Combined 1-Deoxynojirimycin and Ibuprofen Treatment Decreases Microglial Activation, Phagocytosis and Dopaminergic Degeneration in MPTP-Treated Mice.

Inflammation is a predominant aspect of neurodegenerative diseases and experimental studies performed in animal models of Parkinson's disease (PD) suggesting that a sustained neuroinflammation exacerbates the nigrostriatal degeneration pathway. The central role of microglia in neuroinflammation has been studied as a target for potential neuroprotective drugs for PD, for example nonsteroidal anti-inflammatory drugs (NSAIDs) and matrix metalloproteinases (MMP) inhibitors that regulates microglial activation and migration. The aim of this study was to investigate the neuroprotective response of the iminosugar 1-deoxynojirimycin (1-DNJ) and compare its effect with a combined treatment with ibuprofen. MPTP-treated mice were orally dosed with ibuprofen and/or 1-DNJ 1. Open-field test was used to evaluate behavioral changes. Immunohistochemistry for dopaminergic neurons marker (TH+) and microglia markers (Iba-1+; CD68+) were used to investigate neuronal integrity and microglial activation in the substantia nigra pars compacta (SNpc). The pro-inflammatory cytokines TNF-α and IL-6 were analysed by qPCR. Treatments with either 1-DNJ or Ibuprofen alone did not reduce the damage induced by MPTP intoxication. However, combined treatment with 1-DNJ and ibuprofen prevents loss of mesencephalic dopaminergic neurons, decreases the number of CD68+/ Iba-1+ cells, the microglia/neurons interactions, and the pro-inflammatory cytokines, and improves behavioral changes when compared with MPTP-treated animals. In conclusion, these data demonstrate that the combined treatment with a MMPs inhibitor (1-DNJ) plus an anti-inflammatory drug (ibuprofen) has neuroprotective effects open for future therapeutic interventions. Graphical Abstract MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a protoxicant that, after crossing the Blood Brain Barrier, is metabolized by astrocytic MAO-B to MPDP+, a pyridinium intermediate, which undergoes further two-electron oxidation to yield the toxic metabolite MPP+ (methyl-phenyltetrahydropyridinium) that is then selectively transported into nigral neurons via the mesencephalic dopamine transporter. In this study, we demonstrated that MPTP induced death of dopaminergic neurons, microgliosis, increase of gliapses, motor impairment and neuroinflammation in mice, which were inhibited by combined 1-deoxynojirimycin and ibuprofen treatment.

Intake, digestibility, ingestive behavior, production, and composition of goat milk supplemented with detoxified castor bean meal added urea as a replacement of soybean meal.

This study evaluated the castor bean meal detoxified with calcium hydroxide [Ca(OH)2] added urea replacing soybean meal in the diet of lactating goats from milk production and composition, intake, digestibility, and ingestive behavior. Eight Alpine multiparous goats weighting 44.3 ± 5.3 kg and at approximately 60 days of lactation were confined and randomly distributed in 4 × 4 double Latin squares, with four inclusion levels of detoxified castor meal: control (0), 25, 50, and 75 g/kg dry matter (DM) total. Detoxified castor bean meal replacing soybean meal (P > 0.05) in goats diet did not affect intake and digestibility of DM, crude protein, ether extract, neutral detergent fiber (NDF), total carbohydrates, non-fibrous carbohydrates and total digestible nutrients, times spent for eating, and efficiency ratios of rumination and eating. However, the times spent for rumination and idling showed a quadratic trend decrease (P < 0.01) from the level of 50.0-g/kg DM. The milk production, and the milk production correction showed a quadratic trend increase and feeding efficiency a quadratic decrease (P = 0.03) due inclusion of detoxified castor bean meal replacing soybean meal up to the level of 25.0 g/kg. The fat, protein, lactose, total solids, nonfat solids, and milk urea nitrogen content (g/day) presented a quadratic increase (P < 0.05) by detoxified castor meal inclusion. Detoxified castor bean meal added urea in the Alpine goats diet could be included up to the 25.0 g/kg level replacing soybean meal in the diet because improve milk production and composition and feeding efficiency of goats without negatively effect on intake, digestibility and ingestive behavior.

