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Onchocerciasis, or river blindness, is a parasitic disease that affects more than 20 million people globally. The induction of pathology is directly related to the presence and destruction of the microfilarial stages (mf) of this filarial nematode. The disease presents clinically with a wide spectrum of dermal and ocular manifestations, the basis of the variation is believed to involve the immune system. The clinical presentations of infected hosts relate to the intensity of the reactions against the parasite. Anti-microfilarial drugs are also thought to somehow involve the immune system in their pharmacological action. In this study we have investigated some of the factors that might contribute to the pathogenesis, with the aim of gaining a better understanding of the role of immune response in these host inflammatory reactions to Onchocerca volvulus parasite. In the first study we have highlighted the clinically most severe form of dermal onchocerciasis, known as reactive onchocercal dermatitis (ROD), one that is often ignored and has not been properly identified. This form has special characteristics and important biological information that could greatly assist the general understanding of the disease as a whole. Amongst the three major foci of the disease in the study country, Sudan, the prevalence of ROD was found to be associated with different environmental and epidemiological characteristics; strikingly higher in the hypo-endemic areas. Including ROD cases in the prevalence will upgrade the level of endemicity of a locality, and often bring patients much in need of treatment into mass treatment programs that currently only treat localities with medium to high levels of endemicity. In the following research studies, we tried to address the immunological characteristics of the clinically different onchocerciasis patients. Then we also investigated the role of genetic polymorphism in the gene encoding receptor that links innate and adaptive immunity, namely, FcγRIIa.Patients with either of two major forms of the clinical spectrum-mild and severe dermatopathology were studied by assaying the antigen-driven proliferation of peripheral blood mononuclear cells and the ability of patients’ serum antibodies to promote cytoadherence activity to mf in vitro. Immune responses of those with severe skin disease were found to be stronger compared with the mild dermatopathology group. Mectizan® treatment was followed by an increase in immune responsiveness in those with initially poor responses. Thus the degree of dermatopathology is related to the host’s immune response against mf and immunocompetence may be necessary for Mectizan® to clear the infection efficiently.The infection has also been associated with increased levels of circulating immune complexes (CIC) containing parasite antigens and a cytokine response that involves both pro-and anti-inflammatory cytokines. Our fourth paper investigated the effect of IC from the O. volvulus infected patients on the production of pro-and anti-inflammatory cytokines. CIC were increased in all patients studied. The precipitate from plasma treated with polyethylene glycol (PEG) were added to peripheral blood mononuclear cell (PBMC) cultures, and the levels of IL-10, tumor necrosis factor TNF-α, IL-1β and their endogenous antagonists soluble TNF-Rp75 and IL-1-receptor antagonist (IL-1ra) were measured. A significant induction of all cytokines measured occurred in the onchocerciasis patients compared to healthy controls. However, the IL-1ra level was suppressed. The suppression of the production of IL-1ra suggests that the IC containing antigens may have a selectively suppressive effect on the production of this anti-inflammatory cytokine; thus implicating its possible role in counteracting inflammatory responses associated with the disease, and suggesting a potential therapeutic significance. FcgRIIa receptors are involved in many important biological responses, and considered as important mediators of inflammation. A polymorphism in the gene encoding this receptor, that is either arginine (R) or histidine (H) at position 131, affects the binding to the different IgG subclasses. We therefore hypothesized that this polymorphism might be one of the underlying mechanisms to the varied clinical presentations seen in this disease. FcgRIIa genotyping was carried out by gene specific polymerase chain reaction (PCR) and allele-specific restriction enzyme digestion of DNA from clinically characterized patients. The genotype R/R frequencies were found to be significantly higher among patients with the severe form of the disease (including ROD), and it was particularly associated with one tribe (Masaleet) compared to Fulani. Moreover, the H allele was found to be associated with lower risk of developing the severe form. As no significant difference was seen between onchocerciasis cases and controls, the study also implies that this polymorphism influences protection from developing the severe form rather than being related to protection from the infection.

