Fungus-elicited metabolites from plants as an enriched source for new leishmanicidal agents: antifungal phenyl-phenalenone phytoalexins from the banana plant (Musa acuminata) target mitochondria of Leishmania donovani promastigotes

Two antifungal phenyl-phenalenone phytoalexins isolated from the banana plant (Musa acuminata) elicited with the fungus Fusarium oxysporum, together with a methoxy derivative of one of them and two epoxide precursors of their chemical synthesis, were tested for leishmanicidal activity on Leishmania donovani promastigotes and L. infantum amastigotes. Drugs inhibited proliferation of both forms of the parasite with a 50% lethal concentration range between 10.3 and 68.7 micro g/ml. Their lethal mechanism was found linked to the respiratory chain by a systematic approach, including electron microscopy, measurement of the oxygen consumption rate on digitonin-permeabilized promastigotes, and enzymatic assays on a mitochondrial enriched fraction. Whereas the whole set of compounds inhibited the activity of fumarate reductase in the mitochondrial fraction (50% effective concentration [EC(50)] between 33.3 and 78.8 micro g/ml) and on purified enzyme (EC(50) = 53.3 to 115 micro g/ml), inhibition for succinate dehydrogenase was only observed for the two phytoalexins with the highest leishmanicidal activity: anigorufone and its natural analogue 2-methoxy-9-phenyl-phenalen-1-one (EC(50) = 33.5 and 59.6 micro g/ml, respectively). These results provided a new structural motif, phenyl-phenalenone, as a new lead for leishmanicidal activity, and support the use of plant extracts enriched in antifungal phytoalexins, synthesized under fungal challenge, as a more rational and effective strategy to screen for new plant leishmanicidal drugs.     

Emergency axillary brachial plexus block in a patient allergic to atropine

Peripheral nerve blocks can provide a valid alternative for anesthetizing patients with allergy to drugs such as atropine that are often used for general anesthesia. We report the case of a 7-year-old boy (physical status ASA II, weight 28 Kg). Relevant medical history included generalized skin rash and breathing difficulties due to bronchospasm after administration of atropine eyedrops. The boy had never undergone skin testing for allergy. With a diagnosis of distal metaphyseal fracture of the right radius, he was proposed for urgent closed reduction and osteosynthesis of the lesion. After premedication with midazolam, an axillary brachial plexus block with 0.4 mL x Kg(-1) of 1% mepivacaine was performed with the aid of a nerve stimulator. The intervention was uneventful and the patient was free of pain during and after the procedure. Axillary brachial plexus block anesthesia in this pediatric patient was easy to perform, safe, and effective. It provided satisfactory conditions for surgery and made it possible to avoid administering drugs with vagotonic effects that are often used for general anesthesia and require the use of atropine.     

Pancreatic insufficiency in patients with chronic graft-versus-host disease

Diarrhea is a difficult diagnostic problem in patients with chronic graft-versus-host disease (cGVHD) because there are many causes of it. Although intestinal involvement has been reported in early studies of untreated cGVHD, this is now a very rare presentation of the disease. In addition to other etiologies, pancreatic insufficiency should also be considered in patients with cGVHD who demonstrate malabsorption. The pathogenesis of pancreatic insufficiency in these patients is unknown. Pancreatic enzyme supplements can be very effective in treating this rare condition.     

Physical partner abuse during pregnancy: a risk factor for low birth weight in Nicaragua

OBJECTIVE: To assess whether being physically abused during pregnancy increases the risk of a low birth weight (LBW) infant. METHODS: We conducted a hospital-based case-control study in León, Nicaragua. Cases consisted of 101 newborns with a birth weight under 2500 g, and for each case two controls with a birth weight over 2500 g were selected randomly from infants born the same day. Anthropometry of newborns was done immediately after birth, and background information and data on experiences of violence and potential confounders were obtained through private interviews with mothers. Crude and adjusted odds ratios (ORs) and population-attributable proportion were calculated for exposure to partner abuse in relation to LBW. Multivariate logistic regression analysis was used to control for potential confounding. RESULTS: Seventy-five percent of LBW newborns (cases) were small for gestational age and 40% were preterm. Twenty-two percent of the mothers of LBW infants had experienced physical abuse during pregnancy by their intimate partners compared with 5% of controls. Low birth weight was associated with physical partner abuse even after adjustment for age, parity, smoking, and socioeconomic status (OR 3.9; 95% confidence interval 1.7, 9.3). Given a causal interpretation of the association, about 16% of the LBW in the infant population could be attributed to physical abuse by a partner in pregnancy. CONCLUSION: Physical abuse by a partner during pregnancy is an independent risk factor for LBW.     

