Treatment Outcome of Tuberculosis Patients under Directly Observed Treatment Short Course and Factors Affecting Outcome in Southern Ethiopia: A Five-Year Retrospective Study

Tuberculosis (TB) is one of the major public health and socio-economic issues in the 21^st century globally. Assessment of TB treatment outcomes, and monitoring and evaluation of its risk factors in Directly Observed Treatment Short Course (DOTS) are among the major indicators of the performance of a national TB control program. Hence, this institution-based retrospective study was conducted to determine the treatment outcome of TB patients and investigate factors associated with unsuccessful outcome at Dilla University Referral Hospital, southern Ethiopia. Five years (2008 to 2013) TB record of TB clinic of the hospital was reviewed. A total 1537 registered TB patients with complete information were included. Of these, 942 (61.3%) were male, 1015 (66%) were from rural areas, 544 (35.4%) were smear positive pulmonary TB (PTB+), 816 (53.1%) were smear negative pulmonary TB (PTB-) and 177(11.5%) were extra pulmonary TB (EPTB) patients. Records of the 1537 TB patients showed that 181 (11.8%) were cured, 1129(73.5%) completed treatment, 171 (11.1%) defaulted, 52 (3.4%) died and 4 (0.3%) had treatment failure. The overall mean treatment success rate of the TB patients was 85.2%. The treatment success rate of the TB patients increased from 80.5% in September 2008-August 2009 to 84.8% in September 2012–May 2013. Tuberculosis type, age, residence and year of treatment were significantly associated with unsuccessful treatment outcome. The risk of unsuccessful outcome was significantly higher among TB patients from rural areas (AOR = 1.63, 95% CI: 1.21–2.20) compared to their urban counterparts. Unsuccessful treatment outcome was also observed in PTB- patients (AOR = 1.77, 95% CI: 1.26–2.50) and EPTB (AOR = 2.07, 95% CI: 1.28–3.37) compared to the PTB+ patients. In conclusion, it appears that DOTS have improved treatment success in the hospital during five years. Regular follow-up of patients with poor treatment outcome and provision of health information on TB treatment to patients from rural area is recommended.     

Structural implications of weak Ca2+ block in Drosophila cyclic nucleotide–gated channels

Calcium permeability and the concomitant calcium block of monovalent ion current (“Ca²⁺ block”) are properties of cyclic nucleotide–gated (CNG) channel fundamental to visual and olfactory signal transduction. Although most CNG channels bear a conserved glutamate residue crucial for Ca²⁺ block, the degree of block displayed by different CNG channels varies greatly. For instance, the Drosophila melanogaster CNG channel shows only weak Ca²⁺ block despite the presence of this glutamate. We previously constructed a series of chimeric channels in which we replaced the selectivity filter of the bacterial nonselective cation channel NaK with a set of CNG channel filter sequences and determined that the resulting NaK2CNG chimeras displayed the ion selectivity and Ca²⁺ block properties of the parent CNG channels. Here, we used the same strategy to determine the structural basis of the weak Ca²⁺ block observed in the Drosophila CNG channel. The selectivity filter of the Drosophila CNG channel is similar to that of most other CNG channels except that it has a threonine at residue 318 instead of a proline. We constructed a NaK chimera, which we called NaK2CNG-Dm, which contained the Drosophila selectivity filter sequence. The high resolution structure of NaK2CNG-Dm revealed a filter structure different from those of NaK and all other previously investigated NaK2CNG chimeric channels. Consistent with this structural difference, functional studies of the NaK2CNG-Dm chimeric channel demonstrated a loss of Ca²⁺ block compared with other NaK2CNG chimeras. Moreover, mutating the corresponding threonine (T318) to proline in Drosophila CNG channels increased Ca²⁺ block by 16 times. These results imply that a simple replacement of a threonine for a proline in Drosophila CNG channels has likely given rise to a distinct selectivity filter conformation that results in weak Ca²⁺ block.     

Global tuberculosis control: lessons learnt and future prospects

Tuberculosis (TB) is an ancient disease, but not a disease of the past. After disappearing from the world public health agenda in the 1960s and 1970s, TB returned in the early 1990s for several reasons, including the emergence of the HIV/AIDS pandemic and increases in drug resistance. More than 100 years after the discovery of the tubercle bacillus by Robert Koch, what is the status of TB control worldwide? Here, we review the evolution of global TB control policies, including DOTS (directly observed therapy, short course) and the Stop TB Strategy, and assess whether the challenges and obstacles faced by the public health community worldwide in developing and implementing this strategy can aid future action towards the elimination of TB.     

FcgammaRIIB in IgG-mediated suppression of antibody responses: different impact in vivo and in vitro.

