2011年10月4日 星期二

廿一世紀癌症防治大突破–自律神經調控法

廿一世紀癌症防治大突破–
自律神經調控法


楊維邦 博士 2011.08
摘要:
根據近年來發表在世界頂尖學術期刊上的百餘篇論文顯示,癌症之發生、惡化及轉移與交感神經過度亢奮及副交感神經低下有關。若能降低交感神經之活性,且同時提升副交感神經活性,對於癌症之預防治療,降低復發及轉移率均有令人挀奮的效果。
(摘要撰稿:王群光醫師 中華自律神經醫學會 理事長)

一、人類自律神經與免疫系統之關聯性
人類的免疫淋巴系統、血管及源自中樞神經的自律神經系統有緊密的連接。中樞神經就是經由自律神經來管理免疫系統,並對目標物進行攻擊消滅及正常細胞之維護。免疫系統攻擊的目標物包括入侵的細菌、黴菌、病毒、大分子蛋白質、自身老化受損的細胞或是自體免疫疾病中的自身細胞。
交感神經系統是經由釋放一種叫做正腎上腺素(NorepinephrineNE) 的神經傳導因子來刺激免疫系統的運作。其運作方法如下(1)
入侵外物或受損細胞表面會有一層叫LPS(Lipopolysacharide)脂多醣體的化合物,這些LPS 便會把淋巴系統中的單核白血球(monocytes)吸引過來,到達現場後,單核白血球就會自我轉變為巨噬細胞macrophages( MΦ)。這些便開始產生一種叫腫瘤壞死因子(Tumor Necrosis Factor-αTNF-α)的蛋白質,以執行消滅入侵外物或受損細胞的動作。一連串的發炎過程及副產物都因TNF-α 之產生而引起,諸如cytokines(細胞激素)IL-1IL-8 等之合成便是。但這些過程中最重要的一項就是NF-KB活化了,抗癌科學家也已發現,最有力量活化NF-KB的就是TNF-αNF-KB活化後,細胞便不容易死亡,且容易增殖,這便是身體發炎及細胞自我修復之常見現象。
二、發炎與消炎,癌化與去癌化的主角 – NK-KBP53
NF-KB細胞核轉錄因子(Nuclear Factor - Kappa B,簡稱NF-KB)P53即是腫瘤抑制蛋白(Protein 53,簡稱P53)NF-KB 是造成身體發炎的主要調節物質,而P53則是抑制腫瘤產生的主要物質。這兩種物質相互影響而造成身體發炎及癌化與否的一連串事件,也是癌症形成的重要因素。(2)
NF-KB是一蛋白質的複合體,在很多動物(包括人類)的細胞裏都存在著。NF-KB平常都很安靜地躲在細胞質裏,但當其被激發喚醒後,會立刻跑到細胞核及粒腺體裏面。細胞核及粒腺體裏面有著生物的整個基因體,因此NF-KB 便會使得個別基因體產生免疫效果的基因表現出來,同時那些會保護細胞不致於死亡的基因也會表現出來,更甚者那些使細胞增殖的基因亦被表現出來。這原本是件好事,是我們身體為了對抗受傷或是對抗外界入侵的一種自我保護措施。這種NF-KB 所造成身體局部的反應便是所謂發炎的現象。但問題是:如果NF-KB 這些動作一直被激發著,則細胞都將呈現快速增殖及抗拒死亡的特質,這就是細胞癌化及癌症進行的模式。所以,NF-KB 長期被激發就會造成慢性發炎現象;也就會形成了癌症。此種進行模式目前已普遍被醫界所接受。(3)
至於P53,它是一53千道頓的蛋白質分子,它被稱為基因體的守護神,也被稱為天使基因。因為它守護著基因體,使其保持穩定,不被破壞。當細胞要分裂複製時,P53會先把基因體巡視一遍,如果發覺基因體有被破壞時,則會請基因修補分子對基因體進行修補動作。如果基因體被破壞過大或該細胞已夠老化(分裂50~60 ),則P53便會啟動另一程序,使細胞自行死亡,即所謂細胞凋零。所以如果我們身體的P53 都沒有被抑制或被破壞時,則細胞便不能抗拒死亡,所以癌症也就不會產生了。但問題是:NF-KBP53之活化都需要同一種叫做P300(and CBP) 的伙伴。這個P300(and CBP) 伙伴若被NF-KB搶走,則NF-KB 就被活化,但P53便因沒有伙伴而會被抑制。反過來如果P53 搶走了P300(and CBP) 伙伴,則P53 會活化而NF-KB則被抑制。(4)
萬一NF-KB 搶到了P300(and CBP) 伙伴而活化,而抑制了P53的活性,身體就會引起慢性發炎,而NF-KB 也將使得P53不再行使對基因體作為守護天使的天職。因此此現象發生後細胞不再凋零,這便是細胞抗拒死亡、癌化及癌症進行的原因。所以如前面所說的癌症的產生及進行模式更準確的表述如下圖所示:
所以慢性發炎和癌症可說是無法切割的連嬰。(5), (6)
究竟NF-KB P53 是如何搶得它們的P300(and CBP) 伙伴而使其活化呢?這就要靠身體的自律神經系統來決定了!如果交感神經活躍就會幫助NF-KB 取得P300(and CBP),反過來,若副交感神經活躍時,則P53 會取得P300(and CBP)。所以可以說,交感神經的活躍將使發炎加劇,而健全的副交感神經則會抑制炎症的發生與進展。

三、自律神經過度活躍會激化發炎及癌症
如果我們的交感神經過度的活躍,則發炎的故事就會繼續演下去,過度活躍的交感神經會產生大量的去甲腎上腺素,去甲腎上腺素正好是TNF-α 的激化分子;濃度越高的去甲腎上腺素會激化越多的TNF-α。在活躍的交感神經下,去甲腎上腺素飆高,TNF-α 之濃度因而變得超高;NF-KB亦會跟著被大量的活化。以前所說之NF-KB P53 之平衡便被打破:NF-KB 被大量地活化,而P53 則被嚴重的壓抑。交感神經之過度活躍便是打破平衡的這隻手!
更甚者,NF-KB IL-8 等都會啟動一些叫VEGF 因子,這些因子會使血管增生;有足夠的營養,細胞長得更快,又不會凋零,最後還會轉移,這就是癌。說到轉移,最近的研究已指出乳癌細胞的遠程轉移,也是交感神經闖的禍。有一篇文獻的標題是「交感神經是原發乳癌轉移的開關」,由此可見交感神經對於癌症形成及轉移是何等的重要。(7)
上面的過程可以歸納如下

