text:
History of Hanworth
Hanworth is an urban and suburban London district on its south-west edge that is contiguous with Feltham, its post town and with Hampton. Historically in Middlesex, it now forms part of the London Borough of Hounslow. The name is thought to come from the Anglo Saxon words "haen/han" and "worth", meaning "small homestead"
During Edward the Confessor's time, Hanworth was a sparsely populated manor and parish held by Ulf, a "huscarl" of the King. Huscarls were the bodyguards of Scandinavian Kings and were often the only professional soldiers in the Kingdom. The majority of huscarls in the kingdom were killed at the Battle of Hastings in 1066, and William the Conqueror granted Hanworth to Robert under Roger de Montgomery, the Earl of Arundel and Shrewsbury. After his death, his second son held the land until his death in the Mowbray conspiracy of 1098, after which it passed to his eldest son, Robert de Bellesme, who also rebelled against the Crown in 1102 with the result that the lands were confiscated.
Towards the end of the 14th century, the manor was occupied by Sir Nicholas Brembre, who was Mayor of London in 1377 and 1378. Sir Nicholas was hanged at Tyburn in 1387, having been accused of treason.
In 1512 Hanworth came to the Crown, and Henry VIII, who enjoyed hunting on the heath surrounding the village, gave the manor to Anne Boleyn for life. After her execution, the manor returned to the King who held it until his death in 1547 but passing to Katherine Parr, who lived in the house with her stepdaughter Princess Elizabeth. When the princess became Queen, she stayed at Hanworth Manor several times, often hunting on the heath.
In 1784 General Sir William Roy, the military draughtsman, supervised the Principal Triangulation of Great Britain project. That measured a base line from King's Arbour, across Hounslow Heath passing through Hanworth Park, to Hampton Poor House. This measurement, which earned the General the Copley medal of the Royal Society, was the origin of all subsequent surveys of the United Kingdom, and still forms the basis of the Ordnance Survey maps today.
In 1797 the manor house was destroyed by fire, leaving only the stable block, which survives today as flats, and the coach house, which was converted into homes. Tudor House was built in 1875 as a replacement for the house that was built in the manor ruins, and is today used as flats.
By the end of the 19th century, William Whiteley, of Whiteleys in Bayswater, had bought 200 acres (0.81 km2) of farmland that had previously been Butts and Glebe farms. Renamed Hanworth Farms, these supplied all the produce for the store's food hall having been transported daily by horse and cart. Following Whiteley's murder by his illegitimate son in 1907, his legitimate sons sold the farm to a jam manufacturer who operated there until selling the land for new homes in 1933.
The Ambassador to Charles I, negotiating the secret treaty of 1631 with Spain, who had good knowledge of the country, was raised to the peerage as Baron Cottington of Hanworth, referring to his Hanworth Park estate, receiving the honour 'at Greenwich in a very solemn manner.' As the Civil War drew near he declared himself an active Royalist, and after hostilities had broken out he joined the king at Oxford. He was excepted by Parliament from 'indemnity and composition', and spent the remainder of his life abroad, dying in Spain in 1652. His estates were assigned in 1649 to John Bradshaw who had earlier insisted on Charles's execution and were recovered at the English Restoration by his nephew and heir Charles Cottington who sold it in 1670 to Sir Thomas Chamber. Chamber died in 1692 and was succeeded by his son Thomas. Thomas Chamber left two daughters and co-heiresses, and Hanworth passed, through agreement on marriage of the elder, to Vere Beauclerk, who was created Baron Vere, of Hanworth in 1750. The manor was inherited by his son and heir, Aubrey, in 1781, who succeeded his cousin as Duke of St. Albans six years later but who sold it shortly after 1802 to James Ramsey Cuthbert. Frederick John Cuthbert was lord of the manor in 1816 from whom it passed to Henry Perkins. After the death of his heir Algernon Perkins it passed to a firm of solicitors, and the main home was acquired in the early part of the next century by Court of Appeal judge turned politician Ernest Murray Pollock, 1st Viscount Hanworth.
Saint George's Church
Hanworth's main parish church is dedicated to Saint George. There has been a church on the site, in Castle Way, since at least the fourteenth century; the church was first mentioned in 1293. The first known rector was Adam de Brome, founder of Oriel College, Oxford, in 1309.
According to Daniel Lysons, vicar in 1800, the church was made of flint and stone, with a low wooden turret. As the church's living was in the hands of the lord of the manor, only the name of the rector was mentioned.
The original church included stained glass windows of the coats of arms of the Crosby family, who owned the manor in 1471; the Killigrew family, who owned the manor in the latter part of the sixteenth century; and the Royal arms of 1625, incorporating the royal cypher JR. The latter window was moved to the rectory after the church's reconstruction in 1808, before moving to its present site in the V&A in 1975. Monarchs and their consorts who are known to have worshipped here are King Henry VIII, Anne Boleyn, Catherine Parr and Queen Elizabeth I
Baron Cottington of Hanworth took a further interest in Saint George's church. He had his son Charles baptised here on 21 July 1628 in the presence of King Charles I, the Duke of Buckingham and Mary Feilding, wife of the Marquess of Hamilton. Cottington also gave the church a silver chalice and paten, which are still used today.
In 1807, it was decided that the entire church should be dismantled and rebuilt. The building of the new church was done by James Wyatt, a notable architect of the time. Wyatt only just lived to see it completed in 1812, as he was killed in a carriage accident the following year. His family are buried in the churchyard, but Wyatt himself lies in Westminster Abbey.
Saint George's assumed its current form in 1865, when a local architect, Algernon Perkins, volunteered to redesign the church at his own expense. The spire, added at about this time, was designed by S S Teulon.
The lychgate, which forms the main entrance to the church, was built in 1882. It is said to be a copy of the one in Beddington, South London, and was done in memory of the mother-in-law of John Lyndhurst Winslow, rector at the time.
Two of the owners of Hanworth Manor, Thomas Chamber and Aubrey Vere, are buried in the church. The former has a memorial tablet, which is now in the north transept, while the latter has a gravestone on the church floor.
All Saints Church
In 1935, Hanworth had a growing population, owing to the presence of a jam factory belonging to Whiteley's. It was decided that a chapel of ease should be set up. It was founded by Bertram Pollock, Bishop of Norwich, and the Rector of Saint George's. Bishop Pollock had been born at Woodlawn, a house in Hanworth, near Hampton Road West, and part of it was used as the chapel.
After the Second World War, in 1947, it was originally decided that a Nissen hut should be used to house the chapel. However, when the architect Nugent Cachemaille-Day was approached, he decided that a proper church should be built, and a site on the opposite side of Hampton Road West was chosen.
The Parish of All Saints was split off from Saint George's in 1950, and the foundation stone of the new church was laid on 14 July 1951 by the Bishop of Guildford, Henry Montgomery Campbell, in the presence of Lord Latham, Lord-Lieutenant of Middlesex. The church was finally consecrated on 28 September 1957 by Campbell, who by then was Bishop of London.
Hanworth Aerodrome
Hanworth Aerodrome was a grass airfield, operational 1917-1919 and 1929-1947. It was in Hanworth Park; that includes the grounds of Hanworth Park House, an 1802 rebuild of Hanworth Palace. In the 1930s, named London Air Park, it was best known as a centre for private flying, society events, the aircraft manufacturer General Aircraft Limited (GAL) 1934-1949, and the visit by the Graf Zeppelin airship in 1932. Amelia Earhart flew to Hanworth after landing in Ireland at the end of her 1932 crossing of the Atlantic; Walter Sickert recorded Miss Earhart's Arrival in a painting now owned by the Tate Gallery. There is a public house nearby named "The Airman" in recognition of its close proximity to the aerodrome. Feltham District Council purchased the park in 1956. Feltham Swimming Baths was built on parkland beside the Uxbridge Road in 1965, later refurbished and renamed Feltham Airparcs Leisure Centre. That public sports facility was renamed in 2010 as Hanworth Air Park Leisure Centre & Library.
The construction of an elevated M3 feeder road (now part of the A316) in the 1970s cut Hanworth in two; in preparation for this, the library was relocated to Mount Corner, so-named for being opposite the Hanworth Park House icehouse mound. Forge Lane Infants and Junior School was built on the south side of the new road, and the war memorial was relocated.
Sport and leisure
Hanworth has a Non-League football club Hanworth Villa F.C. who play at Rectory Meadow and play in county level leagues.
Hanworth Air Park is the home of Feltham Rugby Football Club, founded 1947.
Staines Rugby Football Club The Reeves play home games and train at a rugby ground in Snakey Lane.
Notable people
- Henry Killigrew (1613-1700), playwright and chaplain to James, Duke of York (the future king), was born in Hanworth.
- Edward Seymour, 1st Earl of Hertford (1539-1621) was in 1563 removed to Hanworth from the Tower of London, where he had been imprisoned on account of his marriage with Lady Catherine Grey.
- The Viscounts Hanworth, particularly the 1st Viscount, a former Court of Appeal judge, who established his family seat at Hanworth Park until his estate parted with it as liable to considerable inheritance tax.
- Bertram Pollock (1863-1943), Bishop of Norwich, was born in Hanworth.
information extracted and adapted from Wikipedia, the free Encyclopedia