Vitamin D Supplementation Seems to Improve Fibromyalgia Symptoms: Preliminary Results.

BACKGROUND: Vitamin D deficiency and insufficiency have been reported in fibromyalgia. However, to the best of our knowledge, only one study has evaluated the role of 25-hydroxyvitamin D [25(OH)D] supplementation on fibromyalgia symptoms. OBJECTIVES: To analyze the effects of 3 months of 25(OH)D supplementation on symptoms of fibromyalgia. METHODS: This study included 11 female patient. Demographic and clinical data, tender points, visual analog scale results, and pre- and post-serum levels of 25(OH)D supplementation were analyzed. The levels of 25(OH)D were measured by a radioimmunologic test. RESULTS: Patients with fibromyalgia diagnosis and 25(OH)D values ≤ 30 ng/ml were recruited to receive 50,000 IU of oral vitamin D once every week for 3 months. The disease was diagnosed based on the American College of Rheumatology criteria. The median age of all patients was 48.5 (28-67) years and 63.4% were Caucasian. Disease duration varied from 1-10 years. The 25(OH)D levels increased significantly after 3 months, 18.4 (15.5-25.8) ng/ml vs. 33.8 (28-58) ng/ml, P = 0.01. Interestingly, an improvement of visual analog scale scores was observed at 3 months, 90 (0-100) vs. 30 (0-80), P = 0.002. Eight patients (72.2%) responded that they experienced a very significant improvement in symptoms. In addition, a trend for reduction of the number of tender points was observed after 3 months, 17 (11-18) vs. 10 (0-18), P = 0.07. CONCLUSIONS: The 25(OH)D levels and disease symptoms in patients with fibromyalgia and vitamin D deficiency/insufficiency seem to improve with vitamin D supplementation.

Decline in macrolide resistance rates among Streptococcus pyogenes causing pharyngitis in children isolated in Italy.

Macrolides are often used to treat group A streptococcus (GAS) infections, but their resistance rates reached high proportions worldwide. The aim of the present study was to give an update on the characteristics and contemporary prevalence of macrolide-resistant pharyngeal GAS in Central Italy. A total of 592 isolates causing pharyngitis in children were collected in the period 2012-2013. Clonality was assessed by emm typing and pulsed-field gel electrophoresis (PFGE) for all macrolide-resistant strains and for selected susceptible isolates. Genetic determinants of resistance were screened by polymerase chain reaction (PCR). Forty-four GAS were erythromycin-resistant (7.4 %). Among them, 52.3 % and 50 % were clindamycin- and tetracycline-resistant, respectively. erm(B)-positive isolates (52.3 %) expressed the constitutive cMLSB phenotype. mef(A) and its associated M phenotype were recorded in 40.9 % of the cases. The remaining erm(A)-positive isolates expressed the iMLSB phenotype. Seventeen tetracycline-resistant isolates carried tet(M) and five isolates carried tet(O). Twenty-five emm types were found among all strains, with the predominance of emm types 12, 89, 1, and 4. Eleven emm types and 12 PFGE clusters characterized macrolide-resistant strains, with almost two-thirds belonging to emm12, emm4, and emm11. Macrolide-susceptible and -resistant emm types 12, 89, 11, and 4 shared related PFGE profiles. There was a dramatic decline in macrolide resistance in Central Italy among pharyngeal GAS isolates in 2012-2013 when compared to previous studies from the same region (p < 0.05), although macrolide consumption remained stable over the past 15 years. We observed a decrease in the proportion of macrolide-resistant strains within emm types commonly associated with macrolide resistance in the past, namely emm12, 1, and 89.

Morphological study of rat skin flaps treated with subcutaneous dimethyl sulfoxide combined with hyperbaric oxygen therapy.