巨噬細胞及其產生之TNF-α 在癌症發展中所扮演的角色早在臨床上被詳細深入及評估過。在很多癌體裏都有被滲透進去的巨噬細胞;并且都有很多的TNF-α 及其他的cytokines IL-1 等。這些滲透到癌體裏的巨噬細胞被稱為Tumor-Associated-Macrophages(TAM)TAM 濃度被發現跟癌症的預後成反比,即TNF-α 愈多則癌發展愈不樂觀。(8)
四、交感神經活性過高的可能原因
HRV自律神經檢測儀可分別定量出交感及副交感神經的活性。最理想的狀態是交感神經活性(LF)、副交感神經活性(HF)以及LF/HF比例都在正常範圍內。交感神經活性 / 副交感神經活性(LF/HF)比例越大,表示交感神經活性越活躍。
交感神經活性過高的可能原因有下列各項:
1、病原菌入侵
當人體遭受細菌、黴菌、病毒等病原入侵時,人體便會啟動交感神經,再驅動巨噬細胞來防衛。
有許多種類的癌症已被證實與慢性感染發炎有關,如EB Virus之於鼻咽癌、B型肝炎病毒之於肝癌等,這都是因為發炎的結果導致NF- KB受到激發而P53受到了抑制。
2、大分子蛋白質入侵
大分子蛋白質經由呼吸道或消化黏膜入侵人體,導致IgGIgE抗體產生,這屬非感染的入侵方式。雖然它也同樣會激化交感神經及NF- KB,同時抑制P53,但到目前為止,尚未有充份證據可證明罹患黏膜滲漏症之患者有較高的罹癌率。
3、精神性因素
情緒上易動怒的人,交感神經活性普遍偏高(LF/HF比值高)。當一個人面對巨大壓力或無法如期完成設定的目標時,身體會自動提升交感神經進入備戰狀態。有些人交感神經活性過高,但其LF/HF比正常,這是因為其副交感也同步提高,進入「超飽和狀態」(Allostatic State),這樣對身體的健康同樣也是不利的。
五、副交感神經是人體的滅火部隊
自律神經可分為交感神經及副交感神經,大家都知道交感與副交感是處於對立及拮抗狀態,例如交感神經亢奮時,會使心跳加快;副交感則會令心跳變慢;但是對於腸胃道而言,副交感則扮演促進功能的角色,而交感神經則表現出抑制的功能。
在「發炎」這課題上,交感神經是扮演促進的角色,而副交感神經則負責「消炎」。
六、副交感神經 抗癌的最新希望(9), (10)
最近幾年,副交感神經能快速、自然地控制發炎的功能被發現了,於是「癌症的神經生物學」(11) 說法蔚為流行。這個消炎的反射功能被稱為膽鹼消炎途徑(Cholinergic Anti-inflammatory Pathway),如果我們的迷走神經功能還健全,則它會自動感應到發炎因子(TNF-αIL-1 )的存在。如果發現這些發炎因子濃度過高時,即會通知大腦,大腦便會透過自律神經,在發炎地區附近釋放出一種叫乙醯膽鹼(Acetycholine,Ach)的神經傳遞物質(neurotransmitter)。這些Ach 會非常有效地抑制巨噬細胞,使其不再分泌TNF-αIL-1 等細胞激素。發炎現象便會自然地停止。這其實就是身體去除消炎最常用的方法。
身體發炎現象痊癒後,TNF-αIL-1 等也會隨之消失,而NF-KB 又會回到細胞質裏,不再進行激化的活動。由於P53 沒有抑制者,便會重新活躍地巡視、守護我們的基因體,就有更大的機會可遠離癌症。所以過度活躍的交感神經會引起慢性發炎,會增進癌症之發展。活化副交感神經會抑制發炎及有害之細胞激素的產生,進而也可抑制癌症的發生與發展。
臨床上如果能提升副交感神經活性並降低交感神經活性,對癌症之治療就會有正面意義。很可惜目前能長時間提升副交感,降低交感神經活性,又沒有副作用的藥物幾乎無處尋覓。倒是有許多天然非藥物的方式可以達到上述目的,將另行為文介紹。
References 英文文獻全文請至「自律神經文獻部落格」下載)
(1) Bellinger DL, Millar BA, Perez S, Carter J, Wood C, ThyagaRajan S, Molinaro C, Lubahn C, Lorton D. Sympathetic Modulation of Immunity: Relevance to disease. Cellular Immunology, 252, p27, 2008.
(2) A.V. Gudkov , K.V. Gurova , and E.A. Komarova. Inflammation and P53: A Tale of TwoStresses. Genes and Cancer, 2, p503, 2011.
(3) Bharat B. Aggarwal, Gautam Sethi, Asha Nair, and Haruyo Ichikawa. Nuclear Factor - B: A Holy Grail in Cancer Prevention and Therapy. Current signal Transduction therapy 1, p25,2006.
(4) A. Ikeda, X. Sun, Y. Li et al. P300/CBP Dependent and Independent Transcriptional Crosstalk Between NF- KB and P53. Mol. Cell Biol. 19, P3458, 1999.
(5) Sergei I. Grivennikov, Florian R. Greten, Michael Karin. Immunity, Inflammation, and Cancer. Cell, 140, p883, 2010.
(6) Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and Cancer: How Hot is the Link? Biochemical Pharmacology. 72, p1605, 2006.
 (7) Erica K. Sloan, Saul J. Priceman, Benjamin F. Cox, Stephanie Yu, Matthew A. Pimentel, Veera Tangkanangnukul, Jesusa M.G. Arevalo, Kouki Morizono, Breanne D.W. Karanikolas, Lily Wu, Anil K. Sood and Steven W. Cole. The Sympathetic Nervous System Induces a Metastatic Switch in Primary Breast Cancer. Cancer Res. 70, p7042, 2010.
(8) Alberto Mantovani, Federica Marchesi, Chiara Porta, Paola Allavena and Antonio Sica. Linking Inflammation Reactions to Cancer: Novel Targets for Therapeutic Strategies. Targeted Therapies in Cancer. 610, p112, 2008.
(9) Tracey KJ. The Inflammation reflex. Nature 420, p853, 2002.
(10) Huston JM, Tracey KJ. The Pulse of Inflammation: Heart Rate Variability, the Cholinergic Anti-inflammatory Pathway and Implications for Therapy. J. of Intern Med. 269, p45, 2011.
(11) Boris Mravec, Yori Gidron and Ivan Hulin. Neurobiology of cancer: Interactions betweennervous, endocrine and immune systems as a base for monitoring and modulating thetumorigenesis by the brain. Seminars in Cancer Biology, 18, p150, 2008.