Mectizan (Ivermectin) has been proved to be central to the control of onchoceriasis through self-sustainable community-based treatment. The possibility of parasitological unresponsiveness to this treatment or selection for drug resistance has emerged recently in many occasions. The reason for the reduced ability of Mectizan to maintain low levels of dermal microfilariae and early recurrent pruritus can only be speculated upon. Here, we report our own findings to address this particular issue.

A study of malaria prevalence and transmission was carried out in Khartoum, the capital of Sudan. The sentinel sites were El manshia, an urban area on the Blue Nile and Ed dekheinat, a lower-income peri-urban area bordering the White Nile. Anopheles arabiensis, the only malaria vector encountered, was present throughout the year although vector density varied seasonally. Plasmodium falciparum was the only species found in El manshia. In Ed dekheinat P. falciparum, Plasmodium ovale and Plasmodium vivax constituted 84.9, 8.2 and 6.9% of the cases, respectively. Plasmodium ovale appears to have recently spread into Khartoum since it has not previously been reported there. We conclude that focal transmission of malaria in the districts bordering both Niles has become established and that the reservoir of human infections has increased in recent years leading to increased risk of malaria epidemics, particularly in the aftermath of seasonal flooding.

Although schistosomiasis affects 200 million persons, 20 million of whom have advanced disease, little is known about the mortality pattern in areas of endemic schistosomiasis mansoni. In an attempt to assess the mortality rates in an endemic area in Sudan, we conducted two demographic surveys in a village in the Gezira area. Clinical, sonographic, and parasitologic examinations were performed in a randomly selected sample of 25% of the population in 1987 and 1994. One of us asked each head of household about the names, sex, and age of family members. Particularly, we asked about death in the family if any, history of schistosomiasis, abdominal swelling, and hematemesis. Possible causes of death were ascertained by reviewing medical records in the village dispensary and the district hospital. There were 42 deaths in the village. Four males died of hematemesis secondary to portal fibrosis. The crude mortality rate of schistosomiasis was is 51/100,000/year. The overall schistosomiasis fatality rate per year was 1/1,000 infected persons, but was as high as 11/100/infected patients with bleeding varices. These findings showed the impact of schistosomiasis on public health in this economically important region of Sudan.

The blood supply to the mycetoma lesion and its vasculature were studied in patients with various types of mycetoma using histological, ultrastructural, angiographic and sonographic techniques. The mycetoma lesion proved to be well vascularized. However, certain vascular abnormalities were demonstrated. In histological sections, the small arteries and arterioles showed medial muscular hypertrophy in 83%, intimal fibrosis in 33%, arteritis in 7% and endarteritis obliterans with narrowed lumen in 7% of the patients. No vascular occlusion, ischaemic changes or arteriovenous shunts were observed. These changes were confirmed ultrastructurally. Angiography of the lesion showed a brisk pathological circulation which was more evident in eumycetoma. The vascular Doppler study showed normal blood flow pattern in the affected limb. Regional intra-arterial chemotherapy for mycetoma is suggested as a possible treatment modality.

Objective : To determine the distribution of ivermectin in plasma and tissues of onchocerciasis patients following a single oral dose of 150 μg kg (1 . Setting: Medical Department at Soba University Hospital, Khartoum. Patients: Twenty five patients and fourteen healthy volunteers. Methods: Serial blood samples were obtained from both groups. Tissue samples were removed from vari- ous patients as full thickness skin punch biopsies or during nodulectomy. Ivermectin concentration was determined by radioimmunoassay. Results: The plasma pharmacokinetic variables for patients were; maximum plasma concentration 52.0 ng ml¯ 1 ; time to achieve maximum concentration, 5.2 h.; elimination half life, 35.0 h; and the area under the plasma concentration curve versus time, 2852 ng·h ml¯ 1 . In healthy volunteers, the plasma iver- mectin distribution was similar to that in patients, and both groups showed a tendency for a second rise in plasma concentration of the drug suggestive of entero- hepatic recirculation. Ivermectin was detected in tis- sues obtained from patients. Fat showed the highest and most persistent levels, whilst values for skin, nodu- lar tissues, and worms were comparable. Subcutaneous fascia contained the lowest concentrations. Conclusion: Infection with O. volvulus does not a⁄ect the pharmacokinetics of ivermectin, and filarial infected tissues and parasites themselves do take up the drug. There may be prolonged retention of ivermectin because of depot formation in fat tissue.

