Zinc Status Alters Alzheimer's Disease Progression through NLRP3-Dependent Inflammation.

Alzheimer's disease is a devastating neurodegenerative disease with a dramatically increasing prevalence and no disease-modifying treatment. Inflammatory lifestyle factors increase the risk of developing Alzheimer's disease. Zinc deficiency is the most prevalent malnutrition in the world and may be a risk factor for Alzheimer's disease potentially through enhanced inflammation, although evidence for this is limited. Here we provide epidemiological evidence suggesting that zinc supplementation was associated with reduced risk and slower cognitive decline, in people with Alzheimer's disease and mild cognitive impairment. Using the APP/PS1 mouse model of Alzheimer's disease fed a control (35 mg/kg zinc) or diet deficient in zinc (3 mg/kg zinc), we determined that zinc deficiency accelerated Alzheimer's-like memory deficits without modifying amyloid ß plaque burden in the brains of male mice. The NLRP3-inflammasome complex is one of the most important regulators of inflammation, and we show here that zinc deficiency in immune cells, including microglia, potentiated NLRP3 responses to inflammatory stimuli in vitro, including amyloid oligomers, while zinc supplementation inhibited NLRP3 activation. APP/PS1 mice deficient in NLRP3 were protected against the accelerated cognitive decline with zinc deficiency. Collectively, this research suggests that zinc status is linked to inflammatory reactivity and may be modified in people to reduce the risk and slow the progression of Alzheimer's disease.SIGNIFICANCE STATEMENT Alzheimer's disease is a common condition mostly affecting the elderly. Zinc deficiency is also a global problem, especially in the elderly and also in people with Alzheimer's disease. Zinc deficiency contributes to many clinical disorders, including immune dysfunction. Inflammation is known to contribute to the risk and progression of Alzheimer's disease; thus, we hypothesized that zinc status would affect Alzheimer's disease progression. Here we show that zinc supplementation reduced the prevalence and symptomatic decline in people with Alzheimer's disease. In an animal model of Alzheimer's disease, zinc deficiency worsened cognitive decline because of an enhancement in NLRP3-driven inflammation. Overall, our data suggest that zinc status affects Alzheimer's disease progression, and that zinc supplementation could slow the rate of cognitive decline.

Diurnal variability in soil nitrous oxide emissions is a widespread phenomenon.

Manual measurements of nitrous oxide (N2 O) emissions with static chambers are commonly practised. However, they generally do not consider the diurnal variability of N2 O flux, and little is known about the patterns and drivers of such variability. We systematically reviewed and analysed 286 diurnal data sets of N2 O fluxes from published literature to (i) assess the prevalence and timing (day or night peaking) of diurnal N2 O flux patterns in agricultural and forest soils, (ii) examine the relationship between N2 O flux and soil temperature with different diurnal patterns, (iii) identify whether non-diurnal factors (i.e. land management and soil properties) influence the occurrence of diurnal patterns and (iv) evaluate the accuracy of estimating cumulative N2 O emissions with single-daily flux measurements. Our synthesis demonstrates that diurnal N2 O flux variability is a widespread phenomenon in agricultural and forest soils. Of the 286 data sets analysed, ~80% exhibited diurnal N2 O patterns, with ~60% peaking during the day and ~20% at night. Contrary to many published observations, our analysis only found strong positive correlations (R > 0.7) between N2 O flux and soil temperature in one-third of the data sets. Soil drainage property, soil water-filled pore space (WFPS) level and land use were also found to potentially influence the occurrence of certain diurnal patterns. Our work demonstrated that single-daily flux measurements at mid-morning yielded daily emission estimates with the smallest average bias compared to measurements made at other times of day, however, it could still lead to significant over- or underestimation due to inconsistent diurnal N2 O patterns. This inconsistency also reflects the inaccuracy of using soil temperature to predict the time of daily average N2 O flux. Future research should investigate the relationship between N2 O flux and other diurnal parameters, such as photosynthetically active radiation (PAR) and root exudation, along with the consideration of the effects of soil moisture, drainage and land use on the diurnal patterns of N2 O flux. The information could be incorporated in N2 O emission prediction models to improve accuracy.