2011年8月15日 星期一

癌症防治新方法 – 生物神經法

楊維邦 博士 2011/8

我們必須先介紹兩位生物神經法的主角,即細胞核轉錄因子(Nuclear Factor - Kappa B,簡稱
NF-KB),及腫瘤抑制蛋白(Protein 53,簡稱P53)。NF-KB 是造成身體發炎的主要調節物質,而P53則是抑制腫瘤產生的主要物質。這兩種物質相互影響而造成身體發炎的一連串事件,也是癌症形成的重要因素。

先來說說NF-KB,它是一蛋白的複合體,在很多動物(包括人類)的細胞裏都存在著。平常都
很安靜地躲在細胞質裏,但當其被激發而被喚醒後(如何被激發喚醒,後有詳細說明),會立刻跑到細胞核及粒腺體裏面。細胞核及粒腺體裏面有著生物的整個基因體,因此NF-KB 便會使得個別基因體產生免疫效果的基因表現出來,同時那些會保護細胞不致於死亡的基因也會表現出來,更甚者那些使細胞增殖的基因亦被表現出來。這原本是件好事,是我們身體為了對抗受傷或是被外界入侵的一種自我保護措施。這種NF-KB 所造成身體局部的反應便是所謂發炎的現象。但問題是:如果NF-KB 這些動作一直被激發著,則細胞都將變成快速增殖及抗拒死亡,這就是細胞癌化及癌症進行的模式。所以,NF-KB 長期被激發就會造成慢性發炎現象;也就會形成了癌症。此種進行模式目前已普遍被醫界所接受。

再來看看P53,它是一53 千道頓的蛋白質分子,它被稱為基因體的守護神,也被稱為天使基
因。因為它守護著基因體,使其保持穩定,不被破壞。當細胞要分裂複製時,P53 會先把基因體巡視一遍,如果發覺基因體有被破壞時,則會請基因修補分子對基因體進行修補動作。如果基因體被破壞過大或該細胞已夠老化(分裂50~60 次),則P53 便會啟動另一程序,使細胞自行死亡,即所謂細胞凋零。所以如果我們身體的P53 都沒有被抑制或被破壞時,則細胞便不能抗拒死亡,所以癌症也就不會產生了。但問題是:NF-KB 和P53 之活化都需要同一種叫做P21 的伙伴。這個P21 伙伴若被NF-KB 搶走,則NF-KB 就被活化,但P53 便因沒有伙伴而會被抑制。反過來如果P53 搶走了P21 伙伴,則P53 會活化而NF-KB 則被抑制。

檔案下載


2011年8月9日 星期二

NFkB/p53 crosstalk - a promising new therapeutic target

Gunter Schneider, Oliver H. Kramer

Abstract

The transcription factors p53 and NFkB determine cellular fate and are involved in the pathogenesis of most-if not all-cancers. The crosstalk between these transcription factors becomes increasingly appreciated as an important mechanism operative during all stages of tumorigenesis, metastasis, and immunological surveillance. In this review, we summarize molecular mechanisms resulating cross-signaling between p53 and NFkB proteins and how dysregulated interactions between p53 and NFkB family members contribute to oncogenesis. We furthermore analyze how such signaling modules represent targets for the design of novel intervention strategies using established compounds and powerful combination therapies.


檔案下載

2011年8月8日 星期一

The Developing Brain and Cancer

The GW Institute for Neuroscience hosts annual symposium.

By Anna Miller
April 28, 2011

Just a few decades ago, the connection between neurobiology and cancer biology was suspected but unspoken.

“Today, it represents one of the most robust interfaces between basic neuroscience and clinical medicine,” said Anthony-Samuel LaMantia, professor of pharmacology and physiology in the GW School of Medicine and Health Sciences (SMHS) and founding director of the GW Institute for Neuroscience (GWIN), at the first annual Neuroscience Symposium on Wednesday.

The symposium featured four leading researchers who highlighted the latest advances in the field of neuroscience that contribute to the understanding of how the brain develops and how cancer can compromise the developing brain.

Held at the Marvin Center, the daylong event brought together close to 80 researchers, graduate students and scientists and was sponsored by SMHS, the Office of the Vice President for Research and the Columbian College of Arts and Sciences — the three entities that support GWIN.

Sally Moody, professor of anatomy and regenerative biology in SMHS, delivered the first keynote address, which highlighted the earliest stages of nervous system development.

“In all vertebrates, we have several steps that take you from the initiation of embryonic cells becoming neural to when you get actual, independent, specified kinds of neurons,” she said.

Using her work with frog embryos as a guide, Dr. Moody hypothesized that the expression of FoxD4/5, one of the earliest genes in the network, plays a key role in neural stem cell fate, particularly through its activation of a group of genes called Sox.

The second keynote speaker was Michael Dyer, a member of St. Jude Children’s Research Hospital in the Department of Developmental Neurobiology and co-leader of the Developmental Therapeutics for Solid Malignancies Program. Dr. Dyer discussed how his work studying retinoblastoma, a childhood cancer of the eye, has helped bridge the gap between developmental neurobiology and cancer genetics.

Among many influential discoveries, Dr. Dyer explained how his lab’s approach to studying tumor cells led to the unpredictable finding that adult neurons can divide without losing their distinctive features.

“What we’ve shown is that everybody was right over the years: These tumors have properties of different cell types. It’s just that nobody considered the possibility that they were all the same cell,” Dr. Dyer said.

Vittorio Gallo, professor of neuroscience at SMHS, director and Wolf-Pack Chair in Neuroscience at Children’s National Medical Center’s Center for Neuroscience Research, presented the third keynote address.

Dr. Gallo discussed how certain signaling pathways help to maintain the balance between specific types of neurons developed in the brain that are critical under both normal conditions and after injury. These pathways contribute to the growth and development of neural progenitor cells, one of the groups of neurons. Because neural progenitor cells and these pathways may influence the formation of brain tumors, they are important to understand for potential clinical applications, Dr. Gallo said.

Scott Loren Pomeroy, Bronson Crothers Professor of Neurology at Harvard Medical School and
Neurologist-in-Chief at Children's Hospital Boston, delivered the final keynote address about medulloblastoma, the most common type of malignant brain tumor in children.

Dr. Pomeroy explained how the reclassification of medulloblastoma into various subtypes is leading to the creation of better targeted therapies. These therapies, he said, may not only improve survival, but they may also help to mitigate the harsh side effects seen with current therapies that treat all medulloblastomas as equals.

“We hope to find common pathways that we will be able to block with a reasonable small number of drugs that don’t have horrible side effects and fundamentally change how we treat the tumors,” said Dr. Pomeroy. “I would say we are much closer to that today than we were 10 years ago.”

Paaqua Grant, Amanda Mathews, Mathew Raymond and Carrie House, graduate students from SMHS’s Institute of Biomedical Sciences, also delivered presentations on their research projects.

The day concluded with a panel hosted by the GW Cancer Institute and moderated by its executive director, Steven Patierno, professor of pharmacology and physiology at SMHS. Panelists included Drs. LaMantia, Dyer and Pomeroy; Javad Nazarian, assistant professor of integrative systems biology at SMHS; Norman Lee, professor in the Department of Pharmacology and Physiology at SMHS; and Weiqun Peng, associate professor of physics in the Columbian College of Arts and Sciences.

The panelists discussed the future challenges and possibilities in the realm of neuroscience research. Dr. Nazarian spoke about the promise of using cerebrospinal fluid as a way to detect and target tumors that cannot be isolated. Other panelists addressed the possibility of the existence of cancer stem cells and raised concerns about computational barriers.

“I still feel like there’s a lot hidden in our data,” said Dr. Dyer. “And I don’t know where it’s going to come from, but I feel there’s going to be a really smart person out there that’s going to figure out a totally out-ofthe-box way to look at this, and it’s going to revolutionize the way we look at all this data.”