Histoplasmosis is a fungal infection caused by Histoplasma capsulatum. In the normal individual, both disseminated histoplasmosis and symptomatic adrenal histoplasmosis are rare. Herein, we describe the case of a 50-year-old gentleman residing in western Sudan who presented with a 7-month history of generalized body weakness, easy fatigue, and frequent attacks of vomiting and diarrhea. Physical examination and laboratory investigations confirmed the diagnosis of Addison's disease due to Histoplasma capsulatum var duboisii infection of the adrenal glands. He was treated with intravenous hydrocortisone, followed by oral prednisolone and itraconazole.

BACKGROUND: In areas of seasonal malaria transmission, treatment of asymptomatic carriers of malaria parasites, whose parasitaemia persists at low densities throughout the dry season, could be a useful strategy for malaria control. We carried out a randomized trial to compare two drug regimens for clearance of parasitaemia in order to identify the optimum regimen for use in mass drug administration in the dry season. METHODOLOGY AND PRINCIPAL FINDINGS: A two-arm open-label randomized controlled trial was conducted during the dry season in an area of distinct seasonal malaria in two villages in Gedarif State in eastern Sudan. Participants were asymptomatic adults and children aged over 6 months, with low-density P. falciparum infection detected by PCR. Participants were randomized to receive artesunate/sulfadoxine-pyrimethamine (AS+SP) combination for three days with or without a dose of primaquine (PQ) on the fourth day. Parasitaemia detected by PCR on days 3, 7 and 14 after the start of treatment and gametocytes detected by RT-PCR on days 7 and 14 were then recorded. 104 individuals who had low density parasitaemia at screening were randomized and treated during the dry season. On day 7, 8.3% were positive by PCR in the AS+SP+PQ group and 6.5% in the AS+SP group (risk difference 1.8%, 95%CI -10.3% to +13.8%). At enrolment, 12% (12/100) were carrying gametocytes. This was reduced to 6.4% and 4.4% by day 14 (Risk difference 1.9% (95%CI -9.3% to +13.2%) in AS+SP+PQ and AS+SP groups, respectively. CONCLUSION: Addition of primaquine to artemisinin combination treatment did not improve elimination of parasitaemia and prevention of gametocyte carriage in carriers with low-density parasitaemia in the dry season. TRIAL REGISTRATION: ClinicalTrials.gov NCT00330902.

Onchocerciasis has been reported in Sudan since 1908 and now prevails in three endemic regions known as the southern, northern and eastern foci. The southern focus is the largest, with nodule and blindness rates exceeding 80% and 12%, respectively, in certain villages. Onchocercal infection in this region causes only a mild skin reaction although microfilarial loads in the skin are high. In contrast, those with onchocerciasis in the northern focus, located between the fourth and fifth Nile cataracts, present with limited but severe skin reactions, low nodule rates (16%), low microfilarial loads in the skin and no ocular involvement. The characteristics of patients from the eastern focus, close to the border with Ethiopian border are similar to those in the north, although most onchocercal skin disease in this area comprises the severe localized pruritus known as sowda.

