Novel Selective Inhibitor of Leishmania (Leishmania) amazonensis Arginase

Arginase is a glycosomal enzyme in Leishmania that is involved in polyamine and trypanothione biosynthesis. The central role of arginase in Leishmania (Leishmania) amazonensis was demonstrated by the generation of two mutants: one with an arginase lacking the glycosomal addressing signal and one in which the arginase‐coding gene was knocked out. Both of these mutants exhibited decreased infectivity. Thus, arginase seems to be a potential drug target for Leishmania treatment. In an attempt to search for arginase inhibitors, 29 derivatives of the [1,2,4]triazolo[1,5‐a]pyrimidine system were tested against Leishmania (Leishmania) amazonensis arginase in vitro. The [1,2,4]triazolo[1,5‐a]pyrimidine scaffold containing R₁ = CF₃ exhibited greater activity against the arginase rather than when the substituent R₁ = CH₃ in the 2‐position. The novel compound 2‐(5‐methyl‐2‐(trifluoromethyl)‐[1,2,4]triazolo[1,5‐a]pyrimidin‐7‐yl)hydrazinecarbothioamide (30) was the most potent, inhibiting arginase by a non‐competitive mechanism, with the Ki and IC₅₀ values for arginase inhibition estimated to be 17 ± 1 μm and 16.5 ± 0.5 μm , respectively. These results can guide the development of new drugs against leishmaniasis based on [1,2,4]triazolo[1,5‐a]pyrimidine derivatives targeting the arginase enzyme.     

Influence of misoprostol,a synthetic prostaglandin E1 analog,on the healing of colonic anastomoses in rats

PURPOSE: This study was designed to examine the influence of misoprostol, a synthetic prostaglandin E ₁ analog, on the healing of colonic anastomoses in rats, with particular regard to changes in collagen levels at the site of the anastomoses and their histopathologic aspects. METHODS: Sixty rats were submitted to resection and anastomosis of the colon, and divided at random into two groups. The test group received misoprostol intragastrically (200 μg/kg body weight), twice daily, from the day of operation until sacrifice. Controls received 0.9 percent NaCl. The animals were sacrificed on the third, seventh, or fourteenth postoperative day, and the results of the histopathologic analyses and hydroxyproline concentrations were compared. RESULTS: Our results show that misoprostol administration increased the hydroxyproline concentration on the fourteenth postoperative day without interfering in the inflammatory response (P<0.05).CONCLUSION: Misoprostol interferes with the balance between the synthesis and degradation of collagen, resulting in an elevation of collagen levels by the fourteenth postoperative day without influencing the inflammatory response.     

Transjugular liver biopsy: histological diagnosis success comparing the trucut to the modified aspiration Ross needle

BACKGROUND: Transjugular liver biopsy is an alternative procedure for patients who present contraindications to standard percutaneous procedure. AIM: To compare the rate of histological diagnosis obtained on transjugular liver biopsy with an automated trucut needle and with a modified Ross needle. PATIENTS / METHOD: Eighty-five patients with suspicion of chronic liver diseases and presenting contraindications for percutaneous liver biopsy (coagulopathy, massive ascites, morbid obesity, or chronic renal problems) were submitted to 89 transjugular liver biopsies between March 1994 and April 2001 at "Hospital S?o José, Irmandade da Santa Casa de Misercórdia", Porto Alegre, RS, Brazil. Thirty-five patients underwent 36 biopsies with an automated trucut needle, and 50 patients underwent 53 biopsies with a modified Ross needle. RESULTS: Histological diagnosis was reached in 32/35 subjects submitted to transjugular liver biopsy with the trucut needle (91%) and in 35/50 (70%) submitted to biopsy with the modified Ross needle. Specimens obtained with the trucut needle were significantly larger and less fragmented than those obtained with the Ross needle. CONCLUSION: Transjugular liver biopsy with the automated trucut needle allowed a higher rate of histological diagnosis when compared to the modified Ross needle in patients with suspicion of chronic liver diseases.     

Effect of granulocyte inhibitory factor on granuloma formation in mice infected with Schistosoma mansoni

Mononuclear cells from patients infected with Schistosoma mansoni were able to produce a soluble material that inhibited the granulocyte cytotoxicity against schistosomula in a complement-dependent killing assay. This granulocyte inhibitory factor (GIF) appears to exist preformed in the mononuclear cells of patients, but it can also be released in the supernatant after antigenic stimulation (lymphokine-like). Only T lymphocytes were able to mediate the inhibition of granulocyte cytotoxicity against schistosomula in vitro. The treatment of S. mansoni-infected mice with GIF induced a significant decrease in the liver granuloma size.     

