Exposure History, Post-Exposure Prophylaxis Use, and Clinical Characteristics of Human Rabies Cases: A Twelve-Year Retrospective Review at a Tertiary Facility in Ghana.

BACKGROUND: Robust monitoring and reporting systems for rabies are lacking thus increasing the risk of underreporting. Highlighting the rabies cases brings to bear the needed urgent attention for more efforts at preventing and controlling the disease. OBJECTIVE: To describe the epidemiological characteristics of patients managed for clinical rabies at the largest referral facility in Ghana. METHODS: A retrospective single-center hospital-based chart review and data extraction were conducted for persons managed for clinical rabies infection at the Korle-Bu Teaching Hospital from January 2008 to December 2019. Data analysis was done using STATA. Descriptive statistics were used to summarize the epidemiological and clinical characteristics. Fisher's exact test, the Kruskal-Wallis test, and Spearman's correlation coefficient were used to explore significant associations. RESULTS: A total of 28 cases were recorded over the period of review. All of them died and most (68%) of them were males. Twenty-one percent of them were less than 15 years old. Their median age interquartile range (IQR) was 31 years (25.5 years) and the median incubation period for rabies (IQR) was 60 days (60 days). The source of rabies for cases was mainly dog bites. The vaccination status of all the animals could not be ascertained. Majority (80%) of the patients took neither anti-rabies vaccine nor immunoglobulin as post-exposure prophylaxis after the dog bite. The median time of admission before death (interquartile range) was 2 days (2 days). Majority (82%) of the cases were furious rabies. CONCLUSION: Attention should be directed at mass vaccination of dogs as dog bites are common. Ensuring availability and access to post-exposure prophylaxis (PEP) is also critical in averting rabies-related deaths.

CONTEXTE: Des systèmes de surveillance et de déclaration robustes pour la rage font défaut, augmentant ainsi le risque de sousdéclaration. Mettre en lumière les cas de rage suscite l'attention urgente nécessaire pour redoubler d'efforts dans la prévention et le contrôle de la maladie. OBJECTIF: Décrire les caractéristiques épidémiologiques des patients traités pour une rage clinique dans le plus grand établissement de référence au Ghana. MÉTHODES: Une revue rétrospective des dossiers médicaux et une extraction de données basées à l'hôpital ont été réalisées pour les personnes traitées pour une infection à la rage clinique à l'Hôpital d'Enseignement Korle-Bu de janvier 2008 à décembre 2019. L'analyse des données a été effectuée à l'aide de STATA. Des statistiques descriptives ont été utilisées pour résumer les caractéristiques épidémiologiques et cliniques. Le test exact de Fisher, le test de Kruskal-Wallis et le coefficient de corrélation de Spearman ont été utilisés pour explorer les associations significatives. RÉSULTATS: Un total de 28 cas ont été enregistrés sur la période examinée. Tous sont décédés et la plupart d'entre eux (68%) étaient des hommes. Vingt et un pour cent d'entre eux avaient moins de 15 ans. Leur âge médian (plage interquartile) était de 31 ans (25,5 ans) et la période d'incubation médiane de la rage (plage interquartile) était de 60 jours (60 jours). La principale source de rage pour les cas était principalement les morsures de chiens. Le statut vaccinal de tous les animaux n'a pas pu être déterminé. La majorité (80%) des patients n'ont pris ni vaccin antirabique ni immunoglobuline en prophylaxie post-exposition après la morsure de chien. Le délai médian d'admission avant le décès (plage interquartile) était de 2 jours (2 jours). La majorité (82%) des cas étaient atteints de rage furieuse. CONCLUSION: L'attention devrait être dirigée vers la vaccination de masse des chiens car les morsures de chien sont courantes. Assurer la disponibilité et l'accès à la prophylaxie post-exposition (PPE) est également crucial pour éviter les décès liés à la rage. MOTS-CLÉS: Rage, morsure de chien, post-exposition, prophylaxie, vaccination de masse.

Willingness to pay for kidney transplantation among chronic kidney disease patients in Ghana.

