May 12, 2009

A New Virus Emerges

Novel influenza A (H1N1) is a new flu virus of swine origin that was first detected in April, 2009. The virus is infecting people and is spreading from person-to-person, and has sparked a growing outbreak of illness in the United States with an increasing number of cases being reported internationally as well.

CDC anticipates that there will be more cases, more hospitalizations and more deaths associated with this new virus in the coming days and weeks because the population has little to no immunity against it. Novel influenza A (H1N1) activity is now being detected in two of CDC’s routine influenza surveillance systems as reported in the May 8, 2009 FluView. FluView is a weekly report that tracks U.S. influenza activity through multiple systems across five categories.

The May 8 FluView found that the number of people visiting their doctors with influenza-like-illness is higher than expected in the United States for this time of year. Second, laboratory data shows that regular seasonal influenza A (H1N1), (H3N2) and influenza B viruses are still circulating in the United States, but novel influenza A (H1N1) and “unsubtypable”* viruses now account for a significant number of the viruses detected in the United States.

It’s thought that novel influenza A (H1N1) flu spreads in the same way that regular seasonal influenza viruses spread; mainly through the coughs and sneezes of people who are sick with the virus.

CDC continues to take aggressive action to respond to the outbreak. CDC’s response goals are to reduce the spread and severity of illness, and to provide information to help health care providers, public health officials and the public address the challenges posed by this new public health threat.

20090513-1

A New Virus Emerges

Novel influenza A (H1N1) is a new flu virus of swine origin that was first detected in April, 2009. The virus is infecting people and is spreading from person-to-person, and has sparked a growing outbreak of illness in the United States with an increasing number of cases being reported internationally as well.

CDC anticipates that there will be more cases, more hospitalizations and more deaths associated with this new virus in the coming days and weeks because the population has little to no immunity against it. Novel influenza A (H1N1) activity is now being detected in two of CDC’s routine influenza surveillance systems as reported in the May 8, 2009 FluView. FluView is a weekly report that tracks U.S. influenza activity through multiple systems across five categories.

The May 8 FluView found that the number of people visiting their doctors with influenza-like-illness is higher than expected in the United States for this time of year. Second, laboratory data shows that regular seasonal influenza A (H1N1), (H3N2) and influenza B viruses are still circulating in the United States, but novel influenza A (H1N1) and “unsubtypable”* viruses now account for a significant number of the viruses detected in the United States.

It’s thought that novel influenza A (H1N1) flu spreads in the same way that regular seasonal influenza viruses spread; mainly through the coughs and sneezes of people who are sick with the virus.

CDC continues to take aggressive action to respond to the outbreak. CDC’s response goals are to reduce the spread and severity of illness, and to provide information to help health care providers, public health officials and the public address the challenges posed by this new public health threat.

Increased Testing

CDC has developed a PCR diagnostic test kit to detect this novel H1N1 virus and has now distributed test kits to all states in the U.S. and the District of Columbia and Puerto Rico. The test kits are being shipped internationally as well. This will allow states and other countries to test for this new virus. This increase in testing will likely result in an increase in the number of confirmed cases of illness reported. This, combined with ongoing monitoring through Flu View should provide a fuller picture of the burden of disease in the United States over time.

CDC is issuing updated interim guidance daily in response to the rapidly evolving situation.

Clinician Guidance

CDC has issued interim guidance for clinicians on identifying and caring for patients with novel H1N1, in addition to providing interim guidance on the use of antiviral drugs. Influenza antiviral drugs are prescription medicines (pills, liquid or an inhaler) with activity against influenza viruses, including novel influenza H1N1 viruses. The priority use for influenza antiviral drugs during this outbreak is to treat severe influenza illness, including people who are hospitalized or sick people who are considered at high risk of serious influenza-related complications.

Public Guidance

In addition, CDC has provided guidance for the public on what to do if they become sick with flu-like symptoms, including infection with novel H1N1. CDC also has issued instructions on taking care of a sick person at home. Novel H1N1 infection has been reported to cause a wide range of symptoms, including fever, cough, sore throat, body aches, headache, chills and fatigue. In addition, a significant number of people also have reported nausea, vomiting or diarrhea. Everyone should take everyday preventive actions to stop the spread of germs, including frequent hand washing and people who are sick should stay home and avoid contact with others in order to limit further spread of the disease.

