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22 juin 2011 3 22 /06 /juin /2011 15:00

(Infection froide?)


La maladie de Horton (MH) est une artérite inflammatoire giganto-cellulaire du sujet âgé.

Une sténose artérielle des membres supérieurs survient chez 13 à 29 % des patients.

Les traitements endovasculaires sont efficaces quand utilisés avant l'apparition d'une occlusion.


Il n'existe cependant aucun paramètre permettant l'identification précoce des personnes à risque d'atteinte ischémique aux membres supérieurs.

Ceci a conduit les auteurs à analyser rétrospectivement les marqueurs biologiques de l'inflammation chez 105 malades (86 femmes, âge moyen 65,2 ans).


Après un suivi moyen de 31 mois (extrêmes 1-157 mois), une angiographie par résonance magnétique (angio IRM) des artères thoraciques y compris les artères sous-clavière, axillaires et brachiales, a été réalisée chez tous les malades.

Il existait au moins une sténose d'une artère du membre supérieur chez 40 patients (groupe A, biopsie positive de l'artère temporale (PTAB) : 45 %), un anévrisme de l'aorte thoracique chez 14 malades (groupe B, PTAB : 29 %) et aucune atteinte extra-crânienne chez 47 malades (groupe C, PTAB: 51%).

Le nombre de globules blancs était significativement plus élevé dans le groupe A par rapport au groupe C (médiane 11 600 vs 10 100/mm3, p = 0,01) et au groupe B+ C (médiane 10 105/mm3, p=0,02).


Un nombre de globules blancs > 14 000/mm3 a été retrouvé dans 25 % des cas où il y avait une sténose, mais chez seulement chez 8,2 % des autres malades.

Pour tous les malades ayant une atteinte artérielle extra-crânienne (groupe A + B), les leucocytes étaient sensiblement plus élevés (p = 0,023) comparativement au groupe C.


Aucune autre différence significative entre tous les groupes n'a été retrouvée tant sur la formule leucocytaire que la protéine C réactive, la vitesse de sédimentation , les plaquettes ou l'hémoglobine.


L'apparition d'une sténose artérielle ne dépendait pas de la durée d'évolution de la MH.


Ces données indiquent que le risque de sténose aux artères du membre supérieur est augmenté chez les patients avec une hyperleucocytose initiale.


Puisque le traitement endovasculaire est plus efficace quand les lésions sont limitées, ces malades doivent être examinés dès l'entrée dans la maladie avec une attention particulière (pouls, tension artérielle, recherche de souffle), ce d'autant que les sténoses artérielles sont souvent peu symptomatiques.





Both M et coll. : High white blood cell count in patients with giant cell arteritis predicts an increased risk of stenosis in upper extremity arteries. Ann Rheum Dis., 2011 ; publication avancée en ligne le 10 mai

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14 juin 2011 2 14 /06 /juin /2011 09:43

NEWS: New UC Davis study says Lyme hides out in lymph nodes

08 June, 2011

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Researchers at the University of California, Davis, have found that Lyme bacteria "have developed a novel strategy for subverting the immune response of the animals they infect." Their study appears on-line in the journal Public Library of Science Biology.

Press release from UC Davis:

Lyme disease bacteria take cover in lymph nodes, study finds


June 8, 2011

The bacteria that cause Lyme disease, one of the most important emerging diseases in the United States, appear to hide out in the lymph nodes, triggering a significant immune response, but one that is not strong enough to rout the infection, report researchers at the University of California, Davis.

Results from this groundbreaking study involving mice may explain why some people experience repeated infections of Lyme disease. The study appears online in the journal Public Library of Science Biology.

“Our findings suggest for the first time that Borrelia burgdorferi, the bacteria that cause Lyme disease in people, dogs and wildlife, have developed a novel strategy for subverting the immune response of the animals they infect,” said Professor Nicole Baumgarth, an authority on immune responses at the UC Davis Center for Comparative Medicine.

“At first it seems counter intuitive that an infectious organism would choose to migrate to the lymph nodes where it would automatically trigger an immune response in the host animal,” Baumgarth said. “But B. burgdorferi have apparently struck an intricate balance that allows the bacteria to both provoke and elude the animal’s immune response.”

About Lyme disease

Lyme disease, the most important tick-borne disease in the United States is caused by Borrelia burgdorferi, corkscrew-shaped bacteria also known as spirochetes. The disease is transmitted to humans and animals through bites from infected deer ticks. The disease occurs mainly in the Northeastern and Great Lakes states, and is present to a lesser extent in Northern California.

Symptoms of Lyme disease are quite variable and may include fever, headache, fatigue and a skin rash. If the infection is not treated, it can spread to the joints, heart and nervous system.

Usually, Lyme disease can be successfully treated with about four weeks of antibiotics; treatment is most successful during the early stages of infection.

The UC Davis study

Swollen lymph nodes, or lymphadenopathy, is one of the hallmarks of Lyme disease, although it has been unclear why this occurs or how it affects the course of the disease. The UC Davis research team set out to explore in mice the mechanisms that cause the enlarged lymph nodes and to determine the nature of the resulting immune response.

They found that when mice were infected with B. burgdorferi, these live spirochetes accumulated in the animals’ lymph nodes. The lymph nodes responded with a strong, rapid accumulation of B cells, white blood cells that produce antibodies to fight infections. Also, the presence of B. burgdorferi caused the destruction of the distinct architecture of the lymph node that usually helps it to function normally.

While B cells accumulated in large numbers and made some specific antibodies against B. burgdorferi, they did not form “germinal centers,” structures that are needed for the generation of highly functional and long-lived antibody responses.

“Overall, these findings suggest that B. burgdorferi hinder the immune system from generating a response that is fully functional and that can persist and protect after repeat infections,” Baumgarth said. “Thus, the study might explain why people living in endemic areas can be repeatedly infected with these disease-causing spirochetes.”

In addition to Baumgarth, members of the UC Davis research team include Stephen Barthold, director of the Center for Comparative Medicine; Emir Hodzic, director of the Real-Time PCR Research and Diagnostics Core Facility; staff scientist Sunlian Feng; graduate student Christine Hastey; and Stefan Tunev, formerly of the Center for Comparative Medicine and now at Medtronic Inc.

Funding for the study was provided by the National Institute of Health.

About UC Davis

For more than 100 years, UC Davis has engaged in teaching, research and public service that matter to California and transform the world. Located close to the state capital, UC Davis has more than 32,000 students, more than 2,500 faculty and more than 21,000 staff, an annual research budget that exceeds $678 million, a comprehensive health system and 13 specialized research centers. The university offers interdisciplinary graduate study and more than 100 undergraduate majors in four colleges — Agricultural and Environmental Sciences, Biological Sciences, Engineering, and Letters and Science. It also houses six professional schools — Education, Law, Management, Medicine, Veterinary Medicine and the Betty Irene Moore School of Nursing.



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Chlamydia pneumoniae and MS: Questions and Answers

What is the life-cycle of C pneumoniae?

Simplifying slightly, C pneumoniae has two major phases to its life cycle. The infectious form is called the Elementary Body (EB). This spore-like form transmits the organism from person to person and, within a person, from cell to cell. The EB is metabolically inert; it has an external membrane which includes potentially unstable proteins. When it attaches to a susceptible host cell a sudden change takes place; the proteins which are embedded in its external membrane become loose and the host cell wall closes behind the entering EB. Entry may be controlled by subversional proteins injected into the host cell via tiny syringes and needles (The type III secretory system. Proteins associated with the TTSS have been found in the EB proteome.)