This study investigated the effects of hyperbaric oxygen therapy (HBOT) and dimethyl sulfoxide (DMSO) in tissue necrosis, genotoxicity, and cell apoptosis. Random skin flaps were made in 50 male Wistar rats, randomly divided into the following groups. Control group (CT), wherein a rectangular skin section (2 x 8 cm) was dissected from the dorsal muscle layer, preserving the cranial vessels, lifted, and refixed to the bed; distilled water (DW) group, in which DW was injected into the distal half of the skin flap; DMSO group, wherein 5% DMSO was injected; HBOT group, comprising animals treated only with HBOT; and HBOT + DMSO group, comprising animals treated with 100% oxygen at 2.5 atmospheres absolute for 1 h, 2 h after the experiment, daily for 10 consecutive days. A skinflap specimen investigated by microscopy. The percentage of necrosis was not significantly different between groups. The cell viability index was significantly different between groups (P < 0.001): 87.40% (CT), 86.20% (DW), 84.60% (DMSO), 86.60% (DMSO + HBO), and 91% (HBO) (P < 0.001), as was the cell apoptosis index of 12.60 (CT), 12.00 (DW), 15.40 (DMSO), 9.00 (HBO), and 12.00 (DMSO + HBO) (P < 0.001). The genotoxicity test revealed the percentage of cells with DNA damage to be 22.80 (CT), 22.60 (DW), 26.00 (DMSO), 8.80 (DMSO + HBO), and 7.20 (HBO) (P < 0.001). Although the necrotic area was not different between groups, there was a significant reduction in the cellular DNA damage and apoptosis index in the HBOT group.

[Septic shock. Update of treatment using hypertonic saline and antidiuretic hormone-vasopressin]. / Shock séptico. Actualización en tratamiento con suero salino hipertónico y hormona antidiurética-vasopresina.

Safety in the use of small volumes of hypertonic saline solution for hypovolaemic shock and in the treatment of intracranial hypertension has been demonstrated in studies in the field of resuscitation. There is little experience of this for septic shock in humans. Beneficial immunomodulatory effects have been detected in pre-clinical studies. Interactions with the pituitary-adrenal axis and with the secretion of anti-diuretic hormone are varied and suggestive, but are not sufficiently understood. On the other hand, vasopressin has cardiovascular, osmoregulatory, and coagulation effects, and also acts on the hypothalamic-pituitary-adrenal axis. There is a relative deficit of vasopressin in septic shock. Its use in these patients does not seem to have any advantages as regards mortality, but may be beneficial in patients at risk from acute renal failure, or those who receive corticosteroids. Terlipressin is a vasopressin analogue that has also been studied. The synergy between vasopressin and hypertonic saline is a hypothesis that is mainly supported in pre-clinical studies. The use of hypertonic saline solution in septic shock, although promising, is still experimental, and must be restricted to the field of controlled clinical trials.

Improvement of dermal burn healing by combining sodium alginate/chitosan-based films and low level laser therapy.

This paper aimed to evaluate the improvement of burn wounds healing by sodium alginate/chitosan-based films and laser therapy. Natural polymers with different biological activities are widely used as film dressings to improve wound healing. Lasers arrays accelerate the healing repair of soft tissue injuries. Burn procedures were performed on the backs of 60 male rats assigned into six groups: untreated (CTR), dressed with cellulose films (CL), dressed with sodium alginate/chitosan-based films (SC), laser-irradiated undressed wounds (LT), laser-irradiated wounds with cellulose (CLLT) and sodium alginate/chitosan-based films (SCLT). Laser therapy was applied for 7 days. Animals of each group were euthanised 8 and 14 days after the burn procedures. The inflammatory reaction was significantly more intense in the CTR group than in the irradiated groups after 8 and 14 days. Laser therapy stimulated myofibroblastic differentiation in 8 days, with or without dressing films. Combined laser therapy and both dressings improved epithelisation, blood vessels formation and collagenization, promoted rapid replacement of type III for type I collagen and favored the better arrangement of the newly formed collagen fibres. The combination of laser therapy and sodium alginate/chitosan-based dressing improves burn healing, apparently by modulating the epithelisation, blood vessels formation and collagenization processes.