text:
Correspondendo a: ha X
- Classificar por:
- Data
- Título
- Curtir/Votos ▼
- Comentários
- Visualizações
MQ on AWS: PoC of high availability using EFS
Arthur Barr Marcações: cloud efs ha aws amazon 2 Comentários 14.171 Visualizações
Amazon recently declared its Elastic File System (EFS) as ready for production. This enables a shared, networked file system, which (importantly) is replicated between multiple physical data centers (availability zones). On paper, this makes...Modificado em por Arthur Barr
What's the talk about in WebSphere Message Broker? (Part 2)
Gregory(Greg)Bowman Marcações: availability encoding wmq ha websphere db mq migrate message install migration services installation xml broker wmb web ssl migrating certificate database high 10.906 Visualizações
I wrote a blog article a while ago entitled " What's the talk about in WebSphere Message Broker? " Several months have passed and now people are discussing some different topics in WebSphere Message Broker (WMB) support. So I thought it was time to...
High Availability for Tivoli's process automation engine based products Blog da Comunidade
Are you interested in solutions that handle high availability for unplanned outages considering all the components of your Tivoli's process automation engine (Tpae) based product? The white paper "Providing High Availability for Tivoli Process...
do Blog: Process Automation
High Availability - Cold, Warm, Hot
RohitShetty Marcações: tsa tivoli hacmp bluemix maximo tnpm cloud tpm ibm tbsm bsm db2 saas tsamp rohit shetty smc samp ha veritas 1 Comentário 64.937 Visualizações
Clustering is the most common technique to achieve High availability for any services by introducing redundancy in software, hardware and data. In a failure the clustering software immediately start the application on the standby system without requiring...Modificado em por RohitShetty
Differentiation: High Availability, Continuous Operations and Continuous Availabiility
RohitShetty Marcações: cloud smc tsa bluemix veritas saas samp tsamp db2 tpm maximo shetty tbsm tivoli hacmp ha tnpm ibm bsm rohit 11.952 Visualizações
Continuous Availability (CA) - Attribute of a system to deliver non disruptive service to the end user 7 days a week, 24 HOURS A DAY (there are no planned or unplanned outages). Continuous Operations (CO) - Attribute of a system to...Modificado em por RohitShetty
High Availability: Planning Redundancy
RohitShetty Marcações: maximo veritas rohit shetty tpm bsm ibm smc ha tsamp cloud tivoli bluemix samp hacmp tnpm tsa db2 saas tbsm 10.014 Visualizações
People are generally confused about the level of redundancy they need to provide while designing a HA solution. The cardinality of the primary to secondary components can be described in the following way and this decides the deployment topology of the various...Modificado em por RohitShetty
High Availability with SAMP
RohitShetty Marcações: tbsm cloud rohit smc bsm ibm maximo veritas tnpm tsamp db2 tpm tivoli hacmp ha saas bluemix tsa shetty samp 1 Comentário 8.690 Visualizações
On demand businesses require high availability and SAMP (Tivoli System Automation for Multi platforms) addresses pain points such as: Application availability Complexity and operations costs Automation implementation and maintenance costs Education...Modificado em por RohitShetty
Resilient network performance monitoring with IBM Tivoli Netcool Performance Manager Blog da Comunidade
A new article has been published at Resilient Network Performance Monitoring with Tivoli Netcool Performance Manager - Wireless Component . This paper explores using IBM® Tivoli® System Automation for Multiplatforms (SA MP) as a clustering solution for...
do Blog: Network and Service Assurance
RedBook: High Availability and Disaster Recovery Configurations for Maximo Blog da Comunidade
Dan_McConomy Marcações: sccd maximo dr ibmeam redbook tpae availability ha 8.490 Visualizações
Interested in HA and DR configuration with SCCD and Maximo? A new RedBook draft is now available for download. In today's global environment, more and more organizations need to reduce their downtime to the minimum possible and look for continuous...
do Blog: Asset Management
Proof of concept: MQ High availability using Ceph block storage
In Arthur's previous proof of concept , he set up an auto scaling group using Amazon's Elastic File System (EFS) to provide a High Availability and Disaster recovery solution for IBM MQ. In this proof...Modificado em por RobParker
How to enable HDFS federation high availability in IBM Spectrum Symphony Blog da Comunidade
7S62_hui_liu Marcações: mapreduce ha hdfs 642 Visualizações
HDFS federation provides MapReduce with the ability to start multiple HDFS namespaces in the cluster, monitor their health, and fail over in case of daemon or host failure. With HDFS High Availabilty (HA), when a NameNode or Secondary NameNode fails, the...
do Blog: IBM Spectrum SymphonyModificado em por Sheryl_M
OMNIbus ObjectServer updates without any probe downtime Blog da Comunidade
renatebahnemann Marcações: objectserver schema netcool ha failover failback omnibus fixpack probes 2.801 Visualizações
It is now possible to change the schema of a live ObjectServer without disrupting the probes that are connected to it. This capability is automatically supported in probes running on an installation of IBM Tivoli Netcool/OMNIbus 8.1 Fix Pack 8 or a later...
do Blog: Network and Service AssuranceModificado em por renatebahnemann
Fault tolerance Vs High availability
RohitShetty Marcações: tsamp veritas ibm saas tsa ha tivoli tbsm bsm samp tnpm bluemix maximo cloud shetty db2 tpm hacmp rohit smc 15.467 Visualizações
Fault tolerance relies on specialized hardware to detect a hardware fault and instantaneously switch to a redundant hardware component whether the failed component is a processor, memory board, power supply, I/O subsystem, or storage subsystem. The fault...Modificado em por RohitShetty
TSA Blog Series: High Availability Concepts - Do I need a TieBreaker?" Blog da Comunidade
Gareth Holl Marcações: db2 samp tsa tiebreaker tsamp ha quorum 2 Comentários 8.512 Visualizações
A Network TieBreaker is a popular configuration option for a Tivoli System Automation for Multiplatforms (TSA MP) managed environment. But what is a TieBreaker and why is it needed ? To understand the what and why, you first need to understand the concept of...
do Blog: Data Center AutomationModificado em por Gareth Holl
FAQ: High Availabilty using Multi-Instance Message Broker
nsrao Marcações: queue mi wmb availability websphere ha multi-instance broker manager faq wmq high 13.114 Visualizações
The introduction of the multi-instance(MI) concept into the Websphere MQ and WebSphere Message Broker products helped several clients to make use of this freely available high availability feature in their infrastructure. The earlier cat 2 HA support packs...

subset: commoncrawl


text:
Slide to see the images
Gorgeous male merle Mini Australian Shepherd pup. Has been raised in the country with lots of children and room to run. Also raised around horses. Mother is a black tri. Father is a blue merle. MASCA registered. Black tri male, one blue merle boy with blue eyes, and one blue merle boy with dark eyes available in the litter. Black tri pups are $450. Blue Merle pups are $500. Pups come with MASCA registration papers, up to date shots and deworming, and a 48 hour health guarantee. We are located in Arthur,Il Deposits to hold a pup are $150 and are collected through paypal. Call or email now to pick out your favorite pup.


text:
Discussion BoardsOpen MenuDiscussion Boards Open Menu
BlogsOpen MenuBlogs Open MenuHP Notebook Battery Recall and ReplacementOpen MenuHP Notebook Battery Recall and Replacement Open Menu
In cooperation with various government regulatory agencies, HP has announced an expansion of its June 2016 worldwide voluntary safety recall and replacement program for certain notebook batteries. Additional batteries are affected.
- HP Support Forum Home
- >
- Notebooks
- >
- OS/Recovery
- >
- HP Pavilion dv4 1131tx Windows 8.1 unable to play dvd but ab...
- Subscribe
- Mark Topic as New
- Mark Topic as Read
- Float this Topic for Current User
- Bookmark
- Subscribe
- Printer Friendly Page
HP Pavilion dv4 1131tx Windows 8.1 unable to play dvd but able to play CDs
- Mark as New
- Bookmark
- Subscribe
- Subscribe to RSS Feed
- Highlight
- Email to a Friend
- Report Inappropriate Content
Hey guys,
Background Info:
I am using HP Pavilion dv4 1131tx, the factory default came with Windows Vista 32 bits, currently running on Windows 8, 64 bits.
I am able to play CDs but I am unable to play DVDs with the inbuilt PIONEER DVD-RW DVRTD08 ATA Device, despite installing HP MediaSmart DVD, VLC players and the what not. When I put in a DVD it will spin very fast and make a lot of noise and I won't be able to get the disc out, unless I manually force stop it by ejecting the whole disc drive, put it back in and swiftly press the eject button before it boots the DVD. Help please!
Here are the things I have tried but doesn't work:
1. http://support.microsoft.com/kb/314060/en-us
2. I have upgrade it to Windows 7 Professional and now Windows 8.1 Professional, the problem persist.
Re: HP Pavilion dv4 1131tx Windows 8.1 unable to play dvd but able to play CDs[ Edited ]
- Mark as New
- Bookmark
- Subscribe
- Subscribe to RSS Feed
- Highlight
- Email to a Friend
- Report Inappropriate Content
06-27-2014 09:08 AM - last edited on 03-07-2017 11:50 AM by OscarFuentes
Hi ZiKai,
Welcome to the HP Forums!
I would like to take a moment and thank you for using the forum, it is a great place to find answers. For you to have the best experience in the HP forum, I would like to direct your attention to the HP Forums Guide First Time Here? Learn How to Post and More.
I regret that you are no longer able to play DVD's.
I see you have tried the Windows troubleshooter with no success. I checked the Pioneer site for a driver and Windows 8 and they do not offer on either.
Unfortunately, it appears that it is not totally compatible with Windows 8. The Windows driver gave you partial functionality but not all.
Have you tried installing the original driver? I do not know if it will work but it does not hurt to try.
Here is a link to Availability of Software and Drivers for Vista. Please note the section on "Reinstall original drivers to get the hardware devices working"
Good Luck!
- HP PCs - How to Change or Reset Password (Windows 10)
- Downloading or Updating Software and Drivers for HP Computers
- HP PCs - Sleep and Hibernate Issues (Windows 10, 8)
- HP PCs - How to Reset Your Computer to Factory Settings (Windows 10, 8, 7)
- HP PCs - Updating Drivers and Software with Windows Update (Windows 10, 8)


text:
Different Allergies to Flowers
Posted on May 27 2012 at 05:43:40 PM in Diseases
Allergies come in all varieties. When we think of allergies to flowers the first group of symptoms we think of is Hayfever with sneezing and watery eyes. These symptoms can be very distressing. Usually when the flower is removed the symptoms gradually subside. Flowers that can affect people are jonquils and daffodils. I love these plants but some members of my family have a strong aversion to them. Buddleia or Butterfly bush, so named because it attracts butterflies can also cause hayfever.
Hayfever is not the only symptom to flowers. Some people have difficulty breathing when near certain plants. This is not necessarily the flower of the plant but the plant or bush itself. Strongly aromatic plants can affect the breathing resulting in asthmatic symptoms for example, wormwood or rosemary.
Some plants will give some people a rash if they are touched. Rhus and Zinnia and Canterbury Bells and Tomatoes are examples of these. If a person reacts to a plant they can react in more than one way at the same time. Their breathing may be affected and they may get a rash at the same time. Or Asthma and Hayfever may come together.
A little known symptoms of reactions to flowers is arthritic like pain. I have experienced this myself. one day I picked a pretty mauve Lilac flower and brought it inside so that I could enjoy its beauty. Within half an hour I experienced severe pains in my arms and legs. These pains were so bad that they put me in bed for three days. When I surfaced and came back to the room with the flowers, they were nearly dead so I threw them out. The pains in my body disappeared.
At the time I made no connection but the pains had been so bad that something like that stays in your memory. Some weeks later I picked another Lilac flower and again brought it inside. When the pains started again I wracked my brain for when this had happened before and remembered the connection with the Lilac flower. Many years later, having forgotten the previous experiences, I did the same and was quickly reminded of my reaction to the beautiful Lilac bush from the pains that began shooting through my limbs.
So if you have arthritic pains that come and go with the seasons, look around your garden and see if there is something flowering there that may be affecting you. If you could have it removed from the garden your pains might go away.
For more information about allergies go to www.allergiesandcfs.com


text:
Keep your hamster busy for hours with this Zhu Zhu Pets Add On Playset Y-Intersection. Your hamster will have a split second to decide whether to go left or right, which way will it go?
This Y-Intersection acts as a toll gate where hamsters have to wait to enter or exit the tunnel. This is a great addition to your hamster world. (Jemma Stockton)
Please Note: Unfortunately the hamster is not included.
|Character Series:
Please remember to add postal time (2-3 working days) to obtain a complete estimate of delivery to your door.
You will receive an email to confirm when your item has been sent.
You can also check the status of your order and individual items by accessing My Account details and following the prompts.
Please allow 10 working days from dispatch of your order before notifying us of any late deliveries.
It may be advisable to check with your neighbours to see if a parcel has been left with them, check any outhouses you might have where it may be left if it cannot fit through your letterbox and contact your local sorting office to see if the item has been returned to the depot as undelivered and awaiting collection.
Please see our returns policy.
There are currently no reviews.


