body cues over time, frequency of classic signs of hypoglycemia, and the frequency of severe lows. Findings have implications for the content, delivery method, and educational materials of diabetes education programs.


Exploiting Polyploidy for Markerless and Plasmid-Free Genome Engineering in Cyanobacteria.
Here we describe a universal approach for plasmid-free genome engineering in cyanobacteria that exploits the polyploidy of their chromosomes as a natural counterselection system. Rather than being delivered via replicating plasmids, genes encoding for DNA modifying enzymes are instead integrated into essential genes on the chromosome by allelic exchange, as facilitated by antibiotic selection, a process that occurs readily and with only minor fitness defects. By virtue of the essentiality of these integration sites, full segregation is never achieved, with the strain instead remaining as a merodiploid so long as antibiotic selection is maintained. As a result, once the desired genome modification is complete, removal of antibiotic selection results in the gene encoding for the DNA modifying enzyme to then be promptly eliminated from the population. Proof of concept of this new and generalizable strategy is provided using two different site-specific recombination systems, CRE-lox and DRE-rox, in the fast-growing cyanobacterium Synechococcus sp. PCC 7002, as well as CRE-lox in the model cyanobacterium Synechocystis sp. PCC 6803. Reusability of the method, meanwhile, is demonstrated by constructing a high-CO2 requiring and markerless Δndh3 Δndh4 ΔbicA ΔsbtA mutant of Synechococcus sp. PCC 7002. Overall, this method enables the simple and efficient construction of stable and unmarked mutants in cyanobacteria without the need to develop additional shuttle vectors nor counterselection systems.


Effect of acute hypoglycemia on human cerebral glucose metabolism measured by ¹³C magnetic resonance spectroscopy.
To investigate the effect of acute insulin-induced hypoglycemia on cerebral glucose metabolism in healthy humans, measured by (13)C magnetic resonance spectroscopy (MRS). Hyperinsulinemic glucose clamps were performed at plasma glucose levels of 5 mmol/L (euglycemia) or 3 mmol/L (hypoglycemia) in random order in eight healthy subjects (four women) on two occasions, separated by at least 3 weeks. Enriched [1-(13)C]glucose 20% w/w was used for the clamps to maintain stable plasma glucose labeling. The levels of the (13)C-labeled glucose metabolites glutamate C4 and C3 were measured over time in the occipital cortex during the clamp by continuous (13)C MRS in a 3T magnetic resonance scanner. Time courses of glutamate C4 and C3 labeling were fitted using a one-compartment model to calculate metabolic rates in the brain. Plasma glucose (13)C isotopic enrichment was stable at 35.1 ± 1.8% during euglycemia and at 30.2 ± 5.5% during hypoglycemia. Hypoglycemia stimulated release of counterregulatory hormones (all P < 0.05) and tended to increase plasma lactate levels (P = 0.07). After correction for the ambient (13)C enrichment values, label incorporation into glucose metabolites was virtually identical under both glycemic conditions. Calculated tricarboxylic acid cycle rates (V(TCA)) were 0.48 ± 0.03 μmol/g/min during euglycemia and 0.43 ± 0.08 μmol/g/min during hypoglycemia (P = 0.42). These results indicate that acute moderate hypoglycemia does not affect fluxes through the main pathways of glucose metabolism in the brain of healthy nondiabetic subjects.


Strategies for assessing pain and pain exaggeration: controlled studies.
To compare structured with intuitive methods of detecting exaggerated pain, in 2 randomized studies, with masked observers, and to compare properties of measures of relative tenderness, as surrogates for measures of pain. Pairs of experienced rheumatologists assessed tenderness and behavior in subjects who were either giving honest responses (Not Acting) or exaggerating their tenderness while hiding the deception (Acting). In Study 1 (20 subjects) the assessments of behavior were descriptive only; for Study 2 (25 subjects) a prestructured format was developed. The challenge to the examiners was to detect Acting. The challenge to the analyst was to develop, from the recorded data, an algorithm that described or bettered the examiners' performance. By exaggerating, nontender patients could meet formal ACR criteria for fibromyalgia. The addition of a prestructured pain behavior assessment in Study 2 was associated with improvement in the observers' ability to detect Acting, with improvement of sensitivity from 60 to 90% (p = 0.0003, Study 2 compared with Study 1). False positive diagnoses of Acting by the observers were uniformly uncommon, with specificity of 85 and 86% in the 2 studies. Formal numerical techniques are required and feasible for separately assessing the structural and psychogenic components of chronic pain.


Biological and mathematical modeling of melanocyte development.
We aim to evaluate environmental and genetic effects on the expansion/proliferation of committed single cells during embryonic development, using melanoblasts as a paradigm to model this phenomenon. Melanoblasts are a specific type of cell that display extensive cellular proliferation during development. However, the events controlling melanoblast expansion are still poorly understood due to insufficient knowledge concerning their number and distribution in the various skin compartments. We show that melanoblast expansion is tightly controlled both spatially and temporally, with little variation between embryos. We established a mathematical model reflecting the main cellular mechanisms involved in melanoblast expansion, including proliferation and migration from the dermis to epidermis. In association with biological information, the model allows the calculation of doubling times for melanoblasts, revealing that dermal and epidermal melanoblasts have short but different doubling times. Moreover, the number of trunk founder melanoblasts at E8.5 was estimated to be 16, a population impossible to count by classical biological approaches. We also assessed the importance of the genetic background by studying gain- and loss-of-function β-catenin mutants in the melanocyte lineage. We found that any alteration of β-catenin activity, whether positive or negative, reduced both dermal and epidermal melanoblast proliferation. Finally, we determined that the pool of dermal melanoblasts remains constant in wild-type and mutant embryos during development, implying that specific control mechanisms associated with cell division ensure half of the cells at each cell division to migrate from the dermis to the epidermis. Modeling melanoblast expansion revealed novel links between cell division, cell localization within the embryo and appropriate feedback control through β-catenin.


