<font color="#000000"><font size="4"><font face="verdana,sans-serif">Dear Hannah,</font></font></font><div><font color="#000000"><font size="4"><font face="verdana,sans-serif"><br></font></font></font></div><div><font color="#000000"><font size="4"><font face="verdana,sans-serif">May be the genetic differences between organisms inducers/non-inducers of diffuse disease can be as discrete as one single SNP, in such a way that only through sequencing we would detect it. The questions is: to sequence the whole genome or to make a bet in certain genes?</font></font></font></div>
<div><font color="#000000"><font size="4"><font face="verdana,sans-serif"><br></font></font></font></div><div><font color="#000000"><font size="4"><font face="verdana,sans-serif">Another point is if the diffuse disease caused by L. amazonensis and L. aethiopica have the same underlying parasite mechanisms. Again, comparative genomics of isolates of both species can give more hints.</font></font></font></div>
<div><font color="#000000"><font size="4"><font face="verdana,sans-serif"><br></font></font></font></div><div><font color="#000000"><font size="4"><font face="verdana,sans-serif">I agree with you that both hosts and parasites contribute to the outcome, but modern genomics is bringing so many new secrets of Leishmania that its role will be seen as more important soon. </font></font></font></div>
<div><font color="#000000"><font size="4"><font face="verdana,sans-serif"><br></font></font></font></div><div><font color="#000000"><font size="4"><font face="verdana,sans-serif">Your findings are very interesting. Do you have the pdf? Please check the recent excellent paper of Cortez et al, 2011, right in the target.</font></font></font></div>
<div><font color="#000000"><font size="4"><font face="verdana,sans-serif"><br></font></font></font></div><div><font color="#000000"><font size="4"><font face="verdana,sans-serif">My best regards, extended to Jennie,</font></font></font></div>
<div><font color="#000000"><font size="4"><font face="verdana,sans-serif"><br></font></font></font></div><div><font color="#000000"><font size="4"><font face="verdana,sans-serif">Carlos.<br></font></font></font><br><div class="gmail_quote">
2011/7/12 Hannah Akuffo <span dir="ltr"><<a href="mailto:Hannah.Akuffo@sida.se">Hannah.Akuffo@sida.se</a>></span><br><blockquote class="gmail_quote" style="margin:0 0 0 .8ex;border-left:1px #ccc solid;padding-left:1ex;">
<div lang="EN-GB" link="blue" vlink="purple">
<div>
<p class="MsoNormal"><span style="font-size:11.0pt;color:#1F497D">Dear Carlos,<u></u><u></u></span></p>
<p class="MsoNormal"><span style="font-size:11.0pt;color:#1F497D">As with so many things the answer is more like “both” Parasite and host. There are proponents for the host being the most relevant and others for the parasite
also playing a role.<u></u><u></u></span></p>
<p class="MsoNormal"><span style="font-size:11.0pt;color:#1F497D"><u></u> <u></u></span></p>
<p class="MsoNormal"><span style="font-size:11.0pt;color:#1F497D">When it comes to
<i>L. aethiopica</i> induced DCL my colleagues and I have done a series of laboratory studies that suggest that the parasite that causes DCL and that which causes LCL, induce different responses (cytokines, proliferation etc)
<i>in vitro</i>. (example of publications </span><i><span>Akuffo HO, Fehniger TE, Britton S. Differential recognition of Leishmania aethiopica antigens by lymphocytes from patients with local and diffuse cutaneous
leishmaniasis. Evidence for antigen-induced immune suppression. J Immunol. 1988 Oct 1;141(7):2461-6</span></i><span>.
<span style="color:#558ED5">
AND </span><i>Akuffo H, Maasho K, Blostedt M, Hojeberg B, Britton S, Bakhiet M. Leishmania aethiopica derived from diffuse leishmaniasis patients preferentially induce mRNA for interleukin-10 while those from localized leishmaniasis patients induce interferon-gamma.
