Effect of conditioning horses every third day at v10 on measures of fitness.

This study examined the effect of exercising horses five times per fortnight with two bouts of 5 min duration at their v(10) with 2 days between consecutive exercise sessions. Five Anglo-Arabian horses were treadmill-conditioned for 6 weeks. A standardized exercise test (SET) was performed at the beginning of the conditioning period (CP) to determine the blood lactate-running speed (BLRS) and the heart rate-running speed (HRRS) relationship and the SET was repeated every 2 weeks. After each SET, the BLRS relation was used to calculate the horse's speed (v = velocity), which produced a blood lactate concentration (LA) of 10 mmol/l (v(10) ) and 4 mmol/l (v(4) ). From the HRRS was calculated the speed at which the horses had a heart rate of 180 b/min (v(180) ). Each horse was then conditioned for the next 2 weeks five times at its individual v(10) for two 5-min bouts. Exercise speed was individually adapted to the new v(10) every 2 weeks. In addition, horses were submitted to another SET prescription to determine the peak oxygen consumption (VO(2 peak) ) before, after 3 weeks and at the end of CP. The v(4) of horses increased during the CP (p < 0.05). v(180) did not change (p > 0.05). VO(2 peak) increased in the first 3 weeks of CP (p < 0.05) and levelled off afterwards (p > 0.05). The conclusion drawn was that exercising horses five times per fortnight at their v(10) for two 5-min bouts with 2 days between consecutive exercise sessions improved v(4) and VO(2 peak) but not v(180).

Epithelial Hic-5/ARA55 expression contributes to prostate tumorigenesis and castrate responsiveness.

Stromal-epithelial interactions dictate prostate tumorigenesis and response to castration. Hydrogen peroxide-inducible clone 5 (Hic-5/ARA55) is a transforming growth factor-beta (TGF-ß)-induced coactivator of androgen receptor (AR) expressed in the prostate stroma. Interestingly, following castration, we identified epithelial expression of Hic-5/ARA55 in mouse and human prostate tissues. To determine the role of epithelial Hic-5 in prostate cancer progression and castration responsiveness, we compared LNCaP cells having Hic-5 stably expressed with the parental LNCaP cells following tissue recombination xenografts with mouse prostate stromal cells. We previously identified knocking out prostate stromal TGF-ß signaling potentiated castrate-resistant prostate tumors, in a Wnt-dependent manner. The LNCaP chimeric tumors containing prostate fibroblasts conditionally knocked out for the TGF-ß type II receptor (Tgfbr2-KO) resulted in larger, more invasive, and castration-resistant tumors compared those with floxed (control) stromal cells. However, the LNCaP-Hic5 associated with Tgfbr2-KO fibroblasts generated chimeric tumors with reduced tumor volume, lack of invasion and restored castration dependence. Neutralization of canonical Wnt signaling is shown to reduce prostate tumor size and restore regression following castration. Thus, we hypothesized that epithelial Hic-5/ARA55 expression negatively regulated Wnt signaling. The mechanism of the Hic-5/ARA55 effects on castration was determined by analysis of the c-myc promoter. C-myc luciferase reporter activity suggested Hic-5/ARA55 expression inhibited c-myc activity by ß-catenin. Sequential ChIP analysis indicated ß-catenin and T-cell-specific 4 (TCF4) bound the endogenous c-myc promoter in the absence of Hic-5 expression. However, the formation of a TCF4/Hic-5 repressor complex inhibited c-myc promoter activity, by excluding ß-catenin binding with TCF4 on the promoter. The data indicate Hic-5/ARA55 expression in response to castration-enabled epithelial regression through the repression of c-myc gene at the chromatin level.

In vivo addition of poly(A) tail and AU-rich sequences to the 3' terminus of the Sindbis virus RNA genome: a novel 3'-end repair pathway.

Alphaviruses are mosquito-transmitted RNA viruses that cause important diseases in both humans and livestock. Sindbis virus (SIN), the type species of the alphavirus genus, carries a 11.7-kb positive-sense RNA genome which is capped at its 5' end and polyadenylated at its 3' end. The 3' nontranslated region (3'NTR) of the SIN genome carries many AU-rich motifs, including a 19-nucleotide (nt) conserved element (3'CSE) and a poly(A) tail. This 3'CSE and the adjoining poly(A) tail are believed to regulate the synthesis of negative-sense RNA and genome replication in vivo. We have recently demonstrated that the SIN genome lacking the poly(A) tail was infectious and that de novo polyadenylation could occur in vivo (K. R. Hill, M. Hajjou, J. Hu, and R. Raju, J. Virol. 71:2693-2704, 1997). Here, we demonstrate that the 3'-terminal 29-nt region of the SIN genome carries a signal for possible cytoplasmic polyadenylation. To further investigate the polyadenylation signals within the 3'NTR, we generated a battery of mutant genomes with mutations in the 3'NTR and tested their ability to generate infectious virus and undergo 3' polyadenylation in vivo. Engineered SIN genomes with terminal deletions within the 19-nt 3'CSE were infectious and regained their poly(A) tail. Also, a SIN genome carrying the poly(A) tail but lacking a part or the entire 19-nt 3'CSE was also infectious. Sequence analysis of viruses generated from these engineered SIN genomes demonstrated the addition of a variety of AU-rich sequence motifs just adjacent to the poly(A) tail. The addition of AU-rich motifs to the mutant SIN genomes appears to require the presence of a significant portion of the 3'NTR. These results indicate the ability of alphavirus RNAs to undergo 3' repair and the existence of a pathway for the addition of AU-rich sequences and a poly(A) tail to their 3' end in the infected host cell. Most importantly, these results indicate the ability of alphavirus replication machinery to use a multitude of AU-rich RNA sequences abutted by a poly(A) motif as promoters for negative-sense RNA synthesis and genome replication in vivo. The possible roles of cytoplasmic polyadenylation machinery, terminal transferase-like enzymes, and the viral polymerase in the terminal repair processes are discussed.