Once inside the host cell, the organism expands to become the Reticular Body (RB). It efficiently uses host membrane to make its own environment within a cell. Then it takes up its position around the host's mitochondria to steal the energy-rich molecules fabricated by these organelles, probably by means of small tubes. The RB then begins to control the direction of the host-cell metabolism, again probably using microscopic syringes and needles. Its own nuclear material eventually divides into many separate individuals, which then condense into EBs. The host cell bursts, scattering EBs into the extracellular milieu. This is the picture in cell-culture and is the likely picture in acute infections.

In chronic infections a different pathway is taken. Under pressure from host defences the organism enters into persistent state, where its metabolic processes are diminished. The organism in this state is called the Cryptic Body (CB). This chronic unresolved infection - which can last for several decades - can initiate the malign process of autoimmunity. To a large extent the form of the disease depends on the host's genetic inheritance. This is why many of the chronic disease forms caused by infections with Chl pneumoniae tend to have inherited characteristics. An excellent and readable account of how peristent unresolved infections can initiate chronic diseases with autoimmune aspects can be found in this dissertation by Tiina Sävykoski: http://herkules.oulu.fi/isbn9514269853/html

How might Chlamydia pneumoniae reach the brain?


The organism settles on some part of the respiratory lining and then invades. A respiratory infection (sinusitis, bronchitis, pharyngitis or pneumonia) results. Host defence cells mop up the organism; some become parasitized. Chl pneumoniae can travel round the body in the blood monocytes - mobile host defence cells - when these are called to deal with a remote infection - perhaps a transient virus infection. As the monocytes pass through the blood vessel walls, Chl pneumoniae are shed; these infect the lining cells. Microcolonies of Chl pneumoniae are set up. This can happen in the brain, in joints, in the vessels which supply the great arteries themselves, and in the skin. See [Gieffers J, et al., Phagocytes transmit Chlamydia pneumoniae from the lungs to the vasculature. Eur Respir J. 2004 Apr;23(4):506-10.]



MS is a many-staged and complex disorder. How can a simple bacterial colonisation/infection cause such complexity?

MS has four variants: relapsing-remitting, where neurological deficits occur suddenly and resolve over a few weeks. Resolution is at first usually complete; later, it is less so. Although called relapsing-remitting, most patients gradually accrue deficits. The disease may change to the secondary-progressive form; remissions are now unusual and deterioration is the rule. The third variant is the primary-progressive form, where the disease worsens from the beginning. The fourth, or so-called benign form, describes rare cases where resolution is always complete; the deficits themselves may cease to happen. (It is unwise to use this term as MS can become aggressive twenty years after its first mild appearance.)

All these forms and stages would correspond well with an established Chlamydia pneumoniae infection in the brain. In the relapsing-remitting form the infection is silent until a new respiratory infection provokes a new host response. This tends to become more severe as time goes on. (Parallels are seen in the increasing severity of pneumonias caused by Chlamydia pneumoniae in those who suffer repeated infections after seroconversion: the severity is caused by the increasing strength of the host response.) In the progressive forms the host response is continuously firing, often against an extracerebral bacterial infection; a patient with early SPMS will often mention chronic sinusitis, chronic middle ear disease or new-onset asthma which began some time before the MS began to slide into the progressive phase. Sarah experienced a prolonged respiratory infection followed by new-onset asthma before her illness became progressive.


MS has a genetic component. It also has a marked geographical distribution. How do you account for this, given that Chl pneumoniae is ubiquitous?

MS has a pronounced geographical distribution. It is most common in the cooler latitudes, becoming rarer as the tropics are approached. Migration from temperate to tropical areas confers protection, provided the move is made before adolescence. People who migrate to temperate areas are more likely to develop MS than those who have remained behind.

The epidemiology of MS is not as simple as this, however. The disease has an increased incidence in certain groups of women in the Middle East. The common factor seems to be a seasonal or cultural reduction in exposure to sunlight; in those with a genetic predisposition a relative lack of Vitamin D develops. Vitamin D deficiency is indeed found in those with MS; it is linked to calcium and magnesium deficiency and to osteoporosis. By contrast MS is extremely rare amongst the Inuit, who, though living through arctic winters, derive ample Vitamin D from a fish-rich diet.

Vitamin D is vital for the maintenance of the blood/brain barrier. Not only may a mild Vitamin D deficiency allow ingress of Chl pneumoniae; it may also activate quiescent infections. The number of active white-matter lesions seen on MRI in persons with MS closely follows the seasonal fluctuation of levels of circulating Vitamin D.


Other infectious agents, notably Human Herpesvirus 6, have been put forward as causative agents in MS. How does this square with a primary Chl pneumoniae infection?

Human Herpes Virus 6 may have a secondary input into MS; read a brief note about this on page 5.



Can a chlamydial cause for MS be proved in an individual patient by serology?

Not at the moment. This because Chl pneumoniae is a common organism and infections with the bacterium are common. Antibody levels tend to rise during life, even in people who are asymptomatic. Patients with extracerebral infections of some duration (particularly reactive arthritis) can show high titres in the microimmunofluorescence test; it is generally reckoned that a titre of 1:512 or above, in the presence of appropriate clinical findings, supports a diagnosis of Chl pneumoniae disease. MS is different; the pathology is at the blood-brain barrier. One would not expect an elevation of circulating antibodies unless an extracerebral component to the infection were also present. This may be the case in progressive disease; there is a statistical elevation of antibodies in a group of such patients. This supports the idea of a chlamydial cause for MS, but makes no prediction in an individual. That is why treatment must at the moment be empirical.


Antibiotics have been around for more than sixty years: surely they must have been tried before.

Neurologists have speculated from the late 19th century that MS might have an infective origin. They were used to dealing with infections, particularly syphilis. I’m sure that penicillin, so effective against syphilis, would have been tried in MS. There is unexpected evidence that penicillins have some activity against chlamydiae; however, in the absence of meningitis but they do not achieve high concentrations in the CNS. By the time tetracycline was invented, neurology, and the received beliefs about the cause of MS, had changed. Neurologists now rarely saw patients with underlying infections and MS was considered a primary auto-immune disorder. And, too, there is a battle-weariness in the neurology establishment. So many hopes about finding a treatable cause for MS have been dashed over the decades. The mind-set of the neurological establishment needs to be changed. This will happen.

And, too, MS sufferers are often seen as people who are difficult to help. When I was a student it was customary to speak of the ‘typical mental attitude’ of those with established MS; this included an impression of blunted insight, a kind of insouciance, even euphoria. In these more politically correct days one does not speak like this any more, but there is an element of truth in it. Now that I think of MS as an infection, the answer becomes clear: this ‘typical mental attitude’ is a state of intoxication with bacterial metabolic products. Once seen it's not forgotten. A similar state is seen in other chronic infections. In the days before antibiotics persons with active tuberculosis were said to have a typical mental state. People who were nursing at the time still vividly remember this.

In addition to this (recalcitrant doctors and recalcitrant patients) the beginnings of recovery with antibiotics are not pleasant. The early bacteriolytic reaction can be alarming. And, as Sarah found, as-yet unorganised repair can cause function to worsen in the short term. This could easily lead to an early impression that antibiotics were unhelpful or even harmful and could have led to their discontinuance.

