Debrah AY et al. (2006) Filaria J "Assessment of microfilarial loads in the skin of onchocerciasis patients after treatment with different regimens of doxycycline plus ivermectin."

Debrah AY, Marfo-Debrekyei Y, Mand S, Larbi J, Adjei O, Hoerauf A

[Filaria J, 2006]

BACKGROUND: Infection with the filarial nematode Onchocerca volvulus can lead to severe dermatitis, visual impairment, and ultimately blindness. Since the currently used drug, ivermectin does not have macrofilaricidal or strong permanent sterilising effects on the adult worm, more effective drugs are needed to complement the use of ivermectin alone. Wolbachia endosymbiotic bacteria in filariae have emerged as a new target for treatment with antibiotics which can lead to long -term sterilization of the adult female filariae. METHODS: In the Central Region of Ghana, 60 patients were recruited, allocated into four groups and treated with 200 mg doxycycline per day for 2 weeks, 4 weeks, 6 weeks respectively. Untreated patients served as controls. Some of the treated patients and the untreated controls were given 150 microg/kg ivermectin 8 months after the start of doxycycline treatment. RESULTS: A follow up study 18 months post treatment showed that when using doxycycline alone there was a significant reduction of microfilarial (mf) loads in patients treated for either 4 or 6 weeks. However, there was no significant difference between the untreated controls and those given the 2 weeks regimen. Although no significant difference was demonstrated between the 4 and 6 weeks regimens, there was a trend observed, in that, microfilarial reduction appeared to have been greater following the 6 weeks regimen. Twelve months after ivermectin (i.e. 20 months after doxycycline) treatment, 8 out of 11 ivermectin-alone treated patients were mf-positive. In contrast, 1 out of the 7 patients treated for 4 weeks with doxycycline and none of the 4 patients treated for 6 weeks doxycycline (who were available for re-examination) were mf-positive after the combined treatment of doxycycline plus ivermectin treatment. CONCLUSION: Treatment of onchocerciasis with doxycycline for 4 weeks is effective. Nonetheless, mf reduction appeared to be greater in the 6 weeks regimen. It is recommended that until further studies are carried out i.e. 4 weeks treatment with doxycycline is proven equivalent to the 6 weeks, selected groups of onchocerciasis patients should be treated for 6 weeks with doxycycline. As discussed earlier, this treatment should be accompanied by two doses of ivermectin.

Batsa Debrah L et al. (2019) Clin Infect Dis "Comparison of repeated doses of ivermectin versus ivermectin plus albendazole for treatment of onchocerciasis - a randomized open-label clinical trial."

Ricchiuto A, Konadu P, Debrah AY, Gruetzmacher B, Weil G, Kazura JW, Klarmann-Schulz U, Dubben B, Hoerauf A, Nadal J, Mubarik Y, King CL, Batsa Debrah L, Osei-Mensah J, Fimmers R, Ayisi-Boateng NK, Fischer K

[Clin Infect Dis, 2019]

BACKGROUND: Improved treatment for onchocerciasis is needed to accelerate onchocerciasis elimination in Africa. Aiming to better exploit registered drugs, this study was undertaken to determine whether annual or semiannual treatment with ivermectin (IVM; 200g/kg) plus albendazole (ALB; 800mg single dose) is superior to IVM alone. METHODS: This trial was performed in Ghana and included 272 microfilaria (MF) -positive participants randomized to 4 treatment arms: 1) IVM annual at 0, 12, and 24 months; 2) IVM semiannual at 0, 6, 12, 18 and 24 months; 3) IVM+ALB annual; 4) IVM+ALB semiannual. Microfiladermia was determined pre-treatment and at 6, 18 and 36 months. The primary outcome was the proportion of fertile and viable female worms in onchocercomata excised at 36 months. RESULTS: Post-treatment nodule histology showed that 15/135 (11.1%), 22/155 (14.2%), 35/154 (22.7%) and 20/125 (16.0%) living female worms had normal embryogenesis in the IVM annual, IVM semiannual, IVM+ALB annual and IVM+ALB semiannual groups respectively (p=0.1229). Proportions of dead worms also did not differ between the 4 groups (p=0.9198). Proportions of patients without MF at 36 months (one year after the last treatment) were 35/56 (63%) after annual IVM, 42/59 (71%) after semiannual IVM, 39/64 (61%) after IVM+ALB annual, and 43/53 (81%) after semiannual IVM+ALB. CONCLUSIONS: The combination treatment with IVM plus ALB was no better than IVM alone for sterilizing, killing of adult worms or achieving sustained MF clearance. However, semiannual treatment was superior to annual treatment for achieving sustained clearance of O. volvulus MF from the skin (p=0.024).