Efeito da vitamina C sobre o hematócrito e glicemia de alevinos de tilápia-do-nilo (Oreochromis niloticus) em transporte simulado / Effect of vitamin C over the haematocrit and glycemia of nile tilapia (Oreochromis niloticus) alevins in simulated transport

Avaliou-se o efeito do ascorbato sobre o hematócrito e glicemia em alevinos de tilápia nilótica (Oreochromis niloticus) submetidos à simulação de práticas relacionadas ao transporte. Foram utilizadas três dietas experimentais com diferentes níveis de vitamina C (16, 500 e 1000mg de vitamina C/kg), fornecidas durante os 14 dias anteriores à simulação do transporte que se estendeu por 14 horas. O tratamento que continha 16mg de vitamina C/kg foi o que apresentou a glicemia mais elevada logo após a simulação, 108,5mg/dl imediatamente após a simulação e 91mg/dl 12 horas após a simulação. A concentração de 1000mg de vitamina C/kg foi a mais eficiente no controle do aumento da glicemia, 94,6mg/dl imediatamente após a simulação e 74,4mg/dl 12 horas após a simulação. Para a concentração de 500mg de vitamina C/kg foram observados os níveis de 91,4mg/dl imediatamente após a simulação e 103,8mg/dl 12 horas após a simulação. Os valores do hematócrito não apresentaram variação significativa (P>0,05). A suplementação com 1000mg de vitamina C/kg por 14 dias anteriores ao transporte pode ser utilizada de forma profilática em alevinos de tilápia nilótica para amenizar o aumento da glicemia relacionado ao estresse

The effects of ascorbate on the haematocrit and blood glucose level were evaluated in Nile tilapia alevins (Oreochromis niloticus) submitted to a transport simulation. Three experimental diets with different levels of vitamin C (16, 500 and 1000mg/kg) were given for 14 days before the simulation of the transport. The treatment containing 16mg of vitamin C showed the highest level of glucose after the simulation (108.5mg/dl immediately after the transport and 91mg/dl 12 hours after the transport). The vitamin C concentration of 1000mg/kg was the most efficient treatment to control glycemia increases (94.6mg/dl immediately after the simulation and 74.4mg/dl 12 hour after simulation). In the 500mg/kg treatment, the glucose level was 91.4mg/dl immediately after the simulation and 103.8mg/dl 12 hours after the simulation. The haematocrit values did not show any significative variation (P<0.05). The supplementation with 1000mg/kg of vitamin C for a 14 days period can be used in a prophylactic way to soften glycemia increases in Nile tilapia alevins submitted to transport stress

[Effects of aqueous extracts of Mentha piperita L. and Chenopodium ambrosioides L. leaves in infective larvae cultures of gastrointestinal nematodes of goats]. / Efeitos dos extratos aquosos de folhas de Mentha piperita L. e de Chenopodium ambrosioides L. sobre cultivos de larvas infectantes de nematóides gastrintestinais de caprinos.

Phitotherapy has been frequently utilized in parasitism control for numerous animal species. The aim of this experiment was to evaluate the in vitro effects of aqueous extracts of Mentha piperita L. and Chenopodium ambrosioides L. leaves in larvae cultures of gastrointestinal nematodes of goats. Six different concentrations of M. piperita extracts (196; 150.7; 115.9; 89.1; 68.5 e 52.7 mg/mL) and C. ambrosioides extracts (110,6; 85; 65,3; 50,2; 38,6 e 29,6 mg/mL) were used for the treatment of larvae cultures, in triple assays. Distilled water and doramectin were used in larvae cultures as negative and positive controls, respectively. The results revealed a reduction of more than 95% of the infective larvae when M. piperita extracts were used in the concentrations of 115.9 and 196 mg/mL, and C. ambrosioides extract in the concentration of 110.6 mg/mL, supporting the effect of these extracts in the in vitro treatment of gastrointestinal nematodes of goats.

Prevalences of hyperhomocysteinemia, unfavorable cholesterol profile and hypertension in European populations.