The Transcriptomic Profile of Monocytes from Patients With Sjögren's Syndrome Is Associated With Inflammatory Parameters and Is Mimicked by Circulating Mediators.
Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by infiltration of the exocrine glands and prominent B cell hyperactivity. Considering the key role of monocytes in promoting B cell hyperactivity, we performed RNA-sequencing analysis of CD14+ monocytes from patients with pSS, non-Sjögren's sicca (nSS), and healthy controls (HC). We demonstrated that the transcriptomic profile of pSS patients is enriched in intermediate and non-classical monocyte profiles, and confirmed the increased frequency of non-classical monocytes in pSS patients by flow-cytometry analysis. Weighted gene co-expression network analysis identified four molecular signatures in monocytes from pSS patients, functionally annotated for processes related with translation, IFN-signaling, and toll-like receptor signaling. Systemic and local inflammatory features significantly correlated with the expression of these signatures. Furthermore, genes highly associated with clinical features in pSS were identified as hub-genes for each signature. Unsupervised hierarchical cluster analysis of the hub-genes identified four clusters of nSS and pSS patients, each with distinct inflammatory and transcriptomic profiles. One cluster showed a significantly higher percentage of pSS patients with higher prevalence of anti-SSA autoantibodies, interferon-score, and erythrocyte sedimentation rate compared to the other clusters. Finally, we showed that the identified transcriptomic differences in pSS monocytes were induced in monocytes of healthy controls by exposure to serum of pSS patients. Representative hub-genes of all four signatures were partially inhibited by interferon-α/β receptor blockade, indicating that the circulating inflammatory mediators, including type I interferons have a significant contribution to the altered transcriptional profile of pSS-monocytes. Our study suggests that targeting key circulating inflammatory mediators, such as type I interferons, could offer new insights into the important pathways and mechanisms driving pSS, and holds promise for halting immunopathology in Sjögren's Syndrome.


Holoparasitic Rafflesiaceae possess the most reduced endophytes and yet give rise to the world's largest flowers.
Species in the holoparasitic plant family Rafflesiaceae exhibit one of the most highly modified vegetative bodies in flowering plants. Apart from the flower shoot and associated bracts, the parasite is a mycelium-like endophyte living inside their grapevine hosts. This study provides a comprehensive treatment of the endophytic vegetative body for all three genera of Rafflesiaceae (Rafflesia, Rhizanthes and Sapria), and reports on the cytology and development of the endophyte, including its structural connection to the host, shedding light on the poorly understood nature of this symbiosis. Serial sectioning and staining with non-specific dyes, periodic-Schiff's reagent and aniline blue were employed in order to characterize the structure of the endophyte across a phylogenetically diverse sampling. A previously identified difference in the nuclear size between Rafflesiaceae endophytes and their hosts was used to investigate the morphology and development of the endophytic body. The endophytes generally comprise uniseriate filaments oriented radially within the host root. The emergence of the parasite from the host during floral development is arrested in some cases by an apparent host response, but otherwise vegetative growth does not appear to elicit suppression by the host. Rafflesiaceae produce greatly reduced and modified vegetative bodies even when compared with the other holoparasitic angiosperms once grouped with Rafflesiaceae, which possess some vegetative differentiation. Based on previous studies of seeds together with these findings, it is concluded that the endophyte probably develops directly from a proembryo, and not from an embryo proper. Similarly, the flowering shoot arises directly from the undifferentiated endophyte. These filaments produce a protocorm in which a shoot apex originates endogenously by formation of a secondary morphological surface. This degree of modification to the vegetative body is exceptional within angiosperms and warrants additional investigation. Furthermore, the study highlights a mechanical isolation mechanism by which the host may defend itself from the parasite.


Unusually Aggressive Primary Testicular Diffuse Large B Cell Lymphoma with Post Therapy Extensive Metastasis.
Primary Testicular Lymphoma (PTL) is a rare intermediate to high grade tumour, diffuse large cell being the most common type. Unlike nodal Diffuse Large B-Cell Lymphoma (DLBCL), testicular DLBCL has a less aggressive course and better prognosis. Metastasis is uncommon in testicular DLBCL. Commonly involved sites are contralateral testes, Waldeyer's ring, skin, lung, Central Nervous System (CNS) and prostate, however the kidneys, liver, bone marrow, pleura and bones are more rarely involved. We report a case of testicular DLBCL which has metastasized to skin and bone marrow with an aggressive clinical course in a year, in-spite of combined modality of therapy given to the patient. Bone marrow infiltration is common and well documented with nodal DLBCL, however there is no published literature for simultaneous bone marrow and skin infiltration in testicular DLBCL till date. Other large studies done in the west have shown that distinct metastasis is usually common but the median progression-free survival is usually in years. This case stresses on shorter period of progression after standard treatment protocol in this part of the world, thus highlighting the need for other extensive studies to define specific treatment protocol for testicular DLBCL.


Hidden in plain sight - Multiple resistant species within a strongyle community.
Ovine parasitic gastroenteritis is a complex disease routinely treated using anthelmintics. Although many different strongyle species may contribute to parasitic gastroenteritis, not all are equally pathogenic: in temperate regions, the primary pathogen is Teladorsagia circumcincta. In this study we investigated benzimidazole and ivermectin resistance on a commercial sheep farm in southeast Scotland. We assessed the impact of species diversity on the diagnosis of resistance using the faecal egg count reduction test and in vitro bioassays, and correlated the results with the frequency of benzimidazole resistance-associated genotypes measured in the T. circumcincta population by pyrosequencing of the β-tubulin isotype-1 gene. Faecal egg count reduction test results showed efficacies of 65% for albendazole and 77% for ivermectin, indicating moderate resistance levels on the farm. However, PCR speciation of the same populations pre- and post-treatment revealed that removal of susceptible species had masked the presence of a highly resistant population of T. circumcincta. Less than 25% of individuals in the pre-treatment populations were T. circumcincta, the remainder consisting of Cooperia curticei, Chabertia ovina, Oesophagostomum venulosum and Trichostrongylus spp. In contrast, post-treatment with albendazole or ivermectin, the majority (88% and 100% respectively) of the populations consisted of T. circumcincta. The egg hatch test for benzimidazole resistance and the larval development test for ivermectin resistance were carried out using eggs obtained from the same populations and the results were broadly consistent with the faecal egg count reduction test. Thirty individual T. circumcincta from each sampling time point were assessed for benzimidazole resistance by pyrosequencing, revealing a high frequency and diversity of resistance-associated mutations, including within the population sampled post-ivermectin treatment. These results highlight the potential diversity of parasite species present on UK farms, and their importance in the diagnosis of anthelmintic resistance. On this particular farm, we demonstrate the presence of a highly dual-resistant population of T. circumcincta, which was strongly selected by treatment with either benzimidazoles or ivermectin, while other potentially less pathogenic species were removed.