*Unsubtypable viruses are viruses that through normal testing cannot be subtyped as regularly occurring human seasonal influenza viruses. In the context of the current outbreak, it’s likely that most of these unsubtypable viruses are novel H1N1.

See Also:
FluView Surveillance Report (PDF 277KB)
For the week ending May 2, 2009

U.S. Human Cases of H1N1 Flu Infection

(As of May 12, 2009, 11:00 AM ET)

States* Laboratory

confirmed

cases

Deaths
Alabama 9  
Arizona 187  
California 193  
Colorado 44  
Connecticut 28  
Delaware 45  
Florida 55  
Georgia 4  
Hawaii 6  
Idaho 2  
Illinois 554  
Indiana 61  
Iowa 55  
Kansas 22  
Kentucky** 10  
Louisiana 20  
Maine 6  
Maryland 23  
Massachusetts 107  
Michigan 133  
Minnesota 24  
Missouri 14  
Montana 1  
Nebraska 19  
Nevada 12  
New Hampshire 16  
New Jersey 7  
New Mexico 30  
New York 192  
North Carolina 11  
Ohio 7  
Oklahoma 14  
Oregon 74  
Pennsylvania 17  
Rhode Island 7  
South Carolina 32  
South Dakota
3
 
Tennessee
54
 
Texas
206
2
Utah 67  
Vermont
1
 
Virginia
17
 
Washington 176 1
Washington, D.C. 7  
Wisconsin
437
 
TOTAL*(45) 3009 cases 3 deaths
International Human Cases of Swine Flu Infection

See: World Health Organization

*includes the District of Columbia

**one case is resident of KY but currently hospitalized in GA.

NOTE: Because of daily reporting deadlines, the state totals reported by CDC may not always be consistent with those reported by state health departments. If there is a discrepancy between these two counts, data from the state health departments should be used as the most accurate number.

Antivirals Should Be Used Only in High-Risk H1N1 Flu Cases

May 12, 2009 – The World Health Organization (WHO) is developing clinical management guidelines for the use of antivirals in the treatment of the novel influenza A (H1N1) strain, and both WHO and the Centers for Disease Control and Prevention (CDC) are advising against overuse except in higher-risk cases, the agencies announced today.

Dr. Nikki Shindo, medical officer in the WHO Global Influenza Program and leader of the clinical team of the WHO response to the H1N1 influenza outbreak, noted during a media briefing that the new guidance will highlight “the fact that most of the patients will not require hospitalization or antiviral therapy.”

The latest WHO estimate of confirmed H1N1 influenza cases is 5251 cases in 30 countries.

According to Dr. Shindo, simple supportive therapy, such as antipyretics and hydration are “sufficient” for many cases. Other supportive therapies include oxygen and antibiotics. The guidelines recommend against using aspirin due to the risk of Reye’s syndrome.

“We have seen a spectrum of disease from mild, typically what you call influenza-like illness…to very severe form of this disease, this is pneumonia sometimes requiring mechanical ventilation,” she said. Many of the severe illnesses and deaths occurred in persons with underlying chronic medical conditions, but it is still unknown why many severe cases were also occurring in healthy adults and children, she said.

Dr. Shindo pointed out that European countries have been using antivirals aggressively compared with countries such as Mexico and the United States, and while it remains to be confirmed, this “could be the reason why we are seeing less severe cases in European countries.” She noted that in seasonal influenza, emergence of resistance does not seem to be directly related to use of antivirals in a given country.

As of today, the CDC is reporting about 3600 probable and confirmed cases in 46 states and Washington, DC, with 3002 confirmed cases in 44 states and Washington, DC, with 3 reported fatalities. A total of 116 hospitalizations have been reported. Currently, 29 states are doing their own confirmatory testing for the novel H1N1 influenza strain.