BACKGROUND: Kidney transplantation is the preferred treatment for patients with end stage renal disease. However, it is largely unavailable in many sub-Sahara African countries including Ghana. In Ghana, treatment for end stage renal disease including transplantation, is usually financed out-of-pocket. As efforts continue to be made to expand the kidney transplantation programme in Ghana, it remains unclear whether patients with Chronic Kidney Disease (CKD) would be willing to pay for a kidney transplant. AIM: The aim of the study was to assess CKD patients' willingness to pay for kidney transplantation as a treatment option for end stage renal disease in Ghana. METHODS: A facility based cross-sectional study conducted at the Renal Outpatient clinic and Dialysis Unit of Korle-Bu Teaching Hospital among 342 CKD patients 18 years and above including those receiving haemodialysis. A consecutive sampling approach was used to recruit patients. Structured questionnaires were administered to obtain information on demographic, socio-economic, knowledge about transplant, perception of transplantation and willingness to pay for transplant. In addition, the INSPIRIT questionnaire was used to assess patients' level of religiosity and spirituality. Contingent valuation method (CVM) method was used to assess willingness to pay (WTP) for kidney transplantation. Logistic regression model was used to determine the significant predictors of WTP. RESULTS: The average age of respondents was 50.2 ± 17.1 years with most (56.7% (194/342) being male. Overall, 90 out of the 342 study participants (26.3%, 95%CI: 21.7-31.3%) were willing to pay for a kidney transplant at the current going price (≥ $ 17,550) or more. The median amount participants were willing to pay below the current price was $986 (IQR: $197 -$1972). Among those willing to accept (67.3%, 230/342), 29.1% (67/230) were willing to pay for kidney transplant at the prevailing price. Wealth quintile, social support in terms of number of family friends one could talk to about personal issues and number of family members one can call on for help were the only factors identified to be significantly predictive of willingness to pay (p-value < 0.05). CONCLUSION: The overall willingness to pay for kidney transplant is low among chronic kidney disease patients attending Korle-Bu Teaching Hospital. Patients with higher socio-economic status and those with more family members one can call on for help were more likely to pay for kidney transplantation. The study's findings give policy makers an understanding of CKD patients circumstances regarding affordability of the medical management of CKD including kidney transplantation. This can help develop pricing models to attain an ideal poise between a cost effective but sustainable kidney transplant programme and improve patient access to this ultimate treatment option.

Knowledge and Willingness to Donate Kidneys for Transplantation in Ghana: A Cross-Sectional Survey.

BACKGROUND: The main treatment modalities for chronic kidney disease (CKD) are dialysis and kidney transplantation. While kidney transplantation provides better survival and quality of life outcomes, it is a new treatment option in Ghana. Finding kidney donors for transplant may be a major challenge due to varied views of the public. METHODS: This cross-sectional study was carried out in 5 purposively selected communities in the Greater Accra region in Ghana. Structured questionnaires and standardized instruments were used to assess sociodemographic characteristics, spirituality, and perception of kidney transplantation. RESULTS: The mean age of the 480 participants was 29.60 ± 10.65 years. The proportion of men was 51%. The average score for knowledge of participants on kidney donation was 4.8 ± 2.6. The level of spirituality score was 25.4 ± 3.89. Approximately 48% (231/480) of participants were willing to donate a kidney while still alive. Willingness to donate when dead was 72% (344/480). Willingness to donate a kidney when dead was significantly lower among the participants in the older age groups. High level of knowledge about kidney transplantation, being employed, basic formal education, and never married were associated with willingness to donate kidney (P < .05). CONCLUSION: Our results suggest that participants have a low level of knowledge regarding kidney transplantation, while about two-thirds are willing to donate only after death. Continuous public education is key to raise public awareness of the need for kidney transplants. This will support the Ministry of Health in their efforts to institute a kidney transplant program in Ghana.

Predictors and outcome of systemic lupus erythematosus (SLE) admission rates in a large teaching hospital in sub-Saharan Africa.

Although it was previously believed that systemic lupus erythematosus was uncommon among Africans, it has become increasingly apparent that the incidence is higher, and socioeconomic challenges such as physician shortages, poor medical facility access, and poor health literacy may worsen prognosis. This retrospective study examines characteristics and outcomes of hospitalized systemic lupus erythematosus patients over a two-year period and serves as a baseline for comparison for future studies to examine the outcomes with the provision of more dedicated care. There were 51 patient admissions over a two-year period, with a mean duration from start of illness to admission of approximately two years. Duration of admission ranged from one to 140 days with a mean period of 26.12 days (SD ± 26.6). There were 22 deaths (43.1% of admissions), which were mainly due to infections and renal complications. Factors associated with risk of death in regression analysis were: infections, fever, disease flare, musculoskeletal involvement, amenorrhea, depression, a clinical finding of hepatomegaly, and chest infection. Understanding the effect and outcome of systemic lupus erythematosus across different countries can elucidate the role of genetic, environmental, and other causative factors in the progression of the disease.

Causes of Death in Hospitalized HIV Patients in the Early Anti-Retroviral Therapy Era.

