Sunday, April 22, 2012

Sleeping Sickness

Human African trypanosomiasis, sleeping sickness [1], the lethargy of Africa, [1] or trypanosomiasis of Congo [1] is a parasitic disease of humans and animals caused by protozoa of species Trypanosoma brucei and transmitted by the tsetse fly. [2] The disease is endemic in parts of Africa, covering about 37 countries and 60 million people. It is estimated that between 50,000 and 70,000 people are currently infected, the number has declined somewhat in recent years. [3] The number of reported cases was below 10,000 in 2009, the first time in 50 years. [4] It is believed that many cases go unreported. Around 48,000 people died of it in 2008 [5] Four major epidemics have occurred in recent history. A 1.896 to 1.906 mainly in Uganda and the Congo Basin, two epidemics in 1920 and 1970 in several African countries, and a recent epidemic of 2008 in Uganda. [6]

 
Signs and symptoms symptomsAfrican trypanosomiasis occur in two stages. The first stage is known as haemolymphatic phase and is characterized by fever, headaches, joint pains and itching. Invasion of the circulatory and lymphatic systems, by parasites is associated with severe inflammation of the lymph nodes, often to large sizes. Winterbottom sign, lymph nodes reveal along the back of the neck, may appear. If untreated, the disease overcomes host defenses and cause more extensive damage, enlargement of the symptoms include anemia, endocrine, cardiac and renal dysfunction. The second stage, called the neurological phase, begins when the parasite invades the central nervous system to pass through the blood-brain barrier. "Sleeping sickness" The term comes from the symptoms of neurological phase. Symptoms include confusion, decreased coordination, and alteration of the sleep cycle, with episodes of fatigue with manic periods leading to interrupted sleep during the day and insomnia at night [citation needed]. Untreated, the disease is invariably fatal, with progressive mental deterioration leading to coma and death. The damage caused in the neurological phase is irreversible. [6]

Tryptophol is a chemical compound that induces sleep in humans. It is produced by the parasite trypanosomes in sleeping sickness. [7]

The life cycle
Life cycle of the parasite Trypanosoma brucei. Source: CDCThe tsetse fly (genus Glossina) is a large fly, biting brown that serves as a host and vector of trypanosomes parasites. While taking the blood of a mammalian host, an infected tsetse fly injects metacyclic trypomastigotes into skin tissue. From the bite, parasites first enter the lymphatic system and then move into the bloodstream. Inside the mammalian host, trypomastigotes transform into blood, and taken to other sites throughout the body, reach other blood fluids (eg, lymph, cerebrospinal fluid), and continue to replicate by binary fission.

The complete life cycle of African trypanosomes is represented by extracellular stages. A tsetse fly becomes infected with bloodstream trypomastigotes when taking a blood meal from a mammalian host infected. In intestine of the fly, the parasites transform into procyclic trypomastigotes, multiply by binary fission, leave the midgut, and transform into epimastigotes. The epimastigotes reach the fly's salivary glands and continue multiplication by binary fission.

The life cycle of the fly is about 3 weeks.

In addition to the bite of the tsetse fly, the disease can be transmitted in the following ways:

Mother to child infection:. Sometimes the trypanosome can cross the placenta and infect the fetus [8]
Laboratories: accidental infections, for example, through handling an infected person's blood and organ transplantation, although this is rare.
Blood transfusion
Sexual contact (This may be possible) [9]
 Diagnosis
Two areas of a blood smear from a patient with African trypanosomiasis. Thin blood smears stained with Giemsa. Typical trypomastigote stages (the stages are only found in patients) with a posterior kinetoplast, a centrally located nucleus, an undulating membrane and flagellum above. The two subspecies of Trypanosoma brucei that cause sleeping sickness, T. b. gambiense and T. b. rhodesiense, are indistinguishable morphologically. Trypanosomes length range is 14 to 33 microns, Source: gold standard for diagnosis is the identification CDCThe of trypanosomes in a patient sample by microscopic examination. Patient samples that can be used for diagnosis include chancre fluid, lymph node aspirates, blood, bone marrow, and, during the stage neurological, cerebrospinal fluid. Detection of trypanosome-specific antibodies can be used for diagnosis, but sensitivity and specificity of these methods are too variable to be used only for clinical diagnosis. Furthermore, seroconversion occurs after the onset of clinical signs during a T. b. rhodesiense infection, and therefore is of limited diagnostic use [Edit].