Pregnant Women at Higher Risk for Complications

Today’s media briefing at the CDC was led by Anne Schuchat, MD, the interim deputy director for Science and Public Health Program, and focused on the effects of H1N1 influenza on pregnant women.

“Pregnant women are at higher risk of complications with influenza…and we are also seeing some severe complications among pregnant women in this year’s novel H1N1 virus problem,” Dr. Schuchat said. “We have about 20 cases under investigation” in pregnant women.

According to Dr. Schuchat, a few of the pregnant patients have had severe complications, including 1 fatality. Influenza can cause worse complications in pregnancy, including pneumonia, and dehydration and problems for newborns.

“We think it’s very important when doctors are caring for pregnant women who they suspect may have influenza, that they issue prompt treatment with antiviral medicines,” she said. “Sometimes physicians are reluctant to treat pregnant women with medicines and pregnant women are reluctant to take medicines…” but “the benefits of using antiviral drugs to treat influenza in a pregnant woman outweigh the theoretical concerns about the drug.”

Oseltamivir or zanamivir can both be used in pregnancy.

It remains unclear how the virus will spread during the fall, Dr. Schuchat told Medscape Infectious Diseases during the press conference. The simultaneous circulation of the highly transmissible novel H1N1 strain, the very virulent H5N1 avian strain, and the oseltamivir-resistant H1N1 seasonal influenza strain is an “unfortunate circumstance,” she added.

From Medscape Medical News

Hitt, PhD

May 12, 2009 – The World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) are both reporting ongoing spread of the influenza A (H1N1) virus, and both agencies caution against thinking that the pandemic is losing steam.

“We believe there is sustained community transmission, person-to-person in 2 countries in 1 region, which is North America,” said Keiji Fukuda, MD, MPH, assistant director-general ad. interim for health security and environment at the WHO.

“We cannot predict the future, so it is possible that we will go up to phase 6…but it is also possible for the current situation to stabilize where it is now and then it is possible that we would go back down to phase 4 in the future,” Dr. Fukuda said today at a media briefing. “Most community transmission is taking place in Mexico and the United States, but not elsewhere in the world,” he added.

The WHO continues to see an increase in H1N1 influenza cases being reported by countries. As of 2 am EDT, 4694 laboratory-confirmed cases from 30 countries were reported, including the first case in China. A total of 53 deaths have been reported.

Stituation Still Evolving

The WHO has repeatedly been asked whether this is a “mild event,” Dr. Fukuda noted. “And we have responded by saying, ‘we are not sure right now – the situation is evolving,’ ” he said.

He added that “most people who get infected develop mild illness, but in fact, some people develop serious illness and some of the people die,” he said. “And we know that among those people who develop serious illness and who die, we know that many of them are young healthy adults.”

To try to get a sense of the differences in severity among countries, one of the things the WHO is doing is to focus more on the disease impact on people, which is the parameter that is “most easy to compare from country to country,” he said.

Third American Death Reported

At a CDC media briefing today, Anne Schuchat, MD, director of the CDC’s National Center for Immunization and Respiratory Diseases, noted that in the United States, 3300 probable and confirmed cases in 46 states and Washington, DC, have been reported, with 2600 confirmed cases in 43 states and Washington, DC. To date, there are 3 known fatalities, 2 in Texas and 1 in Washington state, all 3 of whom had underlying medical problems. A total of 94 confirmed H1N1 influenza cases in the United States have required hospitalization.

According to Dr. Schuchat, 116 CDC personnel have been deployed. In addition, 5 virus isolates have been sent to 8 labs to identify which would be best to develop into a vaccine.

The CDC continues to receive about 300 to 400 specimens a day for testing, but few states currently have significant backlogs, she said.

“The numbers tell us for sure that this virus is circulating throughout the United States and it’s likely that it’s found in every state,” Dr. Schuchat said. “The numbers tell us that more people have become ill and more people are likely to become ill, but we continue to see that most people who are becoming all with this virus tend to recover.”

The CDC estimates that among the various forms of influenza circulating in the United States, about 40% are currently of the influenza A (H1N1) strain.