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2011年8月2日 星期二

Why Cancer and Inflammation?

Seth Rakoff-Nahoum

Abstract

Central to the development of cancer are genetic changes that endow these “cancer cells” with many of the hallmarks of cancer, such as self-sufficient growth and resistance to antigrowth and pro-death signals. However, while the genetic changes that occur within cancer cells  themselves, such as activated oncogenes or dysfunctional tumor suppressors, are responsible for many aspects of cancer development, they are not sufficient. Tumor promotion and  progression are dependent on ancillary processes provided by cells of the tumor environment
but that are not necessarily cancerous themselves. Inflammation has long been associated with the development of cancer. This review will discuss the reflexive relationship between cancer and inflammation with particular focus on how considering the role of inflammation in physiologic processes such as the maintenance of tissue homeostasis and repair may provide a logical framework for understanding the connection between the inflammatory response and cancer.

中文摘要:
癌症之發生主要源自於基因之改變,這些改變是癌症細胞擁有好幾個特徵,即自主生長,能抗拒抑制生長和摧毀凋零之訊息。雖然,引起癌化之基因改變是發生在細胞裡面;諸如癌化基因之啟動或抑制癌化基因之因子失去功能,這些都能引起癌症,但是只有這些是不夠的。腫瘤之進展需要一些由周邊正常細胞所提供之輔助環境條件。發炎很早便被認定與癌症發展有關。本論文會討論癌症和發炎的反射反應關係,特別從發炎之生理過程及其維持生理系統平衡和修補來了解發炎及癌症之因果關係。


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Inflammation and cancer: How hot is the link?

Bharat B. Aggarwal , Shishir Shishodia , Santosh K. Sandur , Manoj K. Pandey , Gautam Sethi

Abstract

Although inflammation has long been known as a localized protective reaction of tissue to irritation, injury, or infection, characterized by pain, redness, swelling, and sometimes loss of function, there has been a new realization about its role in a wide variety of diseases, including cancer. While acute inflammation is a part of the defense response, chronic inflammation can lead to cancer, diabetes, cardiovascular, pulmonary, and neurological diseases. Several pro-inflammatory gene products have been identified that mediate a critical role in suppression of apoptosis, proliferation, angiogenesis, invasion, and metastasis. Among these gene products are TNF and members of its superfamily, IL-1a, IL-1b, IL-6, IL-8, IL-18, chemokines, MMP-9, VEGF, COX-2, and 5-LOX. The expression of all these genes are mainly regulated by the transcription factor NF-kB, which is constitutively active in most tumors and is induced by carcinogens (such as cigarette smoke), tumor promoters, carcinogenic viral proteins (HIV-tat, HIV-nef, HIV-vpr, KHSV, EBV-LMP1, HTLV1-tax, HPV, HCV, and HBV), chemotherapeutic agents, and g-irradiation. These observations imply that antiinflammatory agents that suppress NF-kB or NF-kB-regulated products should have a potential in both the prevention and treatment of cancer. The current review describes in detail the critical link between inflammation and cancer.

中文摘要:
雖然,我們很早便知道發炎是一個為保護受傷、感染、刺激而產生之局部地區之過程,跟而引起之疼痛、紅腫及一些身體之功能消失;現在我們更清楚,發炎其實在很多疾病上扮演著很多種功能,包括癌症。急性發炎是自衛免疫的一部分,但慢性發炎卻會英氣癌症、糖尿病、心血管疾病、肺病及神經性疾病。有數個發炎基因所產生之化學分子已被認出,它們會在抵抗凋零、擴散、血管增生、侵犯、轉移的過程中,扮演主要的角色。這些基因化學分子便是TNF,及一個超級家庭中之IL-1α,IL-1β,IL-6,IL-8,IL-18,化學激素如MMP-9,VEGF,COX-2及5-LOX都在其中。這些基因之表現,是由一個叫NF-Kβ錄制因子所調控,而該錄制因子在腫瘤中非常活躍,且是有致癌物質(如抽煙)、腫瘤催化劑、致癌病毒蛋白質(如HIV-tat、HIV-vpr、HIV-nef、KHSV、EBV-LMP1、HTLV1-tax、HPV、HOV與HBV),化學治療之藥物,及γ-輻射所啟動。這些事實表示抗發炎因素可以經過壓制NF-Kβ或是NF-Kβ之產生化學物來進行癌症之預防及治療。

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2011年8月1日 星期一

Y. 未分類

Y1 神經免疫控制
Neural Control of Immunity【資料來源:Bio-Inspired Technology (2011)】

Y2 NFkB/p53 crosstalk - 一種新的治療指標
NFkB/p53 crosstalk - a promising new therapeutic target【資料來源:Biochimica et Biophysica Acta (2011)】

Neural Control of Immunity

The immune system protects against invasive pathogens through the production of pro-inflammatorycytokines, which initiates a cascade of events to promote tissue repair. However, excessive or unrestrained release of pro-inflammatory cytokines can result in a range of chronic inflammatory conditions and disease states.

The vagus nerve plays a key role in regulating the inflammatory response. The vagus nerve is
composed of approximately 90% afferent (i.e., fibres that carry information from the organs to the brain) and 10% efferent fibres (i.e., fibres that carry information from the brain to the organs). It has a key role in conveying sensory information about the state of the viscera to the central nervous system. The vagus nerve innervates numerous visceral regions including the heart, oesophagus, gastrointestinal tract, liver and pancreas.

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2011年7月31日 星期日

E. 心率變異(HRV)與肥胖

E1 心率變異在減肥者及減重後的變化
Heart Rate Variability in Obesity and the Effect of Weight Loss【資料來源:THE AMERICAN JOURNAL OF CARDIOLOGYT (1999)】

D. 自律神經與糖尿病

16 糖尿病患無意識的致命但能治療的情況沒有症狀的發展
大部分糖尿病患者所未察覺到沒有症狀,可能致死,但原來是可以治療的情況
Most Diabetes Patients Unaware of Deadly but Treatable Condition that Develops Without Symptoms, Survey Says【資料來源:malattiemetaboliche (2001)】

C. 自律神經與癌症

C1 交感神經是誘發原發性乳癌轉移的開關
The Sympathetic Nervous System Induces a Metastatic Switch in Primary Breast Cancer【資料來源:Cancer Research (2010)】

C2 神經內分泌調控癌症的進程
Neuroendocrine modulation of cancer progression【資料來源:Brain, Behavior, and Immunity (2009)】

C3 迷走神經是否可以在臨床上腫瘤發生前;通知大腦並調控它?
Does the vagus nerve inform the brain about preclinical tumours and modulate them?【資料來源:Lancet Oncol (2005)】

C4 心率變異是什麼?它會被腫瘤壞死因子減弱嗎?
What Is “Heart Rate Variability” and Is It Blunted by Tumor Necrosis Factor?【資料來源:Chest (2003)】