J Infect Dis. 1997 Mar;175(3):737-41</i>)</span><span style="font-size:11.0pt;color:#1F497D"> Whether this is because the infecting organism is different or there are changes that occur in the parasite when they are in the
host for some time, has not been studied. However we have not been able to find genetic differences in the organisms derived from DCL versus those derived from LCL. (example of publication
</span><i><span style="font-size:10.0pt">Schönian G, Akuffo H, Lewin S, Maasho K, Nylén S, Pratlong F, Eisenberger CL, Schnur LF, Presber W. Genetic variability within the species Leishmania aethiopica
does not correlate with clinical variations of cutaneous leishmaniasis. Mol Biochem Parasitol. 2000 Mar 5;106(2):239-48</span></i><span style="font-size:11.0pt;color:#1F497D"> ).
<u></u><u></u></span></p>
<p class="MsoNormal"><span style="font-size:11.0pt;color:#1F497D"><u></u> <u></u></span></p>
<p class="MsoNormal"><span style="font-size:11.0pt;color:#1F497D">As we know, the low or non-existent cellular immune response in DCL is antigen specific but in a very small study we did show that the use of intra-lesional
IL-2 did stimulate the local immune response and reduce the number of amstigotes (</span><i><span>Akuffo H, Kaplan G, Kiessling R, Teklemariam S, Dietz M, McElrath J, Cohn ZA. Administration of recombinant interleukin-2
reduces the local parasite load of patients with disseminated cutaneous leishmaniasis. J Infect Dis. 1990 Apr;161(4):775-80</span></i><span>)</span><span style="font-size:11.0pt;color:#1F497D">.
<u></u><u></u></span></p>
<p class="MsoNormal"><span style="font-size:11.0pt;color:#1F497D"><u></u> <u></u></span></p>
<p class="MsoNormal"><span style="font-size:11.0pt;color:#1F497D">I hope this information sheds some light on your question to Jennie. There is so much more to understand about DCL.<u></u><u></u></span></p>
<p class="MsoNormal"><span style="font-size:11.0pt;color:#1F497D">Best regards<u></u><u></u></span></p>
<p class="MsoNormal"><span style="font-size:11.0pt;color:#1F497D">Hannah Akuffo<u></u><u></u></span></p>
<p class="MsoNormal"><span style="font-size:11.0pt;color:#1F497D"><u></u> <u></u></span></p>
<p class="MsoNormal"><span style="font-size:11.0pt;color:#1F497D"><u></u> <u></u></span></p>
<p class="MsoNormal"><b><span lang="EN-US" style="font-size:10.0pt">From:</span></b><span lang="EN-US" style="font-size:10.0pt"> <a href="mailto:leish-l-bounces@lineu.icb.usp.br" target="_blank">leish-l-bounces@lineu.icb.usp.br</a> [mailto:<a href="mailto:leish-l-bounces@lineu.icb.usp.br" target="_blank">leish-l-bounces@lineu.icb.usp.br</a>]
<b>On Behalf Of </b>Carlos Costa<br>
<b>Sent:</b> den 10 juli 2011 23:44<br>
<b>To:</b> Jennie Blackwell<br>
<b>Cc:</b> Leish-L</span></p><div class="im"><br>
<b>Subject:</b> Re: [Leish-l] miltefosine for diffuse leishmaniasis<u></u><u></u></div><p></p>
<p class="MsoNormal"><u></u> <u></u></p>
<p class="MsoNormal">Hi Jennie,<u></u><u></u></p><div><div></div><div class="h5">
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal">Thanks for the drug information. Now, I have to check the permission for its use in Brazil and how to justify its use to the public system in order to be acquired by the government. Meanwhile, we are looking for miltefosine, paramomycin,
and alternative therapies.<u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal">But if the immunosuppression is species specific do you think that a general stimulation would reverse it? Does anyone knows which is the mechanism behind the DCL induced immunosuppression? Parasite or host or both? <u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal">Cheers,<u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal" style="margin-bottom:12.0pt">Carlos.<u></u><u></u></p>
<div>
<p class="MsoNormal">2011/7/7 Jennie Blackwell <<a href="mailto:jmb37@cam.ac.uk" target="_blank">jmb37@cam.ac.uk</a>><u></u><u></u></p>
<div>
<div>
<p class="MsoNormal">Hello Carlos<u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal">My memory from late 80s was that these patients responded well to interferon-gamma treatment. With all the moves to make drugs more affordable for disease endemic countries, has it not been possible to consider this option?<u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal">In psoriasis they use creams with Vitamin D. Has anyone ever tried this for DCL?<u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal">I'm sure this is going to elicit a round of responses - but you know I'm not a clinician so I would just be interested to know!<u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal">Cheers, Jennie <br>