Alterations in pulmonary ultrastructure and morphometric parameters induced by parainfluenza (Sendai) virus in rats during postnatal growth.
The ultrastructural and morphometric effects of viral respiratory disease during postnatal lung growth were examined in weanling (22-day-old) and suckling (5-day-old) rats infected with parainfluenza Type 1 (Sendai) virus. Viral nucleocapsids and budding virions were identified by transmission electron microscopy in ciliated cells, mucous cells, and nonciliated bronchiolar epithelial cells of weanling rats at 5 days after inoculation and were associated with epithelial necrosis and erosion as well as hyperplasia of nonciliated bronchiolar epithelial cells. Interstitial pneumonia characterized in early stages by swelling and sloughing of Type 1 and Type 2 alveolar epithelial cells was also present at 5 and 7 days after inoculation. Lesions persisting at 30, 60, and 90 days after inoculation included multifocal connective tissue polyps in terminal bronchioles that partially obstructed bronchiolar lumens. Specific lung volume was greater (P less than 0.01) in weanling rats at 30 and 60 days following viral infection than in control rats, and specific alveolar surface area was 42% greater (P less than 0.01) in infected rats at 60 days after inoculation. Suckling rats infected during a phase of rapid postnatal lung growth at 5 days of age had 33% greater (P less than 0.02) specific alveolar surface area and 48% greater (P less than 0.001) mean terminal bronchiolar cross-sectional area when compared with control rats at 22 days of age. The results indicate that viral pulmonary infection during early life can induce acute and persistent alterations in pulmonary structure that could adversely affect lung function.


HbA1c and peripheral arterial disease in diabetes: the Atherosclerosis Risk in Communities study.
To assess the relation between HbA(1c) (A1C) and incident peripheral arterial disease (PAD) in a community-based cohort of diabetic adults from the Atherosclerosis Risk in Communities (ARIC) study. A second aim was to investigate whether the association was stronger for severe, symptomatic disease compared with PAD assessed by low ankle-brachial index (ABI). This was a prospective cohort study of 1,894 individuals with diabetes using ARIC visit 2 as baseline (1990-1992) with follow-up for incident PAD through 2002. We assessed the relation between A1C and incident PAD, defined by intermittent claudication, PAD-related hospitalization, or a low ABI (<0.9). During a mean follow-up of 9.8 years, the crude incidence rates were 2.1 per 1,000 person-years for intermittent claudication (n = 41), 2.9 per 1,000 person-years for PAD-related hospitalization (n = 57), and 18.9 per 1,000 person-years for low ABI at visit 3 or 4 (n = 123). The relative risk (RR) (95% CI) of an incident PAD event comparing the second and third tertiles of A1C to the first, respectively, after adjustment for cardiovascular risk factors was strongest for severe, symptomatic forms of disease, e.g., PAD-related hospitalization (RR = 4.56 [1.86-11.18] for the third A1C tertile compared with the first, P trend <0.001) than for low ABI (RR = 1.64 [0.94-2.87], P trend = 0.08). We found a positive, graded, and independent association between A1C and PAD risk in diabetic adults. This association was stronger for clinical (symptomatic) PAD, whose manifestations may be related to microvascular insufficiency, than for low ABI. Our results suggest that efforts to improve glycemic control in persons with diabetes may substantially reduce the risk of PAD.


ORMDL3 expression levels have no influence on the activity of serine palmitoyltransferase.
ORMDL proteins are believed to be negative regulators of serine palmitoyltransferase (SPT), which catalyzes the first and rate limiting step in sphingolipid (SL) de novo synthesis. Several single-nucleotide polymorphisms (SNPs) that are close to the ORMDL3 locus have been reported to increase ORMDL3 expression and to be associated with an elevated risk for early childhood asthma; however, the direct effect of ORMDL3 expression on SPT activity and its link to asthma remains elusive. In this study, we investigated whether ORMDL3 expression is associated with changes in SPT activity and total SL levels. Ormdl3-knockout (Ormdl3-/-) and transgenic (Ormdl3Tg/wt) mice were generated to study the effect of ORMDL3 on total SL levels in plasma and tissues. Cellular SPT activity was measured in mouse embryonic fibroblasts from Ormdl3-/- mice, as well as in HEK293 cells in which ORMDL3 was overexpressed and silenced. Furthermore, we analyzed the association of the reported ORMDL3 asthma SNPs with plasma sphingoid bases in a population-based cohort of 971 individuals. Total C18-long chain bases were not significantly altered in the plasma and tissues of Ormdl3-/- mice, whereas C18-sphinganine showed a small and significant increase in plasma, lung, and liver tissues. Mouse embryonic fibroblast cells from Ormdl3-/- mice did not show an altered SPT activity compared with Ormdl3+/- and Ormdl3+/+ mice. Overexpression or knockdown of ORMDL3 in HEK293 cells did not alter SPT activity; however, parallel knockdown of all 3 ORMDL isoforms increased enzyme activity significantly. A significant association of the annotated ORMDL3 asthma SNPs with plasma long-chain sphingoid base levels could not be confirmed. ORMDL3 expression levels seem not to be directly associated with changes in SPT activity. ORMDL3 might influence de novo sphingolipid metabolism downstream of SPT.-Zhakupova, A., Debeuf, N., Krols, M., Toussaint, W., Vanhoutte, L., Alecu, I., Kutalik, Z., Vollenweider, P., Ernst, D., von Eckardstein, A., Lambrecht, B. N., Janssens, S., Hornemann, T. ORMDL3 expression levels have no influence on the activity of serine palmitoyltransferase.


The ERK-RSK1 activation by growth factors at G2 phase delays cell cycle progression and reduces mitotic aberrations.
Growth factors accelerate G0 to S progression in the cell cycle, however, the roles of growth factors in other cell cycle phases are largely unknown. Here, we show that treatment of HeLa cells with hepatocyte growth factor (HGF) at G2 phase induced the G2/M transition delay as evidenced by FACS analysis as well as by mitotic index and time-lapse analyses. Growth factors such as epidermal growth factor (EGF) and fibroblast growth factor (FGF) also induced G2/M transition delay like HGF. HGF treatment at G2 phase causes a delayed activation of cyclin B1-associated kinase and a diminished nuclear translocation of cyclin B1. Either U0126, a MAPK kinase (MEK) inhibitor, or kinase-dead mutant of ribosomal S6 kinase (RSK) abolished the delay. Additionally, knockdown of RSK1, but not RSK2, with siRNA abrogated the delay, indicating that the extracellular-regulated protein kinase (ERK)-RSK1 mediates the HGF-induced delay. We further found that the delay in G2/M transition of cells expressing oncogenic HGF receptor, M1268T, was abolished by RSK1 knockdown. Intriguingly, we observed that HGF induced chromosomal segregation defects, and depletion of RSK1, but not RSK2, aggravated these chromosomal aberrations. Taken together, the ERK-RSK1 activation by growth factors delays G2/M transition and this might be required to maintain genomic integrity during growth factor stimulation.