Lagatie O et al. (2017) Parasitol Res "Plasma-derived parasitic microRNAs have insufficient concentrations to be used as diagnostic biomarker for detection of Onchocerca volvulus infection or treatment monitoring using LNA-based RT-qPCR."

Batsa Debrah L, Lagatie O, Stuyver LJ, Debrah A

[Parasitol Res, 2017]

River blindness, caused by infection with the filarial nematode Onchocerca volvulus, is a neglected tropical disease affecting millions of people. There is a clear need for diagnostic tools capable of identifying infected patients, but that can also be used for monitoring disease progression and treatment efficacy. Plasma-derived parasitic microRNAs have been suggested as potential candidates for such diagnostic tools. We have investigated whether these parasitic microRNAs are present in sufficient quantity in plasma of Onchocerca-infected patients to be used as a diagnostic biomarker for detection of O. volvulus infection or treatment monitoring. Plasma samples were collected from different sources (23 nodule-positive individuals and 20 microfilaridermic individuals), microRNAs (miRNAs) were extracted using Qiagen miRNeasy kit, and a set of 17 parasitic miRNAs was evaluated on these miRNA extracts using miRCURY Locked Nucleic Acid (LNA) Universal RT microRNA PCR system. Of the 17 miRNAs evaluated, only 7 miRNAs were found to show detectable signal in a number of samples: bma-miR-236-1, bma-miR-71, ov-miR71-22nt, ov-miR-71-23nt, ov-miR-100d, ov-bantam-a, and ov-miR-87-3p. Subsequent melting curve analysis, however, indicated that the signals observed for ov-miR-71 variants and ov-miR-87-3p are non-specific. The other miRNAs only showed positive signal in one or few samples with Cq values just below the cutoff. Our data indicate that parasitic miRNAs are not present in circulation at a sufficiently high level to be used as biomarker for O. volvulus infection or treatment monitoring using LNA-based RT-qPCR analysis.

Lagatie O et al. (2018) Parasite Immunol "Linear epitopes in Onchocerca volvulus vaccine candidate proteins and excretory-secretory proteins."

Stuyver LJ, Van Dorst B, Batsa Debrah L, Verheyen A, Debrah A, Lagatie O

[Parasite Immunol, 2018]

In our previous study, a proteome-wide screen was conducted to identify linear epitopes in this parasite's proteome, resulting in the discovery of three immunodominant motifs. Here we investigated whether such antigenic peptides were found in proteins that were already known as vaccine candidates and excretome/secretome proteins for O. volvulus. This approach led to the identification of 71 immunoreactive stretches in 46 proteins. A deep-dive into the immunoreactivity profiles of eight vaccine candidates that were chosen as most promising candidates for further development (Ov-CPI-2,Ov-ALT-1,Ov-RAL-2,Ov-ASP-1,Ov-103,Ov-RBP-1,Ov-CHI-1, andOv-B20), resulted in the identification of a poly-glutamine stretch in Ov-RAL-2 that has properties for use as a serodiagnostic marker for O. volvulus infection. A peptide ELISA was developed, and the performance of this assay was evaluated. Based on this assessment, it was found that this assay has a sensitivity of 75.0% [95% CI: 64.9%-83.5%] and a specificity of 98.5% [95% CI: 94.6%-99.8%]. Furthermore, 8.7% reactivity in Asian parasite-infected individuals (8 out of 92) was observed. Besides this identification of a linear epitope marker, the information on the presence of linear epitopes in vaccine candidate proteins might be useful in the study of vaccines for river blindness. This article is protected by copyright. All rights reserved.