<br>
Jenefer M. Blackwell<u></u><u></u></p>
<div>
<p class="MsoNormal">TICHR, CCHR, UWA<u></u><u></u></p>
</div>
<div>
<p class="MsoNormal">Phone: +61 8 94897910<u></u><u></u></p>
</div>
<div>
<p class="MsoNormal">From my iPhone<u></u><u></u></p>
</div>
</div>
<div>
<div>
<div>
<p class="MsoNormal" style="margin-bottom:12.0pt"><br>
On 07/07/2011, at 3:04, Carlos Costa <<a href="mailto:chncosta@gmail.com" target="_blank">chncosta@gmail.com</a>> wrote:<u></u><u></u></p>
</div>
<blockquote style="margin-top:5.0pt;margin-bottom:5.0pt">
<div>
<p class="MsoNormal"><span style="font-size:13.5pt;color:black">Dear all,</span><u></u><u></u></p>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal"><span style="font-size:13.5pt;color:black">Maria Cleudimar has cutaneous diffuse leishmaniasis due to
<i>Leishmania amazonensis</i>. She used to be a long time patient form Dr. Jackson Costa, in the countryside of Maranhão State, Brazil, since she was 10 years old, after a disease that started when she was just five. Now, she is under my and Dorcas care, at
the age of 30, living in the city of Teresina.</span><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal"><span style="font-size:13.5pt;color:black">Her long time DCL does not respond to the treatment antimonium anymore. Although we still prescribe liposomal amphotericin B at very low dose (3mg/kg/once a week),
her situation is deteriorating progressively, her renal function does not allow any additional dosing since creatinine is presently above 3mg/dL, and previous biopsy had shown tubular damage apparently secondary to the drug, without evidence of amyloidosis.
We tried several combinations of different drugs, without success. Her situation worsened a lot during her recent pregnancy (the baby is eight months old now).</span><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal"><span style="font-size:13.5pt;color:black">Our hope now stands only in miltefosine, for oral chronic use, but the drug is not licensed or available in Brazil yet (to my knowledge).</span><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal"><span style="font-size:13.5pt;color:black">With her permission I attached some of her pictures, hoping to sensitize critical people in order to help me to get miltefosine and the permission for prescription
in Brazil (or any other oral drug with promising efficacy, and without nephrotoxicity, if known). Moreover, we need to know about the dose adjustment for the renal impairment, and how long the drug could safely be used.</span><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal"><span style="font-size:13.5pt;color:black">One picture shows her face before treatment, and another after the pregnancy, with the baby. One shows the situation of her thighs, another the calf of the leg
and the last one the infiltration of the palate.</span><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal"><span style="font-size:13.5pt;color:black">Hoping a little from friends, my kindest regards,</span><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal"><span style="font-size:13.5pt;color:black">Carlos.</span><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal"><span style="font-size:13.5pt;color:black">PS. Please understand that the pictures are allowed not for publication or public presentation. Cleudimar permission is restricted to this forum.</span><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
<div>
<p class="MsoNormal"><br>
-- <br>
<b><span>Carlos H. N. Costa, MD, DSc.</span></b><u></u><u></u></p>
<div>
<p class="MsoNormal"><b><span>President</span></b><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><b><span>Sociedade Brasileira de Medicina Tropical </span></b><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><b><span>(Brazilian Society of Tropical Medicine)</span></b><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><b><span>Instituto de Doenças Tropicais Natan Portella<br>
Universidade Federal do Piauí</span></b><u></u><u></u></p>
<div>
<p class="MsoNormal"><b><span>Rua Artur de Vasconcelos 151-Sul</span></b><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><b><span>64049-750 Teresina-PI<br>