text:
Normal activity of neurons within the medullary ventral respiratory column (VRC) in or near the pre-Bötzinger Complex (preBötC) is dependent on the balance of inhibitory and excitatory neuromodulators acting at their respective receptors. The role of cholinergic neuromodulation during awake and sleep states is unknown. Accordingly, our objective herein was to test the hypotheses that attenuation of cholinergic modulation of VRC/preBötC neurons in vivo with atropine would: 1) decrease breathing frequency more while awake than during non-rapid-eye-movement (NREM) sleep and 2) increase other excitatory neuromodulators. To test these hypotheses, we unilaterally dialyzed mock cerebrospinal fluid (mCSF) or 50 mM atropine in mCSF in or near the preBötC region of adult goats during the awake (n = 9) and NREM sleep (n = 7) states. Breathing was monitored, and effluent dialysate was collected for analysis of multiple neurochemicals. Compared with dialysis of mCSF alone, atropine increased (P < 0.05) breathing frequency while awake during the day [+10 breaths (br)/min] and at night (+9 br/min) and, to a lesser extent, during NREM sleep (+5 br/min). Atropine increased (P < 0.05) effluent concentrations of serotonin (5-HT), substance P (SP), and glycine during the day and at night. When atropine was dialyzed in one preBötC and mCSF in the contralateral preBötC, 5-HT and SP increased only at the site of atropine dialysis. We conclude: 1) attenuation of a single neuromodulator results in local changes in other neuromodulators that affect ventilatory control, 2) effects of perturbations of cholinergic neuromodulation on breathing are state-dependent, and 3) interpretation of perturbations in vivo requires consideration of direct and indirect effects.
- neuromodulators
- control of breathing
- acetylcholine
- non-rapid-eye-movement sleep
the neuromodulator acetylcholine (ACh) is involved in a variety of central and peripheral neural circuits, including the control of breathing and sleep (7, 12, 16, 19, 25, 39). The effects of ACh are mediated through either nicotinic or muscarinic receptors coupled to second messenger pathways (6, 10, 13, 42). There are five known muscarinic ACh receptor (mAChR) subtypes (M1 to M5) expressed in the brain stem, differing in expression profiles and in effects on breathing (2, 9, 11, 13, 33, 34). For example, the pontine respiratory group (PRG) nuclei express M1-M3 mAChRs (34). The predominant effect of cholinergic modulation of PRG neurons within the Kölliker-Fuse Nucleus (KFN) appears to be excitatory, since reverse dialysis of the nonselective mAChR antagonist atropine reduced minute ventilation (V̇I) and breathing frequency in both the awake state and during non-rapid-eye-movement (NREM) sleep at night, but not while awake during the day in unanesthetized goats (8). These effects were specific to the KFN, since breathing was not decreased during atropine dialysis in three other rostral pontine nuclei. Atropine also decreased concentrations of ACh and choline in effluent dialysate collected from the KFN and other pontine nuclei. These data suggest a role for the KFN in the control of breathing, particularly in the regulation of breathing frequency, at night through a cholinergic mechanism.
Data from multiple studies suggest an important role for mAChRs in intracranial chemosensitivity, upper airway respiratory motoneuron activity, and respiratory rhythm generation. For example, in anesthetized cats, atropine or a M1-specific receptor antagonist applied to the ventral lateral medulla decreases baseline phrenic nerve activity and the phrenic response to hypercapnia (39, 41). Likewise, based on data from carbachol-induced rapid-eye-movement (REM) sleep and in vitro studies, it has been hypothesized that direct and indirect excitatory M2 receptor modulation of hypoglossal motoneurons maintains a patent upper airway during REM sleep (4, 5). Furthermore, strong support for a role for mAChRs in respiratory rhythmogenesis comes from studies using a medullary slice preparation from neonatal rats that found that local application of ACh excites 88% of inspiratory neurons within the pre-Bötzinger Complex (preBötC), a site critical for respiratory rhythm generation in some (55, 57), but not all (51, 53), studies. These preBötC responses to ACh were blocked by atropine and by specific blockers of M3 receptors, but not by specific blockers of M1, M2, or M5 receptors, leading to the conclusion that ACh is excitatory to preBötC neurons (45, 46), likely through the activation of postsynaptic M3 receptors.
Because of a lack of information on the topic, the goal of the present study was to determine the effects on breathing and effluent neurochemical concentrations of reverse dialysis of atropine in or near the preBötC region in awake and sleeping adult goats. Studies were done in both the awake state and during natural NREM sleep to determine whether the effects of atropine were state-dependent. Given the importance of the preBötC region to respiratory rhythmogenesis (48, 49, 55, 57) and evidence for an excitatory role of mAChRs in respiratory control (4, 5, 45, 47), we hypothesized that dialysis of atropine in the preBötC region will decrease V̇I secondary to a decrease in breathing frequency. In addition, because there is evidence of a withdrawal of excitatory input to respiratory centers and a reduction in respiratory output during sleep (5), we further hypothesized that atropine dialysis will attenuate breathing more in the awake state than during NREM sleep. Finally, because there is evidence that attenuation of one excitatory neuromodulator will be compensated by an increase in other excitatory neuromodulators (18), we postulated that dialysis of atropine would result in an increase in multiple excitatory neurochemicals, such as serotonin (5-HT) and substance P (SP), in the effluent dialysate.
A total of 12 adult, nonpregnant female goats weighing 44.4 ± 1.8 kg were studied. Goats were housed and studied in an environmental chamber with a fixed ambient temperature and 12:12-h light-dark cycle (lights on 7:00 A.M.). All goats were allowed ad libitum access to food and water except during study periods and during a 24-h fasting period before surgery. All aspects of the study were reviewed and approved by the Medical College of Wisconsin Animal Care Committee before studies were initiated.
Surgical procedures.
Before all surgical procedures, goats were anesthetized with ketamine (5.0 ml iv), intubated, and mechanically ventilated with 2% isoflurane in 100% oxygen. The nonsteroidal anti-inflammatory analgesic flunixin meglumine (Banamine, 1 mg/kg im) was administered one time before every surgery. Rectal body temperature (Tr), heart rate, and blood oxygen saturation were continuously monitored throughout and immediately after each surgery. To minimize infection, ceftiofur sodium (Naxcel, 4 mg/kg im) was administered daily, and all surgical sites were treated daily with triple antibiotic for ≥7 days postoperatively. Buprenorphine hydrochloride (Buprenex, 0.005 mg/kg im) was administered two times daily for 2 days postoperatively to alleviate pain following all surgeries.
Two surgeries were performed, each under sterile conditions. In the initial surgery, electroencephalogram (EEG) and electrooculogram (EOG) electrodes were implanted in the midline cranium and superior orbital ridge, respectively, to monitor and score sleep state, as previously described (21, 28). After ≥1 wk of recovery, goats underwent a second surgery for chronic bilateral (n = 11) or unilateral (n = 1) implantation of stainless steel microtubules (MTs, 70 mm length, 1.27 mm outer diameter, 0.84 mm inner diameter) in the preBötC region of the medulla (29, 57). An occipital craniotomy was created, the dura mater excised, and the posterior cerebellum and dorsal medulla exposed for visualization of obex. As in previous studies (29, 57), the target site for implanting MTs was 2.5–3.5 mm rostral to obex, 4.0–5.0 mm lateral to midline, and 4.0–6.0 mm from the dorsal surface of the medulla (ventral to nucleus ambiguous). However, in some goats, the site of implantation had to be adjusted to avoid blood vessels on the dorsal medullary surface. After implantation, the MTs were permanently secured with dental acrylic, and the skin incisions were sutured closed. Stainless steel stylets of the same length as the MTs were inserted in the MTs such that they did not penetrate the tissue and were removed only during study periods. Postoperative monitoring and medications were administered as previously described (29, 57).
Physiological variables.
Goats were trained to become accustomed to the equipment used in dialysis studies and given a minimum of 2 wk to recover from the second surgery before beginning studies. For all studies, a custom-made mask was secured to the goat's muzzle, to which was attached a one-way breathing valve connected to inspiratory and expiratory tubing. Ventilatory variables, inspiratory flow (l/min, V̇I), breathing frequency [breaths (br)/min, f], and tidal volume (l/br, VT), were measured with a pneumotachograph attached in series to the inspiratory side of the breathing valve. Expired air was collected at regular intervals in a spirometer (day studies only) for determination of the expired volume and carbon dioxide and oxygen concentrations, allowing for calculation of oxygen consumption (V̇o2, l/min) and carbon dioxide excretion (V̇co2, l/min). During night studies, EEG and EOG activity was recorded for subsequent analysis of sleep state. Tr was measured at regular intervals by insertion of a thermocouple in the rectum. Ventilatory data were continuously recorded using a Windaq data acquisition system and later analyzed.
In vivo dialysis.
Dialysis probes (Harvard Apparatus, formerly CMA Microdialysis, Holliston, MA) were 72 mm in total length, consisting of a 70-mm shaft and a 2-mm membrane (0.5 mm membrane diameter, 20 kDa cut-off, 3 μl internal volume). Probes were inserted through the MTs such that only the membrane penetrated the tissue. The perfusate was either mock cerebrospinal fluid (mCSF: 124 mM NaCl, 2.0 mM KCl, 2.0 mM MgCl2, 1.3 mM K2PO4, 2.0 mM CaCl2, 11 mM glucose, 26 mM NaHCO3−, and pH 7.32 in sterile distilled H2O) alone or atropine (50 mM; Sigma) dissolved in mCSF. Previous in vitro studies in the laboratory have established that atropine crosses the membrane (8). Dialyzed solutions were warmed to 39°C and equilibrated with 6.4% CO2 and 21% O2 balanced with N2 in a tonometer. The syringe pump (Harvard Apparatus) used for delivery of solutions to the probe was outside the animal chamber. Thus, a 150- or 180-cm length of polypropylene tubing was needed to connect the pump to the probe, resulting in an approximate delay of 20 min between the start of the pump and when fresh perfusate reached the probe. Effluent dialysate was collected in modified cryotubes, separated into aliquots, and then frozen at −80°C for subsequent analyses.
Thirty minutes after probe insertion, control data were collected for 30 min followed by three consecutive 1-h dialysis periods (flow rate 25 μl/min) in order: 1) mCSF alone, 2) either mCSF alone or with atropine, and 3) mCSF alone. Effluent dialysate was continuously collected in each hour in separate vials.
Three groups of studies were completed. In group 1 time control studies, mCSF was unilaterally dialyzed in each of the three dialysis periods during the day (goats 1–7; Fig. 1). Group 2 studies differed from group 1 only in that atropine was dialyzed in hour 2 (goats 4–12 during the day and goats 4–10 during the night; Fig. 1). Duplicate dialysis studies (one on each side) were done in three group 1 goats, five group 2 goats during the day, and three group 2 goats during the night. In group 3 studies (goat 10; Fig. 1), mCSF was dialyzed during the day for three consecutive hours on one side while on the contralateral side, mCSF was dialyzed during hours 1 and 3, and atropine was dialyzed during hour 2. Four days later, the study was repeated with the side receiving either mCSF or atropine reversed. The maximum number of probe insertions in the majority of goats was four.
Daytime dialysis studies were completed within the hours of 9:00 A.M. to 2:00 P.M., and night studies were completed within the hours of 8:00 P.M. to 1:00 A.M. There was a minimum of 36 h between all consecutive studies.
mCSF and glutamate receptor agonist injections.
Administration of glutamate receptor agonists to the preBötC elicits a tachypneic ventilatory response (29, 36, 50, 57). Thus, as in past studies, we used injections of a glutamate receptor agonist as physiological evidence that MT placement approximated the preBötC region (29, 57). Breathing was continuously measured over 2 h, and, at 30-min intervals, mCSF or N-methyl-d-aspartic acid (NMDA, 100 mM) was injected (500 nl) in the MTs.
Neurochemical analyses.
Glycine (GLY) and γ-aminobutyric acid (GABA) were measured by reverse-phase high-performance liquid chromatography with fluorescent detection using the following parameters: Waters Resolve C18 column (150 × 3.9), a fluorescent detector with excitation at 229 nm and emission at 470 nm, β-alanine internal standard, and o-phthaldialdehyde derivitization. For detection and measurement of 5-HT, electrochemical detection with the same type of column was used, but with a potential setting of 0.6 volts vs. Ag/AgCl reference electrode and a N-methylserotonin internal standard. Measurement of epinephrine (Epi) and dopamine (DA) was accomplished by using a Waters μBondapak C18 column (300 × 3.9), potential setting of 0.65 volts vs. Ag/AgCl reference electrode, and a 2,5-dihydroxybenzylamine hydrobromide internal standard. A commercially available immunoassay (Assay Designs 900–018, range 9.76–10,000 pg/ml) was used to measure SP via a microplate reader at 405 nm. The ACh/choline analysis was performed using a Bioanalytical Systems analytical column utilizing a polymer packing coupled in series with a postcolumn immobilized enzyme reactor and potential setting of 0.5 volts vs. Ag/AgCl.
Data and statistical analysis.
V̇I, f, VT, and, in the case for night studies, EEG and EOG signals, were analyzed on a breath-by-breath basis. For each study, the inspiratory flow signal was calibrated against known air flow rates. For night studies, EEG and EOG signals were used to visually categorize each breath as being in either the awake, REM sleep, or NREM sleep states.
Breath-by-breath values of ventilatory variables were averaged into 1-, 5-, and 15-min bins and expressed as raw values for statistical analyses and graphical presentation. Analysis of each bin size led to the same general conclusions, and, thus, the 15-min bin size is presented herein (means ± SE). In four goats, data obtained on separate days in the left and right preBötC were analyzed by two-way repeated-measures (RM) ANOVA. Because no significant differences (P > 0.05) were found, data were averaged for each goat. For group 1 and 2 studies, a one-way RM ANOVA was used to determine whether changes in breathing occurred within each of the 210-min protocols. A two-way ANOVA (time and treatment as factors, Holm-Sidak post hoc, when appropriate) was used to compare the effects on breathing of mCSF or atropine dialysis. A two-way RM ANOVA (Holm-Sidak post hoc, when appropriate) was used to compare the effects on breathing of time of day (time and time of day as factors) and the effects of sleep state (time and sleep state as factors). Similarly, a two-way RM ANOVA (time and treatment as factors, Holm-Sidak post hoc, when appropriate) was used to determine whether there was a difference in time spent in the awake state and time spent in NREM sleep in night studies, and a one-way RM ANOVA was used to determine whether atropine dialysis affected time in each state.
Neurochemical values of dialysate concentrations of 5-HT, SP, GLY, GABA, Epi, and DA obtained from measurements from duplicate studies for any goat were averaged. In group 1 and 2 studies, a one-way RM ANOVA was used to determine whether significant changes in neurochemicals occurred within the 3 h of dialysis. A two-way ANOVA (Holm-Sidak post hoc, when appropriate) was used to compare the effects on effluent neurochemicals of mCSF or atropine dialysis (time and treatment as factors). A two-way RM ANOVA (Holm-Sidak post hoc, when appropriate) was used to compare the effects of time of day (time and time of day as factors) on effluent neurochemicals. Paired t-tests were used to determine if there were differences in neurochemicals in hour 1 between day and night studies in four group 2 goats. Because of a limited number of samples for analysis of ACh and choline, values from day and night dialysis studies were combined and averaged for each animal. A one-way RM ANOVA was used to determine whether significant changes in ACh/choline occurred within the 3 h of dialysis. Finally, paired t-tests were used to determine the effects of mCSF and atropine dialysis on Tr.
Histological analysis.
Upon completion of the protocol, goats were anesthetized with ketamine (2.3 ml iv), circulation to the head was isolated, and the goat was killed (B-euthanasia, 10 ml iv). The head was perfused with PBS, followed by 4% paraformaldehyde in PBS. The brain stem was extracted for processing as previously described (29). Nissl-stained 4,000 dots/inch-scanned images of the entire MT tract were captured (Nikon Super Coolscan 9000). Image software (Metamorph) was used to calibrate and measure MT placement in millimeters (relative to midline and the ventral medullary surface) near the middle of the rostral-caudal MT damage range.
Histological and physiological evidence of MT placements.
Our previous studies on goats provided evidence that the preBötC in goats extends from ∼2.5 to 3.5 mm rostral to obex, 4.0–5.0 mm lateral to the midline, and ventral to the nucleus ambiguous (29, 57). For the goats studied herein, histological studies indicated that the center of the distal tip of the implanted MTs was within this range (Fig. 1). Regarding the physiological marker of the preBötC, there were variable degrees of increased breathing after injection of a glutamate receptor agonist (NMDA, 100 mM, 500 nl) at the distal end of the MT (see inset in Fig. 1). The sites of greater NMDA responses corresponded in proximity to the preBötC. For example, for goat 11 left side and goat 12 right side, the MTs were placed relatively caudal and medial, respectively, to preBötC, and there was a low response to NMDA (Fig. 1). On the other hand, for goat 11 right side and goat 12 left side, the MT placements were in the preBötC region, and there was a substantial response to the NMDA injection. There was no significant (P > 0.10) change in breathing when mCSF was injected. Even though the histological and physiological data for each goat did not indicate identical placements of the left and right MTs, we averaged the responses to atropine dialysis in the right and left sides to obtain a single response for each goat, and these values were used for statistical analyses and graphical presentation of the data.
Effects of atropine on ventilatory variables.
As determined by a one-way RM ANOVA, unilateral dialysis of mCSF in the preBötC for three consecutive hours during the day (group 1, time control) did not affect V̇I (F = 1.53, P = 0.124), but there was a significant increase in f (F = 7.05, P < 0.001) and a decrease in VT (F = 2.593, P = 0.005; Fig. 2). These changes may reflect normal physiological variation over time and/or an effect of washout of endogenous neurochemicals.
When atropine was dialyzed during hour 2, V̇I was significantly elevated (+1.0–1.8 l/min) over the last 15 min of atropine dialysis and throughout hour 3 (Fig. 2A). The increase was compared with the predialysis control period (F = 6.94, P < 0.001, 1-way RM ANOVA) and with the time control study (F = 28.9, P < 0.001, 2-way ANOVA). Similarly, over the last 15 min of atropine dialysis and throughout hour 3, f was significantly elevated (+10 br/min) compared with the predialysis control (F = 10.737, P < 0.001, 1-way RM ANOVA) and compared with the time control study (F = 28.9, P < 0.001, 2-way ANOVA; Fig. 2B). VT decreased significantly during atropine dialysis compared with the predialysis control (F = 2.17, P = 0.016, 1-way RM ANOVA). VT tended to be lower throughout the protocol when atropine was dialyzed during hour 2 compared with time control studies, but this was not significant (F = 3.36, P = 0.068, 2-way ANOVA; Fig. 2C).
During dialysis of atropine at night in the awake state, V̇I was significantly increased (+1.7 l/min, F = 2.13, P = 0.021, 1-way RM ANOVA; Fig. 3A), but there was no significant (F = 3.27, P = 0.121) difference in V̇I in the awake state between day and night atropine studies (2-way RM ANOVA). Atropine dialysis at night in the awake state significantly increased f (+9 br/min, F = 5.01, P < 0.001, 1-way RM ANOVA; Fig. 3B), but there was no significant difference in f in the awake state between day and night atropine dialysis studies (F = 1.522, P = 0.263, 2-way RM ANOVA). At night in the awake state, atropine dialysis did not affect VT significantly (F = 0.538, P = 0.89, 1-way RM ANOVA; Fig. 3C), and there was no significant difference in VT between day and night studies in the awake state (F = 0.002, P = 0.969, 2-way RM ANOVA).
During NREM sleep at night, V̇I was not significantly affected by atropine dialysis (F = 1.207, P = 0.294, 1-way RM ANOVA). Compared with atropine dialysis in the awake state at night, V̇I was significantly lower during NREM sleep (F = 14.48, P = 0.009, 2-way RM ANOVA; Fig. 3A). Atropine dialysis during NREM sleep significantly increased f (F = 4.53, P < 0.001, 1-way RM ANOVA). However, during atropine dialysis studies, f during NREM was significantly lower (F = 16.9, P = 0.006, 2-way RM ANOVA) compared with the awake state at night (Fig. 3B). During NREM sleep, atropine dialysis did not significantly affect VT (F = 1.05, P = 0.42, 1-way RM ANOVA). VT was significantly lower during NREM sleep compared with the awake state at night (F = 7.3, P = 0.035, 2-way RM ANOVA; Fig. 3C).
During the night studies, significantly more time was spent in the awake state than during NREM sleep (F = 25.93, P = 0.002, 2-way RM ANOVA, data not shown). There were no significant effects of atropine dialysis on time spent in either the awake (F = 2.07, P = 0.168) or NREM (F = 1.50, P = 0.26) sleep states (1-way RM ANOVA). In the hour before, during, and after atropine dialysis, the average values for time spent in the awake state ranged between 64 and 76% of total time, whereas average values for time spent in NREM sleep ranged between 21 and 33% of total time. These values are in agreement with previously published data on goats (35). However, in past studies (35) on goats, about 10% of total time was spent in REM sleep, whereas herein only two of seven goats showed periods of REM sleep of any duration. The abnormally low REM sleep time was observed throughout the 3-h protocol and was not unique to the period of atropine dialysis; thus, it appears dialysis per se, and not atropine, reduced time in REM sleep.