Skills of general health workers in primary eye care in Kenya,Malawi and Tanzania

Background

Primary eye care (PEC) in sub-Saharan Africa usually means the diagnosis, treatment, and referral of eye conditions at the most basic level of the health system by primary health care workers (PHCWs), who receive minimal training in eye care as part of their curricula. We undertook this study with the aim to evaluate basic PEC knowledge and ophthalmologic skills of PHCWs, as well as the factors associated with these in selected districts in Kenya, Malawi, and Tanzania.

Methods

A standardized (26 items) questionnaire was administered to PHCWs in all primary health care (PHC) facilities of 2 districts in each country. Demographic information was collected and an examination aimed to measure competency in 5 key areas (recognition and management of advanced cataract, conjunctivitis, presbyopia, and severe trauma plus demonstrated ability to measure visual acuity) was administered.

Results

Three-hundred-forty-three PHCWs were enrolled (100, 107, and 136 in Tanzania, Kenya, and Malawi, respectively). The competency scores of PHCW varied by area, with 55.7%, 61.2%, 31.2%, and 66.1% scoring at the competency level in advanced cataract, conjunctivitis, presbyopia, and trauma, respectively. Only 8.2% could measure visual acuity. Combining all scores, only 9 (2.6%) demonstrated competence in all areas.

Conclusion

The current skills of health workers in PEC are low, with a large per cent below the basic competency level. There is an urgent need to reconsider the expectations of PEC and the content of training.

     

Task shifting for cataract surgery in eastern Africa: productivity and attrition of non-physician cataract surgeons in Kenya,Malawi and Tanzania

Background

This project examined the surgical productivity and attrition of non-physician cataract surgeons (NPCSs) in Tanzania, Malawi, and Kenya.

Methods

Baseline (2008-9) data on training, support, and productivity (annual cataract surgery rate) were collected from officially trained NPCSs using mailed questionnaires followed by telephone interviews. Telephone interviews were used to collect follow-up data annually on productivity and semi-annually on attrition. A detailed telephone interview was conducted if a surgeon left his/her post. Data were entered into and analysed using STATA.

Results

Among the 135 NPCSs, 129 were enrolled in the study (Kenya 88, Tanzania 38, and Malawi 3) mean age 42 years; average time since completing training 6.6 years. Employment was in District 44%, Regional 24% or mission/ private 32% hospitals. Small incision cataract surgery was practiced by 38% of the NPCSs. The mean cataract surgery rate was 188/year, median 76 (range 0-1700). For 39 (31%) NPCSs their surgical rate was more than 200/year. Approximately 22% in Kenya and 25% in Tanzania had years where the cataract surgical rate was zero. About 11% of the surgeons had no support staff.Factors significantly associated with increased productivity were: 1) located at a regional or private/mission hospital compared to a district hospital (OR = 8.26; 95 % CI 2.89 – 23.81); 2) 3 or more nurses in the eye unit (OR = 8.69; 95% CI 3.27-23.15); 3) 3 or more cataract surgical sets (OR = 3.26; 95% CI 1.48-7.16); 4) a separate eye theatre (OR = 5.41; 95% CI 2.15-13.65); 5) a surgical outreach program (OR = 4.44; 95% CI 1.88-10.52); and 6) providing transport for patients to hospital (OR = 6.39; 95% CI 2.62-15.59). The associations were similar for baseline and follow-up assessments. Attrition during the 3 years occurred in 13 surgeons (10.3%) and was due to retirement or promotion to administration.

Conclusions

High quality training is necessary but not sufficient to result in cataract surgical activity that meets population needs and maintains surgical skill. Needed are supporting institutions and staff, functioning equipment and programs to recruit and transport patients.

     

Towards a molecular characterization of autism spectrum disorders: an exome sequencing and systems approach

The hypothetical ‘AXAS'' gene network model that profiles functional patterns of heterogeneous DNA variants overrepresented in autism spectrum disorder (ASD), X-linked intellectual disability, attention deficit and hyperactivity disorder and schizophrenia was used in this current study to analyze whole exome sequencing data from an Australian ASD cohort. An optimized DNA variant filtering pipeline was used to identify loss-of-function DNA variations. Inherited variants from parents with a broader autism phenotype and de novo variants were found to be significantly associated with ASD. Gene ontology analysis revealed that putative rare causal variants cluster in key neurobiological processes and are overrepresented in functions involving neuronal development, signal transduction and synapse development including the neurexin trans-synaptic complex. We also show how a complex gene network model can be used to fine map combinations of inherited and de novo variations in families with ASD that converge in the L1CAM pathway. Our results provide an important step forward in the molecular characterization of ASD with potential for developing a tool to analyze the pathogenesis of individual affected families.