The suppressive effect of IgG on Ab responses to particulate Ags such as erythrocytes is well documented. IgG-mediated suppression is used clinically in rhesus prophylaxis to prevent RhD-negative mothers from becoming immunized against their Rh D-positive fetuses. We have recently shown that IgG anti-SRBC, passively administered together with SRBC, can induce efficient suppression of primary Ab responses to SRBC in mice lacking the known FcRs for IgG (FcgammaRI, FcgammaIII, and FcgammaRIIB or the neonatal FcR). The lack of a demonstrable effect of the inhibitory FcgammaRIIB was particularly surprising, and, in this study, the involvement of this receptor is further investigated during broader experimental conditions. The data show that SRBC-specific IgG administered up to 5 days after SRBC can induce suppression both in wild-type and FcgammaRIIB-deficient mice. Suppression of secondary Ab responses to SRBC in vivo was similar in the two strains. In contrast, IgG-mediated suppression of Ab responses in vitro was impaired in cultures with primed FcgammaRIIB-deficient spleen cells. In conclusion, inhibition of in vivo Ab responses to SRBC by passively administered IgG can take place via an FcgammaRIIB-independent pathway. This pathway causes >99% suppression and operates during all experimental conditions studied so far. The nature of the mechanism can at present only be hypothesized. Masking of epitopes and/or rapid elimination of IgG-Ag complexes would both be compatible with the observations.     

N-acetylcolchinol O-methyl ether and thiocolchicine, potent analogs of colchicine modified in the C ring. Evaluation of the mechanistic basis for their enhanced biological properties

Two colchicine analogs with modifications only in the C ring are better inhibitors than colchicine of cell growth and tubulin polymerization. Radiolabeled thiocolchicine (with a thiomethyl instead of a methoxy group at position C-10) and N-acetylcolchinol O-methyl ether (NCME) (with a methoxy-substituted benzenoid instead of the methoxy-substituted tropone C ring) were prepared for comparison with colchicine. Scatchard analysis indicated a single binding site with KD values of 1.0-2.3 microM. Thiocolchicine was bound 2-4 times as rapidly as colchicine, but the activation energies of the reactions were nearly identical (18 kcal/mol for colchicine, 20 kcal/mol for thiocolchicine). NCME bound to tubulin in a biphasic reaction. The faster phase was 60 times as fast as colchicine binding at 37 degrees C, and a substantial reaction occurred at 0 degrees C. The rate of the faster phase of NCME binding changed relatively little as a function of temperature, so the activation energy was only 7.0 kcal/mol. Dissociation reactions were also evaluated, and at 37 degrees C the half-lives of the tubulin-drug complexes were 11 min for NCME, 24 h for thiocolchicine, and 27 h for colchicine. Relative dissociation rates as a function of temperature varied little among the drug complexes. Activation energies for the dissociation reactions were 30 kcal/mol for thiocolchicine, 27 kcal/mol for NCME, and 24 kcal/mol for colchicine. Comparison of the activation energies of association and dissociation yielded free energies for the binding reactions of -20 kcal/mol for NCME, -10 kcal/mol for thiocolchicine, and -6 kcal/mol for colchicine. The greater effectiveness of NCME and thiocolchicine as compared with colchicine in biological assays probably derives from their more rapid binding to tubulin and the lower free energies of their binding reactions.     

Geographical variation in the response of visceral leishmaniasis to paromomycin in East Africa: a multicentre, open-label, randomized trial

Background

Visceral leishmaniasis (VL) is a major health problem in developing countries. The untreated disease is fatal, available treatment is expensive and often toxic, and drug resistance is increasing. Improved treatment options are needed. Paromomycin was shown to be an efficacious first-line treatment with low toxicity in India.

Methods

This was a 3-arm multicentre, open-label, randomized, controlled clinical trial to compare three treatment regimens for VL in East Africa: paromomycin sulphate (PM) at 15 mg/kg/day for 21 days versus sodium stibogluconate (SSG) at 20 mg/kg/day for 30 days; and the combination of both dose regimens for 17 days. The primary efficacy endpoint was cure based on parasite-free tissue aspirates taken 6 months after treatment.

Findings

Overall, 135 patients per arm were enrolled at five centres in Sudan (2 sites), Kenya (1) and Ethiopia (2), when the PM arm had to be discontinued due to poor efficacy. The trial has continued with the higher dose of PM as well as the combination of PM and SSG arms. These results will be reported later. Baseline patient characteristics were similar among treatment arms. The overall cure with PM was significantly inferior to that with SSG (63.8% versus 92.2%; difference 28.5%, 95%CI 18.8% to 38.8%, p<0.001). The efficacy of PM varied among centres and was significantly lower in Sudan (14.3% and 46.7%) than in Kenya (80.0%) and Ethiopia (75.0% and 96.6%). No major safety issues with PM were identified.

Conclusion

The efficacy of PM at 15 mg/kg/day for 21 days was inadequate, particularly in Sudan. The efficacy of higher doses and the combination treatment warrant further studies.     