[The prevalence of cardiovascular pathology in alcoholism patients].
ECG was made in 336 patients with alcoholism that were admitted in a special hospital for alcoholic patients during one year. 146 patients were examined in the state of alcohol withdrawal syndrome, after its arrest and in stress. A prevalence of ECG changes well as stability of such alterations, prognostic criteria for a further course of both alcoholism and cardiovascular pathology were determined. A correlation was established between the cardiovascular changes on the one hand the age of the patients and the type of a course of alcoholism on the other hand.


Computed tomography of primitive neuroectodermal tumors.
The primitive neuroectodermal tumor is a neoplasm of young individuals that occurs predominantly in the supratentorial compartment. It appears on computed tomography as a bulky mass, often with calcification with predominantly homogeneous enhancement but on occasion with cystic or necrotic areas. Cerebrospinal fluid seeding was observed in more than half the cases in our series. The patients had a short survival period (7-24 months). Despite surgery, radiation, and chemotherapy, further growth of this tumor has not been prevented.


The Cartagena-La Unión mining district (SE Spain): a review of environmental problems and emerging phytoremediation solutions after fifteen years research.
After mining in the Cartagena-La Unión Mining District (SE Spain) was discontinued in 1992, various studies have shown that large amounts of toxic metals continue to be transferred with the spread of unstabilized mining wastes to the nearby ecosystems. Local creeks seem to be important pathways carrying eroded materials from the headwaters to the nearby coastal areas of the Mediterranean Sea. Studies have shown the presence of high metal concentrations in the sediments of riverbeds and in river mouths and adjacent coastal marshes (e.g. 500 mg kg(-1) As; 12 000 mg kg(-1) Pb). Also, some nearby agricultural areas are affected (up to 10 mg kg(-1) Pb in lettuce leaves). Metal transfer into biota has been demonstrated in creek sediments in relation to benthic organisms (up to 222 mg kg(-1) Pb in molluscs). The mining wastes in the area are spontaneously colonized by native plant species. On the tailings, most of the plant species are grasses (e.g. Lygeum spartum, Piptatherum miliaceum); in polluted salt marshes, halophytic species dominate (e.g. Arthrocnemum macrostachyum). Metal uptake by plants is in general low (10 mg kg(-1) for Cu; <200 mg kg(-1) Pb; <500 mg kg(-1) Zn). Preliminary tests have shown the suitability of amendments (e.g. lime, fertilizer, pig manure) to improve the establishment of certain vegetation on the tailings. Phytostabilization appears to be a promising technology to decrease erosion in the tailings. However, tailings must be individually analysed in order to determine their geostructural stability, as in addition, mechanical stabilization will be needed in some cases to prevent collapse.


[The aspects of erosive-ulcerative changes of the gastroduodenal tract mucous membrane in atherosclerosis of the aorta and major arteries].
Complex clinico-instrumental examination and surgical treatment of 172 patients with erosive-ulcerative changes of the gastroduodenal zone mucosa and atherosclerotic affection of aorta and main arteries was conducted. Functional peculiarities of erosive-ulcerative changes of the gastroduodenal zone mucosa in atherosclerosis of aorta and main arteries were revealed.


Time-Dependent Afterglow from a Single Component Organic Luminogen.
Pure organic luminogens with long-persistent luminescence have been extensively studied, on account of their fundamental research significance and diverse utilizations in anticounterfeiting, bioimaging, encryption, organic light-emitting diodes, chemo-sensing, etc. However, time-dependent color-tunable afterglow is rarely reported, especially for single-component materials. In this work, we reported an organic luminogen with time-dependent afterglow, namely, benzoyleneurea (BEU), with multiple persistent room-temperature phosphorescence (p-RTP) and thermally activated delayed fluorescence (TADF) in single crystals. While the lifetime of TADF is relatively short (~1.2 ms), those for p-RTP are as long as around 369~754 ms. The comparable but different decay rates of diversified p-RTP emissions endow BEU crystals with obvious time-dependent afterglow. The existence of multiple emissions can be reasonably illustrated by the clustering-triggered emission (CTE) mechanism. Single-crystal structure illustrates that the combination of benzene ring and nonconventional chromophores of ureide helps facilitate divergent intermolecular interactions, which contribute to the formation of varying emissive species. Moreover, its methyl- and chloro-substituted derivatives show similar multiple p-RTP emissions. However, no time-dependent afterglows are observed in their crystals, due to the highly approaching lifetimes. The afterglow color variation of BEU crystals grants its applications in advanced anticounterfeiting field and information encryption.


Glucose Status within Dark-Grown Etiolated Cotyledons Determines Seedling De-etiolation upon Light Irradiation.
Exposure of dark-grown etiolated seedlings to light triggers the transition from skotomorphogenesis/etiolation to photomorphogenesis/de-etiolation. In the life cycle of plants, de-etiolation is essential for seedling development and plant survival. The mobilization of soluble sugars (glucose, sucrose and fructose) derived from stored carbohydrates and lipids to target organs, including cotyledons, hypocotyls and radicles, underpins de-etiolation. Therefore, dynamic carbohydrate biochemistry is a key feature of this phase transition. However, the molecular mechanisms coordinating carbohydrate status with the cellular machinery orchestrating de-etiolation remain largely opaque. Here, we show that the glucose (Glc) sensor HEXOKINASE1 (HXK1) interacts with GROWTH REGULATOR FACTOR5 (GRF5), a transcriptional activator and key plant growth regulator, in Arabidopsis (Arabidopsis thaliana). Subsequently, GRF5 directly binds to the promoter of phyA (phytochrome A), encoding a far-red light (FR) sensor/cotyledon greening inhibitor. We demonstrate that the status of Glc within dark-grown etiolated cotyledons determines the de-etiolation of seedlings when exposed to light irradiation by the HXK1-GRF5-phyA molecular module. Thus, following seed germination, accumulating Glc within dark-grown etiolated cotyledons stimulates a HXK1-dependent increase of GRF5 and an associated decrease of phyA, triggering the perception, amplification and relay of HXK1-dependent Glc signaling, thereby facilitating the de-etiolation of seedlings following light irradiation. Our findings, therefore, establish how cotyledon carbohydrate signaling under subterranean darkness is sensed, amplified and relayed, determining the phase transition from skotomorphogenesis to photomorphogenesis on exposure to light irradiation.