There was a lone voice in the 1950's and 60's who dissented from the strengthening auto-immune school: Dr Paul Le Gac. Page 9 gives links to pdf files of his papers and presentations.


Why doxycycline and roxithromycin (or azithromycin)?

Both are oral, both are active against Chlamydia pneumoniae, both are relatively inexpensive. They are relatively risk-free. They act synergically against test strains of the organism; giving both together would be the equivalent of giving a four-fold increase of each drug were it to be given alone. The drugs work on different steps in the bacterial protein synthesis pathway. Combination therapy reduces the chance of the emergence of resistance. Both drugs pass into the brain. Both reach good levels inside cells. This is very important. Both are well tolerated. Azithromycin is an alternative to roxithromycin. They deplete the organisms slowly: this is very important, as the release of bacterial endotoxins should not be sudden.

Rifampicin may also be considered. It, too, is synergic with doxycycline, penetrates the brain and is active intracellularly. It is not suitable for intermittent use. It is highly active, and, in patients with a large bacterial load, it may give rise to intense reactions.


Why are later short courses of metronidazole to be taken together with these antimicrobials?

Chlamydiae are complex organisms. Long ago their ancestors must once have been free-living bacteria which possessed their own energy-generating pathways. The transformation from EB to RB is an active change, and an active change implies the retention of at least some of these pathways. The ones with the most utility for this purpose would be anaerobic, and thus susceptible to metronidazole.

Doxycycline and roxithromycin block the replicating phase by inhibiting protein synthesis and may be expected to force the organism to maintain itself by using its own primitive anaerobic respiratory mechanisms. In this suspended state it would be susceptible to anti-anaerobic agents such as metronidazole.

This is borne out by clinical evidence. The administration of metronidazole after doxycycline in a patient with likely high-load Chl pneumoniae infection causes a bacteriolytic reaction more severe than that following the original administration of doxycycline.

However, there is a difference: in this leg of treatment there is no risk of the emergence of resistance, for the organism is unable to replicate. Metronidazole need thus be given in courses only as long as can be tolerated. 

Five-day courses of metronidazole at three-week intervals, during continuous treatment with doxycycline and roxithromycin, would seem reasonable; at first, metronidazole may be limited to one or two doses on one or two days to judge the severity of reaction.

The eventual aim would be to give all three agents intermittently. This, the final leg of treatment, would entail a 14 day course of doxycycline and roxithromycin, with metronidazole given from day five for five days. (The reason for continuing doxycycline and roxithromycin for a few days after the metronidazole has been stopped is because these drugs both possess anti-inflammatory activity which may prevent a reaction to the organisms killed by metronidazole.) This course would be given once a month. After several months the intervals between the antibiotics would be cautiously extended.


Why this complex antibiotic regime?

The literature is filled with instances of treatment-failure in serologically-proven chronicChl pneumoniae infections of non-CNS systems, whether macrolides, tetracyclines or rifampicin have been used. When the drug is stopped, even after months of treatment, serology rises, and the patient relapses.

The intensive cyclical regime of combined antimicrobials outlined here corrals the pathogen, initially halting replication, then eliminating stalled intracellular forms. Extracellular forms may be depleted by giving N-acetyl cysteine (see below.)

No single antimicrobial agent can be expected to achieve this effectiveness against every phase of the organism's life.



What are the expected reactions to the antibiotics?

There seems to be two components to the reactions experienced on taking the antibiotics.

The first is caused by elimination of bacterial fragments — endotoxins — and is characterised by shivering, influenzal symptoms and general malaise.

The second is caused by the release of metabolic toxins; waves of giddiness and feelings of unreality are quite common. They are alarming if not known about and understood. The strength and duration of these reactions depends largely on the bacterial load. In MS, particularly early relapsing-remitting MS, the bacterial load is likely to be small, and the reaction brief. In other conditions, particularly those with multi-system involvement, the bacterial load may be large and the reaction to antibiotics unpleasant and prolonged.

It may seem unlikely that doxycycline, roxithromycin and rifampicin can kill chlamydiae; they are, after all, considered to be bacteriostatic agents — normally they inhibit rather than kill bacteria. However, intracellular Chlamydia pneumoniae must continuously elaborate proteins to ensure its own survival within the host-cell.

The reaction to the metronidazole component of treatment is particularly severe as at this stage numerous bacteria are being killed. For this reason it may be best to give an initial course of one single day, followed by review. Prochlorperazine, 10mg orally, may be useful.

The patient can be reassured that a reaction to the antimicrobials are evidence of bacterial destruction and that they will end. And, too, the morale induced by physical improvement has to be set against them.


Isn’t giving antibiotics for a long time is a bad thing?

That depends on the illness. Long-term doxycycline is used fairly routinely for certain kinds of gum disease and for acne. Doxycycline is also used long-term in malaria prophylaxis.

Long-term use of these antibiotics engenders no real risk of an increase of resistance in other bacteria within the wider community.


Does the fact that antibiotics can roll back MS tell us something about the nature of the illness itself?

I think it does. Components of MS, at some stages and in some variants, may be:

A bacterial toxaemia. This may account for the mental fog, blunting of insight, greatly increased reaction times and many other non-specific symptoms which are hard to explain by demyelination alone, including fatigue; indeed, there is evidence of abnormal cortical activity. [Leocani L et al., Neuroimage. 2001;13(6 Pt 1):1186-92.] A toxaemia would be expected to resolve quickly with effective antibiotic treatment, as has happened here.

Early phenomena: local mass oligodendrocyte death and secondary demyelination. This is the sudden stripping away of the insulation of the nerve-fibres in the classical MS relapse. It is reversible, but recovery depends on the replacement of oligodendrocytes, the cells which produce and sustain myelin. Damage to the nerve fibres occurs even in early disease, but becomes more severe with time.

Loss of neurones. 
[reviewed by Minagar A et al., Pathogenesis of brain and spinal cord atrophy in multiple sclerosis. J Neuroimaging. 2004; 14(3 Suppl): 5S-10S.] Neurone-loss has been shown to occur in MS and may cause eventual dementia. One might speculate that appropriate antibiotic treatment would prevent further neuronal loss. (Given that neurones are very susceptible to toxins, and that the brain has evolved an elaborate defence system for keeping toxins out, it is possible to speculate that the neuronal loss seen throughout the course of MS might be a direct result of chronic toxaemia maintained from within the brain itself.) Until fairly recently it was considered that, in the adult, lost neurones could not be replaced; there is now a lot of evidence that neuronal replacement occurs throughout life: neural stem cells are known to occur at various loci, including the hippocampus, sub-pial and periventricular area. [reviewed by Taupin P. Adult neurogenesis in the mammalian central nervous system: functionality and potential clinical interest. Med Sci Monit. 2005l; 11(7): RA247-252.] In addition, the brain is known to have considerable functional plasticity.



Can relapses occur after starting antibiotics?

In relapsing-remitting MS the major cause of relapse, a new respiratory infection withChlamydia pneumoniae, will be prevented by the antibiotics. However, for the first six months or so it is possible for a relapse to occur secondary to a virus infection. This may be particularly likely in a household with young children.