C5 以神經,內分泌和免疫系統之互動,作為經由大腦監視及調控腫瘤生成的基礎
Interactions between nervous, endocrine and immune systems as a base for monitoring and modulating the tumorigenesis by the brain【資料來源:Seminars in Cancer Biology (2008) 】

C6 發炎與癌症:它們之間關聯多深?
Inflammation and cancer: How hot is the link?【資料來源:Biochemical Pharmacology (2006)】

C7 癌症之機制:為什麼癌症與發炎有關?
Why Cancer and Inflammation?【資料來源:Yale Journal of Biology and Medicine (2006)】

C8 大腦與癌症之間的發展
The Developing Brain and Cancer【資料來源:The George Washington University (2011)】

B. 自律神經與發炎

B1 迷走神經與發炎的反應的關係
Vagal tone and the inflammatory reflex【資料來源:CLEVEL AND CLINIC JOURNAL OF MEDICINE(2009)】

B2 發炎反應
The inflammatory reflex【資料來源:NATURE(2002)】

B3 神經系統調節發炎細胞素及心率變異
Nervous system regulation of inflammation, cytokines, and heart rate variability

B4 心率變異是發炎的脈搏,副交感神經的抗發炎路徑及治療上的應用
The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy【資料來源:Journal of Internal Medicine (2011)】

B5 副交感抗發炎路徑的生理及免疫學
Physiology and immunology of the cholinergic antiinflammatory pathway【資料來源:The Journal of Clinical Investigation (2007)】

A. 自律神經基礎文獻

A1 心率變異:測量的標準,生理上的解釋,及臨床應用
Heart rate variability:Standards of measurement, physiological interpretation, and clinical use【資料來源:European Heart Journal (1996) 】

A2 九二一大地震時突然變化的心率變異
Sudden Changes in Heart Rate Variability During the 1999 Taiwan Earthquake 【資料來源:The American Journal of Cardiology (2001)】

A3 九一一事件期間的心率變異
Heart Rate Variability During the Week of September 11, 2001【資料來源:JAMA (2002)】

A4 交感神經 -- 兩個超級系統大腦及免疫系統的介面
The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System【資料來源:Pharmacol Rev (2000)】

2011年7月29日 星期五

Neural Control of Immunity

The immune system protects against invasive pathogens through the production of pro-inflammatory cytokines, which initiates a cascade of events to promote tissue repair. However, excessive or unrestrained release of pro-inflammatory cytokines can result in a range of chronic inflammatory conditions and disease states.

檔案下載

自律神經失調 HRV檢測及治療衛教手冊

為了使HRV的檢測普及化
並讓大眾了解HRV與自律神經的關係
編了一本自律神經失調 HRV檢測及治療衛教手冊

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可直接點選章節方便閱讀
或是您可選擇下載全文:點此處

2011年7月28日 星期四

Most Diabetes Patients Unaware of Deadly but Treatable Condition that Develops Without Symptoms, Survey Says

WAKEFIELD, Mass

According to the results of a national survey released today, ninety-two percent of the estimated 16 million Americans with diabetes have never heard of diabetic autonomic neuropathy, an often deadly but treatable condition that can develop for years without symptoms.

Also according to the survey, eighty-three percent of people with diabetes are unaware of a non-invasive procedure called heart rate variability testing. Physicians are more able to detect the presence of diabetic autonomic dysfunction when they augment their clinical evaluation with the information provided by heart rate variability testing. However, while it is estimated that diabetic autonomic neuropathy may affect more than twenty-five percent of people with diabetes, only two percent of survey respondents said that they have ever been tested for the condition.

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Sudden Changes in Heart Rate Variability During the 1999 Taiwan Earthquake

Jin-Long Huang, MD, Chuen-Wang Chiou, MD, Chih-Tai Ting, MD, PhD, Ying-Tsung Chen, MD, and Shih-Ann Chen, MD

The acute stress of major natural disasters, such as an earthquake, may alter biochemical data,1 affect the psychological state,2 and may be associated with increased cardiovascular mortality.1–9 Although alterations of autonomic tone are hypothesized to be the link between such environmental stressors and mortality, autonomic tone, as reflected by heart rate variability
(HRV), has never been measured during an earthquake. The earthquake that struck the Nan-Tou
area, in the central part of Taiwan, at 1:47 A.M. on September 21, 1999, Richter scale 7.3, was one of the strongest earthquakes ever recorded in a major city in Taiwan. We studied patients who were equipped with Holter electrocardiographic monitors to investigate the effect of an earthquake on the autonomic system.

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Heart Rate Variability During the Week of September 11, 2001

Rachel Lampert, MD;     Suzanne J. Baron, BA;     Craig A. McPherson, MD;     Forrester A. Lee, MD

To the Editor: Catastrophes such as war or earthquake are known to result in increased incidence of sudden cardiac death among survivors, but the physiological mechanisms remain unknown.1​-2 The events of September 11, 2001, produced psychological distress among large numbers of people who were not physically affected by them. We hypothesized that such stress may lead to autonomic dysfunction, which may be reflected in changes in heart rate variability (HRV). Diminished HRV is associated with an increased incidence of cardiovascular and sudden death in patients both with and without coronary artery disease (CAD).


Methods

We measured HRV in 12 patients at the Yale-New Haven Hospital who wore 24-hour ambulatory heart monitors during the week of September 11, as well as 12 in control patients who had worn monitors in the preceding 2 months. Control patients were matched for age (within 10 years), sex, presence of CAD or congestive heart failure, and diabetes. Two patients in each group were using β-blockers. Indications for monitoring included palpitations (4 cases, 4 controls), history of or risk for arrhythmia (6 cases, 5 controls), and syncope (2 cases, 3 controls). All patients had been scheduled for heart monitoring prior to September 11. This study was approved by the Yale Human Investigation Committee.Frequency domain indices of HRV were analyzed using standard power spectrum analysis methods. After editing the R-R interval file to remove ectopic beats and noise, gaps were estimated by interpolated linear splines (recordings with >20% interpolation excluded). The heart rate power spectrum was computed through Fast Fourier Transform and integrated over 5 discrete frequency bands, with high frequency defined as 0.15 to 0.40 Hz.3 Indices of HRV were log-normalized and compared by paired t test.


Results

The logarithm of high-frequency power (a measure of parasympathetic tone) was lower in the subjects monitored after September 11 than in controls (5.54 vs 6.23, P = .047). High-frequency power was lower in 9 of the 12 cases compared with their controls (P = .045). Mean heart rate did not differ between groups (R-R interval: 857 milliseconds [cases] vs 829 milliseconds [controls], P = .64). 