High-dose effects in the treatment of carcinoma of the bladder under air and hyperbaric oxygen conditions.
Twenty-seven patients with carcinoma of the bladder were treated at the Glasgow Institute of Radiotherapeutics as part of a national hyperbaric oxygen trial. These patients were treated on a 4 MeV linear accelerator either in air or in 3 atm, absolute, of oxygen, by random selection. Of these patients, one-third were found to have high-dose effects to an extent which necessitated surgery. No association was found between the incidence of high-dose effects and treatment in air or hyperbaric oxygen. The treatment protocol used in all cases was to give an intended modal tumour dose of 6000 rad in 24 fractions in approximately 5 weeks. As all patients had received the same modal dose, there was no apparent reason why some had developed high-dose effects. However, on the basis of a Cumulative Radiation Effect (CRE) analysis of the treatment regimes given, a close correlation was found between the maximum CRE achieved and the occurrence of high-dose effects. Above a threshold level of 1910 reu in the maximum CRE achieved, there was a high incidence and rapid onset of high-dose effects. The reasons for the occurrence of the exceptionally high CRE values found in some patients are discussed. From a review of clinical results of bladder treatments, it is apparent that at a CRE level of 1910 reu, the tumour control rate is still increasing with CRE. It is proposed that by choosing the dose given on any treatment schedule to keep the maximum value of the CRE achieved just below 1910 reu, the greatest probability of cure would be obtained with minimum complication rate.


Prevalence of unmet supportive care needs reported by individuals ever diagnosed with cancer in Australia: a systematic review to support service prioritisation.
Improved health outcomes for individuals ever diagnosed with cancer require comprehensive, coordinated care that addresses their supportive care needs. Implementing interventions to address these is confounded by a lack of evidence on population needs and a large pool of potential interventions. This systematic review estimates the point prevalence of different supportive care needs stratified by the tool used to measure needs and cancer type in Australia. We searched MEDLINE, Embase, and Scopus from 2010 to April 2023 to identify relevant studies published on the prevalence of supportive care needs in Australia. We identified 35 studies that met the inclusion criteria. The highest prevalent unmet need across all cancers was 'fear of cancer spreading' (20.7%) from the Supportive Care Needs Survey Short-Form 34 (SCNS-SF34), ranging from 9.4% for individuals ever diagnosed with haematological cancer to 36.3% for individuals ever diagnosed with gynaecological cancer, and 'concerns about cancer coming back' (17.9%) from the Cancer Survivors' Unmet Needs (CaSUN), ranging from 9.7% for individuals ever diagnosed with prostate cancer to 37.8% for individuals ever diagnosed with breast cancer. Two studies assessed needs in Aboriginal and Torres Strait Islander populations, reporting the highest needs for financial worries (21.1%). Point prevalence estimates presented here, combined with estimates of the costs and effects of potential interventions, can be used within economic evaluations to inform evidence-based local service provision to address the supportive care needs of individuals ever diagnosed with cancer. Local health services can use local evidence to prioritise the implementation of interventions targeted at unmet needs.


Current approaches to management of bone sarcoma in adolescent and young adult patients.
Bone tumors are a group of histologically diverse diseases that occur across all ages. Two of the commonest, osteosarcoma (OS) and Ewing sarcoma (ES), are regarded as characteristic adolescent and young adult (AYA) cancers with an incidence peak in AYAs. They are curable for some but associated with unacceptably high rates of treatment failure and morbidity. The introduction of effective new therapeutics for bone sarcomas is slow, and to date, complex biology has been insufficiently characterized to allow more rapid therapeutic exploitation. This review focuses on current standards of care, recent advances that have or may soon change that standard of care and challenges to the expert clinical research community that we suggest must be met.


Discovery of KRB-456, a KRAS G12D switch-I/II allosteric pocket binder that inhibits the growth of pancreatic cancer patient-derived tumors.
Currently, there are no clinically approved drugs that directly thwart mutant KRAS G12D, a major driver of human cancer. Here, we report on the discovery of a small molecule, KRB-456, that binds KRAS G12D and inhibits the growth of pancreatic cancer patient-derived tumors. Protein NMR studies revealed that KRB-456 binds the GDP-bound and GCP-bound conformation of KRAS G12D by forming interactions with a dynamic allosteric binding pocket within the switch-I/II region. Isothermal titration calorimetry demonstrated that KRB-456 binds potently to KRAS G12D with 1.5-, 2- and 6-fold higher affinity than to KRAS G12V, KRAS wild-type and KRAS G12C, respectively. KRB-456 potently inhibits the binding of KRAS G12D to the RAS-binding domain (RBD) of RAF1 as demonstrated by GST-RBD pull-down and AlphaScreen assays. Treatment of KRAS G12D-harboring human pancreatic cancer cells with KRB-456 suppresses the cellular levels of KRAS bound to GTP and inhibits the binding of KRAS to RAF1. Importantly, KRB-456 inhibits P-MEK, P-AKT and P-S6 levels in vivo and inhibits the growth of subcutaneous and orthotopic xenografts derived from pancreatic cancer patients whose tumors harbor KRAS G12D and KRAS G12V and who relapsed after chemotherapy and radiation therapy. These results warrant further development of KRB-456 for pancreatic cancer.


