Insulin-like Growth Factor and its Therapeutic Potential for Diabetes Complications - Mechanisms and Metabolic Links: A Review

BACKGROUNDThe insulin-like growth factor (IGF) system is an important system in normal physiological functioning of the body. In diabetes mellitus, alterations of IGF-binding protein (IGFBP) levels have been described, mainly in vascular complications.AIMThe aim of this review was to explore the role of the IGF system in reducing diabetes complications and its role as potential therapeutic target.RESULTSIGF-1 plays a role in neuronal growth and developmental processes. Low concentrations of IGF-1 have been associated with neuropathy and other diabetes complications. Moreover, impaired IGF synthesis and function may result in cellular senescence and impaired vascular endothelial proliferation, adhesion, and integration. Of note, high IGF-1 bioavailability may prevent or delay the inception of diabetes-associated complications in diabetes patients. The mechanism of normal functioning IGF-1 is induced by increasing nitric oxide synthesis and potassium ion channel opening in cardiovascular physiology, which improves impaired small blood vessel function and reduces the occurrence of diabetes complications associated with reduced concentrations of IGF-1.CONCLUSIONSIGF may be considered an alternative therapy for diabetes and diabetes-associated complications. Therefore, future studies should focus on the mechanism of action and therapeutic potential of IGFs in reducing the risk of development and progression of the disease in different clinical settings.     

Assessment of the implementation of HIV-rapid test kits at different levels of health institutions in Ethiopia

OBJECTIVE: Evaluation and monitoring of Human Immunodeficiency Virus (HIV) testing reagents at the point of service is helpful to prevent the occurrence of problems related to testing and interpretation. To evaluate the implementation of HIV rapid test kits at the point of services in voluntarily counseling and testing (VCT) and diagnostic centers in Ethiopia. METHODS: The assessment was the third phase of evaluation of HIV rapid test kits in Ethiopia followed from phase-I and phase-II. Known proficiency testing panels, well-structured questionnaire (addressing type of tests, human resource and problems related to tests), onsite supervision and retesting of samples collected from sites were used to evaluate the performances of reagents and laboratories. RESULTS: Forty-four health institutions were included. Thirty-six (90.0%) health institutions had trained human resource on HIV testing. In 27 (61.4%) three types of HIV rapid test kits (Determine, Capillus and Unigold) were available. Serial-algorithm was used in all the laboratories. In 31 (70.4%) of them external quality control specimens were not used. Twenty two (50.0%) of the laboratories reported frequent shortage of reagents. All (100%) were able to identify negative specimens distributed. Positive proficiency panel samples were identified in 37 (94.8%) of the 39 laboratories. There was 98.3% agreement at a screening level between the sites and the central laboratory. Rate of discrepancy between screening and confirmatory assays was found to be 3.0% and 2.1% at the sites and at central laboratory, respectively. CONCLUSION: The test kits showed a good performance at the point of services in the field sites. However, continuous assessment of HIV test kits at the point of service and training of professionals on newly arrived techniques are recommended to have effective testing performance with acceptable sensitive and specific testing algorithm. Effective quality assurance program should be in place to support programs such as VCT, prevention of mother-to-child-transmission and antiretroviral therapy.     

Phage Display-directed Discovery of LEDGF/p75 Binding Cyclic Peptide Inhibitors of HIV Replication

The interaction between the human immunodeficiency virus (HIV) integrase (IN) and its cellular cofactor lens epithelium-derived growth factor (LEDGF/p75) is crucial for HIV replication. While recently discovered LEDGINs inhibit HIV-1 replication by occupying the LEDGF/p75 pocket in IN, it remained to be demonstrated whether LEDGF/p75 by itself can be targeted. By phage display we identified cyclic peptides (CPs) as the first LEDGF/p75 ligands that inhibit the LEDGF/p75–IN interaction. The CPs inhibit HIV replication in different cell lines without overt toxicity. In accord with the role of LEDGF/p75 in HIV integration and its inhibition by LEDGINs, CP64, and CP65 block HIV replication primarily by inhibiting the integration step. The CPs retained activity against HIV strains resistant to raltegravir or LEDGINs. Saturation transfer difference (STD) NMR showed residues in CP64 that strongly interact with LEDGF/p75 but not with HIV IN. Mutational analysis identified tryptophan as an important residue responsible for the activity of the peptides. Serial passaging of virus in the presence of CPs did not yield resistant strains. Our work provides proof-of-concept for direct targeting of LEDGF/p75 as novel therapeutic strategy and the CPs thereby serve as scaffold for future development of new HIV therapeutics.     