Trypanosomes can be detected from patient samples using two different preparations. A wet preparation can be used to find the motile trypanosomes. Moreover, a fixed (dry) smears can be stained with Giemsa (or field) and examined. Often, the parasite is relatively low in abundance in the sample, so that the techniques for concentrating the parasites could be used before microscopic examination. For blood samples, such as centrifugation followed by an examination of the buffy coat; anion-exchange/centrifugation small, and the quantitative buffy coat (QBC) technique. For samples such as cerebrospinal fluid, concentration techniques include centrifugation followed by an examination of the sediments [citation needed].

Serologic tests are also available for the detection of the parasite: the micro-CATT, wb-CATT and wb-LATEX. The first uses the dried blood, while the other two test samples of whole blood. A 2002 study found the wb-CATT to be most efficient for the diagnosis, while the wb-LATEX is a better test for situations requiring greater sensitivity. [10]

PreventionSee also: Tsetse_fly Number Control_techniques
Two alternative strategies have been used in attempts to reduce trypanosomiasis. The main method focuses on the eradication of tsetse fly, altering transmission rates by reducing the number of flies. The cases of sleeping sickness are reduced by using the sterile insect technique. The second tactic is primarily medical or veterinary and tries to reduce the spread of the parasite through the surveillance, prevention, treatment and monitoring to reduce the number of people or animals that carry the disease [citation needed].

Regular monitoring active participation of the detection and treatment of new infections, and control of the tsetse fly, is the backbone of the strategy used to control sleeping sickness. Systematic screening of communities at risk is the best approach, since each case, the review is not practical in endemic regions. Systematic screening may be in the form of mobile clinics and fixed detection centers, where teams travel daily to areas of high infection rates. These are important efforts to detect because early symptoms are not evident or serious enough to justify gambiense disease patients to seek medical attention, especially in remote areas. Moreover, diagnosis of the disease is difficult and health workers can not be associated with these general symptoms of trypanosomiasis. Systematic screening allows early-stage disease to be detected and treated before the disease progresses, and eliminates the reservoir of human potential. [11] There is no single case of sexual transmission of West African sleeping sickness [12], but this is believed to be an important route of transmission.

 Treatment [edit] First line, first stageThe current standard treatment for early stage (haemolymphatic) disease is:

Pentamidine intravenously or intramuscularly (for Tb gambiense) or
Intravenous suramin (for T.b. rhodesiense)
The drug eflornithine - previously used as an alternative treatment for sleeping sickness due to their workforce management - was found to be safe and effective as first-line treatment for the disease in 2008, according to the science and Sub-Saharan Africa Development Network news updates. [1]. The researchers followed more than 1,000 adults and children in a center in the IBBA, southern Sudan, the first use of eflornithine on a large scale and is very effective in the treatment of the issue.

According to a study of treatment of Trypanosoma gambiense cause human African trypanosomiasis, the use of eflornithine (DMFO) resulted in fewer adverse events than treatment with melarsoprol. [13]

 The first line, second stageThe current standard treatment for the second stage (neurological phase) is the disease:

Intravenous melarsoprol 2.2 mg / kg daily for 12 consecutive days. [14]
Alternative first-line therapies include:

Intravenous melarsoprol 0.6 mg / kg on day 1, 1.2 mg / kg IV melarsoprol on day 2, and 1.2 mg / kg / day IV in combination with oral melarsoprol 7.5 mg / kg nifurtimox twice a day on days 3 to 10, [15] or
Intravenous eflornithine 50 mg / kg every six hours for 14 days. [16]
Combination therapy with eflornithine and nifurtimox is safer and easier than treatment with eflornithine alone, and appears to be equally or more effective. It has been recommended as first-line treatment for second stage of T. b. gambiensis disease. [17]

 resistant areas diseaseIn melarsoprol resistance or in patients who have relapsed after melarsoprol monotherapy, treatment should be:

melarsoprol and nifurtimox, or
eflornithine
 protocolsThe Outdated after traditional systems should no longer be used:

(Old "standard" 26-day melarsoprol treatment) Intravenous melarsoprol therapy (3 sets of 3.6 mg / kg / day intravenously for 3 days, 7 days rest between sets) (this regimen is less convenient and patients are less likely to complete treatment) [18];
(Incremental melarsoprol treatment) 10-day melarsoprol treatment with increasing doses (0.6 mg / kg iv on day 1, 1.2 mg / kg iv on day 2, and 1.8 mg / kg iv on days 3 - 10) (thought to reduce the risk of treatment-induced encephalopathy, but now known to be associated with an increased risk of relapse and an increased incidence of encephalopathy), [15] [18]
 Epidemiology
Deaths per 100,000 population due to African trypanosomiasis country in 2002. [19] The disease is found in two forms, depending on the parasite, either Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense. Humans are the main reservoir for Trypanosoma brucei gambiense, but this species is also found in pigs and other animals. Hunting wild animals and livestock are the main reservoir of infection with T. b. rhodesiense. T. b. gambiense is found in Central and West Africa, but that causes a chronic disease that can remain in a passive phase for months or years before symptoms appear. T. b. rhodesiense is the acute form of the disease, but has a much more limited geographic range. It is located in southern and eastern Africa and the symptoms of the infection appears in a few weeks and is more virulent and faster developing T. b. gambiense. According to recent estimates, years of disability-adjusted life (9 to 10 years) (DALYs) lost due to sleeping sickness are 2.0 million. [20] Recent estimates indicate that more than 60 million people living in about 250 locations are at risk of contracting the disease, and there were fewer than 10,000 cases reported in 2009, according to WHO figures, representing a huge decrease of the approximately 300,000 new cases in 1998. [21] The disease has been recorded as in 36 countries, all in sub-Saharan Africa. It is endemic in southeast Uganda and western Kenya, killing more than 48,000 Africans in 2008. [6]

Horse flies (Tabanidae) and stable flies (Muscidae), possibly playing a role in the transmission of nagana (the animal form of sleeping sickness) and the shape of the human disease. [22]

 HistoryThe condition has been present in Africa, at least since the 14th century, and probably for thousands of years before that. Because there was a lack of travel between indigenous peoples, sleeping sickness in humans had been limited to isolated areas. This changed when Arab slave traders came into the center of Africa from the east along the Congo River, which along parasites. Sleeping sickness Gambia traveled up the Congo River, then further east. In 1901 a devastating epidemic outbreak in Uganda, killing more than 250,000 people, [23], including about two thirds of the population in coastal areas affected by the lake. According to The Cambridge History of Africa "has been estimated that up to half of people who died of sleeping sickness and smallpox in the lands on both sides of the lower Congo River." [24]

 
In 1903, David Bruce recognized the tsetse fly in the arthropod vector vector.The causative agent and were identified in 1903 by David Bruce, and differentiation between the subspecies of the protozoan carried out in 1910. The first effective treatment, atoxyl, an arsenic-based drug developed by Paul Ehrlich and Kiyoshi Shiga, was introduced in 1910, but blindness is a serious side effect. A large number of drugs designed to treat the disease have been introduced since then, [citation needed].

Suramin was introduced in 1920 to treat the first stage of the disease. In 1922, suramin are generally combined with triparsamida (other organo-arsenic pentavalent drug) in the treatment of the second stage of the form gambiense. It was used during the epidemic of glue in West and Central Africa in millions of people and was the mainstay of therapy until the year 1969 [citation needed].