Effects of atropine on neurochemicals in effluent mCSF.
Dialysis of mCSF alone in time control studies during the day had no significant effect on effluent concentrations of 5-HT, SP, GLY, GABA, Epi, or DA throughout all three study hours (P > 0.05; Fig. 4), as determined by one-way RM ANOVA. In addition, there were no significant differences (P > 0.05) in hour 1 values for 5-HT, SP, GLY, or GABA between atropine dialysis studies done in the day and atropine dialysis studies done at night (n = 4, data not shown), as determined by paired t-tests.
Dialysis of atropine during the day significantly increased the effluent dialysate concentrations of 5-HT (F = 15.99, P < 0.001), SP (F = 530.239, P < 0.001), and GLY (F = 13.7, P < 0.001; Fig. 4, A–C, respectively), as determined by one-way RM ANOVA. These neurochemicals were elevated during atropine dialysis (hour 2) and remained elevated during hour 3. Dialysis of atropine during the day had no significant effect (P > 0.05) on effluent GABA, Epi, or DA concentrations, as determined by one-way RM ANOVA (Fig. 4, D–F, respectively). However, GABA concentrations were significantly (F = 11.254, P = 0.002) higher during and after atropine dialysis (Fig. 4D) compared with time control studies, as determined by two-way ANOVA.
Dialysis of atropine at night significantly increased 5-HT (F = 7.37, P = 0.009), SP (F = 90.04, P < 0.001), and GLY (F = 4.418, P = 0.042) but did not significantly (P > 0.05) increase GABA, Epi, or DA in the effluent dialysate (Fig. 5), as determined by one-way RM ANOVA. The effect of atropine dialysis on any measured neurochemical did not differ between day and night studies (P > 0.05), as determined by two-way RM ANOVA (Fig. 5).
Dialysis of atropine did not affect the concentrations of either ACh (F = 1.250, P = 0.337) or choline (F = 1.244, P = 0.338) when data from day and night dialysis studies were combined (1-way RM ANOVA, data not shown).
Local vs. global effects of atropine dialysis on neurochemicals.
In group 3 studies, during dialysis of atropine, effluent 5-HT concentrations were 6.16 and 5.31 nM on the left and right sides, respectively, but, in the contralateral side that received only mCSF, 5-HT was nondetectable (data not shown). Similarly, SP concentrations were 2,199.7 and 2,114.4 pg/ml on the side that received atropine, but, on the contralateral side, SP was either nondetectable or within the range of time control studies (42.5 pg/ml, data not shown). GLY increased on the side receiving atropine by 0.54 and 0.79 μM, while decreasing by 0.35 μM or increasing by 0.32 μM on the contralateral side (data not shown). GABA tended to decrease in both the side receiving atropine and the side receiving mCSF (data not shown). It is important to note that the agreement in measured effluent neurochemicals on the left and right sides was excellent.
Metabolic rate and body temperature effects of atropine.
There were no significant (P > 0.05) changes in V̇o2 and V̇co2 (Fig. 6, A and B, respectively), as determined by one-way RM ANOVA, or in Tr (paired t-test, data not shown) within time control studies. V̇co2 did not change significantly during atropine dialysis (F = 1.45, P = 0.253, 1-way RM ANOVA). However, during atropine dialysis, V̇o2 was significantly increased (F = 4.38, P = 0.014, 1-way RM ANOVA). In addition, both V̇o2 (F = 14.66, P < 0.001) and V̇co2 (F = 10.99, P = 0.002) were significantly higher during atropine studies in the day compared with time control studies, as determined by two-way ANOVA (Fig. 6, A and B, respectively). In addition, Tr increased significantly (P < 0.05) during daytime atropine dialysis, as determined by paired t-tests (data not shown). Metabolic rate was not measured during night studies. Baseline Tr during night atropine dialysis was significantly higher than in daytime atropine studies by 0.46°C, as determined by paired t-test (P = 0.036, data not shown). Atropine dialysis at night did not significantly affect Tr (P > 0.05, paired t-test, data not shown).
Based on mAChR distribution (32) and functional in vitro evidence that neuromodulation of preBötC function by ACh is predominantly excitatory (45, 47), we first hypothesized that dialysis of atropine in the preBötC region of the ventral respiratory column would decrease breathing of awake and sleeping goats. This hypothesis was not validated, since in awake goats, we found that dialysis of atropine in the preBötC region increased rather than decreased breathing frequency and V̇I. In addition, given that excitatory modulation is reduced during sleep (5), our second hypothesis was that atropine dialysis would decrease breathing more while awake than while asleep. This hypothesis was not validated, since atropine increased breathing during both states, but to a greater extent during the awake state. Finally, based on the observation that reductions in one excitatory neuromodulator leads to compensatory increases in other excitatory neuromodulators (18), our third hypothesis was that blocking mAChRs in the preBötC region with atropine would increase 5-HT and SP in the effluent dialysate. This hypothesis was validated, since preBötC atropine dialysis led to local increases in 5-HT and SP levels as measured in the effluent dialysate.
Anatomic sites affected by atropine.
We are unable to state with certainty the degree to which atropine affected preBötC neurons because: 1) the exact anatomic site of the preBötC remains controversial for all species (23, 24, 29, 57), 2) there is no unequivocal physiological marker of the preBötC, and 3) it is problematic to calculate/determine the area of atropine diffusion (31). We have previously provided estimates of the anatomic site of the preBötC and a physiological marker of the preBötC in goats (29, 57). The data on goat 12 are consistent with these estimates, since the right MT was rather caudal and medial to the presumed preBötC region, whereas the left MT was within our estimates of the preBötC region (Fig. 1). As shown in Fig. 7, the breathing frequency response to our physiological marker of the preBötC (NMDA injection) and to atropine dialysis was minimal on the right side and robust on the left side in goat 12. Moreover, although there was substantial variation among goats, the histologically identified MT locations and/or the responses to NMDA (Fig. 1) indicate that the atropine was dialyzed within the preBötC region of the ventral respiratory column in all goats. Accordingly, we conclude it is likely that the atropine reached the preBötC region in all goats to a variable extent and that, in most goats, it is also likely that the atropine affected airway motor neurons in nucleus ambiguous and/or chemoreceptor neurons near the ventral lateral medullary surface (4, 5, 39).
Muscarinic receptor subtypes and their role in preBötC function.
mAChRs are metabotropic G protein-coupled receptors that activate second messenger pathways resulting in an increase or decrease in neuronal excitability, depending on the second messenger pathways activated/inhibited (6, 10, 20). mAChRs are categorized into five subtypes. M1, M3, and M5 mAChRs are preferentially coupled to the Gq/11 subtype, and activation of these receptors leads to an increase in intracellular calcium (10, 20), and can suppress inhibitory currents such as the potassium M current (6, 13), both of which would lead to an increase in neuronal excitability. M2 and M4 mAChRs are preferentially coupled to the Gi/o subtype, and activation of these receptors leads to inhibition of adenylyl cyclase activity, and to a decrease in neuronal excitability and neurotransmitter release (1, 3, 6). mAChRs are extensively distributed in the cortex and brain stem, including respiratory-related nuclei (34, 36, 45), and are found pre- and postsynaptically on cholinergic and noncholinergic neurons (27, 38). Accordingly, the effect of ACh or atropine at any site is dependent on the: 1) subtype of receptors at that site, 2) the balance of pre- vs. postsynaptic expression of the different subtypes, and 3) distribution of these receptors on nerve terminals of neurons that release other excitatory or inhibitory neuromodulators. The latter two factors may determine the capability to compensate for attenuation of one or more excitatory inputs, and thus provide a mechanism by which attenuation of an individual neuromodulator could increase the local levels of other neuromodulators. Differences in the basal levels of the neuromodulators themselves may also be a contributing factor related to the compensatory capacity of each site.
Effects of atropine in the preBötC region while awake.
Findings of Lai et al. suggest that M2 and M3 are the primary mAChR subtypes expressed in the neonatal rat preBötC (32). Other in vitro studies implicate a role for the M3 subtype (45) or nicotinic receptors (47) in mediating excitatory ACh neurotransmission in the preBötC (45), whereas presynaptic activation of the M2 subtype appears to have an inhibitory effect on neurotransmitter release (3, 42, 56). Because dialysis of atropine did not significantly affect ACh or choline, the increase in breathing is unlikely the result of increased ACh release, increased activation of nicotinic receptors (47), or decreased turnover of ACh.
It would seem that the atropine-induced increases in the excitatory neuromodulators, 5-HT and SP (Fig. 4), would contribute to the atropine-induced increase in breathing (Fig. 2). This effect may have been countered by the concurrent increase in GLY (Fig. 4). However, there was no positive correlation between the increase in breathing and the changes in 5-HT, SP, and GLY (Fig. 8). Thus, the increase in these neurochemicals does not readily account for the effect of atropine on breathing.
A potential mechanism by which atropine increased 5-HT and SP is that atropine blocked inhibitory presynaptic M2 receptors on 5-HT/SP terminals, facilitating the release of these neuromodulators. This enhanced release of 5-HT and SP may have led to an increase in GLY release, or atropine had a direct effect on glycinergic neurons. Whatever the mechanism of the changes in neuromodulator levels, the data emphasize that perturbations of a single neuromodulator will result in multiple changes, including what appear to be compensatory (or even overcompensatory) changes, in other neuromodulators (18).
As shown in Fig. 9, the increase in neurochemical release from basal levels with atropine dialysis ranged between 1.16 and 29.8 nM for 5-HT, 1.198 and 1.681 nM for SP, and 595.6 and 3,337.1 nM for GLY. The relatively greater variability in 5-HT and GLY was consistently most extreme in goats 6, 9, and 12 (Fig. 9). The MT placements in these three goats were in close proximity to goats that had a small 5-HT increase with atropine dialysis (compare placement in goats 4 and 6 left side, 3–4 mm rostral to obex; Fig. 1). Note also that there was a large increase in 5-HT (such as in goat 12) even when the left and right MTs were not placed at the same site on each side. For all three neurochemicals, there were generally no significant (P > 0.10) differences between day and night studies (Fig. 5). The greater variability in 5-HT release than in SP release is striking because these neurochemicals are coreleased from 5-HT terminals. Thus, it seems that atropine may have had differential effects on mechanisms regulating 5-HT and SP in the synaptic cleft.
Both V̇o2 and V̇co2 were significantly (P ≤ 0.002) higher during dialysis of atropine than during time control studies. It is well known that V̇I is coupled to metabolic rate (15, 22) during exercise, changes in body weight, and other conditions. Thus, it is possible that changes in metabolic rate contributed to the atropine-induced changes in breathing.
Effects of atropine dialysis in the preBötC region during sleep.
During sleep, the activity of neurons that synthesize several excitatory neuromodulators is lower than during wakefulness (5). Precise measurement of neuromodulators during natural sleep has proven to be difficult, but it is conceivable that excitatory neuromodulation of the preBötC is reduced during natural sleep. Similarly, the levels of GLY and GABA at the preBötC during sleep are also unknown. Whereas there were no statistically significant differences in the baseline values of 5-HT, SP, GLY, and GABA between atropine studies done in the day compared with those done at night (Fig. 5), we did note a trend toward higher GLY concentrations at night, although we cannot determine differences in neurochemical measurements between wakefulness and NREM sleep. Nevertheless, our data suggest that at night, and possibly during NREM sleep, there is a shift toward a relatively greater inhibition of breathing. Such a shift may contribute to the lower breathing during NREM sleep compared with wakefulness (Fig. 3) and also to the reduced tachypnea during atropine dialysis in NREM compared with wakefulness.
We also cannot exclude the contribution of other neuromodulators that we did not measure to the state-dependent effects of atropine on breathing. For example, it is well known that the neuropeptide orexin contributes to arousal state (26) and that orexinergic neurons are more active in the awake state than during sleep (54). These neurons have widespread projections to the brain stem, including respiratory-related nuclei (43, 58), and there is evidence that orexin contributes to chemosensitivity, particularly more in the awake state compared with NREM sleep (17). It is possible that the withdrawal of orexinergic input to the preBötC, or to neurons that project to the preBötC, during NREM may underlie the reduced effect of atropine dialysis on breathing in this state, despite an increase in 5-HT and SP. These data highlight the need to further investigate how attenuation of one neuromodulator affects the levels of other neuromodulators, and the conditions under which these interactions affect physiological behavior.
The state-dependent differences in effects of atropine could also be caused by postulated state-dependent differences in the mechanisms of rhythm generation, which is a concept suggested by mathematical models (44) and supported by experimental data (29, 37). Conceivably, pre- and postsynaptic M2 and M3 receptors may not be equally distributed on neurons primarily responsible for rhythm generation while awake vs. neurons responsible for rhythm generation during sleep.
Difference in response to atropine dialysis within the preBötC and PRG.
Mallios et al. found M1 to M3 mAChR subtypes in the lateral and medial parabrachial nuclei (LPBN and MPBN, respectively) and the KFN of cats (34). Generally, the expression of each mAChR subtype was slightly higher in the LPBN and MPBN than in the KFN. We have documented the presence of M2 mAChRs in all three of these nuclei in goats (8). In addition, dialysis of atropine in the LPBN and MPBN had no effect on breathing during the day and night (awake or NREM sleep) (8). However, dialysis of atropine in the KFN decreased breathing frequency at night while awake and during NREM sleep but had no effect during the day while awake (8). This response is clearly different from the response reported herein on atropine dialysis in the preBötC region. These site-specific differences in the response to atropine between the KFN, LPBN/MPBN, and preBötC region are potentially due to site-specific differences in: 1) mAChR subtypes, 2) the balance of pre- vs. postsynaptic expression of the different subtypes, and 3) distribution of mAChRs on nerve terminals of other neurons releasing excitatory or inhibitory neuromodulators, and/or combinations of these differences.
An alternative explanation for the different effects of atropine dialysis in the KFN and preBötC region is that the differences indicate that the site of respiratory rhythm generation is within the rostral pons and not the preBötC region. Notable were previous findings in decerebrate cats that a presumed respiratory rhythm is sustained in the mylohyoid branch of the trigeminal nerve after the phrenic rhythm is abolished by chemical lesions in the medulla (53). These data led to the conclusion that the neurogenesis of eupnea is within rostral pontine nuclei (53). This conclusion is supported by data showing that chemical destruction of the preBötC in vivo only transiently eliminated respiratory rhythm (51). Moreover, data from other studies have shown that a pontine-medullary circuit is necessary for the three-phase eupneic respiratory rhythm and that the medulla in isolation is only capable of generating the gasping rhythm (48, 52, 53). Accordingly, our findings might be interpreted as indicating that the neurons in the KFN and preBötC region have different functions during eupnea, and the KFN seems more likely to generate the eupneic rhythm than the preBötC region.
Implications of present findings.
Our data suggest that inhibition of mAChRs within the preBötC region leads to an increase in breathing frequency potentially through increases in local 5-HT and SP, thus drawing greater attention to the physiological complications of a specific pharmacological intervention in vivo. Multiple past studies were designed (and data interpreted) based on the assumption that the major response of the primary variable (breathing frequency) was due to a direct effect of the perturbation (atropine dialysis). However, we found that the major effect of atropine on breathing (an increase in breathing frequency) is potentially due to an indirect effect of compensatory increases in 5-HT and SP, which may be partially countered by an increase in GLY. These data emphasize that indirect effects complicate interpretation of data obtained in vivo and emphasize the need for attempts to measure and/or account for indirect effects of pharmacological perturbations for more precise conclusions and better foresight in study design.
Caveats and limitations.
Two limitations of the present study are: 1) because of the length of the inlet tubing, there was a delay between when dialysis of atropine was initiated and when it actually reached the tissue, and 2) because of the manual system of switching between dialysate collection vials, we could not separate collection of effluent dialysate during the awake and sleep states. Thus, neurochemical values reported for night dialysis studies are a mixture of neurochemicals collected during both awake and sleep states. A major emphasis in this and past studies was to minimize extraneous factors potentially disturbing the goats during periods of study. Accordingly, the goats were in an environmental chamber isolated as much as possible from all laboratory equipment and the investigators except for ∼1 min required for exchange of the effluent dialysate collection tubes at the end of each hour of dialysis. This physical separation of the equipment and animals necessitated an extended length (150 or 180 cm) of tubing to deliver the perfusate from the pump to the probe. As a result, when a new dialysis period was initiated, there was an estimated 20-min delay before the fresh perfusate reached the probe due to the length of the perfusion line. Thus, it is likely that the atropine did not reach the tissue until ∼20 min into hour 2, continuing through the first 20 min of hour 3 (mCSF dialysis). These delays may explain why breathing during atropine dialysis did not increase until the latter 30 min of hour 2 and why it remained elevated throughout hour 3. Moreover, the delay may also explain why the local neuromodulator concentrations remained elevated during hour 3. Although it was possible to have flushed the inlet line at the beginning of each new dialysis period or to replace the inlet line between dialysis hours, doing so would have disturbed the animal and risked damaging the probe. Furthermore, there would still be a delay because of the probe itself and the time required for exchange with and diffusion in the tissue. For these reasons, we decided to forego these options to minimize the risk of agitating the animal or damaging the probe. The same problems and risks made it undesirable to separate the effluent mCSF collection between wakefulness and sleep as the goats cycled through these states.
Other limitations were the potential tissue damage resulting from repeated probe insertions and/or the potentially chronic effects of multiple periods of atropine dialysis. Although it is likely that probe insertion created some degree of tissue damage, there were no statistical (1-way RM ANOVA) trends for hour 1 (baseline) levels of 5-HT, SP, GLY, or GABA to change from day 1 to day 2, 3, or 4 even after there had been large increases in neurochemicals in preceding days. These data suggest that any potential chronic effects of atropine dialysis and/or tissue damage had relatively small effects on local neurochemical levels during dialysis of mCSF or in response to atropine.
Small sample size and variability between goats also were potential limitations in some parts of our study. These and the limitations stated above restrict the conclusions we can make from our data; thus, our stated conclusions are conservative, but warranted, despite these limitations.
The major conclusions from the present study are: 1) perturbation of a single neuromodulator system within the preBötC region results in compensatory (or even overcompensatory) changes in other neuromodulators, further supporting the concept that "a modulator's action is determined by the concurrent modulation and interaction with other neuromodulators" (18); 2) disruption of cholinergic neuromodulation within the preBötC region has state-dependent effects on breathing, further supporting the concept that the fundamental mechanisms controlling breathing are state-dependent (18, 44); and 3) interpretation of data from in vivo perturbations within the respiratory control network (and likely elsewhere) must account for direct and indirect effects of the primary perturbation.
This work was supported by National Heart, Lung, and Blood Institute Grants HL-25739 and HL-007852 and also by the Department of Veterans Affairs.
No conflicts of interest, financial or otherwise, are declared by the authors.
Author contributions: C.M. and H.V.F. conception and design of research; C.M., S.E.N., J.M., S.J.O., L.G.P., and H.V.F. performed experiments; C.M., S.E.N., M.R.H., and H.V.F. analyzed data; C.M., M.R.H., and H.V.F. interpreted results of experiments; C.M. and H.V.F. prepared figures; C.M., M.R.H., and H.V.F. drafted manuscript; C.M., S.E.N., J.M., S.J.O., M.R.H., and H.V.F. edited and revised manuscript; C.M., S.E.N., M.R.H., and H.V.F. approved final version of manuscript.