Specht S et al. (2009) Parasitol Res "Newly acquired Onchocerca volvulus filariae after doxycycline treatment."

Buttner DW, Hoerauf A, Adjei O, Debrah A, Specht S

[Parasitol Res, 2009]

Despite successful mass drug administration and vector control programs, the nematode Onchocerca volvulus is far from being eradicated. Therefore, new long-term sterilizing or macrofilaricidal drugs are needed. The depletion of Wolbachia endobacteria using doxycycline leads to long-term sterilizing effects and macrofilaricidal activity against female filariae of more than 60%. The worms die or degenerate 18-27 months after doxycycline. However, during this time patients may be exposed to new infections. We evaluated these newly acquired worms in onchocercomas of doxycycline-treated patients in relation to transmission using morphology, histochemistry, and immunohistology. On an average, 10% of the female filariae had been newly acquired per year in the treated groups. Our observations showed: (a) Sixty-three of 68 newly acquired worms harbored many intact Wolbachia, whereas none of the other surviving worms contained many bacteria. (b) Higher percentages of dead filariae than originally reported were calculated, when the new worms were excluded, indicating a stronger macrofilaricidal activity than previously reported. The difference was significant for female filariae after doxycycline treatment for 6 weeks. (c) Only newly acquired worms presented normal embryogenesis and microfilariae production after sufficient treatment. We conclude that newly acquired filariae have to be considered when evaluating drug efficacy in onchocerciasis.

Mand S et al. (2005) Filaria J "Frequent detection of worm movements in onchocercal nodules by ultrasonography."

Debrah A, Batsa L, Marfo-Debrekyei Y, Pfarr K, Hoerauf A, Adjei O, Mand S, Buettner M

[Filaria J, 2005]

BACKGROUND: Ultrasonography (USG) is known to be a suitable tool for diagnosis in lymphatic filariasis as the adult filarial nematode Wuchereria bancrofti in scrotal lymphatic vessels of infected men can be detected by the characteristic pattern of movement, the Filaria Dance Sign. In onchocerciasis, moving adult worms have not yet been demonstrated by USG. In addition the verification of drug effects on living adult Onchocerca volvulus filariae in trials is hampered by the lack of tools for longitudinal observation of alterations induced by potentially macrofilaricidal drugs in vivo. The present study was carried out to determine the frequency of detection of moving adult filariae of O. volvulus by USG. METHODS: In an endemic region for onchocerciasis in Ghana, 61 patients infected with onchocerciasis were recruited by palpation and onchocercomas examined by USG using an ultrasound system equipped with a 7.5 - 10 MHz linear transducer. Onchocercomas were recorded on videotape and evaluated with regard to location, number and size, as well as to movements of adult filariae. RESULTS: In the 61 patients 303 onchocercomas were found by palpation and 401 onchocercomas were detected by USG. In 18 out of 61 patients (29.5%), altogether 22 nodules with moving adult O. volvulus filariae were detected and are presented in animated ultrasound images as mp-4 videos. CONCLUSION: Ultrasonographical examinations of onchocercomas where living adult filariae can be displayed may serve as a new tool for the longitudinal observation in vivo of patients with onchocerciasis undergoing treatment and as an adjunct to histological evaluation.

Lagatie O et al. (2016) Parasit Vectors "Evaluation of the diagnostic potential of urinary N-Acetyltyramine-O,-glucuronide (NATOG) as diagnostic biomarker for Onchocerca volvulus infection."