Background A 40-year-old male from the White Nile region in Sudan, who had received a kidney transplant 6 years previously, presented with fever, lower abdominal pain and diarrhea stained with blood of 5 months duration. He was on immunosuppressive maintenance therapy, consisting of ciclosporin 75 mg twice daily, prednisolone 10 mg once daily, and azathioprine 75 mg once daily. Investigations Laboratory investigations, liver function tests, renal function tests, stool microscopy, stool culture, abdominal ultrasound, and colonoscopy. Diagnosis Severe, left-sided colitis due to Schistosoma mansoni infection, without granuloma formation. Management Oral antischistosomal therapy with praziquantel at a dose of 40 mg/kg body weight.

A major problem with inappropriate use of antibiotics is the emergence of resistance. Thus, cost-effective interventional strategies are required to improve their use. This study aimed to evaluate the effect of multifaceted interventions on prescribing practices of antibiotics in health centers of Khartoum State, Sudan.Twenty health centers were randomly assigned to receive: (1) no intervention; (2) audit and feedback; (3) audit and feedback + seminar; or (4) audit and feedback + academic detailing. A total of 1,800 patient encounters, 30 from each health center, were randomly collected. The total number of encounters with antibiotics prescribed were determined in each health center and they were evaluated with regard to antibiotic choice, dose and duration of therapy before the study and at 1 and 3 months post-intervention.In comparison to the control group, the prescriber targeted interventions involving audit and feedback, together with academic detailing (4), reduced the mean number of encounters with an antibiotic prescribed by 6.3 and 7.7 (p0.001) at 1 and 3 months post-intervention, respectively. In addition, the mean number of encounters with an inappropriate antibiotic with respect to diagnosis, doses and/ or duration of therapy was reduced by 5.3 and 5.9 (p0.001) at 1 and 3 months post-intervention, respectively. For audit and feedback together with seminars (3) and for audit and feedback alone (2), the corresponding reductions were 5.3, 7.1, 4.4 and 5.1 (p0.001) and 1.4, 2.8, 1.8 and 1.9 (p0.05), respectively.Inappropriate prescribing patterns of antibiotics in health centers of Khartoum State, Sudan, are alarmingly high. Multifaceted interventions involving audit and feedback combined with either academic detailing or seminars appear more effective in changing prescribing practices of antibiotics than audit and feedback alone.

A study to monitor ivermectin acceptability and post-treatment reactions during mass community distribution was carried out in eastern Sudan, where severe reactive onchodermatitis is prevalent. Of 1081 individuals eligible for treatment, 1076 (99.5%) accepted the ivermectin. Post-treatment reactions were monitored by self reporting, 5 d after a single dose of about 150 micrograms/kg (range 103-200 micrograms/kg); 230 persons reported adverse events (21.4%). No reaction was rated as severe. The most common problem was itching with cutaneous papular eruptions (16.2%). Local oedematous swelling was the second most common and the most slowly resolving complaint (5.4%), followed by musculoskeletal pain. There was a high acceptance rate of the treatment and remarkable tolerance of the post-treatment effects, probably due to efforts made to prepare the community to expect reactions to ivermectin, widespread awareness of the beneficial effects of treatment by villagers who had participated in clinical trials previously, and the encouragement we gave to the population to become involved in improvement of their health care services. Single doses of ivermectin resulted in good clinical responses and created much goodwill among villagers. Improvements in physical fitness, ability to work, and freedom from musculoskeletal pain were reported at the 3 months' follow-up. We recommend that, during mass distribution of ivermectin, community involvement in planning overall health improvement should be included, since the treatment initiates the process well. In areas where sowda syndrome is prevalent, medical surveillance for 3 d or more should be considered.