text:
I may have recently discovered a great carry-on kit, but then I got to thinking about how I might just try traveling liquid- and gel-free for my next destination. The current 3-1-1 rule states that you can bring 3.4 ounce bottles of liquids or gels in a one quart bag as carry-on. That's of course, one per person — which I did, indeed, once learn the hard way.
While it might be a little difficult to go completely "dry," I've got some suggestions in my widget below. The good news? It's expected that the TSA will lift the 3-ounce ban sometime later this year, although you'd still have to remove your liquid items for separate scanning. Still, it's great to travel light, no?


text:
2009-05-21 52 10
Thu 21 May 2009 in 52,10:
The Geohashing Day's hashpoint in the Braunschweig graticule happend to be in Edesbüttel. Edesbüttel has 100 inhabitants and it's main attraction seems to be the public pool near the Mittellandkanal.
Expedition by Chrismz[edit]
It was my first expedition for the day and yet the most unsatisfying because the hash was on private property. Getting there was quite easy. I got on the train from Hannover to Calberlah that took me in a range of about 2,5km to the geohash. The hash itself was in the backyard of a farmhouse so I just took fotos and left my hashtag on the pavement. Then I hurried back to the Calberlah train station, missed the train, had to wait an hour and finally headed of to Emmerke for a retro hash in the 52,9 graticule.
I'm claiming for myself:
| Chrismz earned the 2009 Geohashing Day achievement


