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.

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.

     

Snake bites by the jararacucu (Bothrops jararacussu): clinicopathological studies of 29 proven cases in Sao Paulo State, Brazil

The jararacucu, one of the most dreaded snakes of Brazil, southern Bolivia, Paraguay and northeastern Argentina, is a heavily-built pit viper which may grow to a length of 2.2 m. Up to 1000 mg (dry weight) of highly-lethal venom may be milked from its venom glands on a single occasion. It has accounted for 0.8% to 10% of series of snake bites in Sao Paulo State, Brazil. We examined 29 cases of proven jararacucu bites recruited over a 20-year period in two Sao Paulo hospitals. Severe signs of local and systemic envenoming, (local necrosis, shock, spontaneous systemic bleeding, renal failure) were seen only in patients bitten by snakes longer than 50 cm; bites by shorter specimens were more likely to cause incoagulable blood. Fourteen patients developed coagulopathy, six local necrosis (requiring amputation in one) and five local abscesses. Two became shocked and four developed renal failure. Three patients, aged 3, 11 and 65 years, died 18.75, 27.75 and 83 h after being bitten, with respiratory and circulatory failure despite large doses of specific antivenom and intensive-care- unit management. In two patients, autopsies revealed acute renal tubular necrosis, cerebral oedema, haemorrhagic rhabdomyolysis at the site of the bite and disseminated intravascular coagulation. In one survivor with chronic renal failure, renal biopsy showed bilateral cortical necrosis; the patient remains dependent on haemodialysis. Effects of polyspecific Bothrops antivenom were not impressive, and it has been suggested that anti-Bothrops and anti-Crotalus antivenoms should be given in combination.      

Prospective Assessment of Presenting Serum Markers for Cardiac Risk Stratification

Objective: To quantify the association of initial ED serum cardiac markers with the risk for life-threatening events (LEs) or need for lifesaving interventions (Lis) or administration of IV nitroglycerin.
Methods: A prospective, observational study was performed using a cohort of hemodynamically stable, hospitalized patients (age > 25 years) presenting with nontraumatic chest discomfort. Patients with ST-segment elevation on their initial ECGs were excluded. Presenting serum samples were assayed for serum myoglobin and creatine kinase-MB isomer (CK-MB) using the Opus and Stratus systems. Target cases were defined as patients having LEs (e.g., cardiogenic shock, ventricular fibrillation, cardiac arrest), requiring Lis (e.g., intubation, cardioversion, pacing, reperfusion therapy), or needing IV nitroglycerin within 48 hours. Manufacturer's thresholds defined abnormal marker levels. Abnormal ECGs were defined using the Brush criteria.
Results: Of the 178 eligible patients, 44 (25%) were target cases . Most (55%) target cases had blood drawn for assays within four hours of chest discomfort onset. The relative risk and sensitivity of the serum markers and the ECG for target cases follow:
Of the seven patients with an LE/LI, six had blood drawn four hours or less after symptom onset; two LE/LI patients had abnormal myoglobin levels' no LE/LI patient had an abnormal CK-MB level.
Conclusions: Isolated serum myoglobin and CK-MB levels obtained at patient ED presentation were not strongly associated with the 48-hour risk for LEs, Lis, or the use of IV nitroglycerin. Future studies of risk stratification should address the merits of serial serum marker measurements that extend up to 12 hours beyond patient symptom onset.     

Assessment of motivations for return donation among deferred blood donors. American Red Cross ARCNET Study Group

BACKGROUND: The recent addition of a computerized donor deferral registry to American Red Cross blood donation procedures has enabled blood center staffs to identify, before donation, persons who attempt to donate despite previous deferral. The current study investigated reasons that deferred donors return to donate, despite having been notified that they are ineligible. STUDY DESIGN AND METHOD: Anonymous mail surveys requesting demographic information, details of last donation or attempted donation, and assessments of incentives for donating were sent to 311 donors presenting inappropriately at blood drives and 849 matched controls in three American Red Cross regions between April and July 1996. RESULTS: Responses were received from a total of 113 deferred donors and 388 matched controls. Analysis of the 49 permanently deferred donors indicated that they were more likely than controls to donate blood to receive test results or to be awarded community service credit. Responses also revealed that some deferred donors may return to donate blood because of a misunderstanding of the deferral message or erroneous recruitment by blood center staff. CONCLUSION: There is a need before donation for the provision of educational materials regarding the window period of infection and for careful consideration of the use of incentives to attract donors to blood centers. It is also important to provide to donors a clear and consistent message regarding their test results and deferral status.     

An IgG, Gentamicin Sulfate-Dependent Antibody Found during Prenatal Antibody Screening

The serum of a prenatal patient was found to contain an IgG antibody that reacted with all red cells suspended in solutions containing the antibiotic gentamicin sulfate. The antibody was nonreactive with red cells suspended in media containing chloramphenicol, neomycin, hydrocortisone or inosine. Since gentamicin sulfate is used in the suspending medium of some commercial reagent red cell products, difficulties in the interpretation of antibody detection and identification tests may arise when patient sera contain gentamicin-dependent antibodies.     

