An Asian NATO won't be possible for some time without a change in how states conceptualize their security needs.
Is an Asian NATO possible? Before answering that, we need to think about what we mean by "NATO." If we mean a military alliance designed to deter or repel a large regional aggressor, then some sort of agreement triggering military action under certain circumstances might be possible. If we mean "NATO" as we have come to understand the activist collective security organization, then we have a long way to go.
The post-war framers of the U.S.-sponsored collective security system surely did see the potential for an Asian version of NATO. SEATO quietly died after 23 years of pointless existence, the primary focus of its defensive commitment falling to North Vietnamese tanks in 1975.
However, the idea of a collective security organization appeals to some strategists, given the fears that several regional states have about Chinese territorial interest in the East and South China Seas. Aggregating military and political capacity would prevent China from picking off opponents one by one, and would allow for operational coordination between militaries, even if an effective alliance could have negative second order effects.
But it's worth asking what, precisely, NATO is before suggesting that a similar organization is possible in East Asia. NATO has become far more than a military alliance; it serves as a framework for how European states understand their security. Most importantly, the value of the NATO alliance comes primarily through the symbolic importance that European leaders attach to it. The question "Would the United States defend Estonia from Russian attack" is, without the context of NATO, almost non-sensical; the better question becomes "How far will the United States, Germany, and France go to protect the integrity of NATO." European security policy is developed entirely within the context of NATO; the fade or failure of the organization would require extremely difficult political and strategic decisions. Reluctance to take these decisions inclines policymakers towards stasis, which reinforces the NATO affiliation.
This sense of value allows the alliance to persist even when many members don't feel strongly about the intervention in question, or when this varying enthusiasm leads to complex restrictions on military commitments.
By contrast, Asian geopolitics seem marked by what amount to arms length, transactional relationships. For obvious reasons, the United States cannot call upon a long history of cooperation with Vietnam. Even the U.S.-Philippines relationship is fraught with symbolic difficulties. The United States has maintained tight, long-term relationships with South Korea and Japan, but as Robert Kelly has detailed the two continue to have significant problems with one another.
To be sure, many of these same problems afflicted Europe in 1949, but the threat of the Red Army loomed much larger than that of the PLAN. Only sixty years of communal experience could re-create that feeling in the Asia-Pacific. And this sense of obligation to community is particularly important because Chinese aggression in the East China Sea or the South China Sea is less likely to resemble an armored assault into the Fulda Gap than careful "salami slicing." Soviet aggression into Turkey or Germany posed an immediate economic, military, and social threat into most of the rest of the NATO members. China will likely threaten the seizure of a few islands of dubious military and economic importance.
Developing a collective response to salami slicing is always more difficult than to more straightforward aggression, and requires that members place a great deal of value on and faith in the alliance itself. It's a struggle to imagine how that kind of cohesion can develop under the geopolitical conditions that currently hold in the Asia-Pacific.
Are We Prepared for 'Hybrid Warfare'?
From Russia in Ukraine to China in the East China Sea, it is worth assessing how the world may respond.


The most important criterion for voters at election time is trustworthiness of individual politicians, writes Juhan Kivirähk, with party names, slogans and manifestos secondary to that.
Before commenting on party support levels in November, it is worth recalling October's. Since Estonia 200 had not reached party status at that point, respondents were asked , after making their selection from the existing roster of parties, whether they would switch allegiance to Estonia 200 should it be eligible to stand.
The survey results showed 9% would do just that, the majority of whom were current Reform and Social Democratic Party (SDE) supporters.
This came to fruition in the November market research results, where 8% said they would vote for the now-eligible Estonia 200, whereas Reform and SDE were down by five percentage points from October.
Naturally, Estonia 200 itself might not be the sole factor here. Reform seems to be going through a difficult patch, for instance with former members Imre Sooäär and Andrei Korobeinik joining the centre party and being critical of their previous party. There have also been questions as to whether all is well internally in the party, together with the unexpected stepping down of Kert Valdaru as party secretary in early November and his replacement by 27-year-old Erkki Keldo.
Centre has made progress on the other hand. In November it stood at 33% in the opinion polls, versus 23% for Reform, 15% for the Conservative People's Party of Estonia (EKRE), and Estonia 200 on 8% as noted, ahead of the SDE on 7%. Isamaa/Pro Patria were hovering around the electoral threshold of 5%, and the Greens and Free Party below that , on 3% and 1% respectively.
Estonia 200 a protest vote?
The situation looks a little rosier for Reform when looking at their support amongst those who will definitely vote. In this case Centre's support falls to 30% but rises to 25% for Reform. With the other parties the figure remains largely unchanged.
But can Estonia 200 protect its current position and if so what are its options? Many analysts believe its rating right now is partly the result of a protest vote for a newcomer to the scene, which might not translate into actual votes for named party members on an electoral list.
This is a criticism long aimed at EKRE too, that its support in market research is higher than would actually emerge on voting day, given the only well known figures they have are the current Riigikogu MPs. However, it seems that EKRE could overcome this gradually whereas Estonia 200 really is an unknown both in terms of personalities and everything else.
The electorate has heard all the miracle promises in pre-election manifestos time and again before, only for these to fail to materialise once a party is in office. Thus the ''long plan for Estonia'' which Estonia 200 proclaims will in practice mean it can have a hard time on election day.
However, taking account of Estonia 200's platform, it would serve it well to keep its nose clean and to steer clear of political mavericks, decoys or ''entertainers''.
Mr Korobeinik and Mr Sooäär, before joining Centre, had taken a look at Estonia 200 but turned it down. At the same time it would be prudent for parties to ward off those opportunist politicians just looking to ameliorate their positions.
There are only two or three familiar names in the party leadership and it would have been good to introduce members to the public a long time ago, if the party wants to be more than just a group of specialists and experts. Without that, it is difficult for voters to put all their trust in the new party.
Finally, it is important to remember that the political climate has changed so much recently with the controversy over the past week, that even the November results could only be considered valid with the caveat ''before the government crisis''. As this situation resolves itself, we can see how things are looking in party support research in December.
Juhan Kivirähk is research director of market polling firm Turu-uuringute AS.


text:
Potua is een geslacht van rechtvleugeligen uit de familie doornsprinkhanen (Tetrigidae). De wetenschappelijke naam van dit geslacht is voor het eerst geldig gepubliceerd in 1887 door Bolívar.

Soorten
Het geslacht Potua omvat de volgende soorten:
Potua aptera Wagan & Kevan, 1992
Potua coronata Bolívar, 1887
Potua morbillosa Walker, 1871
Potua sabulosa Hancock, 1915

Doornsprinkhanen

redpajama_set_name: RedPajamaWikipedia


i want buy simoom kit from shop and it says im already buy and want to give me crystals buy im not buy it thanks for help.
Don't worry, it is just an agreement. If you haven't purchased it first time successfully. You can do so now. You'll get Simoom kit.
You can change your location in the settings.


text:
Q: how to HTTP GET method to retrieve information from an articles database The query response is paginated and can be further accessed by appending to the query string &page=num where num is the page number.
I have Given a string of author, getArticleTitles must perform the following tasks

*

*i had Query https://jsonmock.hackerrank.com/api/articles?author=authorName&page=num\> (replace authorName and num) but had a issue with it.