Moving Toward Use of Epidemiologic Systems

According to Dr. Schuchat, the CDC is moving toward less of a focus on the individual numbers and more toward reporting H1N1 cases using epidemiologic systems set up for seasonal influenza, such as the weekly “FluView” surveillance report.

“I think there’s a perception out there that we are winding down, that we’re in a lull,” she said. “It’s a time where we really need to guard against complacency…and we don’t know what will happen come the fall.”

A report in the May 15 issue of Science uses surveillance data to create a picture of the H1N1 influenza outbreak to date. “Our early analysis would suggest this is going to be an outbreak comparable to that of 20th-century pandemics regarding the extent of its spread – it’s very difficult to quantify the human health impact at this stage, however,” noted study author Prof. Neil Ferguson of Imperial College London, United Kingdom, in a news release.

The authors estimate that between 6000 and 32,000 infections occurred in Mexico by April 30 and that the death rate is between 0.4% to 1.4%. The outbreak seems to have started in mid-February in the village of La Gloria, Veracruz.

New York Times contributor Roni Caryn Rabin weighs in with a first-hand account of swine flu outbreak in Queens, New York.

Fear was spreading faster than any virus could. Hand sanitizer was flying off the shelves. Then the wet wipes started to disappear. People walking through busy shopping areas, and even back streets, were wearing surgical masks, a habit many Asian immigrants had brought from China. I drove past one car with three mask-clad passengers in back.

When a girl at my daughter’s high school complained of a cough, the nurse gave her a choice of wearing a mask for the rest of the day – or going home. (Guess which she chose?) A lot of schoolkids stayed home; my friend told me of one parent who kept her children home for three days straight, and she lived in another borough.

“Tell them to wash their hands a lot,” was the only advice I could offer.

Reporters like myself often parachute into a region to report about a war or an election, but in this case, I just happen to live here. As journalists we often feel insulated by our status – we’re observers, after all, not participants – and on some unconscious level I think I believed my family and I were immune.

I was wrong.

The fear, meanwhile, fueled rumors. My friend Mary, who lives nearby, said her daughter stayed home from public school because she wasn’t feeling good one day. Her friends called that afternoon and asked if she was alright – they heard she had swine flu. Four of the kids in her class had been to Mexico over spring break, Mary’s daughter told her. The next day she corrected herself: only one had gone, “and that was to Jamaica.”

But it soon became clear it didn’t really matter who you knew or where they had been. The cat was out of the bag.

Some parents wanted the city to close all schools. But while St. Francis was shut down for a week and a half, a lot of students with nothing to do went to hang out in another enclosed gathering place … the mall.

When my own 15-year-old started coughing on Monday evening, I thought little of it. She’s pretty hardy and hadn’t missed a day of school since sixth or seventh grade. But when she woke up at 3 a.m. groaning loudly enough to wake me, I realized I’d been mistaken.

Sure, most years my daughter didn’t get the flu. But this was a novel strain. A new virus.

It was a miserable night – for our whole family, but mostly for her. She didn’t know what hit her. She was hot, and then she was cold. She shivered and coughed and groaned. Her throat was killing her, and by morning she was whispering.

“Will I have to go to the hospital?” she whispered.

“What if I gave it to my friends?”

“Will they shut down my school?”

I was worried, but not nearly as much as I would have been just a few days earlier. It was becoming fairly clear that young people in the United States weren’t dying of this flu strain, and most recovered without being hospitalized. If you weren’t very young or very old or pregnant, and you didn’t have diabetes, heart disease, H.I.V. or a compromised immune system, you probably wouldn’t even get a definitive diagnosis, and any available Tamiflu, the anti-flu drug, would be reserved for someone else.

An infectious disease specialist had told me on Friday that health officials were reassured by the way the outbreak was unfolding here. “If it weren’t for Mexico, this would be a page-15 story,” he’d said.

One thing is clear: we have good surveillance systems. Everyone was collecting data and phoning it in. When the high-school attendance office called, they didn’t just want to know my child was home sick, they wanted a list of symptoms: Did she have a cough? Sore throat? Fever? How high? Fifty kids in the school were absent, up from a daily average of 20 at most.