Thoracoscore fails to predict complications following elective lung resection.

The Thoracoscore mortality risk model has been incorporated into the British Thoracic Society guidelines on the radical management of patients with lung cancer. The discriminative and predictive ability to predict mortality and post-operative pulmonary complications (PPCs) in this group of patients is uncertain. A prospective observational study was carried out on all patients following lung resection via thoracotomy in a regional thoracic centre over 42 months. 128 out of 703 subjects developed a PPC. 16 (2%) patients died in hospital. In a logistic regression analysis the Thoracoscore was not a significant predictor of mortality (OR 1.07, 95% CI 0.99-1.17; p=0.11) but was a significant predictor of PPCs (OR 1.08, 95% CI 1.03-1.13; p=0.002). However, the area under the receiver operator characteristic curve for the Thoracoscore was 0.68 (95% CI 0.56-0.80) for predicting mortality and 0.64 (95% CI 0.59-0.69) for PPCs, indicating limited discriminative ability. In a logistic regression analysis, another risk model, the European Society Objective Score, was predictive of mortality (OR 1.43, 95% CI 1.11-1.83; p=0.006) and PPCs (OR 1.48, 95% CI 1.30-1.68; p<0.0001). Therefore, Thoracoscore may have poor discriminative and predictive ability for mortality and PPCs following elective lung resection.

Protonation and inhibition of Nitrosomonas europaea cytochrome c peroxidase observed with protein film voltammetry.

The impact of protonation and inhibitor binding of the diheme cytochrome c peroxidase (CCP) from Nitrosomonas europaea has been examined by the technique of catalytic protein film voltammetry (PFV). Previous efforts have shown that the low-potential heme active site (L) binds substrate and yields electrocatalysis at an pyrolytic graphite edge electrode, with properties evocative of a high-potential intermediate, with E(m)>540mV (vs. normal hydrogen electrode) [A.L. Bradley, S.E. Chobot, D.M. Arciero, A.B. Hooper, S. J. Elliott, J. Biol. Chem. 279 (2004) 13297-13300]. Here we demonstrate through similar experiments that catalytic PFV generates limiting currents which allow for electrochemically-detected enzymology of the Ne CCP: such as the demonstration that pH-dependent Michaelis-Menten constants (K(m) values) reveal a pK(a) value of 6.5 associated with the "ES" complex. Further, the direct electrocatalysis is shown in the presence of known inhibitors (cyanide and azide), indicating that inhibitor binding occurs at L, and shifts the resulting catalytic midpoint potential in a negative direction. Michaelis-Menten treatment of the limiting currents generated in the presence of variable concentrations of inhibitors showed that cyanide behaved as a competitive inhibitor with a K(i) value of 0.15muM; azide revealed a mixed-mode of inhibition. The observed data were found to support a previous model of electrocatalysis, and the role of proton transfer chemistry in the active site is discussed in terms of a structural model.

Chest wall mechanics before and after diaphragm plication.

BACKGROUND: Following diaphragmatic plication for unilateral paralysis, the effect on global chest wall function are unknown. Our hypothesis was that chest wall function would improve in both sides of the chest after plication of the paralysed side. CASE PRESENTATION: Using Optoelectronic Plethysmography, total and regional chest wall volumes were measured in one patient before and after left diaphragmatic plication. Volumes were recorded at quiet breathing. Respiratory capacity improved during quiet breathing when measured before and 6 months after surgery. These improvements occur at the abdominal-rib cage level in both operated and contralateral. Prior to surgery the abdominal rib cage motion was out of phase to the upper rib cage and abdominal compartment in both sides of the chest. Synchrony of all three compartments was restored after plication. CONCLUSION: This physiological study is the first published data in humans to show improvement in chest wall motion both in operated and contralateral side following diaphragmatic plication for unilateral paralysis.

Exercise improvement after pectus excavatum repair is not related to chest wall function.