Pentamidine, a very effective drug for the first stage of the disease, has been used since 1939. During the fifties, was widely used as a prophylactic agent in West Africa, leading to a sharp decline in infection rates. At that time, it was thought that the eradication of the disease was at hand [citation needed].

Organo-arsenical melarsoprol (Arsobal) was developed in the 1940s, and is effective for patients with second stage of sleep. However, 10.3% of those injected have reactive encephalopathy (convulsions, coma, progressive, or psychotic reactions), and 10-70% of cases resulting in death, but can cause brain damage in patients who survive the encephalopathy . However, because of its effectiveness, melarsoprol is still used today. Resistance to melarsoprol is increasing, and combination therapy with nifurtimox is currently under investigation [citation needed].

Eflornithine (difluoromethylornithine or DFMO), art therapy, developed in the 1970s by Albert Sjoerdsmanot and underwent clinical trials in the 1980s. The drug was approved by the Food and Drug Administration in 1990, but Aventis, the company responsible for manufacturing, production stopped in 1999. In 2001, however, Aventis, in partnership with Doctors Without Borders and the World Health Organization, signed a long-term agreement to manufacture and donate the drug [citation needed].

ResearchThe parasite genome has been sequenced and several proteins have been identified as potential targets for drug treatment. Genome analysis also revealed the reason for the generation of a vaccine for this disease has been so difficult. T. brucei has more than 800 genes that make proteins of the parasite "mix and match" to evade immune system detection. [25]

Recent studies indicate that the parasite can not survive in the bloodstream without the scourge. This insight gives researchers a new perspective with which to attack the parasite. [26]

A new treatment based on a truncated version of apolipoprotein L-1 high density lipoprotein and a single domain antibody has recently been found to work in mice, but was not tested in humans. [27]

The cover story of August 25, 2006 Number of the journal Cell described a breakthrough in understanding how trypanosomes escape the immune system. Dr Lee Soo Hee and colleagues, working at Johns Hopkins investigated the pathway by which trypanosomes myristate, a 14-carbon fatty acid length. Myristate is a component of the variant surface glycoprotein (VSG), the molecule that forms the outer layer of the trypanosome. The outer surface layer of VSG is vital for trypanosome's ability to avoid destruction by the host immune system. Dr. Lee and his colleagues discovered trypanosomes use a novel pathway of fatty acid synthesis involving fatty acid elongases to make myristate and other fatty acids.

An international team of researchers working in the Democratic Republic of Congo, southern Sudan and Angola involving Immtech International and the University of North Carolina at Chapel Hill has completed a Phase IIb clinical trial and began a Phase III trial in year 2005 to test the efficacy of the first oral treatment for sleeping sickness, pafuramidine (DB289). [28] [29] Trypanosomiasis vaccines are being investigated.

Two independent variants APOL1 gene found in African haplotypes carrying the signature of natural selection has been shown to confer protection against acute version of sleeping sickness caused by Trypanosoma brucei rhodesiense, while at the same time increasing the risk of kidney disease when inherited from both parents. [30]

The synthetic approaches and the computer are used to develop new anti-trypanosomal analogs with greater efficacy and oral bioavailability. [31]

See alsoHuman trypanosomiasis
Initiative Drugs for Neglected Diseases
David Bruce (microbiologist)
Sleep disorders
Chagas disease (American trypanosomiasis), another tropical disease caused by human trypanosomes
Nagana (trypanosomiasis Animal)
Tsetse fly
GD Hale Carpenter joined the London School of Hygiene and Tropical Medicine, and took the DM in 1913 with a thesis on the tsetse fly (Glossina palpalis) and sleeping sickness. He has published A Naturalist on Lake Victoria, with an account of sleeping sickness and tsetse flies, 1920. T.F. Unwin Ltd, London; Biodiversity File
 References
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