Comment

We found a decrease in parasympathetic tone during the week of September 11, 2001, which may represent a physiological perturbation among individuals exposed to large-scale psychological stress. Unlike previous studies in which subjects were directly affected by war or natural disaster,1-2 the stress experienced by subjects in our study was purely psychological. It is not yet known whether there was increased cardiac mortality or morbidity as a result of the September 11 attacks. Mental stress can induce coronary ischemia2 and can facilitate lethal arrhythmias.5 These changes in cardiac blood flow and rhythm may in turn be caused by alterations in autonomic nervous system function.6 Our data demonstrate that the September 11 attacks may have produced similarly decreased parasympathetic output, which may increase susceptibility to lethal arrhythmias.7

2011年7月27日 星期三

Heart Rate Variability in Obesity and the Effect of Weight Loss

Kristjan Karason, MD, Henning Mølgaard, MD, PhD, John Wikstrand, MD, PhD, and
Lars Sjo¨stro¨m, MD, PhD

To investigate the effects of obesity and weight loss on cardiovascular autonomic function, we examined 28 obese patients referred for weight-reducing gastroplasty, 24 obese patients who received dietary recommendations, and 28 lean subjects. Body weight, blood pressure, and 24-hour urinary norepinephrine excretion were measured, and time and frequency domain indexes of heart rate variability (HRV) were obtained from 24-hour Holter recordings. A measure of long-term HRV, the SD of all normal RR intervals (SDANN), was used as an index of sympathetic activity and the high-frequency (HF) component of the frequency domain, reflecting
short-term HRV, as an estimate of vagal activity. All 3 study groups were investigated at baseline, and the 2 obese groups were reexamined at 1-year follow-up. Obese patients had higher blood pressure, higher urinary norepinephrine excretion, and attenuated SDANN
and HF values than lean subjects (p <0.01). Obese patients treated with surgery had a mean weight loss of 32 kg (28%), whereas the obese group treated with dietary recommendations remained weight stable (p <0.001). At follow-up the weight-loss group displayed decreases in blood pressure and norepinephrine excretion and showed increments in SDANN and HF values. These changes were significantly greater than those observed in the obese control group (p <0.05). Our findings suggest that obese patients have increased sympathetic
activity and a withdrawal of vagal activity and that these autonomic disturbances improve after weight loss. Q1999 by Excerpta Medica, Inc.

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What Is “Heart Rate Variability” and Is It Blunted by Tumor Necrosis Factor?

David R. Murray

In the 18th century, Albrecht von Haller1 made the initial observation that the beat of a healthy heart is not absolutely regular. Heart rate and rhythm are governed by the intrinsic automaticity of the sinoatrial node and the modulating influence of the autonomic nervous system. Vagal tone dominates under resting conditions,2 and rhythmic variations in heart rate are largely dependent on vagal modulation.3 The vagal and sympathetic nervous system constantly interact. The stimulation of the vagal afferent fibers leads to the reflex excitation of vagal efferent activity and the inhibition of sympathetic efferent activity.4 The opposite reflex events are mediated by the stimulation of sympathetic afferent activity.5 Central oscillators (ie, vasomotor and respiratory centers) and peripheral oscillators (ie, oscillation in arterial pressure and respiratory movements) can further modulate the efferent sympathetic and vagal activities that are directed to the sinus
node.6 These oscillators generate rhythmic fluctuations in efferent neural discharge that are manifested as short-term and long-term oscillation in beat-to-beat intervals and periodic heart rates.6 Heart rate variability (HRV) is a conventionally accepted term that is used to characterize these heart rate fluctuations. The analysis of HRV permits inferences to be made about the
state and function of the central oscillators, autonomic efferent activity, humoral factors, and the sinus node.

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The Sympathetic Nervous System Induces a Metastatic Switch in Primary Breast Cancer

Erica K. Sloan, Saul J. Priceman, Benjamin F. Cox, Stephanie Yu, Matthew A. Pimentel, Veera Tangkanangnukul, Jesusa M.G. Arevalo, Kouki Morizone, Breanne D.W. Karanikolas, Lily Wu, Anil K. Sood, and Steven W. Cole

Abstract

Metastasis to distant tissues is the chief driver of breast caner-related mortality, but little is known about the systemic physiologic dynamics that regulate this process. To investigate the role of neuroendocrine activation in cancer progression, we used in vivo bioluminescence imaging to track the development of metastasis in an orthotopic mouse model of breast cancer. Stress-induced neuroendocrine activation had a negligible effect on growth of the promary tumor but induced a 30-fold increase in metastasis to distant tissues including the lymph nodes and lung. These effects were mediated by B-adrenergic signaling, which increased the infiltration of CD11b'F4/80' macrophages into primary tumor parenchyma and thereby induced a prometastic gene expression signature accompanied by indications of M2 macrophage differentiation. Pharmacologic activation of B-adrenergic signaling induced similar effects, and treatment of stressed animals with the B-antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited tumor spread to distant tissues. The effects of stress on distant metastasis were also inhibited by in vivo macrophage suppression using the CSF-1 receptor kinase inhibitor GW2580. These findings identify activation of the sympathetic nervous system as a novel neural regulator of breast cancer metastasis and suggest new strategies for antimetastic therapies the target the B-adrenergic induction of prometastatic gene expression in primary breast cancers.

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2011年7月26日 星期二

中文文獻目錄


  1. 發炎、消炎及癌症之產生與發展
  2. 自律神經失調 HRV檢測及治療衛教手冊
  3. 廿一世紀癌症防治大突破 – 自律神經調控法

發炎、消炎及癌症之產生

發炎、消炎及癌症之產生與發展
                                 … 都是自律神經的事

楊維邦博士
July 2011

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Interactions between nervous, endocrine and immune systems as a base for monitoring and modulating the tumorigenesis by the brain

Boris Mravec , Yori Gidron , Ivan Hulin

Abstract

The interactions between the nervous, endocrine and immune systems are studied intensively. The communication between immune and cancer cells, and multilevel and bi-directional interactions between the nervous and immune systems constitute the basis for a hypothesis assuming that
the brain might monitor and modulate the processes associated with the genesis and progression of cancer. The aim of this article is to describe the data supporting this hypothesis.

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Physiology and immunology of the cholinergic antiinflammatory pathway

Kevin J. Tracey


Abstract

Cytokine production by the immune system contributes importantly to both health and disease. The nervous system, via an inflammatory reflex of the vagus nerve, can inhibit cytokine release and thereby prevent tissue injury and death. The efferent neural signaling pathway is termed the cholinergic antiinflammatory pathway. Cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases. Stimulation of the vagus nerve prevents the damaging effects of cytokine release in experimental sepsis, endotoxemia, ischemia/reperfusion injury,
hemorrhagic shock, arthritis, and other inflammatory syndromes. Herein is a review of this physiological, functional anatomical mechanism for neurological regulation of cytokine-dependent disease that begins to define an immunological homunculus.

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Does the vagus nerve inform the brain about preclinical tumours and modulate them?

Yori Gidron, Hugh Perry, Martin Glennie

Abstract

The inflammatory microenvironment is thought to play a pivotal part in tumorigenesis. But, can the brain be informed about peripheral preclinical cancer cells? Can it modulate tumour development? One of the key routes for information to reach the brain from visceral regions is through the vagus nerve. Yet, patients with ulcers who have had a vagotomy have been shown to die from cancer more frequently than do those who have not had this procedure, and surgical and chemical vagotomy attenuates tumour-induced anorexia and leads to enhanced tumour progression. We therefore postulate that the vagus nerve participates in informing the brain about tumorigenesis by
transmiting information to the brain about tumour-associated proinflammatory cytokines. Furthermore, activation of the vagus could slow tumorigenesis by suppression of peripheral proinflammatory cytokines.