*then i initialize the titles array to store a list of string elements

*Store the name of each article returned in the data field to the titles array using this logic if title is not null, use title as the name , if title is null, and story title is not null, use story_title as the name , f both title and story_title are null, ignore the article

*Based on the total_pages count, fetch all the data (pagination) and perform step 3 for each.

*Return the array of titles
i am facing issue when getting result output from above scenario.
first i have create article properties and json properties for json
public class Article
    {
        public object title { get; set; }
        public object url { get; set; }
        public string author { get; set; }
        public int num_comments { get; set; }
        public object story_id { get; set; }
        public string story_title { get; set; }
        public string story_url { get; set; }
        public object parent_id { get; set; }
        public int created_at { get; set; }
    }

This is response Property
public class Response
    {
        public int page { get; set; }
        public int per_page { get; set; }
        public int total { get; set; }
        public int total_pages { get; set; }
        public List<Article> data { get; set; }
    }

And final code which i am getting logical issue
internal class Program
{
    public const string API_URL = "https://jsonmock.hackerrank.com/api/articles?author=";
    public static async Task<IEnumerable<Article>> getArticleTitles(string author)
    {
        var articles = new List<Article>();
        var url = API_URL + author;
        int currentPage = 1;
        int totalPages = 0;
        var nextUrl = $"{url}&page={currentPage}";

        using (var httpClient = new HttpClient())
        {
            do
            {
                HttpResponseMessage response = await httpClient.GetAsync(nextUrl);

                if (response.IsSuccessStatusCode)
                {
                    string json = await response.Content.ReadAsStringAsync();
                    var pageResponse = JsonConvert.DeserializeObject<Response>(json);

                    if (pageResponse != null && pageResponse.data.Any())
                    {
                        articles.AddRange(pageResponse.data);
                        totalPages = pageResponse.total_pages;

                        currentPage++;
                        nextUrl = $"{url}&page={currentPage}";
                    }
                    else
                    {
                        break; // or throw exception
                    }
                }
                else
                {
                    break; // or throw exception
                }
            } while (currentPage < totalPages);
        }

        return articles;
    }
    static void Main(string[] args)
    {
        IEnumerable<Article> articles = getArticleTitles("patricktomas").GetAwaiter().GetResult();
        Console.WriteLine($"Retrieved {articles.Count()} articles.");
        Console.ReadKey();
    }
}

redpajama_set_name: RedPajamaStackExchange


text:
Q: Bash: Using Indexes of variables in loops i currently have to programm a script that takes 3 variables and puts them together in all possible ways.
I configured the variables in this way (replaced the actuall "domains" and "front", because i am not sure if i am allowed to reveal them...)
Domains=(".1" ".2" ".3" ".4" ".5")

Front=("1" "2" "3" "4" "5" "6" )

Numbers=({00001..00020})

To add the variables together i made this:
STR1="${Front[0]}${Numbers[0]}${Domains[0]}"

I now have the problem that i don't know how i can make a loop that creates all possible combinations.
In the end, all those combinations should be put behind the command "host" in the shell.
And just a question, is it possible to save all the combinations that had an IP-adress in an file? If the answer is yes, i would be very pleased if someone could help me out with that too....
Kind regards
Elias

A: That seems a lot of brute-force work, but...
First, do you really need the indexes?
for f in "${Front[@]}"; do
  for n in "${Numbers[@]}"; do
    for d in "${Domains[@]}"; do
      echo "$f$n$d"
    done
  done
done

If you do actually need the indexes -
for f in "${!Front[@]}"; do
  for n in "${!Numbers[@]}"; do
    for d in "${!Domains[@]}"; do
      echo ""${Front[f]}${Numbers[n]}${Domains[d]}"";
    done;
  done;
done

If it's a big dataset, probably nicer to your resources to use counters, though it's a lot more maintenance.
f=0; n=0; d=0;
while (( f < ${#Front[@]} )); do
  while (( n < ${#Numbers[@]} )); do
    while (( d < ${#Domains[@]} )); do
      echo "${Front[f]}${Numbers[n]}${Domains[$((d++))]}";
    done;
    d=0; ((n++));
  done;
  n=0; ((f++))
done


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Call our office today at 404 418 8092 or call me directly at 404 246 3210. For your convenience, you can email us at gethelp@jwgroupre.com.


text:
Rediff.com » Business » Labour reforms in India may get going, finally
Labour reforms in India may get going, finally
March 20, 2017 14:16 IST
As the Centre faces multiple hurdles, BJP-governed states such as Rajasthan, Madhya Pradesh and Gujarat have swiftly moved in to usher in radical reforms as they aim to take a larger share of the FDI pie.
On Labour Day (May 1) last year, Union Minister of State for Labour Bandaru Dattatreya wanted to create a feel good factor. He launched a programme of consolidating multiple provident fund accounts.
He invoked BR Ambedkar to announce pro-worker steps like fixing a minimum wage and extending social security schemes to unorganised workers. However, Dattatreya was silent on the long-pending labour reforms.
Refusing to bite the bullet, he said, "As a founding member of the ILO, India is committed to the principle of tripartism. The ministry has put in its best efforts to reach a consensus on all issues and many tripartite discussions have been held before taking decisions."
Under fire from trade unions over multiple issues, the government decided to put its ambitious labour reforms on the backburner. So much so that Prime Minister Narendra Modi, in an interview to a foreign publication, discounted the impact of labour reforms on economic growth.
"States need to understand that such changes will be favourable to them for creating a job market, cooperative federalism is always positive," the official said. According to reports, the Centre has made changes to the draft of the Factories Act, 1948, to allow states to take a call on the number of workers a unit has to employ to be covered under the law.
Rajasthan has been the pioneer in labour reforms. It has relaxed the provisions of the Factories Act, Industrial Disputes Act, Apprentices Act and Contract Labour Act. Madhya Pradesh has amended at least 20 labour laws, including 17 central ones, such as the Industrial Disputes Act, Factories Act and Shops and Establishments Act.
The Maharashtra law department, according to a notification, has amended the Contract Labour (Regulation and Abolition) Act to make it applicable only to establishments in which 50 or more workers are employed.
This means smaller units employing up to 49 workers will not be required to register themselves with the government. "We will ensure strict compliance of the law," Shweta Singhal, deputy secretary, labour, said.
Owen Jolie, a researcher at the Centre for Strategic and International Studies, says, "If the Union government is unable to introduce comprehensive investor-friendly labour laws at the national level due to political resistance, it will remain incumbent on India's states to decide if they want to take the political risks necessary to enact difficult reforms such as deregulating labour laws."
However, with a favourable outcome in Uttar Pradesh, expectations of resuming the process have revived. According to labour ministry officials, the government plans to introduce two labour Bills in the second half of the Budget session, a move that will be opposed by labour unions. These Bills are the Industrial Relations Code Bill, 2016, and the Wage Code Bill, 2016.
If passed, the Industrial Relations Code would facilitate easier hiring and retrenchment in factories, the first official said. A previous draft of the proposed law suggested that companies need not seek approval for retrenching up to 300 employees in the case of an emergency.
The Wage Code will consolidate all wage laws, and the a proposed Social Security Code will amalgamate all social security laws including Employees' Provident Fund and Miscellaneous Provisions Act, Employees' State Insurance Act and Maternity Benefits Act.
Labour ministry officials say all formalities including tripartite consultations with trade unions have been done and the approval of the law ministry secured.
"For nearly two years, the labour law consolidation process is almost in cold storage. Though the labour ministry has done a lot of work over these labour codes for a year, the administration was not very enthusiastic, maybe due to political reasons," said one of the two officials.
The Wage Code Bill was sent to the cabinet by the labour ministry, but has been returned to the GoM, headed by Jaitley, for review.
"If it is not possible to pass these in this session, it expects to definitely do so in the next session," said a senior labour ministry official.
Trade unions say they see no visible positive impact of labour law reforms on the job market. "Have we seen the job situation improving in those states? No. Have we seen vigilance going down? Yes.
These are attempts to snatch away the fundamental rights of workers. We had taken to the streets in Rajasthan, we will oppose this too," Brijesh Upadhyay, general secretary of the Bharatiya Mazdoor Sangh, the trade union wing of the ruling BJP government, told Business Standard.
Will the government be ready to bite the bullet and with electoral support behind it?
Photograph: Adnan Abidi/Reuters
Related News: BJP, Rajasthan, FDI, Madhya Pradesh, Centre for Strategic and International Studies