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Empirical antibacterial treatment of 
infection with Chlamydophila pneumoniae 
in Multiple Sclerosis
David Wheldon MB FRCPath

After much controversy there is now powerful evidence for the respiratory pathogenChlamydophila (Chlamydia) pneumoniae being a causal factor in some variants of the neurological illness multiple sclerosis. A series of remarkable studies finds:

• the presence of C. pneumoniae gene sequences in the cerebrospinal fluid of patients who have the disease, and culture of the organism when sensitive cultural methods are used [Sriram S, Stratton CW, Yao S, Tharp A, Ding L, Bannan JD, Mitchell WM. Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis. Ann Neurol. 1999 Jul;46(1):6-14.]

• an association of new C. pneumoniae respiratory infections with episodes of clinical relapse 
[Buljevac D, Verkooyen RP, Jacobs BC, Hop W, van der Zwaan LA, van Doorn PA, Hintzen RQ. Chlamydia pneumoniae and the risk for exacerbation in multiple sclerosis patients. Ann Neurol. 2003 Dec;54(6):828-31.]

• a statistically significant elevation of C. pneumoniae-specific serum antibody levels when the disease shifts into the progressive form [Munger KL, Peeling RW, Hernán MA, Chasan-Taber L, Olek MJ, Hankinson SE, Hunter D, Ascherio A. Infection with Chlamydia pneumoniae and risk of multiple sclerosis.Epidemiology 2003 14:2 141-147]

• antibodies to C. pneumoniae in the cerebrospinal fluid of patients with the disease 
[(1.) Yao, S., Stratton, C.W., Mitchell, W.M., Sriram, S. (2001). CSF oligoclonal bands in multiple sclerosis represent antibodies against Chlamydophila. Neurology 56, 1168-76. (2.) Fainardi, E., Castellazzi, M., Casetta, I. et al. (2004). Intrathecal production of Chlamydia pneumoniae-specific high-affinity antibodies is significantly associated with a subset of multiple sclerosis patients with progressive forms. Journal of the Neurological Sciences 217, 181-8.]

• evidence of active C. pneumoniae protein synthesis in the central nervous system, with production of a bacterial protein evoking an antibody shown to cause death of oligodendrocyte precursor cells 
[Cid C, Alvarez-Cermeno JC, Camafeita E, Salinas M, Alcazar A. Antibodies reactive to heat shock protein 90 induce oligodendrocyte precursor cell death in culture. Implications for demyelination in multiple sclerosis. FASEB J. 2004 Feb;18(2):409-11.]

a peptide specific to C. pneumoniae causes inflammatory CNS disease (with some parallels to MS) in rats [Lenz DC, Lu L, Conant SB, Wolf NA, Gerard HC, Whittum-Hudson JA, Hudson AP, Swanborg RH. A Chlamydia pneumoniae-specific peptide induces experimental autoimmune encephalomyelitis in rats.
J Immunol. 2001 Aug 1;167(3):1803-8.]

C. pneumoniae gene transcription in the CSF of patients with MS [Dong-Si T, Weber J, Liu YB, Buhmann C, Bauer H, Bendl C, Schnitzler P, Grond-Ginsbach C, Grau AJ. Increased prevalence of and gene transcription by Chlamydia pneumoniae in cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis. J Neurol. 2004 May;251(5):542-547.]

• MRI improvement in antibiotic-treated patients with early disease in a small but fastidious double-blind trial of non-immunomodulatory antibiotics 
[Sriram S, Yao SY, Stratton C, Moses H, Narayana PA, Wolinsky JS. Pilot study to examine the effect of antibiotic therapy on MRI outcomes in RRMS. J Neurol Sci. 2005 Jul 15;234(1-2):87-91.]

• MRI improvement, with reduction of the number of Gd-enhancing lesions, in a second treatment study with minocycline [Metz LM, Zhang Y, Yeung M, Patry DG, Bell RB, Stoian CA, et al. Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol. 2004 May;55(5):756.]

• An association of C. pneumoniae in the CNS with MS is demonstrated by immunohistochemical, molecular and ultrastructural methods. [Sriram S, Ljunggren-Rose A, Yao SY, Whetsell WO Jr. Detection of chlamydial bodies and antigens in the central nervous system of patients with multiple sclerosis. J Infect Dis. 2005;192(7):1219-28.]

The evidence for a causal association of C. pneumoniae with majority subsets of MS has been garnered by a surprisingly diverse array of methods; cultural, molecular (both DNA and RNA based), immunohistological, serological (blood and CSF based), animal model, ultrastructural and therapeutic trial. It is this very diversity of methodology which makes the evidence compelling. The subject has recently been reviewed in some detail by Chuck Stratton and myself [Stratton CW, Wheldon DB. Multiple sclerosis: an infectious syndrome involving Chlamydophila pneumoniaeTrends Microbiol. 2006 Nov;14(11):474-9.]

The results of antichlamydial treatment have been very promising, particularly in early disease.

It should be stressed at the outset that this bacterium is not sexually transmitted. It causes respiratory infection and is spread by droplet infection — coughing and sneezing.

Sarah, my wife, an artist of considerable ability, was given a diagnosis of MS in July 2003. Her illness in fact stretched back to 1989, when she experienced a sudden weakness of the right arm. After a fortnight she recovered its function completely. A few years later she experienced a slight greying of vision in one eye; this resolved over a few weeks. Occasional relapses followed, all with a complete recovery. In 1999 the remissions started to become less complete. Right foot-drop began insidiously and did not resolve. Then, in 2001, shortly after a prolonged upper respiratory infection which led to mild new-onset asthma, Sarah began to enter a new, rapidly progressive stage of the illness. Within two years she was unable able to stand unaided, had to hold furniture, was unable to hold or use a pencil or paint-brush with her right hand, and she felt giddy. She said that she seemed to live in a mental fog: indeed, in the evenings she would fall into a half-sleep from which she obtained no rest. Her speech was becoming slurred. There was a continual sense of flickering and worsening neurological deficit. She suffered tinnitus, hearing the continual sound of distant machinery. She developed L'hermitte's sign, manifested as an electric-shock-like pain down the back on bending the head forward and signifying damage to the cervical spinal cord.

An MRI scan showed many typical active lesions, visible as variably-sized bead-like hyperintensities in the white matter of the brain. The neurologist told Sarah that she had Multiple Sclerosis; the disease had entered a secondary progressive phase for which there was no treatment, and that the illness must be expected to take its course.

I’m much more interventional than he — this goes with the territory of my being a medical microbiologist — and I recommended the following oral antichlamydial regimen:

doxycycline 200mg once daily
roxithromycin 300mg once daily (azithromycin 250mg three days a week is an alternative.)
Short courses of metronidazole will later be added to this regimen.

We started the doxycycline first, as it was immediately available. The results were astonishing. For five days she suffered a worsening of her symptoms; this was accompanied by a flu-like illness, with headache round the eyes, pains in the large joints (hips and shoulders) and night-sweats. This is a typical Herxheimer-like reaction; it is caused when a large bacterial load is broken up by antibiotics or other agents. After five days she lost the mental fog: indeed, she said she felt clearer than for two years. The roxithromycin was added three weeks later, when it became available.

This information has been made available at Sarah's request. It has to be said that, despite all the research which has been published in the scientific literature, the existence — let alone the therapeutics — of chronic infection with C. pneumoniae is barely understood by the medical community.

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Un risque accru d'insuffisance cardiaque avec le VIH

Une atteinte cardiaque est loin d'être exceptionnelle chez les malades infectés par le virus de l'immunodéficience humaine (VIH). Notamment les troubles métaboliques induits par les trithérapies peuvent contribuer à l'apparition d'une maladie coronaire.