OBJECTIVE: To establish the cause(s) of death among persons with HIV and AIDS admitted to the Fevers Unit of the Korle-Bu Teaching Hospital (KBTH) in 2007 and to determine whether they were AIDS-related in the era of availability of HAART. METHOD: Retrospective chart review of all deaths that occurred in the year 2007 among inpatients with HIV infection. Cause of Death (COD) was established with post mortem diagnosis, where not available ICD-10 was reviewed independently by two physicians experienced in HIV medicine and a consensus reached as to the most likely COD. RESULTS: In the year under review, 215 (97%) of the 221 adult deaths studied were caused by AIDS and HIV-associated illnesses. Of these, 123 (55.7%) were due to an AIDS-defining illness as described in CDC Category 3 or WHO stage 4. Infections accounted for most of the deaths 158 (71.5%), many of them opportunistic 82 (51.8%). Tuberculosis was the commonest COD. Clinical diagnosis of TB was accurate in 54% of deaths, but was not validated by autopsy in 36% of deaths. There were few deaths (14.5%) in patients on HAART. CONCLUSION: In a developing country like Ghana where HAART was still not fully accessible, AIDS-related events remained the major causes of death in persons living with HIV. Total scale-up of the ART programme with continuous availability of antiretrovirals is therefore imperative to reduce deaths from AIDS and HIV associated illnesses. There is need for interventions for early diagnosis as well as reduction in late presentation and also better diagnostic tools for tuberculosis.

Solution structure of the catalytic domain of human collagenase-3 (MMP-13) complexed to a potent non-peptidic sulfonamide inhibitor: binding comparison with stromelysin-1 and collagenase-1.

The full three-dimensional structure of the catalytic domain of human collagenase-3 (MMP-13) complexed to a potent, sulfonamide hydroxamic acid inhibitor (CGS 27023) has been determined by NMR spectroscopy. The results reveal a core domain for the protein consisting of three alpha-helices and five beta-sheet strands with an overall tertiary fold similar to the catalytic domains of other matrix metalloproteinase family members. The S1' pocket, which is the major site of hydrophobic binding interaction, was found to be a wide cleft spanning the length of the protein and presenting facile opportunity for inhibitor extension deep into the pocket. Comparison with the reported X-ray structure of collagenase-3 showed evidence of flexibility for the loop region flanking the S1' pocket in both NMR and X-ray data. This flexibility was corroborated by NMR dynamics studies. Inhibitor binding placed the methoxy phenyl ring in the S1' pocket with the remainder of the molecule primarily solvent-exposed. The binding mode for this inhibitor was found to be similar with respect to stromelysin-1 and collagenase-1; however, subtle comparative differences in the interactions between inhibitor and enzyme were observed for the three MMPs that were consistent with their respective binding potencies.

Design and synthesis of thiol containing inhibitors of matrix metalloproteinases.

A series of thiol containing derivatives was prepared. Several of these compounds were found to inhibit matrix metalloproteinases 1, 3, and 9 with selectivity towards 3 and 9. Compounds 15, 20, and 22 were administered to rats orally at 75 mumol/kg. Drug levels of compounds 20 and 22 in the plasma were found to exceed the IC50 values for MMP 3 and 9 four hours after administration.

Inhibition of interleukin-1alpha-induced cartilage oligomeric matrix protein degradation in bovine articular cartilage by matrix metalloproteinase inhibitors: potential role for matrix metalloproteinases in the generation of cartilage oligomeric matrix protein fragments in arthritic synovial fluid.

OBJECTIVE: To determine whether matrix metalloproteinases (MMPs) degrade cartilage oligomeric matrix protein (COMP) to produce fragments similar to those found in synovial fluid (SF) from patients with arthritis. METHODS: COMP fragments were generated in vitro by treating (a) bovine articular cartilage with interleukin-1alpha (IL-1alpha), (b) purified bovine COMP with MMPs, and (c) articular cartilage with MMPs. The fragments generated in each case were analyzed by Western blot, using an antibody to the C-terminal heptadecapeptide of COMP. RESULTS: IL-1alpha stimulation of cartilage resulted in a fragmentation of COMP, which was inhibited by MMP inhibitors CGS 27023A and BB-94. Isolated, recombinant MMPs rapidly degraded purified COMP, as well as COMP residing in cartilage. Several COMP fragments produced in vitro had similar electrophoretic mobility to those in SF of patients with arthritis. CONCLUSION: MMPs may contribute to the COMP fragments found in vivo. Quantitation of MMP-specific fragments may be useful in the evaluation of MMP inhibitors in patients with arthritis.