redpajama_set_name: RedPajamaCommonCrawl


For those without a clue, the Buskepelheit report is intended as satire!
Its 1956! Times are changing so fast my head is spinning. They have hydromatic cars now where you don't have to shift, it does it for you. Imagine, the car runs away with you! And they have something called power steering. I was a riveter lady in the war, I'm as strong as an ox; I need power steering like a hole in the head.
But, never mind that, I want to talk about serious matters like who to vote for. I like Ike! Yes, the general is a real American, not like that Stevenson! You let them win, the next thing you know is that you'll have farmers marrying their sheep! I mean, I'm a modern woman born in 1901! I have nothing against a man marrying his dog or whatever. They already smell like each other, so what's the difference?
But, never mind that; what happens out past the paving across America where the cows are kept has nothing to do with what matters. Its the Communists! That Stalin who wants to take over the world! Only Ike knows how to stop him. I know all about war, I didn't just sit at home, you know. During the war, I worked. I built airplanes, flying fortresses! I even had to wear pants, those overalls with the zipper up the front. Imagine! You'd think I could pee standing up!
But, never mind that, its none of your business how I do my business. What matters is voting for President Eisenhower, Vice President Nixon, and Senator Jacob Javits. These are America's leaders of the modern 1950s! And come 1960, Mr. Nixon will be our next President. What an honest man!
You only have to take one look at Mr. Nixon to know the face of integrity! He'd never take a nickel from a crook. He'd never lie, and he would never be foolish enough to try to make friends with Communists like the Red Chinese! God bless America!
Hildegard Buskepelheit was an imaginary chopped liver lady in the 1950s. The above mimeographed letter was found by her nephew Norman in a trunk in her attic in the Bronx following her demise in 1962. Among other items found in the trunk were an 'I Like Ike' button, an early 1940s union membership card, a pair of men's overalls, some official looking documents apparently typed in Lithuanian, several 78 speed vinyl records featuring Ruth Etting, a crumpled tea stained paper napkin from Schraffts seemingly autographed by Christine Jorgensen, and a pair of large sequined ruby high healed shoes.


text:
Il y a plusieurs Gundulf (ou Gondulph(e), Gondolf(e), Gondolphe, Gondoul ; ancien anthroponyme germanique formé des éléments gund, « guerrier », et ulf, « loup ») :

 Gundulf († probablement en 591), patrice de Provence, puis brièvement évêque de Metz en 591. Il était également grand-oncle de Grégoire de Tours.
 Gundulf (v. 524 – † v. 607), vice-roi d'Austrasie, puis évêque de Tongres de 600 à 607.
 Gundulf († 822), évêque de Metz de 816 à 822.
 Gundulf († 1108), évêque de Rochester de 1077 à 1108.
Homonymie de prénom


The U.S. Immigration and Naturalization Service has fined a Westminster auto-parts company nearly $40,000 for hiring illegal immigrants arrested in a raid of the plant last year.
Marada has not paid the fine and is contesting the amount, which is based on the number of violations.
INS agents raided the manufacturing and assembly factory in February and arrested 29 suspected illegal workers, many of whom voluntarily returned to their native countries.
As reported after the arrests, the company could lose $1.5 million in state aid -- loan money which was to be forgiven if the company met hiring quotas.
The raid spawned an investigation into Marada's employment records, which showed several administrative violations, INS officials said.
"We looked at hiring records and uncovered administrative discrepancies -- probably as many as 150 discrepancies," said John Shallman, an INS spokesman. "The fine is a result of an investigation that followed the raid. A dollar figure was assigned to each violation."
Employers are required by law to confirm an employee's identity by reviewing documents such as a driver's license and the applicant's eligibility to work in the United States. Eligibility can be established with a Social Security card or an INS employment card.
INS served notice of the fine Dec. 3 and gave the company 30 days to respond. Marada has asked for time to negotiate a settlement rather than pay $39,730.
"We are now exploring the settlement," Shallman said. "If our attorneys and Marada's are not able to reach a settlement, the issue will go before an administrative judge."
There is no time limit for reaching a settlement, but if the parties cannot come to an agreement, the courts will handle the matter.
Shallman called the amount "average, from what I have seen of fines in the last two years. If an employer knowingly hires an illegal worker, it can be assessed as much as $2,000 per violation."
To convict an employer of breaking immigration laws, INS officials must show that a business has knowingly hired illegal aliens, many of whom carry forged papers.
Marada employs about 450 workers at its plant on Route 97.
"Ninety-nine percent of the employers in the state comply with the provisions of immigration law," said Shallman. "Our goal is to get the remaining 1 percent. That is what fines are all about."
Criminal convictions of companies are rare, but the Marada case has raised concerns among state and local officials.
The company received about $1.5 million in state aid for economic development and job training four years ago. The money was in the form of low-interest loans, but if the company increased its payroll -- then at 250 workers -- by 150 employees, the loans would become grants.
Marada has added 200 workers, and its officials have asked that the loans be retired.
Jack Spangler, Marada's human resource manager and designated spokesman, said through a secretary Friday that he was not accepting calls from reporters and that he had no comment.
State Department of Business and Economic Development officials said Friday they will wait for the results of the negotiations.
If it turns out that illegal hires helped the company reach its employment quota, the loan conversion probably would not happen, said Jacqueline M. Lampell, a spokeswoman for the state Department of Business and Economic Development.
"We received their letter asking for a conversion after we heard word of the raid," Lampell said yesterday. "We will not take any action until the arbitration is completed."
If Marada has not met the employment targets by Dec. 30, 2000, it would be required to start repaying the loan, Lampell said.