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The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy

J. M. Huston & K. J. Tracey

Abstract. 

Huston JM, Tracey KJ (Department of Surgery, Division of General Surgery, Trauma, Surgical Critical Care, and Burns, Stony Brook University Medical Center, Health Sciences Center, Stony Brook; and Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset; NY, USA). The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway, and implications for therapy (Key Symposium). J Intern Med 2011; 269: 45–53.


Biological therapeutics targeting TNF, IL-1 and IL-6 arewidelyused for treatment of rheumatoidarthritis, inflammatory bowel disease and a growing list of other syndromes, often with remarkable success. Nowadvances inneurosciencehave collidedwiththis therapeutic approach, perhaps rendering possible the development of nerve stimulators to inhibit cytokines. Action potentials transmitted in the vagus nerve culminate in the release of acetylcholine that blocks cytokine production by cells expressing acetylcholine receptors. The molecular mechanism of this cholinergic anti-inflammatory pathway is attributable to signal transduction by the nicotinic alpha 7
acetylcholine receptor subunit, a regulator of the intracellular signals that control cytokine  transcription and translation. Favourable preclinical data support the possibility that nerve stimulatorsmay be added to the future therapeutic armamentarium, possibly replacing somedrugs to inhibit cytokines.

Keywords: heart rate variability, inflammation, neuroimmunology, therapeutics, vagus nerve stimulation.

中文摘要:
瞄準TNF,IL-1,IL-6之生物治療法對類風濕性發炎,發炎性腸胃炎及其他炎症都有意想不到的效果。神經科學之最新進展更推高其可能性,使到用神經刺激方法來抑制細胞激素之產生是一種可行之治療方法。在迷走神經所發之位能會使其釋出乙醯膽鹼,細胞中之乙醯膽鹼接受器會在接受乙醯膽鹼後便會阻斷細胞激素之產生。這些接受器就是叫做尼古丁α-7分子 --- 一個調整細胞激素之分子。正面的臨床前的數據支持下面所說的一個可能性;即神經刺激可代替藥物來抑制細胞激素的產生。


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The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System

ILIA J. ELENKOV, RONALD L. WILDER, GEORGE P. CHROUSOS, AND E. SYLVESTER VIZI


Abstract——

The brain and the immune system are the two major adaptive systems of the body. During an
immune response the brain and the immune system “talk to each other” and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/ neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic
nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the b2-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-a, and interferon-g by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as
IL-10 and transforming growth factor-b. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune
responses, through induction of IL-1, tumor necrosis factor-a, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes,
and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective a2- and b2-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic
fatigue syndrome.

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Neuroendocrine modulation of cancer progression

Guillermo N. Armaiz-Pena , Susan K. Lutgendorf , Steve W. Cole , Anil K. Sood

abstract

Clinical and animal studies now support the notion that psychological factors such as stress, chronic depression, and lack of social support might promote tumor growth and progression. Recently, cellular and molecular studies have started to identify biological processes that could mediate such effects. This review provides a mechanistic understanding of the relationship between biological and behavioral influences in cancer and points to more comprehensive behavioral and pharmacological approaches for better patient outcomes.

中文摘要:
臨床及動物之研究支持下面之觀點:即心理因素諸如壓力長期憂鬱及缺乏社會支持皆可增加腫瘤之生長及發展。最近,細胞學及分子之研究開始指出哪些生物過程可以產生這些效果。本論文提出一個能影響癌症進度之生物及行為表現機制,併指出一些是病人能有所改善之行為及藥物方法。



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2011年7月24日 星期日

Nervous system regulation of inflammation, cytokines, and heart rate variability

As readers here know, inflammation is a fundamental factor in chronic disease and accelerated
aging (neurodegeneration). A functional approach to treatment requires an objective understanding of how this system is working for each patient. Here are several of the many
studies that illustrate how nervous system function and inflammation can be evaluated with heart
rate variability (HRV) analysis and cytokine (‘messenger molecules’ of inflammation) levels.

The practical focus is on restoring parasympathetic nervous system
(PNS) activity which inhibits inflammation. (PNS resources decline with disease, stress and age
resulting in a state of ‘sympathetic nervous system dominance’.) This paper just published in the
journal Shock shows how autonomic nervous system activity (sympathetic and parasympathetic)
as measured by HRV corresponds to inflammatory cytokine activity, in this case when stimulated
by endotoxins (poisons produced by bacterial infections):

“Autonomic inputs from the sympathetic and parasympathetic nervous systems, as
measured by heart rate variability (HRV), have been reported to correlate to the…
responses to infectious challenge… In addition, parasympathetic/vagal activity has
been shown experimentally to exert anti-inflammatory effects via attenuation of
splanchnic tissue TNF-α [cytokine] production. We sought… to determine if baseline
HRV parameters correlated with endotoxin-mediated circulating cytokine responses.”

They documented a strong correspondence regardless of gender, body mass index and resting
heart rate:

“…we found a significant correlation of several baseline HRV parameters…on TNF-α
release after endotoxin exposure.”


This is not a new observation. An interesting study published a few years
ago in the journal Psychosomatic Medicine documents the HRV expression of autonomic activity in response to an inflammatory challenge and its correspondence to cytokine production. They begin by noting that:

“…the autonomic nervous system plays a key role in regulating the magnitude of immune responses to inflammatory stimuli. Signaling by the parasympathetic system inhibits the production of proinflammatory cytokines by activated monocytes/macrophages and thus decreases local and systemic inflammation.”

They examined the relationship of HRV to lipopolysaccharide-induced production of the
inflammatory cytokines interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-{alpha}, and IL-10.
What did the data show?

“Consistent with animal findings, higher derived estimates of vagal activity measured during paced respiration* were associated with lower production of the proinflammatory cytokines TNF-{alpha} and IL-6…These associations persisted after controlling for demographic and health characteristics, including age, gender, race, years of education, smoking, hypertension, and white blood cell count.”


Their conclusion has profound implications for the biological mechanism by which stress causes
inflammation:

“These data provide initial human evidence that vagal activity is inversely related to inflammatory competence, raising the possibility that vagal regulation of immune reactivity may represent a pathway linking psychosocial factors to risk for inflammatory disease.”



How might this show up in heart disease? This paper published not long ago in the journal Brain, Behavior, and Immunity investigates the links between HRV, inflammatory cytokines, coronary heart disease and depression:

“Studies show negative correlations between heart rate variability (HRV) and inflammatory markers [less variability = more inflammation]…We investigated links between short-term HRV and inflammatory markers in relation to depression in acute coronary syndrome (ACS) patients.”

They measured C-reactive protein (CRP), interleukin-6 (IL-6, a cytokine), depression symptoms
and heart rate variability determinants of autonomic function. What did their data show?