Multi-Organ Gland Segmentation Using Deep Learning.
Clinical morphological analysis of histopathology samples is an effective method in cancer diagnosis. Computational pathology methods can be employed to automate this analysis, providing improved objectivity and scalability. More specifically, computational techniques can be used in segmenting glands, which is an essential factor in cancer diagnosis. Automatic delineation of glands is a challenging task considering a large variability in glandular morphology across tissues and pathological subtypes. A deep learning based gland segmentation method can be developed to address the above task, but it requires a large number of accurate gland annotations from several tissue slides. Such a large dataset need to be generated manually by experienced pathologists, which is laborious, time-consuming, expensive, and suffers from the subjectivity of the annotator. So far, deep learning techniques have produced promising results on a few organ-specific gland segmentation tasks, however, the demand for organ-specific gland annotations hinder the extensibility of these techniques to other organs. This work investigates the idea of cross-domain (-organ type) approximation that aims at reducing the need for organ-specific annotations. Unlike parenchyma, the stromal component of tissues, that lies between the glands, is more consistent across several organs. It is hypothesized that an automatic method, that can precisely segment the stroma, would pave the way for a cross-organ gland segmentation. Two proposed Dense-U-Nets are trained on H&E strained colon adenocarcinoma samples focusing on the gland and stroma segmentation. The trained networks are evaluated on two independent datasets, they are, a H&E stained colon adenocarcinoma dataset and a H&E stained breast invasive cancer dataset. The trained network targeting the stroma segmentation performs similar to the network targeting the gland segmentation on the colon dataset. Whereas, the former approach performs significantly better compared to the latter approach on the breast dataset, showcasing the higher generalization capacity of the stroma segmentation approach. The networks are evaluated using Dice coefficient and Hausdorff distance computed between the ground truth gland masks and the predicted gland masks. The conducted experiments validate the efficacy of the proposed stoma segmentation approach toward multi-organ gland segmentation.


Alpha-vascular responses after short-term and long-term inhibition of nitric oxide synthesis.
Apart from the direct actions of nitric oxide (NO) on vascular smooth muscle, this factor may regulate cardiovascular functions through specific actions on alpha-adrenergic constrictor mechanisms. In this study we aim to establish whether the inhibition of the synthesis of this mediator could alter the vasoconstrictor responses mediated by alpha-adrenoceptor stimulation. We have been able to demonstrate that the blockage of the NO synthase really does exist, when both short- and long-term treatments with Nomega-nitro-Larginine methyl ester (L-NAME) are carried out. We have evaluated the concentration-dependent contractions induced by the selective alpha1-adrenoceptor agonists methoxamine and phenylephrine in isolated rat aorta rings in the following groups of animals: control, short-term L-NAME-treated (100 mg/kg i.p. 20 min before subjecting the animals to the experiments) and long-term L-NAME-treated (100 mg/kg per day in the drinking water for 7, 21, or 45 days). We have also evaluated the pressor responses to methoxamine and to the selective alpha-adrenoceptor agonist B-HT 920 using the pithed rat preparation in the same groups of animals. The contractile responses to methoxamine and phenylephrine were similar in the rat aorta preparations from control and short-term L-NAME-treated animals. On the contrary, in the rat aorta preparations from long-term L-NAME-treated animals these responses were clearly reduced when compared with the corresponding responses in those from control animals, the reduction being more marked when the treatment lasted longer. The pressor responses to methoxamine were also similar in control and short-term L-NAME-treated pithed rats. Nevertheless, the responses to B-HT 920 were greater in the latter. On the other hand, the dose-response curves to both alpha-adrenoceptor agonists were shifted to the right in a non-parallel manner in rats treated long term with L-NAME, the shift being, in the case of B-HT 920, more accentuated when the treatment lasted 21 or 45 days than when it lasted only 7 days. These results indicate that the short-term decrease in NO synthesis does not modify the vascular smooth muscle responses mediated by alpha1-adrenoceptor stimulation, but it does induce a potentiation of sympathetic vasoconstriction mediated by alpha2-adrenoceptors. Nevertheless, the long-term inhibition of NO synthesis causes a compensating decrease in the alpha1- and alpha2-vascular smooth muscle contractile responses.


The Role of Electronic Medical Records in Reducing Unwarranted Clinical Variation in Acute Health Care: Systematic Review.
The use of electronic medical records (EMRs)/electronic health records (EHRs) provides potential to reduce unwarranted clinical variation and thereby improve patient health care outcomes. Minimization of unwarranted clinical variation may raise and refine the standard of patient care provided and satisfy the quadruple aim of health care. A systematic review of the impact of EMRs and specific subcomponents (PowerPlans/SmartSets) on variation in clinical care processes in hospital settings was undertaken to summarize the existing literature on the effects of EMRs on clinical variation and patient outcomes. Articles from January 2000 to November 2020 were identified through a comprehensive search that examined EMRs/EHRs and clinical variation or PowerPlans/SmartSets. Thirty-six articles met the inclusion criteria. Articles were examined for evidence for EMR-induced changes in variation and effects on health care outcomes and mapped to the quadruple aim of health care. Most of the studies reported positive effects of EMR-related interventions (30/36, 83%). All of the 36 included studies discussed clinical variation, but only half measured it (18/36, 50%). Those studies that measured variation generally examined how changes to variation affected individual patient care (11/36, 31%) or costs (9/36, 25%), while other outcomes (population health and clinician experience) were seldom studied. High-quality study designs were rare. The literature provides some evidence that EMRs can help reduce unwarranted clinical variation and thereby improve health care outcomes. However, the evidence is surprisingly thin because of insufficient attention to the measurement of clinical variation, and to the chain of evidence from EMRs to variation in clinical practices to health care outcomes.


Type II Secretion-Dependent Degradative and Cytotoxic Activities Mediated by Stenotrophomonas maltophilia Serine Proteases StmPr1 and StmPr2.
Stenotrophomonas maltophilia is an emerging opportunistic pathogen that primarily causes pneumonia and bacteremia in immunocompromised individuals. We recently reported that S. maltophilia strain K279a encodes the Xps type II secretion system and that Xps promotes rounding, actin rearrangement, detachment, and death in the human lung epithelial cell line A549. Here, we show that Xps-dependent cell rounding and detachment occur with multiple human and murine cell lines and that serine protease inhibitors block Xps-mediated rounding and detachment of A549 cells. Using genetic analysis, we determined that the serine proteases StmPr1 and StmPr2, which were confirmed to be Xps substrates, are predominantly responsible for secreted proteolytic activities exhibited by strain K279a, as well as the morphological and cytotoxic effects on A549 cells. Supernatants from strain K279a also promoted the degradation of type I collagen, fibrinogen, and fibronectin in a predominantly Xps- and protease-dependent manner, although some Xps-independent degradation of fibrinogen was observed. Finally, Xps, and predominantly StmPr1, degraded interleukin 8 (IL-8) secreted by A549 cells during coculture with strain K279a. Our findings indicate that while StmPr1 and StmPr2 are predominantly responsible for A549 cell rounding, extracellular matrix protein degradation, and IL-8 degradation, additional Xps substrates also contribute to these activities. Altogether, our data provide new insight into the virulence potential of the S. maltophilia Xps type II secretion system and its StmPr1 and StmPr2 substrates.