(Kerger) Anesthesiologist, Department of Bioengineering.
(Saltzman, Tsai) Research Scientist, Department of Bioengineering.
(Gonzales) Laboratory Technician, Department of Medicine.
(Ackern) Professor of Medicine, Department of Anesthesiology, University of Heidelberg.
(Winslow) Professor of Medicine, Department of Medicine.
(Intaglietta) Professor of Bioengineering, Department of Bioengineering.
Received from the University of California, San Diego, La Jolla, California, and the Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany. Submitted for publication December 8, 1995. Accepted for publication October 3, 1996. Supported by USPHS Grant HLBI 48018. Dr. Kerger is the recipient of a fellowship from the University of Heidelberg, Germany.
Address reprint requests to Dr. Kerger: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093–0412.
Sodium pentobarbital anesthesia may also substantially compromise oxygen delivery at the systemic  and organ levels  due to changes in the cardiovascular and respiratory systems. This appears to be particularly true when severe perturbations, such as hemorrhage or extensive ischemia, are induced, even if such supportive therapeutic measures as mechanical ventilation or oxygen insufflation are used to preserve systemic oxygen uptake. [20,21] Although the impact of PB anesthesia on systemic oxygen delivery, a function of oxygen content and blood flow (cardiac output [CO]), can be assessed accurately, this may not be indicative of oxygen delivery at the microcirculatory level, where local and central regulatory mechanisms may differently alter blood flow and the actual amounts of oxygen delivered to individual tissues.
We simultaneously evaluated macro-(mean arterial pressure [MAP], heart rate, cardiac index [CI]) and microhemodynamic (vessel diameter, red blood cell [RBC] velocity, and blood flow) conditions and respiratory and metabolic parameters to show the extent to which microvascular oxygen delivery and resulting interstitial oxygenation would be affected by alterations at the systemic or microcirculatory level introduced with this type of anesthesia. We made measurements in animals breathing spontaneously or mechanically ventilated with air during anesthesia to address the effect of respiratory depression on the regulation of microcirculatory partial pressure of oxygen (PO2) levels.
We induced PB anesthesia by intravenous injection and subsequently maintained it by continuous infusion, a procedure providing controlled and reproducible levels of anesthesia. We analyzed systemic and microcirculatory parameters during and in various intervals after discontinuation of PB infusion to determine the extent to which this type of anesthesia would compromise microvascular oxygen delivery and interstitial oxygenation during different anesthetic planes and after a recovery period.
We analyzed the effects of PB anesthesia on systemic and microcirculatory parameters in male Syrian golden hamsters (50–70 g body weight) fitted with a dorsal skinfold chamber window preparation,  which provided microscopic access to the vasculature of subcutaneous skeletal muscle. Chamber implantation and catheterization of the carotid artery and jugular vein were performed under PB anesthesia (50 mg/kg body weight injected intraperitoneally; Nembutal, Abbott Laboratories, North Chicago, IL), and experiments were done after a recovery period of 2–3 days after surgical procedures. Only animals with a healthy appearance and integrity of the skinfold preparation (as evident by the absence of inflammation, bleeding, edema, and low flow states) were used in investigations.
For each experiment, anesthesia was induced by an initial intravenous injection of PB (30 mg/kg body weight) from a 10-mg/ml stock solution made from a 50-mg/ml commercial preparation (Nembutal) by dilution with 0.9% sodium chloride (Elkins-Sinn, Cherry Hill, NJ). The PB injection rate was 1 mg/min, which resulted in an induction time of approximately 90–120 s. After 5 min, a continuous infusion of PB at a rate of 2 mg [center dot] kg-1[center dot] min-1was started and continued for 15 min to maintain anesthesia. As previously described for rats, [6,27] anesthesia depth and duration were assessed by the judgment of consciousness, motor activity, muscle tone, and the responses to nonaversive (palpebral, corneal, and jaw reflex) and noxious stimulation. To evaluate noxious stimulus perception, an alligator clip producing 50 g/mm2force was attached for 2 s to the animals' abdomens, tails, and hind paw toes. Any withdrawal or other movements were recorded as positive for nociception.
To investigate the impact of respiratory depression on microvascular and interstitial PO2levels, animals were divided into two groups, one group spontaneously breathing room air throughout experimentation, and the other group of animals tracheally cannulated and subsequently mechanically ventilated with air (FIO2= 0.21). Tracheal cannulation was performed after intravenous PB injection by inserting a small tube (PE 190) into the upper part of the trachea. After tracheal cannulation, animals were immediately connected to a respirator (Rodent Respirator, Harvard Apparatus, Millis, MA) for normal ventilation. Controlled ventilation was performed during PB infusion and for 30 min afterward. Thereafter experimentation was discontinued, because animals began breathing against the respirator and showed symptoms of discomfort.
Mean Arterial Pressure and Heart Rate.
Mean arterial pressure was monitored continuously using a carotid artery catheter connected to a transducer linked to an analog recording system (Beckman R611, Beckman Instruments, Schiller Park, IL). Heart rate was determined both from chart recordings and with a digital monitor specialized for high heart rates (J&MO Technologies, San Diego, CA).
Cardiac Output and Cardiac Index.
Cardiac output measurements were performed in a separate group of ten anesthetized animals spontaneously breathing room air throughout the experiment. These animals were larger in size and body weight (150–200 g) than the animals used to analyze microcirculatory parameters, a technical requirement for the thermodilution technique  used. Cardiac output measurements involved placement of a 1-Fr thermoprobe (Columbus Instruments, Columbus, OH) into the aortic arch via the right carotid artery, which was not feasible in smaller animals. Cardiac output was calculated by a thermodilution CO computer (Cardiotherm 500, Columbus Instruments) that continuously recorded aortic blood temperature and the exact temperature of the 0.175-ml volume of 0.9% sodium chloride injectate (15–20 degrees C), providing an instantaneous digital CO reading of the following saline injection. To provide comparable experimental conditions, animals used for CO measurements also had a dorsal skinfold window installed before experimentation, whereas a PE-50) catheter was inserted into the left jugular vein. For CO experiments, initial intravenous PB injection was performed at a rate of 3 mg/min to maintain the induction period of 90–120 s used in the animals weighing 50–70 g.
Cardiac output was not measured in ventilated animals, because basic macro- and microhemodynamic parameters (MAP, heart rate, microvessel diameter, microvascular blood flow, and RBC velocity) were not substantially different from animals spontaneously breathing air. To exclude the possibility of significant changes in hemodynamics and body temperature related to the repeated cold saline injections over time and the volume of PB injection and infusion, CO was also determined (during a period of 24 h) in five animals that had 0.9% sodium chloride (NaCl) infused. For data presentation, CO (ml/min) was converted into CI (ml [center dot] min-1[center dot] kg-1) accounting for the animals' body weights.