Stuyver LJ, Debrah A, Dillen L, Vinken P, Lagatie O, Diels L, Njumbe Ediage E, Nolten C, Silber S, Batsa Debrah L

[Parasit Vectors, 2016]

BACKGROUND: Onchocerciasis, also known as river blindness is one of the neglected tropical diseases affecting millions of people, mainly in sub-Saharan Africa and is caused by the filarial nematode Onchocerca volvulus. Efforts to eliminate this disease are ongoing and are based on mass drug administration programs with the microfilaricide ivermectin. In order to monitor the efficacy of these programs, there is an unmet need for diagnostic tools capable of identifying infected patients. We have investigated the diagnostic potential of urinary N-acetyltyramine-O,-glucuronide (NATOG), which is a promising O. volvulus specific biomarker previously identified by urine metabolome analysis. METHODS: A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was used to assess the stability characteristics of NATOG and to evaluate the levels of NATOG in study samples. An LC-fluorescence method was also developed. RESULTS: Stability characteristics of NATOG were investigated and shown to be ideally suited for use in tropical settings. Also, an easy and more accessible method based on liquid chromatography coupled to fluorescence detection was developed and shown to have the necessary sensitivity (limit of quantification 1M). Furthermore, we have evaluated the levels of NATOG in a population of 98 nodule-positive individuals from Ghana with no or low levels of microfilaria in the skin and compared them with the levels observed in different control groups (endemic controls (n=50), non-endemic controls (n=18) and lymphatic filariasis (n=51). Only a few (5%) of nodule-positive individuals showed an increased level (>10M) of NATOG and there was no statistical difference between the nodule-positive individuals and the control groups (P>0.05). CONCLUSIONS: Results of the present study indicate the limited potential of NATOG as a diagnostic biomarker for O. volvulus infection in amicrofilaridermic individuals.

Brattig NW et al. (2010) Parasitology "Immunohistological studies on neoplasms of female and male Onchocerca volvulus: filarial origin and absence of Wolbachia from tumor cells."

Buttner M, Fischer PU, Hoerauf A, Liebau E, Bandi C, Brattig NW, Debrah A, Buttner DW

[Parasitology, 2010]

Up to 5% of untreated female Onchocerca volvulus filariae develop potentially fatal pleomorphic neoplasms, whose incidence is increased following ivermectin treatment. We studied the occurrence of 8 filarial proteins and of Wolbachia endobacteria in the tumor cells. Onchocercomas from patients, untreated and treated with antibiotics and anthelminthics, were examined by immunohistology. Neoplasms were diagnosed in 112 of 3587 female and in 2 of 1570 male O. volvulus. The following proteins and other compounds of O. volvulus were expressed in the cells of the neoplasms: glutathione S-transferase 1, lysosomal aspartic protease, cAMP-dependent protein kinase, alpha-enolase, aspartate aminotransferase, ankyrin E1, tropomyosin, heat shock protein 60, transforming growth factor-beta, and prostaglandin E(2). These findings prove the filarial origin of the neoplasms and confirm the pleomorphism of the tumor cells. Signs indicating malignancy of the neoplasms are described. Wolbachia were observed in the hypodermis, oocytes, and embryos of tumor-harbouring filariae using antibodies against Wolbachia surface protein, Wolbachia HtrA-type serine protease, and Wolbachia aspartate aminotransferase. In contrast, Wolbachia were not found in the cells of the neoplasms. Further, neoplasm-containing worms were not observed after more than 10 months after the start of sufficient treatment with doxycycline or doxycycline plus ivermectin.

Quartey MO et al. (2021) Sci Rep "The A(1-38) peptide is a negative regulator of the A(1-42) peptide implicated in Alzheimer disease progression."

Pennington PR, Heistad RM, Nyarko JNK, Barnes JR, Bolanos MAC, Parsons MP, Knudsen KJ, De Carvalho CE, Leary SC, Mousseau DD, Buttigieg J, Maley JM, Quartey MO

[Sci Rep, 2021]

The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).

Danielle Thierry-Mieg et al. (2003) Worm Breeder's Gazette "www.wormgenes.org , a new gene centered database"

Vahan Simonyan, Michel Potdevin, Mark Sienkiewicz, Yuji KOHARA, Jean Thierry-Mieg, Danielle Thierry-Mieg, Tadasu SHIN-I

[Worm Breeder's Gazette, 2003]

Wormgenes is a new resource for C.elegans offering a detailed summary about each gene and a powerful query system.