Diclazuril Protects against Maternal Gastrointestinal Syndrome and Congenital Toxoplasmosis

BACKGROUND: Toxoplasmosis is a common cause of foodborne, gastrointestinal and congenital syndrome with particularly severe or unknown health consequences. There is no safe and effective preventive or therapeutic modality against congenital toxoplasmosis or to eliminate the persistent chronic infection. HYPOTHESIS: Diclazuril to be safe in pregnancy and effective against gastrointestinal toxoplasmosis. METHODS: CD1 programmed pregnant mice were divided into groups and administered a diet containing diclazuril, or sham control. Treatments were initiated on Day 5 of pregnancy and continued until Day 16 when dams were euthanatized. On Day 8 of pregnancy dams were infected intraperitoneally with escalating doses of tachyzoites (0, 100, 300, 600) from Type II strain. Dams were monitored daily for distress, pain, and abortion and samples collected at the end of the experiments. RESULTS: Infected dams developed moderate to severe Toxoplasma related complications in tachyzoites dose dependent manner. Animals became anemic and showed hydrothorax, and ascities. Diclazuril effectively protected dams from ascities and anemia (p \u3c 0.05). Infected dams showed splenomegaly, with massive infiltration of epithelioid cells compared with the protective effect of diclazuril in treated animals. Infected dams exhibited severe hepatitis (score 0 to 4 scale = 3.5 ± 0.01) with influx of inflammatory and plasma cells, dysplastic hepatocytes, multinucleated giant cell transformation and hepatic cells necrosis. Diclazuril treatment significantly protected dams from hepatitis, also in tachyzoites dose (100, 300, 600) dependent manner (respectively infected-treated versus infected controls, p \u3c 0.001, p \u3c 0.01 and p \u3c 0.05). Colonic tissues were significantly shortened in length, with infiltration of lymphocytes, and macrophages and microabscess formations in the cryptic structures, with significant improvement in diclazuril treated animals. Additionally, the number of fetuses, fetal length and fetal weight were preserved in diclazuril treated dams. CONCLUSIONS: This is the first report describing of diclazuril safety in pregnancy as well as efficacy against mild to moderate hepato-gastrointestinal syndrome in dams and fetal toxoplasmosis (Special issue, Treatment of Liver Diseases )

Atovaquone Ameliorate Gastrointestinal Toxoplasmosis Complications in a Pregnancy Model

Background: Toxoplasma is an important source of foodborne hospitalization with no safe and effective therapy against chronic or congenital Toxopalsmosis. Atovaquone is a drug of choice but not approved for use in congenital Toxoplasmosis. We hypothesized atovaquone to be safe and effective against feto-maternal Toxoplasmosis. Material/Methods: Programmed pregnant mice were i.p. infected with 50–2400 Tachyzoites from Type II strain (clone PTG). Dams were treated daily with atovaquone or sham and monitored for pain, and complications. Results: Dams developed pain related abdominal hypersensitivity (allodynia) to mechanical stimuli in a Tachyzoites dose dependent manner. Infected dams were anemic and exhibited ascities and severe hepatitis (score 3.6±0.01 on scale 0 – normal to 4 – severe) with influx of inflammatory and plasma cells, multinucleated dysplastic hepatocytes and necrosis. In addition, dams expressed mild to severe pancreatitis with mononuclear cell invasion, loss of islets and necrosis. This was consistent with splenomegaly (X3 Fold), and massive infiltration of epithelioid cells and loss of germinal structure. Colon became significantly shortened in length (p \u3c 0.01) with semi-normal content. Pathological manifestation included, shortening of crypts with numerous microabscess formations, infiltration of lymphocytes, and macrophages. The severe clinical complications led to abortion (50%), early birth (25%) or still birth (25%) consistent with the high dose of Tachyzoites inoculation. Atovaquone treatment partially but significantly protected the dams from the severity of hepatitis, splenomegaly, colitis, myocarditis, and pain related responses as well as fetal demise. Conclusions: This is a valuable model for therapeutic evaluation of feto-maternal Toxoplasmosis and gastrointestinal complications. Atovaquone protects dams and their fetuses against some infectious/inflammatory aspects of the disease

Characterizing the Youngest Herschel-detected Protostars I. Envelope Structure Revealed by CARMA Dust Continuum Observations

We present CARMA 2.9 mm dust continuum emission observations of a sample of 14 Herschel-detected Class 0 protostars in the Orion A and B molecular clouds, drawn from the PACS Bright Red Sources (PBRS) sample (Stutz et al.). These objects are characterized by very red 24 \micron\ to 70 \micron\ colors and prominent submillimeter emission, suggesting that they are very young Class 0 protostars embedded in dense envelopes. We detect all of the PBRS in 2.9 mm continuum emission and emission from 4 protostars and 1 starless core in the fields toward the PBRS; we also report 1 new PBRS source. The ratio of 2.9 mm luminosity to bolometric luminosity is higher by a factor of $\sim$5 on average, compared to other well-studied protostars in the Perseus and Ophiuchus clouds. The 2.9 mm visibility amplitudes for 6 of the 14 PBRS are very flat as a function of uv-distance, with more than 50\% of the source emission arising from radii $<$ 1500 AU. These flat visibility amplitudes are most consistent with spherically symmetric envelope density profiles with $\rho$~$\propto$~R$^{-2.5}$. Alternatively, there could be a massive unresolved structure like a disk or a high-density inner envelope departing from a smooth power-law. The large amount of mass on scales $<$ 1500 AU (implying high average central densities) leads us to suggest that that the PBRS with flat visibility amplitude profiles are the youngest PBRS and may be undergoing a brief phase of high mass infall/accretion and are possibly among the youngest Class 0 protostars. The PBRS with more rapidly declining visibility amplitudes still have large envelope masses, but could be slightly more evolved.Comment: Accepted to ApJ, 40 pages, 9 Figures, 4 Table