Blood Gases, Base Excess, pH, Hemoglobin, and Hematocrit Concentration.
Blood samples for determination of arterial PO2, arterial carbon dioxide tension (PCO2), base excess and pH (Ciba Corning 238 pH/Blood Gas Analyzer, Ciba Corning Diagnostics, Pleasanton, CA), hemoglobin (B-Hemoglobin Photometer Hemocue AB, Angelholm, Sweden), and hematocrit concentrations (Readacrit Centrifuge, Clay Adams Division of Becton, Dickinson, Parsippany, NJ) were collected in 40- micro liter heparin-washed microtubes (Microhematocrit Capillary Tubes, Scientific Products, Division of Travenol Laboratories, McGraw Park, IL). All blood samples were analyzed immediately and the animals' prevailing central body temperatures were considered when determining blood gas and metabolic parameters.
Body core temperature was measured rectally and dorsal skin temperature was assessed epidermally in three different locations of the outside skinfold preparation area using a microthermometer (model BAT-12, Physitemp Instruments, Clifton, NJ). In animals in which CO measurements were performed, body core temperature was measured continuously with the aortic thermoprobe. Ambient room temperature was maintained at 25 degrees Celsius during the experiments.
Microvessels in the subcutaneous skeletal skin muscle were observed with an inverted microscope (IMT-2, Olympus, New Hyde Park, NY) using a 40x water immersion objective (Olympus WPlan, NA = 0.7) and transillumination technique. Microscopic images were recorded using a camera (Cohu 4815–2000) and transferred to a TV-VCR (Sony Trinitron PVM-1271Q monitor [Tokyo, Japan] and Panasonic AG-7355 video recorder [Tokyo, Japan]).
Before experimentation, microvessels were classified according to branching order in light modification of a nomenclature previously used for the microvasculature in rat skeletal muscle.  Arterioles were grouped into large feeding arterioles (A1), small arcading arterioles (A2), transverse arterioles (A3), and terminal arterioles (A4). Venules were divided into two groups, small collecting (Vc) and large venules (V1). Capillaries and interstitial (tissue) segments (Int) were supplied and drained by the selected arteriolar and venular tree, thus forming a functional unit with these microvessels.
Microvessel Diameter and Red Blood Cell Velocity.
Microvessel diameters and RBC velocities were analyzed on-line in arterioles and venules. Vessel diameter  was measured with an image-shearing system (Digital Video Image Shearing Monitor, model 908, I.P.M., Inc., San Diego, CA), and RBC velocity  was analyzed by photodiodes (Fiber Optic Photo Diode Pickup System, I.P.M., Inc.) and the cross-correlation technique (Velocity Tracker Mod-102 B, I.P.M., Inc.). In capillaries, RBC velocity was measured off-line from video recordings using dual-window and cross-correlation techniques.
Blood flow (Qb) in arterioles and venules was calculated from microvessel diameters (d) and RBC velocity (vRBC) readings according to the formula Equation 1.
Functional capillary density was analyzed on-line from four to six video-recorded microscopic fields exhibiting three to six different capillaries each. It was defined as the number (percentage) of perfused capillaries in which functionality was assumed only if there was RBC flow over the entire capillary length (400–800 micro meter). We selected 15–20 different capillaries supplied from different terminal (A4) arterioles branching from the selected transverse (A3) arteriole. Because each A3 arteriole feeds 60–80 capillaries, measurements covered approximately 20–25% of anatomic capillary density related to this blood vessel. This corresponds to a tissue area of about 0.24–0.96 mm2, which is. 0.3–1.2% of the entire skinfold preparation area.
Subcutaneous microvascular and interstitial PO2were determined with the previously described phosphorescence decay technique. [24–26] Based on the oxygen-dependent quenching of phosphorescence emitted by albumin-bound metalloporphyrin complexes after pulsed light excitation, the method allows noninvasive assessment of intravascular and interstitial PO2, because intravascularly injected porphyrin complexes extravasate into the interstitium over time. The relation between phosphorescence lifetime tau and oxygen tension is given by the Stern-Volmer Equation 2where tauOand tau (micro s) are the phosphorescence lifetimes in the absence of molecular oxygen and at a given PO2, respectively, and kq (Torr [center dot] s-1) is the quenching constant, both factors being pH and temperature dependent.
Palladium-meso-tetra (4-carboxyphenyl) porphyrin (Porphyrin Products, Logan, UT) after previous binding to serum albumin and dilution in sodium chloride 0.9%(Elkins-Sinn) to a concentration of 15 mg/ml was used as a phosphorescent probe (tauO= 600 micro s, kq = 325 Torr/s at pH 7.4 and 37 degrees C) and intravenously injected (30 mg/kg body weight).
Although initial studies with albumin-bound palladium-porphyrin did not show consistent extravasation of the dye into the interstitium over time,  subsequent refinements of the technique permitted fewer light pulses and an increased observation period without evidence of vasoconstriction and revealed the presence of the porphyrin compound in the interstitium. The reflection coefficient for albumin in subcutaneous tissue ranges from 0.8–0.9, causing natural and continuous extravasation, which in this preparation yields a measurable (steady-state) concentration of the albumin-bound porphyrin complex about 20–30 min after dye injection. The dye is evenly distributed in the interstitium, because there is no evidence for significant variability in signal strength when no underlying blood vessels are present. In addition, size of the sampled (interstitial) volume, which is determined by the adjustable slit, does not significantly alter PO2readings as long as there is no spatial interference with the adjacent microvasculature. In these experiments, all microvascular and interstitial PO2measurements were performed within 5–10 min after the initial equilibration period of 20–30 min after dye injection.
Systemic and microcirculatory effects of PB anesthesia were investigated in 42 animals, with 28 animals spontaneously breathing (PB-S) and 14 animals tracheally cannulated and mechanically ventilated with air (PB-V) during experimentation. In nonventilated animals, repeated measurements of systemic and microhemodynamic parameters were performed before, during PB infusion, and at 30-min, 90-min, and 24-h intervals thereafter. The effect of PB anesthesia on CO and CI was investigated in a separate group of 10 (nonventilated) animals in identical intervals. In ventilated animals, experiments were discontinued 30 min after PB infusion.
In both anesthetized groups (PB-S and PB-V), microvascular and interstitial PO2values were analyzed in groups of seven animals independently for each time point during and after PB infusion, respectively. Systemic and microhemodynamic parameters in these animals did not differ statistically relative to each measuring time point. Repeated PO2measurements over time in the same animals were avoided to exclude microcirculatory side effects due to excessive light exposure and resulting porphyrin excitation. Control PO2measurements were assembled in an independent group of seven animals.