[Early complications and long-term results of the LeVeen peritoneo-venous shunt in the treatment of refractory ascites]. / Complicanze precoci e risultati a lungo termine dello shunt peritoneo-venoso di LeVeen nel trattamento dell'ascite refrattaria.

Results concerning 14 cirrhotic patients who underwent LeVeen peritoneo-venous shunt for refractory or complicated ascites are discussed. The most relevant early complications regard coagulation disorders (35.7%) with a 14.3% postoperative mortality. The functional result appears largely satisfactory, also in terms of long-term efficiency. Utility of a wide evacuation of ascitic fluid during the operation is underlined. Ascites drainage at operation doesn't compromise shunt function or renal resumption, furthermore it may prevent some life-threatening complications like DIC, esophageal varices rupture and congestive heart failure.

[Alternative methods of the pancreatico-jejunal anastomosis in resective pancreatic surgery]. / Metodiche alternative alle anastomosi pancreatico-digiunali nella chirurgia resettiva pancreatica.

Pancreaticojejunostomy is still followed by an unacceptable mortality and it warns the necessity to find and to verify more safe alternative methods in the management of pancreatic stump. In this work we analyze the results concerning 14 cases of pancreatic resections in which a pancreaticojejunostomy was not performed but the stump was closed with a mechanical stapler. Distal pancreatectomy with stapler was characterized by a low morbidity (11%) without mortality; this technique is therefore certainly reliable and it may be preferred for its facility and its rapidity. Pancreaticoduodenectomy with stapler has not appeared sufficiently sure, however, some technical improvements, as additional ligation of the pancreatic duct, the pharmacological inhibition of the exocrine secretion and a more extensive resection, seem to be able to make this technique as much reliable.

Pharmacokinetics of oxatomide given percutaneously to healthy volunteers.

The percutaneous absorption of oxatomide gel at 5 per cent concentration was studied after single and repeated administration (85 mg b.i.d.) in six male and six female healthy volunteers, aged 25.7 +/- 0.8 years (mean +/- SEM) weighing 64.4 +/- 4.5 kg and the results compared with those obtained following a single oral dose (30 mg). The measurement of oxatomide was by means of a new sensitive and specific HPLC assay with limits of detection of 0.2 ng ml-1 in plasma and 1.0 ng ml-1 in urine. Poor percutaneous absorption was confirmed by the peak plasma concentrations which were 5.03 +/- 0.79 ng ml-1 following application of the gel for 7 days and 10.08 +/- 1.29 ng ml-1 following oral administration; the corresponding amounts of unchanged oxatomide recovered from 24 h urine collections were 1.42 +/- 0.39 micrograms and 3.93 +/- 0.92 micrograms.

In vitro and ex vivo effects of recent and new macrolide antibiotics on chemotaxis of human polymorphonuclear leukocytes.

The effects of five macrolide antibiotics: erythromycin, josamycin, miokamycin, roxithromycin and rokitamycin, on human polymorphonuclear leukocyte (PMN) chemotaxis was studied in vitro and ex vivo. At therapeutic concentrations none of the antibiotics tested affected in vitro PMN chemotaxis. In vitro, erythromycin, josamycin, miokamycin, roxithromycin and rokitamycin decreased PMN chemotaxis significantly only at the concentration of 10 mg/l, which is not usually reached in vivo. Ex vivo studies after the ingestion of therapeutic doses of erythromycin, josamycin, miokamycin and roxithromycin by five volunteers showed a significant effect on PMN chemotaxis. However, further studies are needed to confirm and better evaluate the clinical significance of recent and novel macrolides on PMN chemotaxis.

Bioavailability of intranasal neostigmine: comparison with intravenous route.