text:
Volatile organic compounds (VOCs) are carbon containing chemicals that vaporize and can enter the body through normal breathing. VOCs can come from many sources. They are used as ingredients in paints, cleaning products, and adhesives. They are released by building materials such as carpet, linoleum, composite wood products, and insulation to name a few. Office equipment such as printers, copiers, and fax machines may also emit VOCs.
VOCs are chemicals that have high vapor pressures and fairly low boiling points and that tend to vaporize from the liquid or solid state under normal atmospheric conditions. Vapor pressure relates to the equilibrium of a substance between its solid or liquid state and its gas state, that is, the rate at which a liquid evaporates or a solid sublimates. If the vapor pressure is high, then the substance will move to the gas phase more quickly. Substances with high vapor pressure at room temperature are said to be volatile. VOCs also often have low boiling points (often below room temperature) that contribute to their vaporization. Examples of some common VOCs are formaldehyde, benzene, toluene, limonene, and hexane.
Using an activated carbon (a carbon or charcoal that is very porous and has a large surface area) filter is the most reliable way to remove VOCs from the air. VOCs attach to and accumulate on the activated carbon in the process known as adsorption. These filters become exhausted or "spent" and must be frequently replaced. Otherwise, the adsorbed VOCs may desorb, or leave the surface of the activated carbon and return to the air.
Part of the mission of the Indoor Air Quality (IAQ) Section is the reduction of exposure to indoor, airborne chemicals. In 2008, CDPH published the first health based standard for testing building materials for chemical emissions (Section 01350). Along with other agencies, CDPH has written purchasing guidelines that include IAQ criteria that mandate low chemical emissions. The department supports the California Air Resources Board's (CARB) formaldehyde regulation, which limits formaldehyde emissions from composite wood products.VOC Publications
In order to determine the effect of materials with recycled content in relation to indoor air quality, it became clear that emissions data were required for standard building materials and their alternative sustainable counterparts. This concern prompted the CIWMB to fund a laboratory-based, three-phase study by the Public Health Institute (PHI), with the Department of Health Services (DHS) being the principal investigator. The study focused entirely on those building materials with indoor air quality implications.
The guidelines presented in this document are the result of Chapter 1229 of the Statutes of 1990 (AB 3588, Speier - see Appendix A) that required the Indoor Air Quality Program (now Indoor Air Quality Section) of the California Department of Health Services (CDHS) to "develop nonbinding guidelines for the reduction of exposure to volatile organic compounds (VOCs) from construction materials in newly constructed or remodeled office buildings." The originating legislation was the result of concern about increasing complaints of sick building syndrome (SBS). This is a situation in which building occupants report symptoms, such as mucous membrane irritation, headaches, stuffiness, lethargy, and drowsiness, and which the occupants associate with a building. Researchers have reported that VOCs play a role in many SBS complaints, particularly in new or newly renovated office buildings, which often have substantial amounts of building and furnishing materials that emit VOCs.
Recommendations of the California Air Resources Board and Department of Health Services
When a classroom has been measured with elevated formaldehyde levels (more than 27 parts per billion--ppb), we recommend that the school implement the basic measures listed below. Classrooms with formaldehyde levels below 27 ppb would benefit from these measures as well, because formaldehyde is a carcinogen, and it is desirable to achieve the lowest formaldehyde levels reasonably feasible. However, achieving very low indoor levels (below 5-10 ppb) generally is not possible. Outdoor levels average about 3 ppb, but can range up to 20 ppb in some areas, such as near traffic.
The development of California's first building-related environmental specification started in early 2000, when the Department of General Services' (DGS's) Procurement Division was in the process of issuing a request for bids for a three-year, $60 million open office systems furniture contract. To address this issue, the several state agencies worked with DGS, the systems furniture industry, and private consultants to issue a benchmark environmental specification for procuring open office systems furniture. This specification was issued in December 2000, and included testing and selection criteria for indoor air quality as well as requirements for recycled contents and lighting.
In 1999, the State Legislature directed the Department of General Services (DGS) to incorporate sustainable practices in the design and construction of 1.5 million ft2 of the Capitol Area East End Complex (CAEEC). To address the Legislature's directive, a multi-agency team, known as the Green Team, was formed under the leadership of the Secretary of the State and Consumer Services Agency and, in partnership with the Department of Health Services, California Integrated Waste Management Board, California Energy Commission, California Air Resources Board, and Department of Water Resources worked with DGS to develop sustainable criteria for the CAEEC. These criteria, among others, included several to ensure good indoor air quality, including setting target limits on chemical emissions from interior finishing building materials and conducting airborne contaminant testing after completion of the construction and prior to occupancy. Two design/build teams were selected: one for Building 225 and another for the remaining four buildings (171, 172, 173, 174). The design/build teams were responsible for the design of the buildings (the basic shell design had been done previously by the State) and the construction.
Volume 2 of the report contains detailed data and graphs for all sampled locations.
It has been five years since the Indoor Air Quality Program issued the Standard Practice for the Testing of Volatile Organic Emissions from Various Sources Using Small-Scale Environmental Chambers (Standard Practice) on behalf of the California Sustainable Building Task Force. We recognized from the start that maintenance of this document would be required to keep up with changes in the field and to track current health standards. Limitations in staff resources have delayed this effort till now. It is our intention that the update of the Standard Practice will be a continuous process, and this document presents an initial effort.
It has been more than 6 years since the Indoor Air Quality Program issued the Standard Method for the Testing and Evaluation of VOC Emissions from Indoor Sources Using Environmental Chambers Version 1.1 in 2010. We have been receiving comments regarding potential improvements/updates to this document, one of which is to adopt the new benzene chronic Reference Exposure Level (REL). In this updated version 1.2 (2017), the pass/fail level for benzene emissions has been amended to 1.5 μg/m^3 (½ of current chronic REL), effective on April 01, 2017.
Material Emission Testing: Certification Programs and Testing Labs
Certification Programs
Carpet and Rug Institute (CRI)
CHPS Low-Emitting Materials (LEM) Table
Scientific Certification Systems (SCS)
UL GreenGuard
Testing Labs
Berkeley Analytical Associates (BAA)
Eurofins Product Testing
Materials Analytical Services (MAS)
UL Air Quality Sciences
| Conditions of Use
| Privacy PolicyCopyright ©