To exclude the possibility of significant time-related changes due to the volume of solution required for the PB infusion, blood sampling or deterioration of the preparation, systemic and microhemodynamic parameters were also investigated in a group of 14 animals (NaCl) that received an identical quantity of 0.9% sodium chloride. Repeated microvascular and interstitial PO2measurements over time were not performed in these animals, because there was no evidence of significant time variability in hemodynamic, respiratory, or metabolic parameters. Repeated measurements of CO and CI were also performed in a group of five animals that received infusions of 0.9% NaCl.
Data are shown as means +/- SDs. Because this study was to show time-related changes due to alterations in anesthesia depth and state of consciousness, all statistical comparisons within the different groups (PB-S, PB-V, and NaCl) were made by repeated measures analysis of variance and post hoc tests whenever indicated. Statistical comparisons between the PB-S and PB-V groups were also made by analysis of variance. For all statistical tests, 5%(P < 0.05) was the minimum level of significance considered.
After sporadic incidences of excitation, shown by vigorous body movements,  animals rapidly lost consciousness during initial PB injection. A surgical anesthetic plane adequate for moderately painful procedures was present throughout the following infusion period. This could be concluded (in nonventilated animals) from the response to nonaversive and noxious stimulation indicating the absence of muscle tone, the palpebral and jaw reflex, and tolerance of abdominal and tail pinches. [6,27] It was also shown in the group of ventilated animals that tolerated tracheal cannulation subsequent mechanical ventilation without evidence of symptoms of pain or distress. A light anesthetic plane adequate for minimally painful interventions was still maintained 30 min after discontinuation of PB infusion. Shortly after this point, ventilated animals began to fight the respirator and showed symptoms of discomfort. Nonventilated animals, which were followed for 24 h, all regained consciousness and normal motor activity 90 min after PB infusion. Recovery from anesthesia was associated with sporadic occurrences of animal excitation.  Even though the animals' airways were not secured by tracheal cannulation and no supplemental oxygen was provided, the experimental procedure was tolerated very well, as evident by normal sleeping and feeding habits and normal motor activity 24 h after the experiments.
Sodium pentobarbital anesthesia caused substantial macrohemodynamic depression as shown by decreases in CO, CI, and MAP (Figure 1). In nonventilated animals, CO and CI decreased by 22% from 60.8 +/- 9.4 ml/min and 330.9 +/- 24.1 ml [center dot] min-1[center dot] kg (-1) at baseline (Bsln) to 47.4 +/- 8.3 ml/min and 257.4 +/- 20.6 ml [center dot] min-1[center dot] kg-1during PB infusion (Inf). Cardiac output and CI readings (Bsln) were in a range previously reported for this animal species.  Mean arterial pressure decreased from 113.2 +/- 14.7 mmHg (Bsln) to 83.1 +/- 20.3 mmHg (Inf) in animals spontaneously breathing air, whereas MAP decreased from 101.7 +/- 15.5 mmHg (Bsln) to 71.1 +/- 18.1 mmHg (Inf) in ventilated animals. Cardiac output and CI were not determined in ventilated animals, because basic macro- and microhemodynamic parameters were not significantly different from those in animals spontaneously breathing air. Although CO, CI, and MAP increased during the recovery period, values did not return to normal levels 90 min after PB infusion. Induction of PB anesthesia was associated with a light, but not significant, increase in MAP and heart rate (not shown in Figure 1). Heart rates declined relatively during PB infusion, but changes were not significant. Macrohemodynamic parameters (CO, CI, MAP, and heart rate) did not change significantly over time in animals that received 0.9% NaCl (Figure 1).
Figure 1. Mean arterial pressure (MAP), heart rate, and cardiac index (CI) during sodium pentobarbital (PB) anesthesia. Bsln = baseline. Inf = PB infusion. All statistical comparisons were made against baseline in each group (anesthetized animals breathing spontaneously [PB-S] or ventilated with air [PB-V] and nonanesthetized animals [NaCl] receiving 0.9% sodium chloride) and between the PB-S and PB-V groups. *Significantly different from baseline (P < 0.05).
Hemoglobin and hematocrit concentrations did not change significantly during PB infusion and after 30 min but were slightly, although significantly (P < 0.05), decreased in nonventilated animals 90 min (13.9 +/- 1.4 g/dl and 44 +/- 3.2%) and 24 h (14.2 +/- 0.8 g/dl and 45.7 +/- 1.7%) after infusion (Table 1). A comparable reduction in both parameters was observed in nonanesthetized animals.
Sodium pentobarbital anesthesia also caused a significant (P <0.05) decrease in rectal and skin temperatures in all animals, which were approximately 2 degrees C and 1 degree Celsius, respectively (Table 1). In anesthetized animals in which CO and CI were determined, aortic temperature decreased by [nearly equal] 1.5 degrees C during PB infusion and after 30 min. Normal temperature levels were sustained during the entire 24-h observation period in animals receiving 0.9% NaCl.
Sodium pentobarbital anesthesia caused significant (P < 0.05) respiratory depression in nonventilated animals, as shown by the decrease in systemic arterial PO2values +/- 18.2 mmHg (Bsln) to 56 +/- 12.8 mmHg (Inf) and the increase of PCO2values from 43.8 +/- 8.4 mmHg (Bsln) to 57.7 +/- 9.1 mmHg (Inf)(Figure 2). These changes were associated with a decline in arterial blood pH from 7.37 +/- 0.05 (Bsln) to 7.22 +/- 0.05 (Inf). This reduction of blood pH exhibited predominantly respiratory acidosis, because base excess only slightly decreased from 1.8 +/- 3.8 mM (Bsln) to -1.8 +/- 3.4 mM (Inf). This decline persisted during the following 90 min. Relative increase of PO2and decrease of PCO2levels at that time were indicative of a tendency of hyperventilation; changes, however, not reaching significance.
Figure 2. Arterial blood gases, base excess, and pH during sodium pentobarbital (PB) anesthesia. Bsln = baseline. Inf = PB infusion. All statistical comparisons were made against baseline in each group (anesthetized animals breathing spontaneously [PB-S] or ventilated with air [PB-V] and nonanesthetized animals [NaCl] receiving 0.9% sodium chloride) and between the PB-S and PB-V groups. *Significantly different from baseline. **Significantly different between the PB-S and PB-V groups (P < 0.05).
In ventilated animals, systemic arterial PO2values increased from 61.4 +/- 12.6 mmHg (Bsln) to 115.9 +/- 14.6 mmHg (Inf) and 109.0 +/- 16.1 mmHg during the following 30-min period (Figure 2). Although PCO2values and pH (46.1 +/- 7.1 mmHg and 7.36 +/- 0.05 at Bsln) were maintained at normal levels in these animals, base excess decreased from 3.3 +/- 2.5 mM (Bsln) to 0.2 +/- 2 mM (Inf) and -0.4 +/- 2.1 mM at 30 min. In saline-infused animals, blood gas and metabolic parameters did not change significantly over time.
At the microcirculatory level, PB anesthesia caused a significant reduction of oxygen tension in arterioles and venules and in the interstitium of this preparation. In feeding (A1) arterioles, PO(2) values declined from 58.6 +/- 4.9 mmHg at control (Ctrl) to 46.8 +/- 4.9 mmHg and 43.2 +/- 10.4 mmHg (Inf) in ventilated and nonventilated animals, respectively (Figure 3). Resulting PO2, values (Inf) in terminal (A4) arterioles were 23.6 +/- 7.3 mmHg (ventilated animals) and 20.9 +/- 7.8 mmHg (nonventilated animals) versus 35.2 +/- 7.9 mmHg at Ctrl. Correspondingly, interstitial PO2decreased from 23.9 +/- 5.6 (Ctrl) to 15.2 +/- 7 mmHg and 13.1 +/- 9.1 mmHg (Inf) in the ventilated and nonventilated groups, respectively (Figure 4). In both groups, there was also a significant decrease in oxygen tension of 45–55% in the venular system of this preparation (Figure 4). Although microvascular and interstitial PO2levels were slightly higher in ventilated animals, when compared with animals spontaneously breathing air, these differences were not significant. In both groups, microvascular and interstitial PO2values were restored to low-normal levels 30 min after PB infusion, an effect that was sustained in nonventilated animals during the following 90-min and 24-h periods.