Misoprostol coadministered with diclofenac for prevention of gastroduodenal ulcers

The objective of this study was to determine the long-term efficacy of misoprostol in preventing diclofenac-induced gastroduodenal ulcers in rheumatoid arthritis and osteoarthritis patients. Three hundred eighty-four patients who had an endoscopically confirmed gastric or duodenal lesion that had healed with misoprostol therapy were randomized to receive misoprostol or placebo coadministered with diclofenac for up to 52 weeks. Endoscopic examinations were repeated at weeks 12, 24, and 52. The development of a gastric and/or duodenal ulcer was considered a prophylaxis failure. Results in the evaluable cohort of patients demonstrated that gastroduodenal ulcer incidences were lower with misoprostol than placebo for all study periods (0–12 weeks, 7% vs 23%; 0–24 weeks, 11% vs 26%; and 0–52 weeks, 15% vs 31%). Misoprostol did not interfere with the antiarthritic effects of diclofenac. In conclusion, misoprostol coadministered with diclofenac for 12 months to patients with rheumatoid arthritis or osteoarthritis significantly reduced the incidence of diclofenac-induced gastroduodenal ulcers (P0.018).     

Release of lubricating synovial surfactant by intra-articular steroid

This study was undertaken to determine whether glucocorticosteroids promote the secretion of lubricating surfactant, i.e. surface-active phospholipid (SAPL), into the joint. A standard clinical dose (100 mg) of methylprednisolone acetate (MPA) in 2.5 ml of saline was injected into the load-bearing right radiocarpal joint of five horses and 2.5 ml of saline injected into each of the contralateral joints used as controls. Synovial fluid (SF) was aspirated from all 10 joints before injection and at intervals of 16 and 32 h after injection, and then analysed by standard methods. All test joints showed an elevated level of SAPL, the increases averaging 112% after 16 h and 76% after 32 h, which were highly significant relative to the control joints. A large increase at 16 h was also found in proteolipid as a possible further marker of surfactant release. Significant quantities of proteolipid were also found in human SF. Since intra-articular steroids can dramatically improve joint mobility in both humans and horses, it is proposed that part of the benefit may be derived from improved lubrication arising from the remarkable ability of SAPL to lubricate under high load. Other possible benefits of elevating surfactant levels in the joints include control of cartilage hydration, promotion of macrophage activity and the ability to scavenge oxygen free radicals.      

Serum interleukin-3 levels following autologous or allogeneic bone marrow transplantation: effects of T-cell depletion, blood stem cell infusion, and hematopoietic growth factor treatment

Engraftment of marrow following autologous or allogeneic bone marrow transplantation (BMT) may be influenced by quantity and function of stem cells. T lymphocytes, supporting microenvironmental cells, and hematopoietic growth factors (HGF). To elucidate the physiologic role of interleukin-3 (IL-3) in the engraftment process, serum IL-3 levels were measured in over 400 samples from 77 transplant recipients before and for up to 3 weeks following transplantation using a novel enzyme- linked immunoabsorbent assay (ELISA) with a sensitivity of > or = 78 pg/mL. Thirty-seven patients received two to three log T-cell-depleted allografts. In the remaining 40 patients (18 autologous marrow, 12 allogeneic marrow, and 10 autologous peripheral blood [PB] stem cell), T cells were not depleted (non-TCD) from the grafts. A burst of IL-3 (peak levels, 1,500 to 6,000 pg/mL) was detected in the immediate posttransplant period between day 0 and day 14 in all non-TCD recipients and in 21 of 37 (57%) of TCD recipients. A strong inverse relationship between IL-3 levels and absolute neutrophil count (ANC) was observed in both non-TCD recipients (r = -.796) and in TCD recipients (r = -.897). However, both peak IL-3 levels and mean IL-3 levels from day 0 through 14 were significantly lower in TCD recipients compared with either autologous or unmodified allogeneic marrow recipients (P < .01). The lowest peak or mean day 0 through 14 IL-3 levels were observed in matched related recipients undergoing the most aggressive (2.5 to 3.0 log) T-cell-depleted BMT. Autografted patients receiving blood stem cell transplants alone or posttransplant granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) also had significantly lower peak IL- 3 levels (P < .01). In patients receiving TCD grafts, administration of antithymocyte globulin (ATG) posttransplant significantly increased peak IL-3 levels compared with patients not treated with ATG (P < .04). This study shows that endogenous release of IL-3 is strongly associated with myeloid engraftment and inversely related to ANC. Removal of T lymphocytes from donor marrow or acceleration of engraftment by use of stem cells or growth factors appears to blunt the endogenous release of IL-3 whereas use of ATG posttransplant increases IL-3 release.