Treatment of Infections in Young Infants in Low- and Middle-Income Countries:A Systematic Review and Meta-analysis of Frontline Health Worker Diagnosis and Antibiotic Access

BACKGROUND: Inadequate illness recognition and access to antibiotics contribute to high case fatality from infections in young infants (<2 months) in low- and middle-income countries (LMICs). We aimed to address three questions regarding access to treatment for young infant infections in LMICs: (1) Can frontline health workers accurately diagnose possible bacterial infection (pBI)?; (2) How available and affordable are antibiotics?; (3) How often are antibiotics procured without a prescription? METHODS AND FINDINGS: We searched PubMed, Embase, WHO/Health Action International (HAI), databases, service provision assessments (SPAs), Demographic and Health Surveys, Multiple Indicator Cluster Surveys, and grey literature with no date restriction until May 2014. Data were identified from 37 published studies, 46 HAI national surveys, and eight SPAs. For study question 1, meta-analysis showed that clinical sign-based algorithms predicted bacterial infection in young infants with high sensitivity (87%, 95% CI 82%-91%) and lower specificity (62%, 95% CI 48%-75%) (six studies, n = 14,254). Frontline health workers diagnosed pBI in young infants with an average sensitivity of 82% (95% CI 76%-88%) and specificity of 69% (95% CI 54%-83%) (eight studies, n = 11,857) compared to physicians. For question 2, first-line injectable agents (ampicillin, gentamicin, and penicillin) had low variable availability in first-level health facilities in Africa and South Asia. Oral amoxicillin and cotrimoxazole were widely available at low cost in most regions. For question 3, no studies on young infants were identified, however 25% of pediatric antibiotic purchases in LMICs were obtained without a prescription (11 studies, 95% CI 18%-34%), with lower rates among infants <1 year. Study limitations included potential selection bias and lack of neonatal-specific data. CONCLUSIONS: Trained frontline health workers may screen for pBI in young infants with relatively high sensitivity and lower specificity. Availability of first-line injectable antibiotics appears low in many health facilities in Africa and Asia. Improved data and advocacy are needed to increase the availability and appropriate utilization of antibiotics for young infant infections in LMICs. REVIEW REGISTRATION: PROSPERO International prospective register of systematic reviews (CRD42013004586). Please see later in the article for the Editors' Summary

Effects of pentoxifylline, 7-nitroindazole, and imipramine on tumor necrosis factor-&alpha; and indoleamine 2,3-dioxygenase enzyme activity in the hippocampus and frontal cortex of chronic mild-stress-exposed rats

Bassim MSA Mohamed,1,6 Sawsan Aboul-Fotouh,2,5 Eman A Ibrahim,3 Hanan Shehata,4 Amal A Mansour,4 Nemat AZ Yassin,1 Wafaa El-Eraky,1 Ahmed M Abdel-Tawab2,5 1Department of Pharmacology, National Research Centre, Cairo, Egypt; 2Department of Pharmacology, 3Department of Pathology, 4Department of Medical Biochemistry and Molecular Biology, 5Clinical Pharmacology Unit, Ain Shams University, Cairo, Egypt; 6Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, Canada Objectives: This study aimed to investigate the role of tumor necrosis factor (TNF)-&alpha; and the neuronal nitric oxide synthase enzyme in dysregulation of indoleamine 2,3-dioxygenase (IDO) enzyme, and hence serotonin availability in chronic mild stress (CMS), an animal model of depression. Methods: Rats were divided into five groups: two control and CMS-exposed for 6 weeks, and another three groups exposed to CMS and administered pentoxifylline 50 mg/kg/day intraperitoneally, 7-nitroindazole 40 mg/kg/day subcutaneously, or imipramine 20 mg/kg/day intraperitoneally for the previous 3 CMS weeks. Rats were assessed for neurochemical and immunohistochemical abnormalities. Results: Pentoxifylline-, 7-nitroindazole-, and imipramine-treated rats showed amelioration of CMS-induced behavioral deficits that was accompanied by significant reduction in kynurenine/serotonin molar ratio and nitrates/nitrites in frontal cortex and hippocampus. In the pentoxifylline and 7-nitroindazole groups, serum TNF-&alpha; was reduced relative to the CMS group (18.54 &plusmn; 0.85 and 19.16 &plusmn; 1.54 vs 26.20 &plusmn; 1.83 pg/mL, respectively; P < 0.05). Exposure to CMS increased TNF-&alpha; and IDO immunohistochemical staining scores in both hippocampus and midbrain raphe nuclei. 7-Nitroindazole and pentoxifylline significantly (P < 0.05) reduced TNF-&alpha; immunostaining in hippocampus and raphe nuclei, with significant (P < 0.01) reduction of IDO immunostaining in raphe nuclei. Likewise, imipramine reduced TNF-&alpha; immunostaining (P < 0.05) in hippocampus. Conclusion: Neuronal nitric oxide synthase and TNF-&alpha; may play a concerted role in modulating IDO enzyme activity in CMS-exposed rats and provide additional evidence for possible alternative approaches to switch the neurobiological processes in depression. Keywords: chronic mild stress, TNF-&alpha;, kynurenine, serotonin, nNOS, immunohistochemistr