text:
The Atlanta Hawks arrived in Boston last night without a win since Antoine Walker left them and returned to the Celtics two weeks ago. But leading late in the fourth quarter, the visitors had to wonder if the basketball gods were finally smiling upon them in the FleetCenter. If they couldn't win without Walker, maybe they could win against him.
Unfortunately for Atlanta, fate has been more cruel than kind this season. That certainly seemed to be the case in the closing stages of last night's game.
Walker turned his familiarity with the Hawks against them, easily figuring out what they would do down the stretch and guarding go-to guy Al Harrington. With 34.9 seconds left and the Celtics clinging to a 1-point lead, Walker stole the ball from Harrington to start a fast break that Ricky Davis finished with a layup. The sequence deflated Atlanta and put Boston in position to close out a 95-91 victory.
The crowd of 16,089 had to hold its breath after Harrington hit a long distance shot with 12.5 seconds remaining that appeared might be a tying 3-pointer but wasn't because Harrington's right toe was on the arc.
Paul Pierce, who went 5 for 6 from the line in the final 16.5 seconds and scored 16 of his 27 points in the fourth, sealed the victory.
"Some way, somehow we've got to pull games out like this," said Pierce, who added 10 rebounds. "I really didn't have it going most of the night, but in the fourth quarter my teammates made a concentrated effort to get me the ball and put me in position to score, and I was able to do that."
In the closing minutes, Walker (15 points, 9 rebounds, 3 steals) showed his desire to defeat his former team and improve the Celtics' position in the Atlantic Division standings. Boston now has a three-game lead on Philadelphia.
A Walker 3-pointer tied the game, 79-79, with 5:43 remaining, finally waking up Boston and placing the home team in position to take its first lead. An 18-footer from Pierce with 3:54 remaining gave Boston its first advantage of the contest. A missed free throw by Pierce left the door open for the Hawks, but the Walker steal kept the Celtics from losing the lead in the closing minute.
Asked if he wanted to defend Harrington late in the fourth, Walker said, "Oh yeah, I just wanted to guard him. I knew from playing against him [in practice], some of his characteristics, what he likes to do. I knew every play they were going to run. It was going to be simple: Al Harrington. I just knew what it was and I wanted the challenge of guarding him. I think Paul would have been trying to be too physical with him."
What the Celtics lacked in intensity they made up for with perseverance in the face of early offensive struggles. While they knew better than to take the worst team in the league lightly, even though Atlanta took to the parquet for the second of back-to-back road games and with a 12-game losing streak, Boston muddled through the first half and entered the break behind, 52-46. Shooting 46 percent from the field despite missing a number of layups and all eight attempts from 3-point range, the Celtics were a frustrated group.
While Atlanta benefited in the first half from timely offensive rebounding (10 second-chance points) and the ability to get to the line more than twice as many times as the Celtics, Boston made it even harder on itself by failing to take advantage of Walker in the post. The coaching staff estimated the Celtics went 13 possessions without feeding the ball to Walker in the post, forcing coach Doc Rivers to take an early timeout and remind his players of the preferred strategy on offense.
Still, Boston trailed, 70-64, entering the fourth, so the win left Rivers thankful and hoping his team would be able to avoid a repeat performance.
"Sometimes you just can't get a read when you try to predict how your team is going to perform," said Rivers. "If I had to predict, I thought we were really going to come out with a lot of energy, just by the way we practiced. But we didn't and we survived. From the third quarter on, I knew it was going to be a survival game. You could feel it. We let them stick around. They started believing and making shots. Then, you could see our guys physically try to get themselves going.
"I don't want to get in the habit [of playing poorly and winning]. You can't do that too many times because you're going to get burned. The basketball gods will get upset at you and you'll lose the games."
Atlanta can only hope the basketball gods reverse fortunes sometime soon.