Figure 3. Microvascular PO2in A1-A4 arterioles of the skinfold preparation during sodium pentobarbital (PB) anesthesia. Ctrl = control. Inf = PB infusion. All statistical comparisons were made against control and between anesthetized animals breathing spontaneously (PB-S) or ventilated with air (PB-V). *Significantly different from control (P <0.05).
Figure 4. Interstitial and venular PO2in the skinfold preparation during sodium pentobarbital (PB) anesthesia. Int = interstitium. Vc = small collecting venule. V1 = large venule. Ctrl = control. Inf = PB infusion. All statistical comparisons were made against control and between anesthetized animals breathing spontaneously (PB-S) or ventilated with air (PB-V). *Significantly different from control (P <0.05).
Sodium pentobarbital anesthesia also caused significant alterations in arteriolar and venular (micro-) hemodynamics. During and 30 min after PB infusion, vessel diameters of feeding (A1) arterioles significantly (P < 0.05) decreased in both groups (Figure 5). A significant decline of vessel diameters was also observed in arcade (A2) arterioles in the ventilated and in transverse (A3) arterioles in the nonventilated animals during PB infusion. Microvessel diameters did not change significantly in A4 arterioles and venules and in animals receiving 0.9% NaCl. Vasomotion was not seen in the anesthetized or nonanesthetized groups at any time.
Figure 5. Diameter changes (%) in arterioles (A1-A4) and venules (Vc and V1) of the skinfold preparation during sodium pentobarbital (PB) anesthesia. Vc = small collecting venule. V1 = large venule. Bsln = baseline. Inf = PB infusion. All statistical comparisons were made against baseline in each group (anesthetized animals breathing spontaneously [PB-S] or ventilated with air [PB-V] and nonanesthetized animals [NaCl] receiving 0.9% sodium chloride) and between the PB-S and PB-V groups. *Significantly different from baseline (P < 0.05). Baseline microvessel diameters in each group are summarized in Table 2.
In all anesthetized animals, there was a significant (P < 0.05) reduction of microvascular blood flow in the arteriolar and venular system of this preparation, which was approximately 25–55%(Figure 6) and paralleled by a comparable decrease in microvascular RBC velocities (not shown in Figure 6). Blood flow and velocity rates were not significantly different in ventilated and nonventilated animals. Normal values were not restored in all microvessels 30 and 90 min after PB infusion, although blood flow and RBC velocity increased relatively over time. Both parameters were not significantly altered in animals receiving 0.9% NaCl. Baseline microhemodynamics in anesthetized and nonanesthetized animals are summarized in Table 2.
Figure 6. Blood flow changes (%) in arterioles (A1-A4) and venules (Vc and V1) of the skinfold preparation during sodium pentobarbital (PB) anesthesia. Vc = small collecting venule. V1 = large venule. Bsln = baseline. Inf = PB infusion. All statistical comparisons were made against baseline in each group (anesthetized animals breathing spontaneously [PB-S] or ventilated with air [PB-V] and nonanesthetized animals [NaCl] receiving 0.9% sodium chloride) and between the PB-S and PB-V groups. *Significantly different from baseline (P < 0.05). Baseline blood flow and corresponding red blood cell velocity in each group are summarized in Table 2.
During PB infusion, functional capillary density decreased by 15–20%, with no significant difference between ventilated and nonventilated animals (Figure 7). In both groups, capillary RBC velocity declined by 35–45%(Inf) and was not restored to normal levels 30 min thereafter. Normal functional capillary density and capillary RBC velocity were sustained in nonanesthetized animals receiving 0.9% NaCl. Baseline capillary RBC velocities in the anesthetized and nonanesthetized groups are summarized in Table 2.
Figure 7. Changes (%) of functional capillary density (FCD) and capillary red blood cell (RBC) velocity in the skinfold preparation during sodium pentobarbital (PB) anesthesia. Bsln = baseline. Inf = PB infusion. All statistical comparisons were made against baseline in each group (anesthetized animals breathing spontaneously [PB-S] or ventilated with air [PB-V] and nonanesthetized animals [NaCl] receiving 0.9% sodium chloride) and between the PB-S and PB-V groups. *Significantly different from baseline (P < 0.05). Baseline capillary RBC velocities in each group are summarized in Table 2.
The principle finding of this study was that intravenously induced and maintained PB general anesthesia caused a significant (P <0.05) reduction of microvascular and interstitial PO2levels in subcutaneous skeletal muscle. This decrease in oxygen tension at the microcirculatory level was not prevented by mechanical ventilation, even though systemic arterial PO2values were significantly increased. Marked macro- and microhemodynamic depression coincided with a temporary oxygen supply deficit observed in this microcirculatory environment.
The PB-induced decrease in CO would appear to account for the MAP reduction, which was of similar time, course, and magnitude. The reduced CO and resulting MAP decrease may constitute an important mechanism for microvascular blood flow reduction observed in this microcirculatory environment. This may also be concluded from the similar time course of changes in these parameters during anesthesia and after the recovery period. Furthermore, a low intravascular driving pressure caused a significant decrease in arteriolar and venular RBC velocities, a result that can also be attributed to the decrease in CO.
Microvascular blood flow impairment exceeded CO and MAP reduction, and there was also a significant (P < 0.05) decrease in arteriolar diameters during PB infusion and after the 30-min recovery period. These effects, however, may be due only in part to vasoconstriction caused by increased sympathetic tone and related to the presence of severe hypothermia. [17,32] This is supported by previous investigations in which PB was shown to suppress plasma catecholamine levels and to decrease reflex responses of sympathetic nerve activities controlling different organs in response to stimulation of arterial baro- and chemoreceptors. [2,17,18] Although these suppressive effects may vary considerably,  observed decreases in vessel diameters may also be due to enhanced microvascular tone secondary to the decrease in blood flow and resulting from suppressed release of endothelial flow-dependent relaxing factors. [33,34] Microvascular blood flow impairment may also be, in part, the consequence of a blood flow reduction and redistribution occurring in closer proximity to the systemic circulation, but this could not be visualized in this microcirculatory model.
Findings on microvascular reactivity in this study do not correspond with previous results, in which PB anesthesia caused arterial (arteriolar) and venous (venular) vasodilation, [14–16] attributed to the inhibition of calcium influx through voltage-dependent and receptor-operated channels of plasma membranes. [14,16] Differences in experimental models and superimposition of local and central regulatory mechanisms, however, may explain the discrepancy in results.