OBJECTIVES: In patients undergoing corrective surgery for pectus excavatum, there is evidence of improvement in cardiopulmonary function. It is unclear how much of this improvement is attributable to improved chest wall function. Thus, we observed changes in chest wall function in response to an incremental load exercise pre- and postoperatively. METHODS: Using optoelectronic plethysmography, total and regional chest wall volumes were measured in 7 male patients with severe pectus excavatum who underwent a Nuss correction. Rib cage and abdominal volumes were recorded at rest and during exercise (incremental cycle ergometry), pre- and postoperatively in conjunction with spirometry. RESULTS: Tidal volume increases during exercise are blunted compared with baseline measurements at 6 days (-36 ± 7%) partially recovering at 6 months postoperatively (-18 ± 22%). This is mirrored by changes in spirometry. Tidal volume decreased during exercise initially in all compartments, but persisted in the rib cage compartment. An increase of 44% (P = 0.009) in exercise tolerance was found 6 months after surgical correction. CONCLUSIONS: Six months after Nuss correction in pectus patients, there was a decrease in rib cage mobility. Despite reduction, patients had a significant improvement in exercise tolerance. Therefore, we conclude that early postoperative improvement in exercise capacity is not due to changes in chest wall function. The longer term effects on chest wall function are yet to be defined.

Does repair of pectus excavatum improve cardiopulmonary function?

A best evidence topic was written according to a structured protocol. The question addressed was 'Does repair of pectus excavatum (PE) improve cardiopulmonary function?' One hundred and sixty-eight papers were found using the reported search, 19 level III evidence papers and three meta-analyses were relevant. Studies were divided into four groups based on the surgical technique applied and pulmonary and cardiac functions in these groups were analysed. The meta-analyses show conflicting results for improvements in pulmonary and cardiac functions when comparing surgical techniques, while four more recent studies show improved long-term results using the Nuss technique. The best evidence of papers studying the PE repair using the minimally invasive Nuss technique demonstrates a decrease in pulmonary function during the early postoperative period, however, there is a small but significant improvement during the late postoperative period and after bar removal. The best evidence for cardiac function in this group suggests an early improvement that is sustained during further follow-up. The best evidence of papers studying the PE repair using the Ravitch technique shows that pulmonary function decreased during the early postoperative period, however, there is a small but significant improvement during the late postoperative period. The best evidence for cardiac function in this group suggests an early improvement that is sustained during further follow-up. The best evidence of papers studying the PE repair using other techniques (modified Daniel's technique, modified Baronofsky's technique, sterno-costal turn-over technique and sterno-costal elevation technique) or where surgical techniques used were not described (preceding year 1985) suggests that there is no improvement in pulmonary function after surgery. There is some evidence that certain aspects of cardiac function improved after surgery in this group.

Pulmonary rehabilitation programme for patients undergoing curative lung cancer surgery.

OBJECTIVES: The aim of the study was to develop a multistranded pragmatic rehabilitation programme for operable lung cancer patients, that looks into feasibility, process indicators, outcome measures, local adaptability, compliance and potential cost benefit. METHODS: An outpatient-based complex intervention, rehabilitation for operated lung cancer (ROC) programme, was developed to optimize physical status, prepare for the inpatient journey and support through recovery after surgery. It includes exercise classes, smoking cessation, dietary advice and patient education and was tested in an enriched cohort study within a regional thoracic unit over 18 months. RESULTS: A multistranded pragmatic rehabilitation programme pre- and post-surgery is feasible. Fifty-eight patients received the intervention and 305 received standard care. Both groups were matched for age, lung function comorbidity and type of surgery. Patients in the intervention group attended exercise classes twice a week until surgery, which was not delayed. Patients attended four sessions presurgery (range 1-15), resulting in an improvement of 20 m (range -73-195, P = 0.001) in a 6-min walk test and 0.66 l in forced expiratory volume in 1 s (range -1.85 from 1.11, P = 0.009) from baseline to presurgery. Fifty-four percentage of smokers in the intervention group stopped smoking. Sixteen percentage of patients were identified as being at risk of malnourishment and received nutritional intervention. There was a trend in patients in the intervention group towards experiencing fewer postoperative pulmonary complications than those in the non-intervention group (9 vs 16%, respectively, P = 0.21) and fewer readmissions to hospital because of complications (5 vs 14% respectively, P = 0.12). CONCLUSION: Chronic obstructive pulmonary disease-type pulmonary rehabilitation before and after lung cancer surgery is viable, and preliminary results suggest improvement in physical measures. A multicentre, randomized controlled trial is warranted to confirm clinical efficacy. ISRCTN REGISTRATION NUMBER: ISRCTN00061628.