Summary A hospital-based study was carried out in Gedarif town, eastern Sudan, an area of markedly unstable malaria transmission. Among the 2488 diagnosed malaria patients, 4.4% fulfilled the WHO criteria for severe malaria, and seven died of cerebral malaria. The predominant complication was severe malarial anemia (45.4%), followed by convulsions (21%), cerebral malaria (16. 4%) and hypotension (11.8%). Severe malaria was recognized in all age groups, but 44.5% of patients were aged 2 to 4 years. The mean ages of patients with severe anemia (5.6 years) and convulsions (5.9 years) were significantly lower than the mean ages of patients with cerebral malaria (14.1 years) or hypotension (35.2 years). Patients with convulsions and cerebral malaria had significantly higher mean parasite count (69 972 and 56 110 parasites/μL, respectively) than patients with severe anemia (24 637parasites/μL) or hypotension (13 667 parasites/μL). The mean blood glucose level was higher in patients with cerebral malaria than in patients with anemia, and higher in patients who died than in patients who survived. In this setting, the clinico-epidemiological pattern of severe malaria varies considerably from that of hyperendemic regions in sub-Saharan Africa, and there is considerable variation between the individual complications of severe malaria.

Onchocerciasis in Sudan exists in three distinct foci which exhibit differing clinical presentations. Previous studies have demonstrated that a tandemly repeated Onchocerca sequence family with a unit repeat length of 150 bp (the O-150 family) is a useful marker for deducing relationships among different O. volvulus populations. In the current study, the O-150 repeat families of O. volvulus from Sudan were analyzed and compared to each other and to those of parasites from West Africa. Similar to West African and American O. volvulus, the O-150 families of the Sudanese parasites could be divided into clusters within which little or no intracluster variation was evident, suggesting that the O-150 family in these parasites was subject to the forces of concerted evolution. Statistical analysis of the O-150 families from the different Sudanese parasite isolates, employing a nested algorithm based on an analysis of variance, revealed that O. volvulus endemic to the northern focus at Abu Hamed were significantly different from all other O. volvulus populations examined to date. In contrast, parasites from the southern and eastern foci of Sudan were indistinguishable from those endemic to the West African savanna. The significance of these data are discussed in light of knowledge of the biogeography and biology of transmission of O. volvulus in Africa.

The northernmost focus for Onchocerca volvulus Leuckhart (Nematoda: Onchocercidae), the causative agent of human onchocerciasis, is found along the Nile near the town of Abu Hamed in Sudan. The vector for O. volvulus at this focus is a single monomorphic population of Simulium (Edwardsellum) damnosum Theobald. This black fly population is limited to a small area between the fourth and fifth cataracts of the Nile River that is isolated geographically from all other populations of S. damnosum sensu lato. Phylogenies produced from cytological analyses and sequence data derived from the NADH dehydrogenase subunit 4 and 16S rRNA genes indicate that Abu Hamed black flies are similar to, but distinct from, the savanna-dwelling sibling species of S. damnosum s.l., Simulium (Edwardsellum) damnosum sensu strictu Theobald, and S. (Edwardsellum) sirbanum Vajime & Dunbar. The DNA sequence and the cytological data support the hypothesis that the black fly population present in Abu Hamed may represent a new sibling species of S. damnosum s.l. We propose that this population be informally designated as the hamedense form of the Simulium damnosum complex.

Ivermectin efficacy and post-treatment reactions in asymmetric severe reactive ochodermatitis (sowda) were studied in 8 patients with sowda syndrome and 6 with mild generalized onchodermatitis in Sudan. Initial skin snips from 12 patients contained microfilariae (1-9 per mg skin). Patients were treated in hospital with a single oral dose of c. 150 micrograms/kg ivermectin (103-200 micrograms/kg) and monitored for frequency and severity of post-treatment reactions for 4 weeks. Serial samples of heparinized blood were collected over the first 24 h after treatment for determination of ivermectin pharmacokinetics. Skin snips from all patients on days 3 and 28 revealed no microfilariae. Post-treatment reactions were more common and severe in individuals with sowda; they consisted mainly of musculoskeletal pain, local swellings with pitting oedema, and lymph gland tenderness and enlargement. No relation was established between these reactions, the microfilarial infection intensity, or the plasma pharmacokinetic profiles. A single oral dose of ivermectin cleared the skin of microfilariae and led to improvement of symptoms and dermatological signs of sowda, but resulted in more marked reactions than in cases of generalized onchodermatitis.