Ceci étant, le VIH peut-il favoriser la survenue d'une insuffisance cardiaque (IC), indépendamment de toute athéromatose des artères coronaires ? Ce n'est pas impossible si l'on en croit les résultats de deux étude de cohorte rétrospectives « communicantes », en vérité du type cas-témoins, menée aux Etats-Unis.

Les patients recrutés sont des vétérans enrôlés entre 2000 et 2007 dans une étude dite VACS-VC ( Veterans Aging Cohort Study-Virtual Cohort) et une autre dite LHS ( Large Health Study of Veteran Enrollees). Parmi les 8 486 participants sélectionnés, 28,2 % présentaient une infection par le VIH.

Au cours du suivi d'une durée médiane de 7,3 années, 286 IC ont été diagnostiquées. Après ajustement pour l'âge et l'ethnie, l'incidence est de 7,12 pour 1 000 sujets-années dans le groupe VIH+, et 4,82 pour 1 000 sujets-années dans le groupe des témoins (VIH-). La comparaison intergroupe montre qu'en cas d'infection par le VIH, le risque relatif d'IC, en fait l'odds ratio ajusté (ORA) est de 1,81 (versus VIH-). Cette association n'est pas affectée par l'existence d'une coronaropathie, d'un alcoolisme chronique ou encore d'une toxicomanie (ORA 1,96). Un nombre basal élevé de copies de l'ARN viral (> 500) a été associé à un ORA d'IC de 2,28 (p<0,001 versus nombre de copies < 500 ; ORA=1,10).

Si l'on en croit les résultats de ces études cas-témoins, l'infection par le VIH augmenterait le risque d'IC, indépendamment de toute maladie coronaire, a fortiori quand il existe une réplication virale biologiquement patente.


Dr Philippe Tellier


Butt AA et coll. : Risk of Heart Failure With Human Immunodeficiency Virus in the Absence of Prior Diagnosis of Coronary Heart Disease. Arch Intern Med 2011; 171: 737-743.

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4 mai 2011 3 04 /05 /mai /2011 09:16

Sclérose en plaques et virus Epstein-Barr (EBV)


L'infection à virus Epstein-Barr (EBV), responsable de mononucléose infectieuse, semble interagir avec le niveau d'exposition aux UVB dans le risque de survenue d'une sclérose en plaques, suggère une étude anglaise publiée dans Neurology.

La sclérose en plaques (SEP) semble se développer chez des sujets présentant des facteurs de susceptibilité génétique, en interaction avec des facteurs de l'environnement.

Cette hypothèse du rôle de facteurs environnementaux est appuyée par la distribution géographique de la maladie, avec un gradient Nord-Sud assez prononcé.

Un autre facteur environnemental potentiel dans la SEP est l'infection à virus Epstein-Barr (EBV), qui peut provoquer une mononucléose infectieuse : le risque de SEP semble accru chez les sujets infectés.

Une équipe du Wellcome Trust Centre for Human Genetics, à l'université d'Oxford (Royaume-Uni), a examiné la distribution de la SEP et celle de la mononucléose infectieuse, en regard de l'exposition aux UVB à travers le Royaume-Uni. Pour cela, les auteurs ont analysé, dans les bases de données des hôpitaux du National Health Service (NHS), les dossiers de 56 681 cas de SEP et de 14 621 cas de mononucléose infectieuse sur sept ans. Ils ont aussi étudié les données de la NASA sur l’intensité des UVB sur l'Angleterre.

Résultats, publiés dans Neurology : la SEP est fortement corrélée à la fois à la latitude et à la mononucléose infectieuse. Et le lien entre SEP et UVB, quelle que soit la saison, est plus fort que le lien entre SEP et mononucléose infectieuse.

La régression linéaire multivariée suggère que l'exposition aux UVB seule pourrait expliquer 61% de la variation de la prévalence de la SEP à travers l'Angleterre. Lorsque l'exposition aux UVB et la mononucléose infectieuse sont associées, elles pourraient expliquer 72% de cette variation.

Les chercheurs émettent l’hypothèse qu’une exposition plus faible aux UVB réduirait la synthèse cutanée de vitamine D, ce qui perturberait la réponse du système immunitaire à l'EBV et favoriserait la survenue d'une mononucléose infectieuse. Des études supplémentaires sont nécessaires pour examiner le lien entre vitamine D, mononucléose infectieuse et SEP.

L'infection à virus Epstein-Barr (EBV), responsable de mononucléose infectieuse, semble interagir avec le niveau d'exposition aux UVB dans le risque de survenue d'une sclérose en plaques, suggère une étude anglaise publiée dans Neurology.


La sclérose en plaques (SEP) semble se développer chez des sujets présentant des facteurs de susceptibilité génétique, en interaction avec des facteurs de l'environnement. Cette hypothèse du rôle de facteurs environnementaux est appuyée par la distribution géographique de la maladie, avec un gradient Nord-Sud assez prononcé. Un autre facteur environnemental potentiel dans la SEP est l'infection à virus Epstein-Barr (EBV), qui peut provoquer une mononucléose infectieuse : le risque de SEP semble accru chez les sujets infectés.

Une équipe du Wellcome Trust Centre for Human Genetics, à l'université d'Oxford (Royaume-Uni), a examiné la distribution de la SEP et celle de la mononucléose infectieuse, en regard de l'exposition aux UVB à travers le Royaume-Uni. Pour cela, les auteurs ont analysé, dans les bases de données des hôpitaux du National Health Service (NHS), les dossiers de 56 681 cas de SEP et de 14 621 cas de mononucléose infectieuse sur sept ans. Ils ont aussi étudié les données de la NASA sur l’intensité des UVB sur l'Angleterre.

Résultats, publiés dans Neurology : la SEP est fortement corrélée à la fois à la latitude et à la mononucléose infectieuse. Et le lien entre SEP et UVB, quelle que soit la saison, est plus fort que le lien entre SEP et mononucléose infectieuse.

La régression linéaire multivariée suggère que l'exposition aux UVB seule pourrait expliquer 61% de la variation de la prévalence de la SEP à travers l'Angleterre. Lorsque l'exposition aux UVB et la mononucléose infectieuse sont associées, elles pourraient expliquer 72% de cette variation.

Les chercheurs émettent l’hypothèse qu’une exposition plus faible aux UVB réduirait la synthèse cutanée de vitamine D, ce qui perturberait la réponse du système immunitaire à l'EBV et favoriserait la survenue d'une mononucléose infectieuse. Des études supplémentaires sont nécessaires pour examiner le lien entre vitamine D, mononucléose infectieuse et SEP.


J Neurol Neurosurg Psychiatry. 2011 Jan 6. [Epub ahead of print]

Geography of hospital admissions for multiple sclerosis in England and comparison with the geography of hospital admissions for infectious mononucleosis: a descriptive study.

Ramagopalan SV, Hoang U, Seagroatt V, Handel A, Ebers GC, Giovannoni G, Goldacre MJ.


Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.


Objective It is well recognised that variation in the geographical distribution of multiple sclerosis (MS) exists.

Early studies in England have shown the disease to have been more common in the North than the South.

However, this could be an artefact of inaccurate diagnosis and ascertainment, and recent data on MS prevalence are lacking.

In the present study, data were analysed to provide a more contemporary map of the distribution of MS in England and, as infectious mononucleosis (IM) has been shown to be associated with the risk of MS, the geographical distribution of IM with that of MS was compared.