Wheeze, allergic sensitization and geohelminth infection in Butajira, Ethiopia

BACKGROUND: The effect of geohelminth infection on wheeze and allergen sensitization is inconsistent across different epidemiological studies. OBJECTIVE: To investigate the association between self-reported wheeze, self-reported asthma, allergic sensitization and geohelminth infection in urban and rural areas of Butajira, southern Ethiopia. METHODS: Questionnaire data on wheeze, asthma and a range of confounding variables was gathered in a cross-sectional study of 7649 people aged 5 years or more from the Butajira Rural Health Project database. Allergic skin sensitization to Dermatophagoides pteronyssinus and cockroach was measured, and a stool sample collected for qualitative and quantitative geohelminth analysis. RESULTS: Wheeze was weakly associated with allergic sensitization to D. pteronyssinus and cockroach (odds ratios (OR) 1.21, 95% confidence interval (CI) 0.98-1.51, and 1.27, 95% CI 1.00-1.62, respectively). Self-reported asthma was related to sensitization to D. pteronyssinus only (OR 4.09, 95% CI 2.86-5.84). Geohelminths were present in 33.8% of participants, and the median egg load in infested individuals was 6 eggs/g. Overall, presence of any geohelminths was associated with a diminished risk of cockroach sensitization (adjusted OR 0.82, 95% CI 0.68-0.99) but there were no significant protective effects of any geohelminth infection against wheeze or asthma. CONCLUSION: In a developing country community with relatively low geohelminth prevalence and intensity, we found weak association between allergic sensitization and wheeze, but no evidence of a protective effect of geohelminths against wheeze or asthma.     

Treatment outcome of tuberculosis patients under directly observed treatment in Addis Ababa,Ethiopia

BackgroundTuberculosis is one of the leading causes of mortality among infectious diseases worldwide. For effective tuberculosis control, it is a pre-requisite to detect the cases as early as possible, and to ensure that the tuberculosis patients complete their treatment and get cured. However, in many resource-constrained settings treatment outcome for tuberculosis has not been satisfactory.ObjectiveThe aim of the study was to assess the treatment outcome of tuberculosis patients and investigate the association of demographic and clinical factors with treatment success of patients enrolled in Directly Observed Treatment Short Course program in government owned health centers over the course of five consecutive years in Addis Ababa, Ethiopia.MethodsA register based historical cohort study covering the period of July 2004 to June 2009 was conducted to determine the treatment outcome of Directly Observed Treatment Short Course in government owned health centers in Addis Ababa. Sex and age of tuberculosis patients, health center at which the patient was treated, year of treatment, type of tuberculosis for which the patient was treated, type of treatment offered to the patient, follow-up status and documented treatment outcome were extracted from the Directly Observed Treatment Short Course clinics of three randomly selected health centers.ResultRecords of 6450 registered tuberculosis patients (n = 3147 males and 3433 females) were included in this document review. Of these patients 18.1% were reported as being cured, 64.6% were documented as treatment completed, 3.7% died during follow-up, 5.1% were reported as defaulters, 0.4% were documented as treatment failure and 8.2% were transferred out to another health institution. Treatment center and year of enrollment were significantly associated with treatment success.ConclusionYear of enrollment and treatment center were significantly associated with treatment success. Although the overall treatment success obtained in this study is in line with the World Health Organization (WHO) target, continuous follow-up of patients with frequent supportive supervision during the course of treatment, and further investigate the cause for the observed difference in treatment success across treatment centers are recommended.     

Incidence and predictors of loss to follow-up among adult HIV-infected patients taking antiretroviral therapy at North Shewa zone public Hospitals,Northeast Ethiopia: A retrospective follow-up study

BackgroundPatients who are lost to follow-up while on treatment compromise their own health and the long-term success of antiretroviral therapy (ART) programs. Besides, loss to follow-up (LTFU) increases HIV-related morbidity and mortality. Therefore, this study aimed to determine the incidence of LTFU and its predictors among adult HIV positive patients on anti-retroviral therapy at North Shoa zone public hospitals, Northeast Ethiopia.MethodsA retrospective follow up study of 517 people living with HIV/AIDS and attending an ART clinic between 2015 and 2020 was conducted at North Shewa zone, public hospitals. Kaplan-Meier failure function together with log rank test was used to compare failure function. Multivariable Cox proportion hazards regression model was used to determine predictors of LTFU.ResultThe incidence density rate of lost to follow up among HIV positive adult on ART was found to be 8.9 per 100 adult years observation (95%CI; 7.45, 10.68). In multivariable cox proportional regression analysis, WHO clinical stage-IV (AHR = 1.50; 95% CI: 1.08, 3.75), comorbidity disease (AHR = 0.54; 95% CI; 0.30, 0.97), body mass index less than 18kg/m2 (AHR = 1.60; 95% CI; 1.02, 2.51), cotrimoxazole preventive therapy (AHR = 1.57; 95% CI;1.09, 2.53), and a low CD4 count (AHR = 1.66; 95% CI; 1.29, 3.49) were found to be a significant predictors of lost to follow up.ConclusionThe current study showed that the incidence rate of loss to ART follow-up was high. Body mass index score less than 18kg/m2, advanced WHO clinical stage, CD4<200cell/mm³, had comorbidity disease, and cotrimoxazole therapy were a significant predictors of lost to ART follow up. Therefore, appropriate mitigation measures in the at-risk group need to be instigated to advance retention rate.     