We must emphasize that, even under normal conditions, arterioles play a key role in (interstitial) tissue oxygenation by direct oxygen unloading because the vessel wall is a limited barrier to the diffusion of oxygen, having a diffusion constant similar to that of water. [37,38] Even if under the conditions of anesthesia arteriolar oxygen was unloaded relatively faster, this process could not compensate for the oxygen deficit generated at the capillary level, as indicated by significantly decreased PO2values in terminal (A4) arterioles and thus preserve normal interstitial oxygenation. This is due to the fact that the absolute amounts of oxygen exiting the arteriolar vessel lumen are smaller than normal due to decreased intravascular oxygen availability.
Considering that the capillary network represents the largest area of oxygen transfer to the tissue (interstitium), marked decreases (40–45%) in interstitial PO2values may also be related to a slight decrease in functional capillary density during PB infusion and to substantially reduced capillary RBC velocities, an effect that was sustained throughout the 30-min follow-up period. Capillary perfusion impairment was a consequence of arteriolar blood flow and RBC velocity reduction.
Substantial blood flow impairment during PB anesthesia was also found previously in other vascular beds, including the heart,  brain,  splanchnic organs, [3,4,9] and skeletal muscle circulation,  using different animal models and measuring techniques such as microspheres  or the Doppler flow method. [4,9] Considering that in unanesthetized animals different levels of motor activity shown by periods of sleep, sleepiness, or vigorous body movements did not translate into significant changes of CO, MAP, microvascular blood flow, and capillary perfusion, we cannot conclude that in PB-anesthetized animals hemodynamic depression and the resulting PO2decrease at the microcirculatory level were primarily due to a lower activity state in these animals.
In animals spontaneously breathing air, PB anesthesia caused respiratory depression resulting in significant pulmonary hypoventilation as shown by the decrease in arterial PO2and increase in arterial PO2levels that was associated with mild, predominantly respiratory acidosis. [11–13] Previous investigations in hamsters have shown that PB anesthesia may substantially alter normal lung and airways mechanics, resulting in significantly decreased lung volume and compliance and in multiple-resistance increase.  These factors could substantially compromise pulmonary gas exchange and imply the occurrence of severe arterial hypoxemia, but we did not find this in our study because there was only a moderate decrease in arterial oxygen tension (56 +/- 12.8 mmHg compared with 69.4 +/- 18.2 mmHg at Bsln). This is a notable finding, because the animals' airways were not secured by tracheal cannulation and no supplemental oxygen was provided.
Although respiratory depression by decreasing arterial blood oxygen content may have contributed to the decreased oxygen availability at the microcirculatory level in these animals, this effect cannot be considered as the principle mechanism of impaired microvascular oxygen delivery and interstitial oxygenation. This is emphasized by the fact that in ventilated animals, in which systematic arterial PO2values were maintained at high levels (> 100 mmHg), microvascular and interstitial PO2values were not significantly increased compared with animals breathing air spontaneously. This is a remarkable finding because there was no significant difference in macro- and microhemodynamic conditions between ventilated and nonventilated animals. This suggests that a similar extent of hemodynamic depression in both groups was the principle mechanism of temporary oxygen supply deficit in this microcirculatory environment.
In all animals, microvascular and interstitial PO2s were restored to normal levels 30 min after PB infusion was discontinued, even though a light anesthetic plane, adequate for minimal invasive procedures, was maintained. A relative increase in systemic arterial PO2values to normal levels, however, may not be the principle mechanism of microcirculatory PO2recovery in nonventilated animals, because in ventilated animals, under comparable hemodynamic conditions, high systemic PO2s were sustained. Therefore, recovery of microvascular and interstitial PO2levels may be primarily related to a relative improvement in macro- and microhemodynamics, although normal conditions were not yet restored. Persisting hemodynamic depression may explain why microvascular and interstitial PO2levels were still in a "low normal" range at that time. In nonventilated animals, which were followed for 24 h, slight hemodynamic depression was maintained 90 min after PB infusion was discontinued, even though all animals regained consciousness and exhibited normal motor activity. This finding further emphasizes that changes in hemodynamics and oxygen delivery during PB anesthesia cannot be related primarily to a lower level activity state but must be attributed to direct cardiovascular effects of this anesthetic agent.
In conclusion, PB anesthesia caused significant impairment of microvascular oxygen delivery and interstitial oxygenation in the hamster skinfold preparation. These effects were related to marked macro- and microhemodynamic depression as shown by significant decreases in CO, MAP, and microvascular blood flow. Controlled ventilation, increasing arterial blood oxygen content, did not significantly improve interstitial oxygenation. This suggests that respiratory depression was not a principle mechanism of impaired oxygen delivery. Normal microvascular and interstitial PO2levels were restored 30 min after PB infusion was discontinued, even though a light anesthetic plane was maintained. Prolonged macro- and microhemodynamic depression, however, suggest that caution may be warranted when using PB as an anesthetic in cardiovascular investigations (that is, those involving hemorrhage).
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When caught in a storm of biblical proportions, it pays to have Russell Crowe in your corner.
The "Gladiator" star is front and center in a visually dazzling first look at Darren Aronofsky's "Noah." The adaptation of the First Testament story adheres to the part about Noah constructing an ark to transport the world's animal population to higher ground with some heavenly assistance, but heightens the action.
The trailer shows Crowe facing off against some nasty looking warriors who seem hellbent on taking over the ark for themselves.
"I have men at my back and you stand alone and defy me," Ray Winstone as Noah's nemesis Tubal-cain, says at one point in the spot.
"I'm not alone, " Crowe intones in response. Smack.
The film itself has been controversial, with reports of budget overruns and unease among members of various religious organizations bubbling up in advance of its release next spring, but the early footage seems both reverent and galvanizing.
The cast is all top shelf, featuring Jennifer Connelly, Logan Lerman, Anthony Hopkins and Emma Watson. Moreover, the flood looks pretty dazzling.
"Noah" debuts on March 27, 2014.


We observed the birth of a common bottlenose dolphin (Tursiops truncatus) followed immediately by a possible infanticide attempt in the estuary near Savannah, Georgia. Our report is unique in several ways: first, we witnessed the birth of the calf; second, we observed infanticidal behavior almost immediately afterward; and third, we obtained acoustic recordings concurrent with the possible infanticidal behavior. Our observations provide insight into aggressive, possible infanticidal, behavior in bottlenose dolphins.


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