Methods Analysis of linked statistical abstracts of hospital data for England between 1999 and 2005. Results There were 56 681 MS patients. The admission rate for MS was higher in females (22/10(5); 95% CI 21.8 to 22.3) than males (10.4/10(5); 95% CI 10.2 to 10.5). The highest admission rate for MS was seen for residents of Cumbria and Lancashire (North of England) (20.1/10(5); 95% CI 19.3 to 20.8) and the lowest admission rate was for North West London residents (South of England) (12.4/10(5); 95% CI 11.8 to 13.1). The geographical distributions of IM and MS were significantly correlated (weighted regression coefficient (r (w))=0.70, p<0.0001). Admission rates for MS were lowest in the area quintile with the highest level of deprivation and they were also lowest in the area quintile with the highest percentage of population born outside the UK. A significant association between northernliness and MS remained after adjustment for deprivation and UK birthplace.



The results show the continued existence of a latitude gradient for MS in England and show a correlation with the distribution of IM.

The data have implications for healthcare provision, because lifetime costs of MS exceed £1 million per case in the UK, as well as for studies of disease causality and prevention.


PMID: 21212107 [PubMed - as supplied by publisher]




PLoS One. 2011 Jan 27;6(1):e14606.

The epidemiology of multiple sclerosis in Scotland: inferences from hospital admissions.

Handel AE, Jarvis L, McLaughlin R, Fries A, Ebers GC, Ramagopalan SV.


Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.



Multiple sclerosis (MS) is a neurological disorder with a highly characteristic disease distribution. Prevalence and incidence in general increase with increasing distance from the equator. Similarly the female to male sex ratio increases with increasing latitude. Multiple possible risk factors have been hypothesised for this epidemiological trend, including human leukocyte antigen allele frequencies, ultraviolet exposure and subsequent vitamin D levels, smoking and Epstein-Barr virus. In this study we undertook a study of medical records across Scotland on an NHS health board level of resolution to examine the epidemiology of MS in this region.


We calculated the number and rate of patient-linked hospital admissions throughout Scotland between 1997 and 2009 from the Scottish Morbidity Records. We used weighted-regression to examine correlations between these measures of MS, and latitude and smoking prevalence. We found a highly significant relationship between MS patient-linked admissions and latitude (r weighted by standard error (r(sw)) = 0.75, p = 0.002). There was no significant relationship between smoking prevalence and MS patient-linked admissions.


There is a definite latitudinal effect on MS risk across Scotland, arising primarily from an excess of female MS patients at more Northerly latitudes. Whether this is a true gradient or whether a threshold effect may apply at particular latitude will be revealed only by further research. A number of genetic and environmental factors may underlie this effect.


Neurology. 2011 Feb 1;76(5):425-31.

Association of UV radiation with multiple sclerosis prevalence and sex ratio in France.

Orton SM, Wald L, Confavreux C, Vukusic S, Krohn JP, Ramagopalan SV, Herrera BM, Sadovnick AD, Ebers GC.


Wellcome Trust Centre for Human Genetics and Department of Clinical Neurology, University of Oxford, Oxford, UK.


French farmers and their families constitute an informative population to study multiple sclerosis (MS) prevalence and related epidemiology. We carried out an ecological study to evaluate the association of MS prevalence and ultraviolet (UV) radiation, a candidate climatologic risk factor.


Mean annual and winter (December-March) UVB irradiation values were systematically compared to MS prevalence rates in corresponding regions of France. UVB data were obtained from the solar radiation database (SoDa) service and prevalence rates from previously published data on 2,667 MS cases registered with the national farmer health insurance system, Mutualité Sociale Agricole (MSA). Pearson correlation was used to examine the relationship of annual and winter UVB values with MS prevalence. Male and female prevalence were also analyzed separately. Linear regression was used to test for interaction of annual and winter UVB with sex in predicting MS prevalence.


There was a strong association between MS prevalence and annual mean UVB irradiation (r = -0.80, p < 0.001) and average winter UVB (r = -0.87, p < 0.001). Both female (r = -0.76, p < 0.001) and male (r = -0.46, p = 0.032) prevalence rates were correlated with annual UVB. Regression modeling showed that the effect of UVB on prevalence rates differed by sex; the interaction effect was significant for both annual UVB (p = 0.003) and winter UVB (p = 0.002).


The findings suggest that regional UVB radiation is predictive of corresponding MS prevalence rates and supports the hypothesis that sunlight exposure influences MS risk.

The evidence also supports a potential role for gender-specific effects of UVB exposure.

PMID: 21282589 [PubMed - indexed for MEDLINE] PMCID: PMC3034408 [Available on 2011/7/26]


Neuroepidemiology. 2009;32(4):257-62. Epub 2009 Feb 11.

Association of infectious mononucleosis with multiple sclerosis. A population-based study.


Wellcome Trust Centre for Human Genetics, Oxford, UK.



Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Several studies have attempted to correlate exposure to viral illness with the subsequent development of MS. Here in a population-based Canadian cohort, we investigate the relationship between prior clinical infection or vaccination and the risk of MS.



Using the longitudinal Canadian database, 14,362 MS index cases and 7,671 spouse controls were asked about history of measles, mumps, rubella, varicella and infectious mononucleosis as well as details about vaccination with measles, mumps, rubella, hepatitis B and influenza vaccines. Comparisons were made between cases and spouse controls.



Spouse controls and stratification by sex appear to correct for ascertainment bias because with a single exception we found no significant differences between cases and controls for all viral exposures and vaccinations. However, 699 cases and 165 controls reported a history of infectious mononucleosis (p < 0.001, corrected odds ratio 2.06, 95% confidence interval 1.71-2.48). Females were more aware of disease history than males (p < 0.001).


The data further confirms a reporting distortion between males and females. Historically reported measles, mumps, rubella, varicella and vaccination for hepatitis B, influenza, measles, mumps and rubella are not associated with increased risk of MS later in life.

A clinical history of infectious mononucleosis is conspicuously associated with increased MS susceptibility.

These findings support studies implicating Epstein-Barr virus in MS disease susceptibility, but a co-association between MS susceptibility and clinically apparent infectious mononucleosis cannot be excluded.

[PubMed - indexed for MEDLINE]


Neurol Clin. 2011 May;29(2):207-17.

Epidemiology of multiple sclerosis.

Ramagopalan SV, Sadovnick AD.


The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; Department of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Level 3 West Wing, Oxford OX3 9DU, UK.

Multiple sclerosis (MS) is the most common disease of the central nervous system that causes permanent disability in young adults. Based on strong circumstantial evidence, MS is considered to be putative autoimmune disorder, but much remains to be understood about the etiology and clinical onset of the disease. It seems unlikely that MS results from a single causative event, but rather is the result of genetic and environmental factors and the interactions thereof. This articlediscusses the epidemiology of MS.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID: 21439437 [PubMed - in process]


J Neurol Sci. 2011 Mar 25. [Epub ahead of print]

Vitamin D metabolic pathway genes and risk of multiple sclerosis in Canadians.

Orton SM, Ramagopalan SV, Para AE, Lincoln MR, Handunnetthi L, Chao MJ, Morahan J, Morrison KM, Sadovnick AD, Ebers GC.


Wellcome Trust Centre for Human Genetics and Department of Clinical Neurology, University of Oxford, Oxford, UK.