Emerging role of the KRAS-PDK1 axis in pancreatic cancer.
Pancreatic cancer is a highly aggressive tumour that is very resistant to treatments and it is rarely diagnosed early because of absence of specific symptoms. Therefore, the prognosis for this disease is very poor and it has the grim supremacy in terms of unfavourable survival rates. There have been great advances in survival rates for many types of cancers over the past few decades but hardly any change for pancreatic cancer. Mutations of the Ras oncogene are the most frequent oncogenic alterations in human cancers. The frequency of KRAS mutations in pancreatic cancer is around 90%. Given the well-established role of KRAS in cancer it is not surprising that it is one of the most attractive targets for cancer therapy. Nevertheless, during the last thirty years all attempts to target directly KRAS protein have failed. Therefore, it is crucial to identify downstream KRAS effectors in order to develop specific drugs able to counteract activation of this pathway. Among the different signalling pathways activated by oncogenic KRAS, the phosphoinositide 3-Kinase (PI3K) pathway is emerging as one of the most critical KRAS effector. In turn, PI3K activates several parallel pathways making the identification of the precise effectors activated by KRAS/PI3K more difficult. Recent data identify 3-phosphoinositide-dependent protein kinase 1 as a key tumour-initiating event downstream KRAS interaction with PI3K in pancreatic cancer.


Substance dependence and mental health in northern Iran.
Today, substance dependence and illegal trading of narcotics is considered as a global issue. Since mental disorder has been reported in about 90% of the substance dependents, this study aimed at determining the rate of mental health in the substance dependents in Sari Township in 2011. In this study, 500 substance-dependent patients were selected using convenience sampling method. To collect data, SCL-90-R was used for the evaluation of their mental health and a demographic questionnaire was employed for identifying their personal information. The obtained data were analyzed by descriptive and inferential statistics using the SPSS software. It was found that 90.4% of the participants were susceptible to mental disorder. Most of them suffered from depression, psychoticism, interpersonal sensitivity, anxiety, and paranoia. Also, there was significant relationship between the mental health of single, divorced and married addicts (P < 0.21). Due to the presence of mental disorder in the substance-dependent patients, it is recommended to help treat them by providing them with education, psychotherapy, and psychiatric medication.


[Paediatric screening for malnutrition still in its infancy].
Disease-related malnutrition occurs frequently in hospitals. It adversely affects the patients' recovery and increases the risk for complications. It is therefore one of the denominators the government uses to assess the quality of care. Essential for the treatment of malnutrition is the recognition of the problem by means of 'screening'. Unfortunately, it often remains unclear whether this refers to the assessment of the nutritional status or the risk for the development of malnutrition. In our opinion, the knowledge of both aspects is very limited in paediatric medicine, mainly due to methodological issues. The latter also applies to the first national study on the prevalence of malnutrition in hospitalised children in the Netherlands. When it comes to assessing the risk for the development of malnutrition, there is a clear lack of consensus as to what instrument should be used. To make matters worse, the tools available also lack sensitivity and specificity.


Frequency Changes in Terminal Alkynes Provide Strong, Sensitive, and Solvatochromic Raman Probes of Biochemical Environments.
The C≡C stretching frequencies of terminal alkynes appear in the "clear" window of vibrational spectra, so they are attractive and increasingly popular as site-specific probes in complicated biological systems like proteins, cells, and tissues. In this work, we collected infrared (IR) absorption and Raman scattering spectra of model compounds, artificial amino acids, and model proteins that contain terminal alkyne groups, and we used our results to draw conclusions about the signal strength and sensitivity to the local environment of both aliphatic and aromatic terminal alkyne C≡C stretching bands. While the IR bands of alkynyl model compounds displayed surprisingly broad solvatochromism, their absorptions were weak enough that alkynes can be ruled out as effective IR probes. The same solvatochromism was observed in model compounds' Raman spectra, and comparisons to published empirical solvent scales (including a linear regression against four meta-aggregated solvent parameters) suggested that the alkyne C≡C stretching frequency mainly reports on local electronic interactions (i.e., short-range electron donor-acceptor interactions) with solvent molecules and neighboring functional groups. The strong solvatochromism observed here for alkyne stretching bands introduces an important consideration for Raman imaging studies based on these signals. Raman signals for alkynes (especially those that are π-conjugated) can be exceptionally strong and should permit alkynyl Raman signals to function as probes at very low concentrations, as compared to other widely used vibrational probe groups like azides and nitriles. We incorporated homopropargyl glycine into a transmembrane helical peptide via peptide synthesis, and we installed p-ethynylphenylalanine into the interior of the Escherichia coli fatty acid acyl carrier protein using a genetic code expansion technique. The Raman spectra from each of these test systems indicate that alkynyl C≡C bands can act as effective and unique probes of their local biomolecular environments. We provide guidance for the best possible future uses of alkynes as solvatochromic Raman probes, and while empirical explanations of the alkyne solvatochromism are offered, open questions about its physical basis are enunciated.


Predicting failure of detection of peritonsillar abscess with ultrasound in pediatric populations.
Some patients require additional imaging following ultrasound (US) to definitively diagnose a peritonsillar abscess (PTA), delaying intervention and disease resolution. We seek to evaluate patient characteristics which may predispose to a secondary imaging requirement to diagnose PTA, in order to better understand ultrasound limitations and predict who will require additional studies. Retrospective chart review of patients with an US for suspected PTA between July 2017 and July 2020. Patient age, weight, and clinical characteristics, such as pain, trismus, and reduced neck range of motion (ROM) were collected. The need for additional imaging, subsequent surgical intervention, and hospital length of stay (LOS) were also recorded. Of 411 qualifying patients, 73 underwent additional imaging. Patients who required additional imaging were younger (9.8 vs 11.3 years, p = 0.026) and more likely to have decreased neck ROM (17.8 vs 5.3 %, p = 0.001). Surgical intervention was performed more commonly (27.4 vs 14.8 %, p = 0.015) and hospital LOS was longer (24.0 vs 5.0 h, p < 0.001) in those with secondary imaging. Specific patient characteristics, such as younger age and decreased neck range of motion, are associated with a higher need for additional imaging. Additionally, the need for additional imaging is associated with a longer hospital LOS and increased likelihood of surgical intervention. Nearly 18 % of patients who underwent US evaluation of PTA required secondary imaging. Although transcervical US remains an excellent tool for diagnosing PTA, this data supports the utility of secondary imaging in certain instances.