text:
The Phase II clinical trial of FX06 (F.I.R.E. study) in 234 patients with acute myocardial infarcts was completed in March 2008, with data indicating a statistically significant reduction in myocardial necrosis compared to placebo following intravenous application of FX06 during reperfusion treatment . FX06 is a peptide that binds to vascular endothelial (VE) cadherin, thereby inhibiting tissue inflammation and injury as well as preserving endothelial barrier function. These effects are deemed to be important for the prevention of the paradoxical additional damage to the heart muscle known as reperfusion injury.
"We are delighted that FX06 has demonstrated efficacy in this Phase II trial" stated Dr. Rainer Henning, President and CEO of Fibrex Medical. "FX06 is a first in class product and we have demonstrated that it can provide clinical benefit by preventing reperfusion injury for the huge number of patients who survive heart attacks each year. FX06 can clearly be expected to become an important addition to the armamentarium of the cardiologist in the catheter lab."
"Re-establishment of blood flow either by catheter-based balloon-intervention (PCI) or by thrombolysis, is necessary and life-saving in the treatment of acute myocardial infarctions, however such interventions can lead to tissue damage due to resulting free radicals and an acute inflammatory response," said Dan Atar, Professor of Cardiology at the Aker University Hospital, University of Oslo, Norway, who is the Coordinating Investigator for the F.I.R.E. Study. "Based on the F.I.R.E. results, we believe that FX06 can inhibit this inflammatory response and thus prevent reperfusion injury in patients. We predict that FX06 may become a novel treatment for STEMI patients undergoing PCI representing a major advance in acute cardiac care."
Fibrex is now planning an ambitious development program to bring this promising new product to registration and expect to carry this program out together with a licensing partner. This program will be discussed with regulatory agencies in US and Europe later this year.
About Fibrex Medical Inc.
Fibrex Medical Inc. is a privately held company headquartered in Cambridge, MA, USA with operations in Vienna, Austria. The Company is developing innovative therapeutics for acute and intensive care in cardiovascular and inflammatory conditions based on novel mechanisms of action. Fibrex Medical started operations in 2001, and has raised a €13 M in investments from top tier venture capital investors including Atlas Venture, Global Life Science Ventures, EMBL Ventures and Mulligan Biocapital.
Fibrex Medical, Inc.
Dr. Rainer Henning, CEO, +43 (0)1 86 63 49 27 0
College Hill
Dr. Douglas Pretsell
Account Director, Munich Bureau Chief
+49 (0)89 57 00 18 06
Source: Fibrex Medical


text:
Ashby Monk, Ph.D., executive director of the Global Projects Center at Stanford University and a senior research associate at the University of Oxford, has been blogging about sovereign and pension funds since 2008.
Follow him on Twitter at @sovereignfund.
Dear Pensions and Endowments: Do Unto Wall Street as We Do to Ourselves
Individually Rational and Collectively Crazy
Why I Go to Australia. A Lot.
When it comes to investing edge: Advantage, Giants.
Register today for inside access to our thought-provoking coverage of the global financial markets!
A new report by PRI offers some really
useful information for investors interested in accessing
farmland opportunities... which, let's be honest, should be
most of you out there. (Or at least all the long-term
investors.) Why should you be interested? Let me whet your
farmland appetite with the PRI introduction:
Farmland investments can be labeled as simple
property transactions which involve the acquisition and
possibly development of land with agricultural potential for
the production of crops or livestock or of leases to land...
Farmland investments present investors with opportunities to
capture superior risk and inflation-adjusted returns. Unlike
other physical assets considered an inflation hedge such as
gold, farmland generates an annual income, and capital values
are driven by demand for agricultural commodities rather than
the dynamics of financial markets. This makes investing in
farmland particularly attractive to those wishing to hold
productive assets that are not affected by volatility in
financial markets.
So farmland is an uncorrelated, cash-flow-generating asset
that will appreciate as the global population grows (which it
will) and demands more food (which it will). That seems a
pretty sound bet to me! (And for those of you that need to see
a track record before you'll commit to buying your own
groceries, over the past four decades US agriculture has
outperformed stock and bond markets. Boom: Track
And so farmland is a real opportunity for long-term
investors, which brings us back to the issue of access.
Heres the PRI report again:
There are various ownership and/or operating
models that institutional investors can adopt for farmland,
Hmmmm. That sounds pretty tough. And this, dear readers, is
ultimately why most institutional investors dont get
involved: Attractive access points require investors to be
direct and operational-minded, which is 1) hard and 2) uncommon
(especially among the public pensions and sovereign funds that
would be most likely to find these investments attractive).
And so this is where I'd like to give a plug to my friends
over at TIAA-CREF, as they deserve real kudos for their work in
this space. For example, earlier this year the fund seeded a new
company to invest its own assets as well as those of peers
in farms in the developed and developing world. Heres how
Anders Stromblad, head of external
managers, at AP2 (an investor in the vehicle) described the
TIAA-CREF opportunity:
TIAA-CREF offers investors access to this
important, emerging asset class through a sustainable,
transparent platform. Importantly, TIAA-CREFs interests
are aligned with ours.
As far as an external vehicle to access farmland is
concerned, that sounds pretty awesome. That's an investment
model that I'd like to see become the 'future of finance'; one
that is grounded in the real economy.
Anyway, you can download the entire PRI report here its worth
reading in its entirety, as it also has five case studies of
funds making farmland investments.
© 2017 Institutional Investor LLC. All material subject to strictly enforced copyright laws.
Please read our
Term and Conditions and
Privacy Policy before using the site.


text:
Need an Online Appraisal? Ask an Appraisal Expert
Hello,.My name is***** will be happy to help you.. Brief Explanation of how the appraisers work on Just Answer for you. The appraisers do not work for the just answer site. We come to the site to answer questions customers ask there. We do not send customers any messages through email. We only communicate with a customer in this message box. We do not send emails asking for anything. After we type a communication to you, you get notified by the site we sent you a message. Just like when you send us a response we get notified so we come to this message area to respond to you. We are not at the Just Answer site, we are independent Appraisers who come to the site. .Please Note: I am sorry I am unable to do live conversation per phone. There is data that needs to be obtained, this is always best in written form, in order to give a correct, honest appraisal. ..The Menu autographed by Charles Schultz 1971 has an estimated value on the current market for an average of $450.00-600.00, depending on the condition and where it is for sale at. These will typically sell higher in an Antique Shop or Private sale compared to an auction. If you are thinking of selling, you might want to check your local Antique Shops in the area to see what yours or one like it would sell for or has sold for, then you can decide to sell online or locally. . Keep in mind that not all estimated values are obtained, your geographic area plays a big role in what prices can be obtained. If you plan on selling this I would list this for sell on the internet where it will have the largest shopping market. There are some great sites you can sell from. You can sell in your local area or a larger city near you with Craigslist, it is free, and when they item sells the buyer picks it up..You can sell on Etsy, which is a great place to sell from, you list Vintage Items, they can stay until they sell. Much like having a little store online. There is also Rubylane, which is a more upscale site where people sell more expensive items. There is also Tias and GoAntiques, which is on the same scale of Rubylane. There is Amazon Market Place, ArtFire and of course Ebay. All of these sites get you a lot of World Wide exposure and bring the best traffic. They are all great! If you sell to a dealer, antique shop or resell shop you can expect to get about 30-40% of what it is worth since they have to resell the item..If you have more items you would like to ask me about, just start a new question addressed to "Glenda" it would be my pleasure to help you.. Thank you so much! GlendaPS:I would greatly appreciate it if you took a moment to rate my answer to you. You do so by clicking the stars, this is the only way I am paid for my time answering your question. Doing so does not cost you any additional money, I am paid by the Just Answer site, not the customer.
Hi, I'm just checking in once again to see how things are going. Let me know if you still need help with this questions, as I see it is not rated yet. If there was a problem with the answer I provided for you?.Thank you so much!Glenda


text:
Passo del Grimsel
- Suited for road bikes
|26 km
|start height
|625 m
|end height
|2165 m
|highest point
|2165 m
|1540 m
|distance uphill
|26 km
|average ascent percentage
|5.9 %
|maximum ascent percentage
|5.9 %
- Distance: 0
- Elevation: 0
Did you ride this climb/route? share your story, information or comments.Since 1894 there is a real road over the pass of the Grimsel, the only way to get over the Bernese Alps in Wallis. The pass is 2065 meters high and is open for traffic from June 15 to October 31.
|start point
|Dorfstrasse 3, 3862 Innertkirchen, Switzerland
|end point
|Dorfstrasse 3, 3862 Innertkirchen, Switzerland
No items added
Delete this media item?
You and this route
You have not yet filled out your time for this route.
Others and this route
There were no times added yet for this route.
Add comment


text:
Global Power Discrete Market 2012-2016
TechNavio's analysts forecast the Global Power Discrete market to grow at a CAGR of 10.9 percent over the period 2012-2016. One of the key factors contributing to this market growth is the increasing demand for power discrete devices from the renewable energy segment. The Global Power Discrete market has also been witnessing the increasing focus on power discrete semiconductor chip optimization. However, the high cost of power discrete could pose a challenge to the growth of this market.
TechNavio's report, the Global Power Discrete Market 2012-2016, has been prepared based on an in-depth market analysis with inputs from industry experts. The report covers the Americas, and the EMEA and APAC regions; it also covers the Global Power Discrete market landscape and its growth prospects in the coming years. The report also includes a discussion of the key vendors operating in this market.
The key vendors dominating this market space are Fairchild Semiconductor International Inc., Fuji Electric Holdings Co. Ltd., Infineon Technologies AG, International Rectifier Corp., and Renesas Electronics Corp.
Key questions answered in this report:
What will the market size be in 2016 and what will the growth rate be?
What are the key market trends?
What is driving this market?
What are the challenges to market growth?
Who are the key vendors in this market space?
What are the market opportunities and threats faced by the key vendors?
What are the strengths and weaknesses of the key vendors?
01. Executive Summary
02. Introduction
03. Market Coverage
Market Overview
04. Market Landscape
04.1. Market Size and Forecast
04.2. End-user Segmentation 2012
04.3. Five Force Analysis
05. Geographical Segmentation
06. Vendor Landscape
07. Buying Criteria
08. Market Growth Drivers
09. Drivers and their Impact
10. Market Challenges
11. Impact of Drivers and Challenges
12. Market Trends
13. Key Vendor Analysis
13.1. Fairchild Semiconductor International Inc.
13.1.1. Business Overview
13.1.2. SWOT Analysis
13.2. Fuji Electric Holdings Co. Ltd.
13.2.1. Business Overview
13.2.2. SWOT Analysis
13.3. Infineon Technologies AG
13.3.1. Business Overview
13.3.2. SWOT Analysis
13.4. International Rectifier Corp.
13.4.1. Business Overview
13.4.2. SWOT Analysis
13.5. Renesas Electronics Corp.
13.5.1. Business Overview
13.5.2. SWOT Analysis
14. Other Reports in this Series
List of Exhibits:
Exhibit 1: Global Power Discrete Market 2012–2016 (US$ billion)
Exhibit 2: Global Power Discrete Market by End-user Segmentation 2012
Exhibit 3: Global Power Discrete Market by Geographical Segmentation 2012
Exhibit 4: Global Power Discrete Market by Vendor Segmentation 2012


text:
BLT law blog [look it up for yourself] reports that Blackwater [the military and security subcontractor] is suing Zuckerman Spaeder in legal malpractice. Here it is from the BLT:
"Wiley Rein has hired attorneys at Zuckerman Spaeder to represent the firm in the $30 million Blackwater suit. In D.C. Superior Court, the private security contractor filed suit against Wiley Rein and former attorney Margaret Ryan in late January for legal malpractice.
Elizabeth Taylor and Mark Foster of Zuckerman Spaeder are handling the representation. The firm has until March 13 to file an answer to the complaint. See this Legal Times article for more about the lawsuit ."