BACKGROUND: Hyperhomocysteinemia (HHCY) is a risk factor for cardiovascular diseases (CVD). HHCY may interact with hypertension (HTEN) and an unfavorable cholesterol profile (UNFAVCHOL) to alter the risk of CVD. OBJECTIVES: To estimate the prevalences of HHCY (1) isolated and (2) in combination with UNFAVCHOL and/or HTEN in different age categories. To provide information that may improve the screening and treatment of subjects at risk of CVD. DESIGN: Cross-sectional data on 12,541 men and 12,948 women aged 20 + y were used from nine European studies. RESULTS: The prevalence of isolated HHCY was 8.5% in subjects aged 20-40 y, 4.7% in subjects aged 40-60 y and 5.9% in subjects aged over 60 y. When combining all age groups, 5.3% had isolated HHCY and an additional 5.6% had HHCY in combination with HTEN and/or UNFAVCHOL. The combinations of risk factors increased with age and, except for HHCY&UNFAVCHOL, were more prevalent than predicted by chance. Of the young subjects (20-40 y), 24% suffered from one or more of the investigated CVD risk factors. This figure was 75.1% in the old subjects (60+ years). CONCLUSIONS: A substantial number of subjects in selected European populations have HHCY (10.9%). In half of these cases, subjects suffer also from other CVD risk factors like UNFAVCHOL and HTEN. Older people in particular tend to have more than one risk factor. Healthcare professionals should be aware of this when screening and treating older people not only for the conventional CVD risk factors like UNFAVCHOL and HTEN but also HHCY, as this can easily be reduced through increased intake of folic acid via supplement or foods fortified with folic acid.

Protection against lipopolysaccharide-induced death by fluoroquinolones.

Because fluoroquinolones have an immunomodulatory effect on cytokine production by lipopolysaccharide (LPS)-treated human monocytes, we examined the effect of fluoroquinolones on the survival of mice injected with a lethal dose of LPS. Trovafloxacin (100 mg/kg), ciprofloxacin (250 mg/kg), and tosufloxacin (100 mg/kg) protected 75% (P = 0.0001), 25% (P = 0.002), and 50% (P = 0.002), respectively, of mice against death. The fluoroquinolones significantly reduced serum levels of interleukin-6 and tumor necrosis factor alpha in LPS-treated mice. The protective effects of fluoroquinolones in LPS-induced shock in mice may also occur in humans.

Trovafloxacin is active against Toxoplasma gondii.

Drugs currently used for treatment of toxoplasmosis in pregnant women, congenital infections, immunocompromised patients, and patients with the ocular disease are not always effective or may be dangerous to use; therefore, there is a need for more-effective and less-toxic drugs. Recently, we examined a group of fluoroquinolones for in vitro and in vivo activities against Toxoplasma gondii. Among those examined in vitro (ciprofloxacin, fleroxacin, ofloxacin, temafloxacin, and trovafloxacin), only trovafloxacin significantly inhibited intracellular replication of T. gondii without significant toxicity for host cells. In a murine model of acute toxoplasmosis, 100 or 200 mg of trovafloxacin per kg of body weight per day for 10 days protected 100% of infected mice against death. A dose of 50 mg/kg/day protected 90% of the mice, and a dose of 25 mg/kg/day effected prolongation of time to death. The other fluoroquinolones did not have such in vivo activities. These results indicate that trovafloxacin may be useful for treatment of toxoplasmosis in humans.

Potential use of WR6026 as prophylaxis against transfusion-transmitted American trypanosomiasis.