The effect of vaginal closure technique on early post-operative pain following vaginal prolapse surgery: a feasibility pilot study and qualitative assessment.
Surgery for pelvic organ prolapse is a common surgical procedure. There is little research studying post-operative pain, contrasting with extensive literature on pain after childbirth trauma which shows that suture method has a significant effect on pain. We designed a protocol for a trial comparing suture techniques and post-operative pain, and conducted a pre-protocol pilot to inform our trial design. Routine surgical data, post-operative pain scores (from 10 cm Visual Analogue Scales, VAS) and analgesic requirements were obtained from the notes of a cohort of women undergoing vaginal prolapse surgery. Median VAS scores at 4, 12 and 24 hours were compared by suture material used and method of closure (single continuous suture or interrupted sutures). The women whose data were obtained were invited to attend focus groups of up to six people in the twelve weeks following surgery. A semi structured question guide was used, and interviews were recorded, transcribed anonymously and analysed using the constant comparative method of grounded theory. Ethical approval was not sought because formal pre-protocol work is exempt for UK ethical requirements, but formal written consent on standard forms was obtained for publishing outcomes and anonymised comments from participants. Complete VAS data and operative details were available from 41 women. Surgery was completed using absorbable polyglactin sutures with continuous suturing (17 women) or interrupted sutures (24 women). Pain scores at 4 and 12 hours were similar; pain at 24 hours was greater in the women with interrupted sutures (median VAS 3 (range 0-8) versus 1.5 (0-8) (p = 0.0513). Analgesic needs were similar. Two focus groups (nine participants) revealed that women regarded post-operative pain as insignificant and not a topic worthy of formal research. It was apparent that the use, and especially removal of, vaginal packs was a practice associated with pain which women remembered as a significant part of their post-operative experience. Formal pre-protocol work is informative; we found a moderate difference in our proposed outcomes, suggesting a trial was feasible but women themselves were unconvinced of the need for formal research into pain following vaginal surgery.


Soft drink consumption is positively associated with increased waist circumference and 10-year incidence of abdominal obesity in Spanish adults.
The accumulation of abdominal fat increases risk of metabolic disorders and premature death. There is a dearth of prospective data on the association between caloric beverage consumption and surrogate markers of abdominal adiposity. The aim of this study was to assess the relation between consumption of nonalcoholic caloric beverages, including soft drinks, fruit juice, whole milk, and skim and low-fat milk, and changes in waist circumference (WC) and odds of 10-y incidence of abdominal obesity. We conducted a prospective, population-based study of 2181 Spanish men and women aged 25-74 y who were followed from 2000 to 2009. We measured weight, height, and WC, and recorded data on diet and leisure-time physical activity (LTPA) with the use of validated questionnaires. We fit multivariable linear and logistic regression models. A 100 kcal increase in soft drink consumption was associated with a 1.1 cm increase in WC (P = 0.018) after 10 y of follow-up. Substitution of 100 kcal of soft drinks with 100 kcal of whole milk or 100 kcal of juice was associated with a 1.3 cm (95% CI: 0.3, 2.4) and 1.1 cm (95% CI: 0.03, 2.2) decrease in WC, respectively. Increasing consumption of soft drinks from baseline to follow-up led to WC gain compared with maintaining nonconsumption. Greater soft drink consumption was positively associated (P = 0.029) with increased odds of 10-y incidence of abdominal obesity. Adults' consumption of soft drinks was associated with increased WC and odds of 10-y incidence of abdominal obesity. This association was moderate but consistent in all statistical models.


Hemodynamic monitoring using thoracic bioimpedance - an optimal solution for the treatment of hypertension.
Hypertension is a major issue of public health because of its increasing prevalence and multiple complications caused by failing to achieve an efficient blood pressure control. Considering hypertension as a hemodynamic disorder allows to prescribe a tailored therapy guided by individual hemodynamic parameters, therefore leading to an increased rate of control. We present the case of a 59 years old diabetic, dyslipidemic and obese male who, although treated with 5 classes of antihypertensive drugs had uncontrolled hypertension that caused left ventricular failure. Using the HOTMAN system of hemodynamic monitoring using thoracic electrical bioimpedance allowed a quick identification of the cause and guided the therapy, achieving blood pressure control after 5 days of treatment. Treating hypertension by identifying the underlying hemodynamic imbalance allows prescribing a tailored therapy and shortens the initiation and stabilization phases of treatment.


An objective measure for selecting microphone modes in OMNI/DIR hearing aid circuits.
Studies have shown that listener preferences for omnidirectional (OMNI) or directional (DIR) processing in hearing aids depend largely on the characteristics of the listening environment, including the relative locations of the listener, signal sources, and noise sources; and whether reverberation is present. Many modern hearing aids incorporate algorithms to switch automatically between microphone modes based on an analysis of the acoustic environment. Little work has been done, however, to evaluate these devices with respect to user preferences, or to compare the outputs of different signal processing algorithms directly to make informed choices between the different microphone modes. This study describes a strategy for automatically switching between DIR and OMNI microphone modes based on a direct comparison between acoustic speech signals processed by DIR and OMNI algorithms in the same listening environment. In addition, data are shown regarding how a decision to choose one microphone mode over another might change as a function of speech to noise ratio (SNR) and spatial orientation of the listener. Speech and noise signals were presented at a variety of SNR's and in different spatial orientations relative to a listener's head. Monaural recordings, made in both OMNI and DIR microphone processing modes, were analyzed using a model of auditory processing that highlights the spectral and temporal dynamics of speech. Differences between OMNI and DIR processing were expressed in terms of a modified spectrotemporal modulation index (mSTMI) developed specifically for this hearing aid application. Differences in mSTMI values were compared with intelligibility measures and user preference judgments made under the same listening conditions. A comparison between the results of the mSTMI analyses and behavioral data (intelligibility and preference judgments) showed excellent agreement, especially in stationary noise backgrounds. In addition, the mSTMI was found to be sensitive to changes in SNR as well as spatial orientation of the listener relative to signal and noise sources. Subsequent mSTMI analyses on hearing aid recordings obtained from real-life environments with more than one talker and modulated noise backgrounds also showed promise for predicting the preferred microphone setting in varied and complex listening environments.