We had good information, and it was easily accessible to the public, not just through the traditional media but through the internet and twitter.

You could go to the Centers for Disease Control and Prevention Web site and find out whether face masks work (unclear), what you can do to minimize your risk (wash your hands, stay away from crowds, don’t touch your nose and face) and what you can do to help (sneeze into a tissue or your sleeve, stay home if you’re sick).

I still don’t know if my daughter actually has swine flu. The doctor who examined her was pretty sure she did – he called it A(H1N1), which somehow sounded less sinister. But there was no need for a test, and she was otherwise healthy and therefore not a candidate for Tamiflu anyway.

He listened to her lungs, proclaimed them all clear, and swabbed her throat for a strep culture, which was negative. The prescription was the usual for flu: Motrin, lots of fluids, rest. Oh, and ice-pops for the sore throat. We were to watch out for shortness of breath, worsening fever or unusual behavior.

She had completely lost her voice by then, so she borrowed my phone as we drove home and texted into it. “Throat like sandpaper stop 4 ice pops.”

By evening she was over the worst of it. She sat with us at dinner but had drunk so much tea she wasn’t really hungry. Every time she coughed we dove under the table. But I knew she was much better when, as she prepared for a world history exam, she had just one question, “What am I going to do about my chem test?”

And I have one lingering concern myself. If – and when – this rolls around again, in a fiercer form, will people think health officials are crying wolf and be blase about it? If this current flu does turn out to be much better than feared – and we all hope it does – the public health campaign must not stop. People need very clear explanations about why and how this virus could mutate into something worse.

PNAS

Proceedings of the National Academy of Sciences of the United States

May 12, 2009

1.       Qiyun Zhua,1,

2.       Vladimir G. Zarnitsynb,1,

3.       Ling Yea,1,

4.       Zhiyuan Wena,

5.       Yulong Gaoa,

6.       Lei Pana,

7.       Ioanna Skountzoua,

8.       Harvinder S. Gilla,

9.       Mark R. Prausnitzb,2,

10.  Chinglai Yanga,2 and

11.  Richard W. Compansa,2

+Author Affiliations

1.     aDepartment of Microbiology and Immunology and Emory Vaccine Center, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322; and

2.     bSchool of Chemical and Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Drive, Atlanta, GA 30332-0100

  1. Edited by Max D. Cooper, Emory University, Atlanta, GA, and approved March 16, 2009

  2. 1Q.Z., V.G.Z., and L.Y. contributed equally to this work. (received for review December 11, 2008)

Abstract

Influenza prophylaxis would benefit from a simple method to administer influenza vaccine into skin without the need for hypodermic needles. In this study, solid metal microneedle arrays (MNs) were investigated as a system for cutaneous vaccine delivery using influenza virus antigen. The MNs with 5 monument-shaped microneedles per array were produced and coated with inactivated influenza virus A/PR/8/34 (IIV). As much as 10 μg of viral proteins could be coated onto an array of 5 microneedles, and the coated IIV was delivered into skin at high efficiency within minutes. The coated MNs were used to immunize mice in comparison with conventional intramuscular injection at the same dose. Analysis of immune responses showed that a single immunization with IIV-coated MNs induced strong antibody responses against influenza virus, with significant levels of hemagglutination inhibition activities (>1:40), which were comparable to those induced by conventional intramuscular immunization. Moreover, mice immunized by a single dose of IIV coated on MNs were effectively protected against lethal challenge by a high dose of mouse-adapted influenza virus A/PR/8/34. These results show that MNs are highly effective as a simple method of vaccine delivery to elicit protective immune responses against virus infection.