Arterial thrombosis resulting in amputation in a child with poorly controlled type 1 diabetes and heterozygous Factor V Leiden mutation

Children with venous thromboses have greater than 50% likelihood of carrying a genetic thrombophilic defect, and two-thirds of such defects will be a mutation in the factor V gene referred to as Factor V Leiden. Poorly controlled type 1 diabetes mellitus (T1DM) increases the risk for thrombosis. We report a massive arterial thrombosis resulting in unilateral below-the-knee amputation in a 12-yr-old white girl with a heterozygous Factor V Leiden mutation and a 2-yr history of poorly controlled T1DM. This report emphasizes the need to test for thrombophilic defects in children with thrombosis or with a family history of thrombosis. Good metabolic control is especially important in children with T1DM and known thrombophilic defects.     

Evaluation of Acanthamoeba Myosin-IC as a Potential Therapeutic Target

Members of the genus Acanthamoeba are facultative pathogens of humans, causing a sight-threatening keratitis and a fatal encephalitis. We have targeted myosin-IC by using small interfering RNA (siRNA) silencing as a therapeutic approach, since it is known that the function of this protein is vital for the amoeba. In this work, specific siRNAs against the Acanthamoeba myosin-IC gene were developed. Treated and control amoebae were cultured in growth and encystment media to evaluate the induced effects after myosin-IC gene knockdown, as we have anticipated that cyst formation may be impaired. The effects of myosin-IC gene silencing were inhibition of cyst formation, inhibition of completion of cytokinesis, inhibition of osmoregulation under osmotic stress conditions, and death of the amoebae. The finding that myosin-IC silencing caused incompletion of cytokinesis is in agreement with earlier suggestions that the protein plays a role in cell locomotion, which is necessary to pull daughter cells apart after mitosis in a process known as “traction-mediated cytokinesis”. We conclude that myosin-IC is a very promising potential drug target for the development of much-needed antiamoebal drugs and that it should be further exploited for Acanthamoeba therapy.     

The isolation of Balamuthia mandrillaris from environmental sources from Peru

Balamuthia mandrillaris is an opportunistic free-living amoeba that has been reported to cause skin lesions and the fatal Balamuthia amoebic encephalitis (BAE) in humans and other animals. Currently, around 200 human BAE cases have been reported worldwide, although this number is considered to be underestimated. The highest number of BAE cases has been reported in the American continent, mainly in the southwest of the USA. Peru seems to be another hotspot for BAE with around 55 human cases having been identified, usually involving cutaneous infection, especially lesions in the central face area. The isolation of Balamuthia from environmental sources has been reported on only three prior occasions, twice from Californian soils and once from dust in Iran and so it seems that this amoeba is relatively rarely encountered in samples from the environment. We investigated that possibility of finding the amoebae in soil samples from different regions where clinical cases have been reported in Peru. Twenty-one samples were cultured in non-nutrient agar plates and were checked for the presence of B. mandrillaris-like trophozoites and/or cysts. Those samples that were positive for these amoebae by microscopic criteria were then confirmed by PCR amplification and DNA sequencing of the mitochondrial 16S rDNA gene of B. mandrillaris. We have detected the presence of B. mandrillaris in four samples collected in the regions of Piura (3) and Lima (1) where infection cases have been previously reported. We hypothesize that B. mandrillaris is present in Peru in soil and dust which therefore constitutes a source of the infection for the BAE cases previously reported in this country. Further studies should be carried out in the area to confirm the generality of this finding.     

Effect of postoperative physical training on activity after curative surgery for non-small cell lung cancer: a multicentre randomised controlled trial

Objective

To evaluate the effect of a combined hospital plus home exercise programme following curative surgery for non-small cell lung cancer (NSCLC).

Design

Randomised controlled trial.

Setting

Teaching hospital.

Participants

One hundred and thirty-one subjects with NSCLC admitted for curative surgery.

Interventions

Participants were randomised to usual care or a hospital plus home exercise programme.

Outcomes

The primary outcome was the between-group difference in physical activity 4 weeks after surgery. Secondary outcomes were the difference in quadriceps strength, exercise tolerance and quality of life [Short Form-36 (SF-36) and European Organisation for Research and Treatment of Cancer (EORTC) QLQ-LC13] from pre-operatively (baseline) to 4 weeks after surgery.

Results

The participants (n = 131) had a mean age of 68 [standard deviation (SD) 11] years and mean forced expiratory volume in 1 second of 2.4 (SD 1.1) l. There were no significant differences in physical activity between the groups 4 weeks after surgery [mean difference adjusted for baseline 12 minutes/day, 95% confidence interval (CI) −20.2 to 44.1]. In addition, there were no significant differences in total SF-36 or EORTC QLQ-LC13 scores from baseline to 4 weeks after surgery. Both groups had recovered their pre-operative walking distance 4 weeks after surgery, and there were no differences between the groups (mean difference in Incremental Shuttle Walk Test from baseline to 4 weeks after surgery (−26 m, 95% CI −94.2 to 42.3).

Conclusions

A hospital plus home exercise programme showed little benefit in unselected patients with NSCLC following surgery. Regardless of group allocation, the patients had recovered their pre-operative exercise tolerance levels by 4 weeks after surgery.