Multiple sclerosis (MS) is determined by interactions between genes and environment and the influence of vitamin D adequacy has been proposed. Previous studies have shown that serum 25-hydroxyvitaminD (25(OH)D) levels are genetically influenced. Polymorphisms in vitamin D pathway genes are candidates for association with MS susceptibility.


MS patients (n=1364) and their unaffected first-degree relatives (n=1661) were ascertained through the Canadian Collaborative study. Seventy-one SNPs, across four genes [vitamin D receptor (VDR), 1-alpha-hydroxylase (CYP27B1) enzyme, vitamin D binding protein (DBP), 24-hydroxylase (CYP24)], were genotyped and tested for association with MS susceptibility using TDT in PLINK. Secondary analyses included stratification for HLA-DRB1*15 and parent of origin transmission effects.


We found no significant association of vitamin D pathway genes with MS susceptibility after correction for multiple comparisons. However, the VDR Fok1 variant (rs2228570), selected for previously positive associations with MS susceptibility and 25(OH)D levels in MS patients showed marginally distorted transmission in DRB15-negative patients (p=0.03). There was no evidence for differential maternal versus paternal allele transmission.


The findings fail to directly connect vitamin D metabolism genes to MS susceptibility, despite a large sample size and comprehensive gene coverage.


Copyright © 2011 Elsevier B.V. All rights reserved.

PMID: 21440908 [PubMed - as supplied by publisher]


J Neurol. 2011 Mar;258(3):353-8. Epub 2010 Nov 2.

The emerging role of vitamin D binding protein in multiple sclerosis.


Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7BN, UK.


Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). A growing body of evidence supports a role for vitamin D in MS aetiology.

Vitamin D binding protein (DBP) is the major plasma carrier of vitamin D metabolites and genetic differences in DBP gene have been found to influence vitamin D levels.

We review here evidence supporting a role of DBP in MS.

Several recent studies show that DBP levels in the cerebrospinal fluid correlate with MS course, being lower during relapses and higher in the secondary progressive phase.

Further studies are needed to elucidate the potential use of DBP as a biological marker of MS course, but may be of use given the current lack of diagnostic tools for the prediction of MS development and progression.

[PubMed - in process]

Neurology. 2010 Jun 8;74(23):1905-10.

Multiple sclerosis, vitamin D, and HLA-DRB1*15.


Wellcome Trust Centre for Human Genetics and the Department of Clinical Neurology, University of Oxford, Oxford, UK.



Multiple sclerosis (MS) has a remarkable geographic distribution inversely paralleling that of regional ultraviolet radiation, supporting the hypothesis that vitamin D plays a central role in the disease etiology.

The major histocompatibility complex exerts the largest genetic contribution to MS susceptibility, but much risk remains unexplained and direct gene-environment interaction is a strong candidate for this additional risk. Such interactions may hold the key for disease prevention.



Several recent studies strengthen the candidacy of vitamin D as a key player in the causal cascade to MS.

This includes a newly identified gene-environment interaction between vitamin D and the main MS-linked HLA-DRB1*1501 allele and evidence showing that vitamin D levels are significantly lower in patients with MS as compared to controls.

Also, a recent study in twins with MS supports the notion that vitamin D levels are under regulation by genetic variation in the 1alpha-hydroxylase and vitamin D receptor genes, perhaps pointing to their importance in the disease pathogenesis.


These findings have important practical implications for studies of disease mechanisms and prevention.

Missing genetic risk may partly be explained by gene-environment interactions.

More practically important is that these observations highlight a pressing need to determine if vitamin D supplementation can reduce the risk of multiple sclerosis (MS).

However, the timing of action and the tissues in which this interaction takes place are not clear and future studies in prospective cohorts and animal models will be essential for deciphering the role of vitamin D in MS.

[PubMed - indexed for MEDLINE] 
PMCID: PMC2882222
 [Available on 2011/6/8]

Eur J Neurol. 2010 Sep;17(9):1210-4. Epub 2010 Mar 22.

Genetic and environmental factors and the distribution of multiple sclerosis in Europe.


Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.


The observation that the incidence of multiple sclerosis (MS) increases further from the equator has prompted considerable interest in the factors that might underlie this latitude gradient. Potential candidates include population frequencies of disease-associated Human Leukocyte Antigen (HLA) alleles which are the major genetic component of MS susceptibility. Ultraviolet (UV) exposure and smoking have also been implicated as key environmental risk factors.


We used multiple sources of published data on MS prevalence, HLA allele frequencies, UV index and cigarette smoking to assess the contributions of both nature and nurture to the distribution of MS within Europe.


We observed that HLA alleles unequivocally interact with a population-wide level to determine disease risk. The UV index and smoking behaviour was also shown to correlate with disease distribution in Europe. For countries with HLA, UV and smoking data, these three factors were shown to account for 75% of the variance in MS prevalence.



Genetic (HLA) and environmental (UV and smoking) risk factors thus interact in a complex manner with each other to determine a large proportion of MS susceptibility within Europe.

[PubMed - indexed for MEDLINE]
PLoS Genet. 2009 Feb;5(2):e1000369. Epub 2009 Feb 6.

Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D.


Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Multiple sclerosis (MS) is a complex trait in which allelic variation in the MHC class II region exerts the single strongest effect on genetic risk. Epidemiological data in MS provide strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of this disease.

Growing evidence implicates sunlight or vitamin D as a key environmental factor in aetiology. We hypothesised that this environmental candidate might interact with inherited factors and sought responsive regulatory elements in the MHC class II region.

Sequence analysis localised a single MHC vitamin D response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among non-MS-associated haplotypes.

Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15.

Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15 gene promoter showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 (P = 0.002) that was lost both on deletion of the VDRE or with the homologous "VDRE" sequence found in non-MS-associated HLA-DRB1 haplotypes.

Flow cytometric analysis showed a specific increase in the cell surface expression of HLA-DRB1 upon addition of vitamin D only in HLA-DRB1*15 bearing lymphoblastoid cells.

This study further implicates vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility.

These findings support a connection between the main epidemiological and genetic features of this disease with major practical implications for studies of disease mechanism and prevention.



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Et si en matière d’AVC, les parodontopathies étaient plus inductrices que le diabète !


Les accidents cardio-vasculaires (AVC) sont la proie des statisticiens qui voudraient bien cerner les pathologies ayant la particularité d’en accroître la prévalence.

La structure des parois des vaisseaux, notamment leur rigidité, leur fragilité et leur texture, perturbée par un métabolisme déviant constitue le principal soubassement du risque ; et on sait que le diabète altère profondément ces paramètres et constitue ainsi un facteur de risque d’AVC.

Mais la nidation bactérienne qui imprègne les parois des vaisseaux s’avère également être une composante du risque vasculaire.

A cet égard, il a été établi que la parodontopathie pourrait représenter un risque d’AVC non fatal deux fois supérieur au risque imputable au diabète !


Lors d’une conférence tenue au 89° Congrès de l’International Association for Dental Research (IADR au mois de mars 2011), il a même été affirmé que la maladie parodontale serait plus agissante que l’hypertension sur le risque d’AVC non fatal !



Gum disease bigger risk than diabetes

4th Apr 2011

New research suggests that gum disease carries a higher risk of causing a stroke than diabetes, and its impact is nearly the equivalent of high blood pressure as a major cause of strokes.

High blood pressure (hypertension) and diabetes (diabetes mellitus) are widely recognised as major risks contributing to non-fatal strokes (ischemic strokes).