“…all HRV measures were negatively and significantly associated with both inflammatory markers…HRV independently accounted for at least 4% of the variance in CRP in the depressed, more than any factor except BMI.”


Interestingly, they also noted that:

“Relationships between measures of inflammation and autonomic function are stronger among depressed than non-depressed cardiac patients. Interventions targeting regulation of both autonomic control and inflammation may be of particular importance.”

The research of another group published in the Journal of Critical Care used sepsis as their model.

“The aim of the study was to investigate possible associations between different heart
rate variability (HRV) indices and various biomarkers of inflammation in 45 septic
patients.”

They examined the correlation between HRV, C-reactive protein, and the cytokines interleukin 6
and interleukin 10:

“Our data suggest that low HRV and sympathovagal balance during septic shock are associated with both an increased hyperinflammatory and antiinflammatory response.”


The antiinflammatory response corresponds to high HRV and interleukin-10, the cytokine that is
also increased by vitamin D.


How can we reduce inflammation by increasing HRV and reducing inflammatory cytokines? There are numerous methods; one is to increase cholinergic activity in the nervous system (parasympathetic activity mediated by the neurotransmitter acetylcholine). We can increase this with natural precursor support for acetylcholine. This study published recently in the Journal of Internal Medicine shows the connection between vagal parasympathetic function (as shown by HRV), inflammatory cytokines, cholinergic activity and rheumatoid arthritis:

“The central nervous system regulates innate immunity in part via the cholinergic  anti-inflammatory pathway, a neural circuit that transmits signals in the vagus nerve that suppress pro-inflammatory cytokine production…Vagus nerve activity is significantly suppressed in patients with autoimmune diseases, including rheumatoid arthritis (RA). It has been suggested that stimulating the cholinergic anti-inflammatory pathway may be beneficial to patients…”


They found that increasing cholinergic signaling in stimulated whole blood cultures suppressed
cytokine production in rheumatoid arthritis patients whose vagal activity was deficient:

“These findings suggest that it is possible to pharmacologically target the α7nAChR dependent control of cytokine release in RA patients with suppressed vagus nerve activity.”


In a functional medicine practice, of course, we use natural acetylcholine precursors.

This is a drop in the bucket, but here’s one more fascinating paper published recently in the journal Brain, Behavior, and Immunity that shows how acetylcholine activity in the brain (the upper level of autonomic regulation) controls systemic cytokine levels through vagal function:
“The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the “cholinergic anti-inflammatory pathway,” defined as neural signals transmitted via the vagus nerve that inhibit cytokine release…Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks…Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF [cytokine] production during endotoxemia.”

They demonstrated that inhibiting the breakdown of acetylcholine† markedly reduced proinflammatory serum TNF levels through the resulting increasing vagus nerve signaling which
prevented inflammatory damage. What do they conclude from their research?

“These findings show that inhibition of brain acetylcholinesterase [that breaks down acetylcholine] suppresses systemic inflammation through a central…mediated and
vagal…dependent mechanism. Our data also indicate that a clinically used centrallyacting
acetylcholinesterase inhibitor† can be utilized to suppress abnormal inflammation to therapeutic advantage.”

* There are numerous therapies to reduce inflammation by increasing parasympathetic function.
Breathing is a powerful stimulus to the autonomic nervous system. We train breathing with
biofeedback while simultaneously monitoring for CO2 (capnography) and coherence in HRV to hit the physiological “sweet spot”.

† Agents that inhibit the breakdown of neurotransmitters including reuptake inhibitors do not
restore the body’s ability to make its own. Precursor therapy provides the natural ingredients that have been depleted or are insufficient to meet genetic needs so neurotransmitters can be
increased naturally.

The inflammatory reflex

Kevin J. Tracey

Laboratory of Biomedical Science, North Shore-LIJ Research Institute, 350 Community Drive, Manhasset, New York 11030, USA (e-mail: kjtracey@sprynet.com)

Inflammation is a local, protective response to microbial invasion or injury. It must be fine-tuned and
regulated precisely, because deficiencies or excesses of the inflammatory response cause morbidity and shorten lifespan. The discovery that cholinergic neurons inhibit acute inflammation has qualitatively expanded our understanding of how the nervous system modulates immune responses. The nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible ‘hard-wired’ neural systems.

“The mind has great influence over the body, and maladies often have their origin there.” Molière (1622–1673).

survival is impossible without vigilant defence against attack and injury. The innate immune
system continuously surveys the body for the presence of invaders. When it encounters an
attack, it involuntarily sets in motion a discrete, localized inflammatory response to thwart most
pathogenic threats. The magnitude of the inflammatory response is crucial: insufficient responses result in immunodeficiency, which can lead to infection and cancer; excessive responses cause morbidity and mortality in diseases such as rheumatoid arthritis, Crohn’s disease, atherosclerosis, diabetes, Alzheimer’s disease, multiple sclerosis, and cerebral and myocardial ischaemia. If inflammation spreads into the bloodstream, as occurs in septic shock syndrome, sepsis, meningitis and severe trauma, the inflammatory responses can be more
dangerous than the original inciting stimulus. Homeostasis and health are restored when inflammation is limited by anti-inflammatory responses that are redundant, rapid, reversible, localized, adaptive to changes in input and integrated by the nervous system.

中文摘要:
發炎是一種對付微生物入侵或受傷之局部防衛反應。這種反應必需要細密的控制,因為不足或過分之發炎反應,都會造成病害或簡短壽命。神經系統所產生之膽鹼能控制發炎之發被發現,使我們對神經系統操控免疫系統功能之過程有所了解。神經系統以反射反應之即使方法來控制發炎,正如其能及時的操控心跳及其他的主要功能。現在有可能利用這個新機會來開發出一種可選擇的及可逆的神經處理發炎之方法。

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2011年7月22日 星期五

Vagal tone and the inflammatory reflex

JULIAN F. THAYER, PhD
Professor, Department of Psychology,
The Ohio State University, Columbus, OH
Mannheim Institute of Public Health, Social and Preventive Medicine,
Mannheim Medical Faculty, Heidelberg University,
Mannheim, Germany

ABSTRACT
Inhibition of sympathoexcitatory circuits is influenced by cerebral structures and mediated via vagal mechanisms. Studies of pharmacologic blockade of the prefrontal cortex together with neuroimaging studies support the role of the right hemisphere in parasympathetic control of the heart via its connection with the right vagus nerve. Neural mechanisms also regulate infl ammation; vagus nerve activity inhibits macrophage activation and the synthesis of tumor necrosis factor in the reticuloendothelial system through the release of acetylcholine. Data
suggest an association between heart rate variability and infl ammation that may support the concept of a cholinergic anti-infl ammatory pathway.


The neurovisceral integration model of cardiac vagal tone integrates autonomic, attentional,
and affective systems into a functional and structural network. This neural network can be indexed by heart rate variability (HRV). High HRV is associated with greater prefrontal inhibitory
tone. A lack of inhibition leads to undifferentiated threat responses to environmental challenges.


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