Since transmission of Chagas' disease by the insect vector is under control in Brazil, transmission by blood transfusion is acquiring special relevance in areas where the disease is endemic and also in countries whose populations are free of infection but that are receiving immigrants from areas where the disease is endemic. Gentian violet, a phenylmethane dye, was the first agent used for the chemical prophylaxis of blood destined for transfusion. A concentration of 0.6 mmol of this dye per liter is effective at eliminating trypomastigotes from blood after 24 h of incubation at 4 degrees C. It is the only effective trypanosomicidal agent available. In the search of alternate compounds, we examined a number of synthetic compounds. They were screened for their activities against blood trypomastigotes of the Y, CL, and B229 strains of Trypanosoma cruzi by using two or more dilutions of each compound. We found that compound Q45, a 6-methoxy-8(diethylaminohexylamino)lepidine dihydrochloride, was highly effective at clearing parasites from infected blood. Doses of 65 and 130 micrograms of this compound eliminated trypomastigotes from blood experimentally contaminated with T. cruzi parasites. These results indicate that Q45 is remarkably active against circulating trypomastigotes. Further studies evaluating Q45 as a prophylactic agent for preventing the transmission of T. cruzi by blood transfusion are of interest.

In vivo activity of the macrolide antibiotics azithromycin, roxithromycin and spiramycin against Toxoplasma gondii.

The macrolide antibiotics azithromycin, roxithromycin and spiramycin were examined in parallel for in vivo activity against Toxoplasma gondii. Azithromycin was considerably more active in protecting mice against death due to acute toxoplasmosis even when the other two antibiotics were used at twice its dose. The higher activity of azithromycin prompted a further examination of its activity against five different strains of Toxoplasma gondii, including two isolated from patients with AIDS. Although variable degrees of protection against death were noted, treatment with 200 mg/kg/day for ten days was sufficient to promote survival of 100% of mice infected with inocula as high as 1 x 10(5) tachyzoites of Toxoplasma gondii. 90% of mice inoculated with 1 x 10(5) tachyzoites of strain MO, isolated from an AIDS patient, and treated orally with 200 mg/kg/day for ten days survived the infection whereas only 40% of mice infected with the same inoculum of the SOU strain, also isolated from an AIDS patient, survived. Tissue concentrations of azithromycin were examined in treated infected and non-infected mice. In both groups of mice azithromycin attained high concentrations in liver, spleen and heart, which exceeded concurrent serum levels by 25- to 200-fold. The concentrations in the brain were almost tenfold higher than the concentrations in serum after treatment with 200 mg/kg/day for ten days. Moreover, the concentrations in brains of infected mice were approximately two-fold higher than in brains of non-infected mice.

[Effect of oral contraceptives upon the metabolism of vitamin B6, folic acid, serum iron, glycemia, hemoglobin and hematocrit (author's transl)]. / Efeito das pilulas anticoncepcionais sobre o metabolismo da vitamina B6, acido folico, ferro serico, glicemia, hemoglobina e hematocrito.

PIP: The authors present a review of the medical literature about the effect of oral contraceptives (OCs) on the metabolism of hydrocarbonates, serum iron, vitamins, folic acid, hemoglobin, and hematocrit. This is the 1st Brazilian study clinical about these phenomena. This study examined 21 patients taking OCs for 1 or more years. These female patients followed a regimen of vitamin-mineral supplementation over the course of 2 months when new clinical and laboratory controls were made. Of 21 patients, 18 had adverse symptoms and 3 were asymptomatic. Of the 18 symptomatic, 10 found relief from disturbances. There was also a statistically significant increase in serum folic acid levels. There wre no statistically significant alterations of hematocrit or serum iron in accordance with the literature. (author's)^ieng

Hydatid disease transmission in California. A study of the Basque connection.

A descriptive epidemiologic and anthropologic study was designed to determine by field observation and interview the extent of Basque involvement in the sheep industry of California, the nature of the sheep and dog husbandry practices of California Basques as they might influence Echinococus granulosus transmission, and the "folk knowledge" of hydatid disease possessed by California Basques, particularly as it might indicate the early presence of this infection in California and provide evidence for or against possible intensification or spread of transmission in the recent past. Basques were found to dominate the sheep industry of California's Central Valley from Sacramento south, but to be virtually absent from other sheep-raising areas of the state. In contrast to most other California sheep ranchers, Basques practice a transhumant form of husbandry in which bands of sheep are moved from location to location under the control of contract Basque shepherds from Spain and France and a number of sheep dogs.