Solution structure of the catalytic domain of human stromelysin-1 complexed to a potent, nonpeptidic inhibitor.

The full three-dimensional structure of the catalytic domain of human stromelysin-1 (SCD) complexed to a novel and potent, nonpeptidic inhibitor has been determined by nuclear magnetic resonance spectroscopy (NMR). To accurately mimic assay conditions, the structure was obtained in Tris buffer at pH 6.8 and without the presence of organic solvent. The results showed that the major site of enzyme-inhibitor interaction occurs in the S1' pocket whereas portions of the inhibitor that occupy the shallow S2' and S1 pockets remained primarily solvent exposed. Because this relatively small inhibitor could not deeply penetrate stromelysin's long narrow hydrophobic S1' pocket, the enzyme was found to adopt a dramatic fold in the loop region spanning residues 221-231, allowing occupation of the solvent-accessible S1' channel by the enzyme itself. This remarkable conformational fold at the enzyme binding site resulted in constriction of the S1' loop region about the inhibitor. Examination of the tertiary structure of the stromelysin-inhibitor complex revealed few hydrogen-bonding or hydrophobic interactions between the inhibitor and enzyme that can contribute to overall binding energy; hence the resultant compact structure may in part account for the relatively high potency exhibited by this inhibitor.

Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits.

Structure-activity relationships of a lead hydroxamic acid inhibitor of recombinant human stromelysin were systematically defined by taking advantage of a concise synthesis that allowed diverse functionality to be explored at each position in a template. An ex vivo rat model and an in vivo rabbit model of stromelysin-induced cartilage degradation were used to further optimize these analogs for oral activity and duration of action. The culmination of these modifications resulted in CGS 27023A, a potent, orally active stromelysin inhibitor that blocks the erosion of cartilage matrix.

Bioactive conformation of stromelysin inhibitors determined by transferred nuclear Overhauser effects.

The transferred nuclear Overhauser effect has been used to determine the biologically active conformations of two stromelysin inhibitors. Both inhibitors used in this study were hydroxamic acids generated via chemical synthesis. These structures, representing the conformation of each inhibitor bound to stromelysin, superimposed with excellent agreement. The study also provided information on the shape and orientation of the S2' and S1' pockets of the enzyme relative to thermolysin. Comparisons were made between stromelysin and thermolysin inhibitors to critically examine thermolysin as a template for stromelysin-inhibitor design. The enzyme-bound conformations of these stromelysin inhibitors were determined for use as a template in conformationally restricted drug design.

Biochemical and molecular characterization of stromelysin synthesized by human osteoarthritic chondrocytes stimulated with recombinant human interleukin-1.

OBJECTIVE: To study the biochemical and molecular characterization of stromelysin synthesized by human chondrocytes derived from osteofemoral heads. METHODS: First passage human chondrocyte cultures were incubated with recombinant human interleukin-1 alpha or recombinant human interleukin-1 beta (10-1000 pg ml-1) for either 24 or 48 hrs. The medium compartment of these cultures was assayed for stromelysin activity. Total cellular RNA was used to determine: (i) the molecular structure of the stromelysin synthesized by these cells; and (ii) whether or not these chondrocytes expressed the Type II procollagen gene (COL2A1). RESULTS: Human osteoarthritic chondrocytes released into the medium on enzyme requiring tryspin activation that possessed Substance P (SP) cleaving activity. SP cleaving activity was completely inhibited by EDTA. Casein zymography showed lysis zones produced by trypsin-activated chondrocyte culture medium that co-migrated with casein lysis zones produced by recombinant human prostromelysin. The majority of SP cleaving activity was eluted from a Zn-Sepharose column with 0.25 M glycine. Enzyme activity eluted from Zn-Sepharose produced casein lysis zones which co-migrated with lysis zones produced by recombinant human prostromelysin. Immunoblotting revealed the presence of prostromelysin (M(r), 55-57 kDa) in the pooled chondrocyte culture media applied to Zn-Sepharose and in the 0.25 M glycine eluate. Trypsin-activation converted prostromelysin to a mature stromelysin form (M(r), 45-47 kDa). Polymerase chain reaction (PCR) amplification of human chondrocyte cDNA demonstrated COL2A1 transcripts. A PCR product of expected size (680 bp) was produced by amplification of chondrocyte cDNA using stromelysin-1 oligonucleotide primers. The cloned and sequenced PCR product showed 100% homology between the chondrocyte stromelysin-1 mRNA-derived cDNA and the stromelysin-1 mRNA-derived cDNA of cultured human synovial, gingival and skin fibroblasts. CONCLUSIONS: By several criteria, human osteoarthritic chondrocytes synthesized stromelysin which was biochemically and antigenically identical, and molecularly homologous with human fibroblast stromelysin-1. These results suggest that a quantitative imbalance between stromelysin-1 and endogenous stromelysin-1 inhibitors rather than the transcription of a new stromelysin gene is the mechanism underlying the increased proteoglycan degradation seen in osteoarthritic cartilage.