First PCR Confirmed anthrax outbreaks in Ethiopia—Amhara region, 2018–2019

BackgroundAnthrax is a disease that affects humans and animals. In Ethiopia, anthrax is a reportable disease and assumed to be endemic, although laboratory confirmation has not been routinely performed until recently. We describe the findings from the investigation of two outbreaks in Amhara region.MethodsFollowing reports of suspected outbreaks in Wag Hamra zone (Outbreak 1) and South Gondar zone (Outbreak 2), multi-sectoral teams involving both animal and public health officials were deployed to investigate and establish control programs. A suspect case was defined as: sudden death with rapid bloating or bleeding from orifice(s) with unclotted blood (animals); and signs compatible with cutaneous, ingestion, or inhalation anthrax ≤7 days after exposure to a suspect animal (humans). Suspect human cases were interviewed using a standard questionnaire. Samples were collected from humans with suspected anthrax (Outbreak 1 and Outbreak 2) as well as dried meat of suspect animal cases (Outbreak 2). A case was confirmed if a positive test was returned using real-time polymerase chain reaction (qPCR).ResultsIn Outbreak 1, a total of 49 cows died due to suspected anthrax and 22 humans developed symptoms consistent with cutaneous anthrax (40% attack rate), two of whom died due to suspected ingestion anthrax. Three people were confirmed to have anthrax by qPCR. In Outbreak 2, anthrax was suspected to have caused the deaths of two livestock animals and one human. Subsequent investigation revealed 18 suspected cases of cutaneous anthrax in humans (27% attack rate). None of the 12 human samples collected tested positive, however, a swab taken from the dried meat of one animal case (goat) was positive by qPCR.ConclusionWe report the first qPCR-confirmed outbreaks of anthrax in Ethiopia. Both outbreaks were controlled through active case finding, carcass management, ring vaccination of livestock, training of health professionals and outreach with livestock owners. Human and animal health authorities should work together using a One Health approach to improve case reporting and vaccine coverage.     

IgG2a-mediated enhancement of antibody and T cell responses and its relation to inhibitory and activating Fc gamma receptors

A number of studies in experimental animal models point to an important role of Fc gamma Rs in autoimmunity and allergy. In this study, we investigate how the production of IgG, an early step in the chain of events leading to inflammation, is regulated by activating and inhibitory Fc gamma Rs. IgG Abs are known to feedback-enhance Ab responses to soluble Ags, and this effect requires activating Fc gamma Rs. To test proliferation of Th cells, mice were adoptively transferred with CD4(+) T cells expressing a transgenic OVA-specific TCR before immunization with IgG2a anti-2,4,6-trinitrophenyl (TNP) plus OVA-TNP or with OVA-TNP alone. IgG2a induced a significant increase in OVA-specific T cell numbers, which preceded the OVA-specific Ab response and was dependent on the Fc gamma chain. The role of the inhibitory Fc gamma RIIB in Ab responses was studied in mice lacking this receptor. Although IgG2a enhanced primary Ab responses, development of germinal centers, and immunological memory in wild-type mice, enhancement was markedly stronger in Fc gamma RIIB(-/-) mice. The presented data are compatible with the hypothesis that the mechanism behind IgG2a-mediated up-regulation of Ab responses involves increased Ag presentation to CD4(+) T cells by Fc gamma R(+) APCs. Our observations also illustrate the intricate immunoregulatory role of IgG Abs. On the one hand, they enhance Ab responses via activating Fc gamma Rs, and on the other hand, they set an upper limit for the same Ab response via Fc gamma RIIB.     

Diet overlap of non‐native common carp and native Nile tilapia: A potential cause for population reduction of Nile tilapia stock in Lake Ziway,Ethiopia

Lake Ziway harbours indigenous and exotic fish species including Nile tilapia (Oreochromis niloticus) and common carp (Cyprinus carpio). Nile tilapia was the dominant and preferred fish. However, its contribution to total catch has dramatically declined from 89.3% in 1994 to 27% in 2014 while the introduced common carp has increased from 0% before 2012 to 25% in 2014. Common carp potentially compete with Nile tilapia for available resources and could be a cause for the decline. Thus, the study explored the dietary overlap of the two species from April to August 2017. Schoener's overlap index (α) revealed significant dietary overlap between the two species (α = 0.84, between juveniles and α = 0.63, between adults). Juveniles fed mainly on animal origin (zooplankton and insects), while adult Nile tilapia have consumed plant origin (macrophyte and phytoplankton), and adult common carp fed on macrophytes and detritus. The presence of significant dietary overlap between the two species, particularly due to intense competition among juveniles, might cause the reduction of Nile tilapia stock because the native species has shown a competitive disadvantage for food in the presence of common carp. This study provides baseline information to researchers and decision makers working towards the sustainable resource utilisation of the system.