Small-molecule inhibitors of the LEDGF/p75 binding site of integrase block HIV replication and modulate integrase multimerization

Targeting the HIV integrase (HIV IN) is a clinically validated approach for designing novel anti-HIV therapies. We have previously described the discovery of a novel class of integration inhibitors, 2-(quinolin-3-yl)acetic acid derivatives, blocking HIV replication at a low micromolar concentration through binding in the LEDGF/p75 binding pocket of HIV integrase, hence referred to as LEDGINs. Here we report the detailed characterization of their mode of action. The design of novel and more potent analogues with nanomolar activity enabled full virological evaluation and a profound mechanistic study. As allosteric inhibitors, LEDGINs bind to the LEDGF/p75 binding pocket in integrase, thereby blocking the interaction with LEDGF/p75 and interfering indirectly with the catalytic activity of integrase. Detailed mechanism-of-action studies reveal that the allosteric mode of inhibition is likely caused by an effect on HIV-1 integrase oligomerization. The multimodal inhibition by LEDGINs results in a block in HIV integration and in a replication deficiency of progeny virus. The allosteric nature of LEDGINs leads to synergy in combination with the clinically approved active site HIV IN strand transfer inhibitor (INSTI) raltegravir, and cross-resistance profiling proves the distinct mode of action of LEDGINs and INSTIs. The allosteric nature of inhibition and compatibility with INSTIs underline an interest in further (clinical) development of LEDGINs.     

Growing Ignorance of COVID-19 Preventive Measures in Ethiopia: Experts' Perspective on the Need of Effective Health Communication Strategies

Despite the recent surge of COVID-19 infections in Ethiopia, we are observing a profound ignorance of preventive measures by the general public and leaders at different levels. This is presenting considerable challenges in the effort to contain and control the pandemic. We believe that the current health communication approach implemented by the health authorities and media outlets need to be redesigned to bring a sustainable COVID-19 preventive behavior. The purpose of this perspective paper, therefore, is to stimulate discussions on effective health communication strategy to help the public persistently practice COVID-19 preventive measures over the long term. We undertook a series of discussions amongst the authors in order to synthesize individual viewpoints into ‘experts'' perspective’ driven by our daily observations and our expertise in the health service research. In light of this, we suggested that an effective health communication strategy need to address context specific situations to avoid temptation to ignore the ramifications of this very serious pandemic. This strategy includes trying to make sense of daily reported COVID-19 cases, being highly selective regarding sources of information, and being sensitive and responsive to religious and cultural factors. The media, health professionals, and leaders need to teach us how to live with the pandemic informed by robust scientific sources.     

Trends and Challenges in Access to Essential Medicines in Ethiopia and the Contributions of Local Pharmaceutical Production

Decades ago, the United Nations declared that access to essential medicines was a key element of universal human rights. Accordingly, member states have been striving to address this issue through strategic policies and programs. Strengthening local pharmaceutical production has been a pivotal strategy adopted by many developing countries including Ethiopia. The government of Ethiopia identified local pharmaceutical production as a key industrial sector and has been implementing a ten-years strategic plan to improve capabilities and attract investment. Such support is needed because local production could satisfy only 15 to 20% of the national demand, typically from a limited portfolio of medicines in conventional dosage forms. The increasing prevalence of chronic diseases has accentuated the need for a more sustainable supply to reduce reliance on imports and increase access to essential medicines. A full understanding of the structure, constraints and complexities of the Ethiopian pharmaceutical market structure is vital to direct effective policies, target most impactful investments and exploit opportunities for leapfrogging. Hence, the purpose of this review was to assess the trends and challenges in access to essential medicines and local pharmaceutical production in Ethiopia. Literature search through major databases and review of policy documents and performance reports from relevant sector institutions were made to extract information for the review.