In recent years, there has been growing evidence of the link between gum disease (periodontitis) and strokes.

New research indicates people are twice as likely to suffer a non-fatal stroke as a result of gum disease compared to diabetes.

The data also suggests its impact is equivalent to people with high blood pressure.

The research, presented at the 89th International Association for Dental Research (IADR) General Session and Exhibition in San Diego last month, is another reminder of the serious impact that poor oral health poses to general health and wellbeing.

Dr Nigel Carter, chief executive of the British Dental Health Foundation, said: ‘Obesity, alcohol abuse, poor diet and smoking are generally well-known risk factors that can cause strokes. Less well-known are the risks caused by gum disease.

‘This research is significant because it helps to quantify the importance of oral health compared to other risk factors. The findings are startling. The fact that high blood pressure carries a similar risk to gum disease is in itself a significant finding. The other finding that shows that gum disease nearly doubles the risk of non-fatal strokes, compared to diabetes, is totally unexpected.

‘The research sends a clear message that the risks caused by poor oral health should not be overlooked or considered less important when compared to others factors.'


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Zona et psychose : plus qu'une coïncidence

Une étude rétrospective taïwanaise a permis de quantifier le risque d'infection à virus varicelle zona (VVZ) dans une population de malades atteints de troubles psychiatriques. La cohorte, qui se compose de plus de 42 300 patients de plus de 18 ans souffrant d'une maladie psychiatrique diagnostiquée depuis 2004 a été comparée à une cohorte témoin de 169 360 personnes.

Après élimination des éventuels facteurs confondants tels que existence d'une affection hématologique ou de traitements immunosuppresseurs au long cours, apparaît une augmentation du risque de zona dans la population des malades psychiatriques par rapport aux contrôles (hazard ratio (HR), 1,29; IC 95 % : 1,18-1,38).

L'analyse par sous groupe en fonction des pathologies psychiatriques montre que l'association reste significative chez les patients de moins de 60 ans qu'ils soient affectés de psychose affective, de névrose grave ou de troubles de la personnalité. En revanche au-delà de 60 ans, l'association zona et maladie psychiatrique n'est significative que chez les malades présentant des états névrotiques et des troubles de la personnalité.

Cette association entre maladie psychiatrique et infection à VVZ vient corroborer le concept d'une immunité cellulaire déficiente chez les patients souffrant d'affections psychiatriques.


Dr Patrice Plantin

Yang YW et coll. : Risk of herpes zoster among patients with psychiatric diseases: a population-based study. JEADV 2011; 25: 447-63


J Eur Acad Dermatol Venereol. 2011 Apr;25(4):447-53. doi: 10.1111/j.1468-3083.2010.03811.x.

Risk of herpes zoster among patients with psychiatric diseases: a population-based study.


Department of Dermatology, Taipei Medical University Hospital, Taipei, Taiwan.



Psychiatric disorders have been shown to be associated with impaired immune response, including decreased cellular immunity to varicella-zoster virus. However, the risk of herpes zoster (HZ) in psychiatric patients is, to date, unknown.


The aim of this study was to determine the risk of herpes zoster (HZ) in psychiatric patients compared with the general population.


We used data from the Taiwan Longitudinal Health Insurance Database from 2004 to 2006. Our study cohort consisted of patients aged 18 years and older diagnosed with psychiatric disorders in 2004 (N=42 340). The comparison cohort (N=169 360) consisted of four age- and gender-matched controls randomly selected for every patient in the study cohort. All subjects were followed from the date of cohort entry until they developed HZ or the end of 2006, whichever was earliest. Stratified Cox proportional hazard regressions were performed to compute the 2-year HZ-free survival rates.


After adjusting for potential confounders, we found patients with psychiatric disorders were more likely to have an episode of HZ than the control population [adjusted hazard ratio (HR), 1.29; 95% confidence interval (CI), 1.18-1.38]. When stratified by age and psychiatric diagnostic categories, in patients aged ≤60 years, the adjusted HRs for HZ were 1.34 (P=0.026) for patients with affective psychoses, 1.42 (P<0.001) for those with neurotic illness or personality disorders and 1.53 (P<0.001) for patients with other mental disorders. However, in patients aged >60years, only neurotic illness or personality disorders were significantly associated with an increased risk of HZ (adjusted HR, 1.26; P=0.003).


Our analysis suggests that patients with psychiatric disorders are at increased risk of HZ, especially those aged ≤60 years. Further study is required to elucidate the nature of this association.

© 2010 The Authors. Journal of the European Academy of Dermatology and Venereology © 2010 European Academy of Dermatology and Venereology.

[PubMed - in process]

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Sex Transm Dis. 2011 Feb 4. [Epub ahead of print]

Extracts of Canadian First Nations Medicinal Plants, Used as Natural Products, Inhibit Neisseria gonorrhoeae Isolates With Different Antibiotic Resistance Profiles.


From the *Department of Biology, University of Ottawa, Ottawa, Ontario, Canada; and †Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.



Neisseria gonorrhoeae (Ng) has developed resistance to most antimicrobial agents and the antibiotics recommended for therapy are restricted, for the most part, to third generation cephalosporins.

In order to investigate new potential sources of antimicrobial agents, the antibacterial properties of 14 Canadian plants used in traditional First Nations' medicine were tested against Ng isolates having differing antimicrobial susceptibility profiles.



Ethanolic extracts of 14 Canadian botanicals, analyzed by high-performance liquid chromatography, were tested for their antimicrobial activity (disc diffusion and/or agar dilution assays) against susceptible Ng reference strains and a panel of 28 Ng isolates with various antimicrobial resistance profiles.




Extracts of Arctostaphylos uva ursi (kinnikinnick or bearberry), Hydrastis canadensis (goldenseal), Prunus serotina (black cherry), and Rhodiola rosea (roseroot) inhibited the growth of all Ng isolates with minimum inhibitory concentrations of 32 μg/mL, 4 to 32 μg/mL, 16 to >32 μg/mL, and 32 to 64 μg/mL, respectively.


Extracts of Acorus americanus (sweet flag), Berberis vulgaris (barberry), Cimicifuga racemosa (black cohosh), Equisetum arvense (field horsetail), Gaultheria procumbens (wintergreen), Ledum groenlandicum (Labrador tea), Ledum palustre (marsh Labrador tea), Oenothera biennis (common evening primrose), Sambucus nigra (elderberry), and Zanthoxylum americanum (prickly ash) had weak or no antimicrobial activity against the Ng isolates with minimum inhibitory concentrations ≥256 μg/mL.


The phytochemical berberine from H. canadensis inhibited the growth of all Ng isolates. The phytochemicals, salidroside and rosavin, present in R. rosea, also showed inhibitory activity against Ng strains.



Canadian botanicals represent a potential source of novel compounds which inhibit Ng, including isolates resistant to antibiotics.

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29 avril 2011 5 29 /04 /avril /2011 16:27
Fitoterapia. 2007 Jul;78(5):379-81. Epub 2007 Apr 11.

Antimicrobial activity of four species of Berberidaceae.


School of Life Science, Nanjing University, Nanjing, China. ai800102@sohu.com

Ethanolic extracts of the stems and leaves of Nandina domestica, Mahonia fortunei, Mahonia bealei and Berberis thunbergii were tested for their antibacterial and antifungal activity.


Most of the extracts have been proved to be active against Gram(+) bacteria.

[PubMed - indexed for MEDLINE]
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