Thopaz Portable Suction Systems in Thoracic Surgery: an end user assessment and feedback in a tertiary unit.

BACKGROUND: Thoracic surgical patients have chest drains inserted to enable re-expansion of lungs, to clear contents from the pleural cavity which sometimes require negative suction. Suction impedes mobility, may have variable suction delivery and increases risk of infection. Assessment of air-leak in conventional drains is not scientific and is subjective. Thopaz chest drain system is a portable suction unit which allows mobilization of the patient, with scientific digital flow recordings and an in built alarm system. METHODS: We evaluated the utility, staff and patient feedback of this device in a pilot evaluation in a regional thoracic unit in a structured format over a period of two months. Staff responses were graded on a scale of 1 to 6 [1 Excellent to 6 Poor]. RESULTS: 120 patients who underwent elective bullectomy/pleurectomy, VATS lung biopsies, VATS metastectomy and lung resections were evaluated. The staff feedback forms were positive. The staff liked the system as it was more scientific and accurately recordable. It made nursing and physiotherapy easier as they could mobilise patients early. The patients liked the compact design, weightlessness and the silence. It enabled mobilisation of the patients and scientific removal of chest drain. CONCLUSIONS: Thopaz digital suction units were found to be user friendly and were liked by the staff and patients. The staff feedback stated the devices to be objective and scientific in making decisions about removal and enabled mobilisation.

Synthesis of dopamine transporter selective 3-[2-(diarylmethoxyethylidene)]-8-alkylaryl-8-azabicyclo[3.2.1]octanes.

A series of 3-[2-(diarylmethoxyethylidene)]-8-alkylaryl-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine and serotonin transporters. The 8-phenylpropyl analogues 8a (K(i)=4.1 nM) and 8b (K(i)=3.7 nM) were the most potent compounds of the series with binding affinities 3 times greater than GBR-12909. In addition, 8a (SERT/DAT=327) was over 300-fold more selective for the dopamine transporter than the serotonin transporter.

A distinctive electrocatalytic response from the cytochrome c peroxidase of nitrosomonas europaea.

Here the cytochrome c peroxidase (CcP) from Nitrosomonas europaea is examined using the technique of catalytic protein film voltammetry. Submonolayers of the bacterial diheme enzyme at a pyrolytic graphite edge electrode give catalytic, reductive signals in the presence of the substrate hydrogen peroxide. The resulting waveshapes indicate that CcP is bound non-covalently in a highly active configuration. The native enzyme has been shown to possess two heme groups of low and high potential (L and H, -260 and +450 mV versus hydrogen, respectively), and here we find that the catalytic waves of the N. europaea enzyme have a midpoint potential of >500 mV and a shape that corresponds to a 1-electron process. The signals increase in magnitude with hydrogen peroxide concentration, revealing Michaelis-Menten kinetics and K(m) = 55 microm. The midpoint potentials shift with substrate concentration, indicating the electrochemically active species observed in our data corresponds to a catalytic species. The potentials also shift with respect to pH, and the pH dependence is interpreted in terms of a two pK(a) model for proton binding. Together the data show that the electrochemistry of the N. europaea cytochrome c peroxidase is unlike other peroxidases studied to date, including other bacterial enzymes. This is discussed in terms of a catalytic model for the N. europaea enzyme and compared with other cytochrome c peroxidases.

Synthesis and dopamine transporter binding affinities of 3alpha-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes.

A series of 3alpha-benzyl-8-(diarylmethoxyethyl)-8-azabicyclo[3.2.1]octanes was synthesized and the binding affinities of the compounds were determined at the dopamine transporter. The unsubstituted analogue 7b (K(i)=98nM) was the most potent compound of the series with binding affinity three-times greater than cocaine and only 5-fold less than GBR-12909. The structure-activity data for 7a-f suggests that these compounds may be binding at the dopamine transporter in a similar fashion to GBR 12909.