Brazil<br>
Telephones: +55 86 3221-3413 (work); +55 86 8838-3303 (mobile).<br>
</span></b><span><br>
</span><span style="font-size:10.0pt">Aviso: As informações contidas nesta mensagem são CONFIDENCIAIS, protegidas pelo sigilo legal, por direitos autorais e destinadas exclusivamente à pessoa ou organização para a qual a mensagem
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</div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
</div>
</blockquote>
</div>
</div>
<div>
<blockquote style="margin-top:5.0pt;margin-bottom:5.0pt">
<div>
<p class="MsoNormal"><cleu antes grav 13jan09.jpg><u></u><u></u></p>
</div>
</blockquote>
<blockquote style="margin-top:5.0pt;margin-bottom:5.0pt">
<div>
<p class="MsoNormal"><cleu e nene.jpg><u></u><u></u></p>
</div>
</blockquote>
<blockquote style="margin-top:5.0pt;margin-bottom:5.0pt">
<div>
<p class="MsoNormal"><cleu santada recorte.jpg><u></u><u></u></p>
</div>
</blockquote>
<blockquote style="margin-top:5.0pt;margin-bottom:5.0pt">
<div>
<p class="MsoNormal"><cleu panturrilhas.jpg><u></u><u></u></p>
</div>
</blockquote>
<blockquote style="margin-top:5.0pt;margin-bottom:5.0pt">
<div>
<p class="MsoNormal"><cleu palato.jpg><u></u><u></u></p>
</div>
</blockquote>
<blockquote style="margin-top:5.0pt;margin-bottom:5.0pt">
<div>
<p class="MsoNormal">_______________________________________________<br>
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</blockquote>
</div>
</div>
</div>
<p class="MsoNormal"><br>
<br clear="all">
<br>
-- <br>
<b><span>Carlos H. N. Costa, MD, DSc.</span></b><u></u><u></u></p>
<div>
<p class="MsoNormal"><b><span>President</span></b><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><b><span>Sociedade Brasileira de Medicina Tropical </span></b><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><b><span>(Brazilian Society of Tropical Medicine)</span></b><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><b><span>Instituto de Doenças Tropicais Natan Portella<br>
Universidade Federal do Piauí</span></b><u></u><u></u></p>
<div>
<p class="MsoNormal"><b><span>Rua Artur de Vasconcelos 151-Sul</span></b><u></u><u></u></p>
</div>
<div>
<p class="MsoNormal"><b><span>64049-750 Teresina-PI<br>
Brazil<br>
Telephones: +55 86 3221-3413 (work); +55 86 8838-3303 (mobile).<br>
</span></b><span><br>
</span><span style="font-size:10.0pt">Aviso: As informações contidas nesta mensagem são CONFIDENCIAIS, protegidas pelo sigilo legal, por direitos autorais e destinadas exclusivamente à pessoa ou organização para a qual a mensagem
foi destinada.<br>
Warning: This message is meant only for the intended recipient of the transmission. It is forbidden any unauthorized use, alteration, reproduction and distribution. If you are not the correct recipient, please notify us immediately by return e-mail and delete
this message from your system. </span><u></u><u></u></p>
</div>
</div>
<p class="MsoNormal"><u></u> <u></u></p>
</div>
</div></div></div>
</div>
</blockquote></div><br><br clear="all"><br>-- <br><font face="verdana, sans-serif"><b>Carlos H. N. Costa, MD, DSc.</b></font><div><font face="verdana, sans-serif"><b>President</b></font></div><div><span style="font-family:verdana, sans-serif"><b>Sociedade Brasileira de Medicina Tropical </b></span></div>
<div><b><span style="font-family:verdana, sans-serif"></span></b><span style="font-family:verdana, sans-serif"><b>(Brazilian Society of Tropical Medicine)</b></span></div><div><font face="verdana, sans-serif"><b>Instituto de Doenças Tropicais Natan Portella<br>
Universidade Federal do Piauí</b></font><div><font face="verdana, sans-serif"><b>Rua Artur de Vasconcelos 151-Sul</b></font></div><div><font face="verdana, sans-serif"><b>64049-750 Teresina-PI<br>Brazil<br>Telephones: +55 86 3221-3413 (work); +55 86 8838-3303 (mobile).<br>
</b><br><span style="font-size:x-small">Aviso: As informações contidas nesta mensagem são CONFIDENCIAIS, protegidas pelo sigilo legal, por direitos autorais e destinadas exclusivamente à pessoa ou organização para a qual a mensagem foi destinada.<br>
Warning: This message is meant only for the intended recipient of the transmission. It is forbidden any unauthorized use, alteration, reproduction and distribution. If you are not the correct recipient, please notify us immediately by return e-mail and delete this message from your system. </span></font></div>
</div><br>
</div>