1.       Grazia Gallia,

2.       Kathy Hancockb,

3.       Katja Hoschlerc,

4.       Joshua DeVosb,

5.       Michaela Prausd,

6.       Monia Bardellia,

7.       Carmine Malzonea,

8.       Flora Castellinoa,

9.       Chiara Gentilee,

10.  Teresa McNallyf,

11.  Giuseppe Del Giudicea,

12.  Angelika Banzhoffd,

13.  Volker Brauerd,

14.  Emanuele Montomolie,

15.  Maria Zambonc,

16.  Jacqueline Katzb,

17.  Karl Nicholsonf and

18.  Iain Stephensonf,1

+Author Affiliations

1.     aTranslational Medicine, Novartis Vaccines, Siena, Italy 53100;

2.     bInfluenza Division, Centers for Disease Control and Prevention, Atlanta, GA 30333;

3.     cHealth Protection Agency, Colindale, London NW9 5HT, United Kingdom ;

4.     dRegulatory Affairs and Statistics, Novartis Vaccines, 35041 Marburg, Germany;

5.     eUniversity of Siena, 53100 Siena, Italy; and

6.     fDepartment of Inflammation, Infection and Immunity, University of Leicester, Leicester LE1 9HN, United Kingdom

  1. Communicated by Rino Rappuoli, Novartis Vaccines, Siena, Italy, March 24, 2009 (received for review February 16, 2009)

Abstract

Proactive priming before the next pandemic could induce immune memory responses to novel influenza antigens. In an open-label study, we analyzed B cell memory and antibody responses of 54 adults who received 2 7.5-μg doses of MF59-adjuvanted A/Vietnam/1194/2004 clade 1 (H5N1) vaccine. Twenty-four subjects had been previously primed with MF59-adjuvanted or plain clade 0-like A/duck/Singapore/1997 (H5N3) vaccine during 1999-2001. The prevaccination frequency of circulating memory B cells reactive to A/Vietnam/1194/2004 was low in both primed and unprimed individuals. However, at day 21 after boosting, MF59-adjuvanted primed subjects displayed a higher frequency of H5N1-specific memory B cells than plain-primed or unprimed subjects. The immune memory was rapidly mobilized by a single vaccine administration and resulted in high titers of neutralizing antibodies to antigenically diverse clade 0, 1, and 2 H5N1 viruses already at day 7. In general, postvaccination antibody titers were significantly higher in primed subjects than in unprimed subjects. Subjects primed with MF59-adjuvanted vaccine responded significantly better than those primed with plain vaccine, most notably in early induction and duration of cross-reacting antibody responses. After 6 months, high titers of cross-reactive antibody remained detectable among MF59-primed subjects. We conclude that distant priming with clade 0-like H5N3 induces a pool of cross-reactive memory B cells that can be boosted rapidly years afterward by a mismatched MF59-adjuvanted vaccine to generate high titers of cross-reactive neutralizing antibodies rapidly. These results suggest that pre-pandemic vaccination strategies should be considered.

1.       Cynthia Chena,

2.       Peter N. Sedwickb and

3.       Mukul Sharmaa,1

+Author Affiliations

1.     aRadiogenic Isotope Geochemistry Laboratory, Department of Earth Sciences, Dartmouth College, 6105 Sherman Fairchild Hall, Hanover, NH 03755; and

2.     bDepartment of Ocean, Earth and Atmospheric Sciences, Old Dominion University, 4600 Elkhorn Avenue, Norfolk, VA 23529

  1. Edited by Karl K. Turekian, Yale University, New Haven, CT, and approved March 27, 2009 (received for review November 19, 2008)

Abstract

Osmium is one of the rarer elements in seawater, with typical concentration of ≈10 × 10-15 g g-1 (5.3 × 10-14 mol kg-1). The osmium isotope composition (187Os/188Os ratio) of deep oceans is 1.05, reflecting a balance between inputs from continental crust (≈1.3) and mantle/cosmic dust (≈0.13). Here, we show that the 187Os/188Os ratios measured in rain and snow collected around the world range from 0.16 to 0.48, much lower than expected (>1), but similar to the isotope composition of ores (≈0.2) that are processed to extract platinum and other metals to be used primarily in automobile catalytic converters. Present-day surface seawater has a lower 187Os/188Os ratio (≈0.95) than deep waters, suggesting that human activities have altered the isotope composition of the world’s oceans and impacted the global geochemical cycle of osmium. The contamination of the surface ocean is particularly remarkable given that osmium has few industrial uses. The pollution may increase with growing demand for platinum-based catalysts.