Antioxidant, Anti-Cancer Activity and Phytochemicals Profiling of <i>Kigelia pinnata</i> Fruits

Over the past few years, research studies on the therapeutic benefits of medicinal plants with potent antioxidant activity and few side effects have grown significantly. This has sparked interest in determining whether naturally occurring antioxidants could take the place of synthetic antioxidants, which are currently being constricted because of their toxic and carcinogenic properties. The identification and quantification of phytochemicals in the methanolic extract of Kigelia pinnata fruits was measured using gas chromatography–mass spectrometry (GC-MS) and ultra-high-performance liquid chromatography–mass spectrometry (UPLC-MS/MS) techniques. Additionally, the methanolic extract of fruits was used to determine antioxidant activity. Free radical-scavenging (DPPH) and ferric ion-reducing antioxidant power were measured using spectrophotometry, and total antioxidant capacity (TAC) was compared with two common antioxidants, vitamin C and α-tocopherol. Moreover, mature fruits have high DDPH, ferric ion-reducing antioxidant power and total antioxidant capacity. Furthermore, mature fruits have high levels of total phenolic, flavonoid, and tannin content; these compounds are thought to be the sources of the antioxidant activity. The major constituents of the methanolic extracts from the mature fruits of K. pinnata were found to be larixinic acid, 3,5-Dihydroxy-6-methyl-2,3-dihydro-4H-pyran-4-one (DMDP), and 5-Hydrxoymethylfurfural. We performed the elemental analysis of the whole fruit. Huh-7 (liver cancer), PANC-1 (pancreatic cancer), Colo-205 (colorectal cancer), HT-29 (colorectal cancer), SNU-16 (gastric carcinoma), SW620 (colorectal adenocarcinoma) and HCT116 (colon carcinoma) were tested in vitro for anticancer activity. Both methanolic and ethyl acetate extracts of mature fruits had a positive effect on all cancer cell lines as compared to the doxorubicin drug. In addition, the methanolic extracts of mature fruits showed more potent cytotoxic effects than the ethyl acetate extracts. Moreover, the most pronounced cytotoxic effects of the methanolic extract were detected in SW620 (colorectal adenocarcinoma), with an IC50 value of 6.79 μg/mL, SNU-16 (gastric carcinoma), with and IC50 value of 8.69 μg/ ml, and in PANC-1 (pancreatic cancer) with an IC50 value of 10.34 μg/mL. Moreover, the results show that the water, ethyl acetate and methanolic extracts of mature fruits have antioxidant capacity, ferric ion-reducing antioxidant power, DPPH scavenging activity and also anticancer activity. Therefore, the present study suggests that the phytochemical profiles of mature fruits of K. pinnata may be used as potential natural antioxidants and anti-cancer cell lines