HIV-1 transactivator protein Tat induces proliferation and TGF beta expression in human articular chondrocytes.

The human immunodeficiency virus-1 (HIV-1) protein Tat binds to cell surface antigens and can regulate cellular responses. Tat has similar immunosuppressive effects as transforming growth factor-beta (TGF beta) and both inhibit lymphocyte proliferation. TGF beta is expressed by primary human articular chondrocytes and is their most potent growth factor. The present study analyzed the interactions of TGF beta and HIV Tat in the regulation of human articular chondrocytes. Synthetic or recombinant full-length Tat (1-86) induced chondrocyte proliferation and this was of similar magnitude as the response to TGF beta. Tat peptides that did not contain the RGD motif had similar chondrocyte stimulatory activity as full-length Tat. Among a series of Tat peptides, peptide 38-62 which contains the basic domain was the only one active, suggesting that this region is responsible for the effects on chondrocyte proliferation. Full-length Tat and peptide 38-62 synergized with TGF beta and induced proliferative responses that were greater than those obtained with any combination of the known chondrocyte growth factors. Further characterization of the interactions between Tat and TGF beta showed that Tat increased synthesis and TGF beta activity and TGF beta 1 mRNA levels. The stimulatory effects of Tat and peptide 38-62 on chondrocyte proliferation were reduced by neutralizing antibodies to TGF beta and by TGF beta antisense oligonucleotides. These results identify a virally encoded protein and a synthetic peptide derived from it as novel and potent chondrocyte growth stimuli which act at least in part through the induction of TGF beta.

Interleukin-11, an inducible cytokine in human articular chondrocytes and synoviocytes, stimulates the production of the tissue inhibitor of metalloproteinases.

This study on the regulation of interleukin (IL)-11 expression in human connective tissue cells shows that IL-11 expression is not restricted to cells of hematopoietic origin but can also be induced in articular chondrocytes and synoviocytes. IL-11 mRNA was induced in chondrocytes in response to transforming growth factor (TGF)-beta 1 and IL-1 beta. Stimulation with IL-6 or growth factors, such as basic fibroblast growth factor, leukemia inhibitory factor, and platelet-derived growth factor-AA, had only weak or no detectable effects. Activation of protein kinase C by phorbol esters and inhibition of protein synthesis by cyclohexamide increased IL-11 transcripts, whereas calcium ionophore A23817 or dibutyryl cyclic AMP had no effect. Immunoprecipitations revealed the synthesis of IL-11 protein in response to TGF-beta 1, IL-1 beta, as well as phorbol 12-myristate 13-acetate, and a synergistic action of TGF-beta 1 and IL-1 beta was observed. Similar findings on IL-11 expression were made in synoviocytes. Analysis of effects on cell function showed that IL-11 stimulated the production of the tissue inhibitor of metalloproteinases in chondrocytes and synoviocytes but did not affect chondrocyte proliferation or increase stromelysin activity. These results suggest that IL-11 does not contribute to connective tissue degradation but conversely induces protective effects in joint tissue.

A stromelysin assay for the assessment of metalloprotease inhibitors on human aggregated proteoglycan.

Human proteoglycan was aggregated to an immobilized hyaluronan solid phase on a 96-well ELISA plate. This complex was then degraded by recombinant human stromelysin. The remaining proteoglycan fragments were detected using a monoclonal antibody probe directed against the chondroitin sulfate (CS) region of the core protein. Stromelysin degraded the aggregate in a time and dose dependent manner as reflected by the loss of the CS epitope. Assay sensitivity was 0.125 U/well with total loss of the CS epitope occurring at 4 U/well. o-phenanthroline (IC50 = 52 microM) and U24522 (IC50 = 9 microM) inhibited degradation, while phosphoramidon did not. Serine and cysteine protease inhibitors had no effect. A comparative analysis of this assay with a reference method, substance P assay, gave similar inhibitor profiles. The use of aggregated human proteoglycan (native conformation) as a substrate, may better reflect how stromelysin inhibitors behave in the presence of complex substrates such as cartilage matrix.