 

1.       Mary Helen Immordino-Yanga,b,

2.       Andrea McColla,

3.       Hanna Damasioa,c and

4.       Antonio Damasioa,1

+Author Affiliations

1.     aBrain and Creativity Institute,

2.     cDornsife Cognitive Neuroscience Imaging Center, and

3.     bRossier School of Education, University of Southern California, Los Angeles, CA 90089

1. Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved March 10, 2009 (received for review October 21, 2008)

Abstract

In an fMRI experiment, participants were exposed to narratives based on true stories designed to evoke admiration and compassion in 4 distinct categories: admiration for virtue (AV), admiration for skill (AS), compassion for social/psychological pain (CSP), and compassion for physical pain (CPP). The goal was to test hypotheses about recruitment of homeostatic, somatosensory, and consciousness-related neural systems during the processing of pain-related (compassion) and non-pain-related (admiration) social emotions along 2 dimensions: emotions about other peoples’ social/psychological conditions (AV, CSP) and emotions about others’ physical conditions (AS, CPP). Consistent with theoretical accounts, the experience of all 4 emotions engaged brain regions involved in interoceptive representation and homeostatic regulation, including anterior insula, anterior cingulate, hypothalamus, and mesencephalon. However, the study also revealed a previously undescribed pattern within the posteromedial cortices (the ensemble of precuneus, posterior cingulate cortex, and retrosplenial region), an intriguing territory currently known for its involvement in the default mode of brain operation and in self-related/consciousness processes: emotions pertaining to social/psychological and physical situations engaged different networks aligned, respectively, with interoceptive and exteroceptive neural systems. Finally, within the anterior insula, activity correlated with AV and CSP peaked later and was more sustained than that associated with CPP. Our findings contribute insights on the functions of the posteromedial cortices and on the recruitment of the anterior insula in social emotions concerned with physical versus psychological pain.

1.       Chirag Pungaliyaa,

2.       Jagan Srinivasanb,

3.       Bennett W. Foxa,

4.       Rabia U. Malika,

5.       Andreas H. Ludewiga,

6.       Paul W. Sternbergb and

7.       Frank C. Schroedera,1

+Author Affiliations

1.     aBoyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853; and

2.     bHoward Hughes Medical Institute and Division of Biology, California Institute of Technology, Pasadena, CA 91125

1. Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved March 3, 2009 (received for review November 22, 2008)

Abstract

Small molecule metabolites play important roles in Caenorhabditis elegans biology, but effective approaches for identifying their chemical structures are lacking. Recent studies revealed that a family of glycosides, the ascarosides, differentially regulate C. elegans development and behavior. Low concentrations of ascarosides attract males and thus appear to be part of the C. elegans sex pheromone, whereas higher concentrations induce developmental arrest at the dauer stage, an alternative, nonaging larval stage. The ascarosides act synergistically, which presented challenges for their identification via traditional activity-guided fractionation. As a result the chemical characterization of the dauer and male attracting pheromones remained incomplete. Here, we describe the identification of several additional pheromone components by using a recently developed NMR-spectroscopic approach, differential analysis by 2D NMR spectroscopy (DANS), which simplifies linking small molecule metabolites with their biological function. DANS-based comparison of wild-type C. elegans and a signaling-deficient mutant, daf-22, enabled identification of 3 known and 4 previously undescribed ascarosides, including a compound that features a p-aminobenzoic acid subunit. Biological testing of synthetic samples of these compounds revealed additional evidence for synergy and provided insights into structure-activity relationships. Using a combination of the three most active ascarosides allowed full reconstitution of the male-attracting activity of wild-type pheromone extract. Our results highlight the efficacy of DANS as a method for identifying small-molecule metabolites and placing them within a specific genetic context. This study further supports the hypothesis that ascarosides represent a structurally diverse set of nematode signaling molecules regulating major life history traits.

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