Phenylbutazone in the horse: a review

Phenylbutazone is an acidic, lipophilic, nonsteroidal anti-inflammatory drug (NSAID). It is extensively metabolized in the horse. The metabolites so far identified, oxyphenbutazone, y-hydroxyphenylbutazone and y-hydroxyoxyphenbutazone. account for some 25-30% of administered dose over 24 h. The plasma half-life of phenylbutazone and termination of its pharmacological action are determined primarily by its rate of hepatic metabolism. Phenylbutazone acts by inhibiting the cyclooxygenase enzyme system, which is responsible for synthesis of prostanoids such as PGE?. It appears to act on prostaglalidin-H synthase and prostacyclin synthase, after conversion by prostaglandin-H synthase to reactive intermediates. It markedly reduces prostanoid-dependent swelling, edema, erythema, and hypersensitivity to pain in inflamed tissues. Its principal use in the horse is for treatment of soft tissue inflammation. Phenylbutazone is highly bound (\u3e 98%) to plasma protein. After i.v. injection, blood levels decline with an elimination half-life of 3-10 h. The plasma kinetics of phenylbutazone may be dose dependent, with the plasma half-life increasing as the drug dosage level increases. Plasma residues of the drug at 24 h after a single i.v. dose of 2 g/450 kg average about 0.9 pg/ml, but considerable variation occurs. If dosing is repeated, the plasma residue accumulates to give mean residual blood levels of approxiniately 4.5 pg/ml on Day 5 after 4 days of dosing. Approximately similar blood levels are found after a combination of oral and i.v. dosing. Experiments on large numbers of horses in training have been undertaken to ascertain the population distributions of residual blood levels after such dosing schedules. Absorption of phenylbutazone from the gastrointestinal tract is influenced by the dose administered and the relationship of dosing to feeding. Access to hay can delay the time of peak plasma concentration to 18 h or longer. Under optimal conditions, the bioavailability of oral phenylbutazone is probably in the region of 70%. Paste preparations may be more slowly absorbed than other preparations and yield higher residual plasma levels at 24 h after dosing, but further controlled studies are required. Phenylbutazone is easily detected in the plasma and urine of horses but concentrations in saliva are low. It is quantitated for forensic purposes by HPLC. The variability of this method between laboratories is about k 25%. Increasing urinary pH increases the urinary concentration of phenylbutazone and its metabolites up to 200-fold. However, urinary pH has little effect on the plasma half-life of phenylbutazone, which is determined mainly by hepatic metabolism and possibly by biliary secretion. Phenylbutazone has a narrow therapeutic index in the horse. If the administered dose is greater than recommended by the manufacturer, toxic effects may be produced, especially if high dose administration is maintained for more than a few days. Signs of toxicity include anorexia, depression, oral and GI ulcers, plasma protein losing enteropathy, and death from shock. Other side-effects include toxic neutropenia, hepatotoxicity and renal papillary necrosis; the latter may occur if access to water is restricted. If phenylbutazone is withdrawn in the early stages of toxicity, the prognosis is good. Late withdrawal is associated with delayed recovery. Death may occur up to 50 days after withdrawal of the drug. This toxicity can be antagonized by administration of prostaglandins

HOPS 383: An Outbursting Class 0 Protostar in Orion

We report the dramatic mid-infrared brightening between 2004 and 2006 of HOPS 383, a deeply embedded protostar adjacent to NGC 1977 in Orion. By 2008, the source became a factor of 35 brighter at 24 microns with a brightness increase also apparent at 4.5 microns. The outburst is also detected in the submillimeter by comparing APEX/SABOCA to SCUBA data, and a scattered-light nebula appeared in NEWFIRM K_s imaging. The post-outburst spectral energy distribution indicates a Class 0 source with a dense envelope and a luminosity between 6 and 14 L_sun. Post-outburst time-series mid- and far-infrared photometry shows no long-term fading and variability at the 18% level between 2009 and 2012. HOPS 383 is the first outbursting Class 0 object discovered, pointing to the importance of episodic accretion at early stages in the star formation process. Its dramatic rise and lack of fading over a six-year period hint that it may be similar to FU Ori outbursts, although the luminosity appears to be significantly smaller than the canonical luminosities of such objects.Comment: Accepted by ApJ Letters, 6 pages, 4 figures; v2 has an updated email address for the lead autho