The pharmacokinetics of intranasal (i.n.) neostigmine was compared with the intravenous (i.v.) route in 6 healthy volunteers with a mean age of 25.5 years and a mean weight of 65.8 kg in a crossover design. The doses used were 0.5 mg i.v. and 21.6 mg i.n. Neostigmine was determined by HPLC. The plasmatic profiles of the two routes were similar. An early peak of plasmatic concentration after i.n. administration was observed. The absolute bioequivalence of the i.n. route was ten-fold greater than the oral one.

Pharmacokinetics of rokitamycin after single administration to healthy volunteers.

The pharmacokinetics of rokitamycin tablets were studied in 12 healthy volunteers in a randomized cross-over design. The doses tested were 200 mg, 300 mg, 400 mg and 600 mg, as single oral administration. Rokitamycin was absorbed quickly with Tmax for all doses around 30 min after drug intake. Total AUC and Cmax values were linearly related to the administered dose. The buffer formulation determined a low interindividual variation. The overall findings show a good similarity with the data obtained in Japanese subjects. Tolerability was very good.

Pharmacokinetics of fluocinolone acetonide in patch versus cream formulations.

The pharmacokinetics of the fluocinolone acetonide patch containing 8 mcg/cm2 and a 0.025% cream were studied in a cross-over trial in 12 healthy volunteers 6 male and 6 female mean age 24.9 years. Each subject was treated with 0.8 mg of both fluocinolone acetonide formulations for 12 h on non-consecutive days. The high performance liquid chromatography method was used to determine the plasma and urine levels of the drug. Minor fluctuations in the plasma profile after patch application were observed, even if no significant difference was found between the two formulations with regard to peak plasma concentration, time to reach peak levels, area under the concentration curve and half-life.

[Study of intestinal absorption of calcium using 47Ca and whole body counter in renal calculosis with hypercalciuria]. / Studio dell'assorbimento intestinale del calcio mediante 47Ca e misure con whole body counter nella calcolosi renale con ipercalciuria.

Intestinal calcium absorption was studied using orally administered 47Ca and whole body counting. Using this method, we examined 82 patients suffering from recurrent calcium urolithiasis associated with idiopathic hypercalciuria, to evaluate the incidence of elevated intestinal absorption of this ion. An oral dose of 111 kBq (3 microCi) of 47Ca chloride, together with 250 mg of stable calcium as carrier, was given to each patient. Two hours and one week later, the total body radioactivity of each subject was measured. The retention of 47Ca, as percentage of the administered dose, was then calculated. The measurements were performed with a whole body counter consisting of a two-crystal moving system with shadow shield. Forty age-matched healthy volunteers were also examined. The whole body retention of 47Ca resulted significantly higher (p less than 0.0002) in the group of patients than in the control sample, whose m +/- SD was 22.0 +/- 6.0%. In particular, by defining the normality range as 10-34% (m +/- 2SD of control results), enhanced intestinal absorption of calcium was found in 28% of the examined patients. The use of this simple examination seems to be helpful in the physiopathologic assessment of subjects suffering from calcium urolithiasis and idiopathic hypercalciuria and consequently, in their appropriate management.

Intestinal calcium absorption in rheumatoid arthritis. A study using whole body counting.

Conflicting results are reported in the literature concerning the changes in intestinal calcium absorption in rheumatoid arthritis (RA). In the present work, intestinal calcium absorption was studied in 27 postmenopausal women with RA, using whole body counting as the study method and orally administered Ca-47 as the tracer. Nobody was on corticosteroid therapy, but all received non-steroidal anti-inflammatory drugs and hydroxy chloroquine or gold compounds. The mean calcium absorption was 22.3% of the dose administered, with a standard deviation of 8.0%. The results obtained were not significantly different from those of 40 age- and sex-matched controls (mean +/- SD: 22.0% +/- 6.0%). Our findings seem to exclude the hypothesis of calcium malabsorption as one of the causes leading to osteoporosis in RA.

Duration of immunity to hepatitis B vaccination in institutionalized mentally retarded patients.

Susceptible individuals of an institution for the mentally retarded (20 residents and six staff members) were vaccinated with Hevac B Pasteur (5 micrograms, months 0, 1, 2, 14). There were protective levels of anti-HBs in 75% of residents and 100% of staff members after 15 months from the first dose of the vaccine. After a 4-year follow-up period, there were persistent and protective levels of anti-HBs in 80% of residents, compared with 66% in staff members. In addition, no clinical hepatitis B infections were observed during this period.

The pharmacokinetics of clotiazepam after oral and sublingual administration to volunteers.

We have studied the single dose pharmacokinetics of 5 mg clotiazepam drops, oral tablets, and sublingual tablets in a cross-over study in 6 healthy volunteers (median age 28 years). The formulations had similar systemic availability. Compared with oral tablets the sublingual route gave a lower peak concentration and a delayed peak time, while drops gave a greater maximum concentration with a similar peak time. The use of drops is suggested for a more marked initial effect and the sublingual route for easier administration, especially in the elderly.

Effect of rokitamycin on human polymorphonuclear leukocyte chemotaxis.

The effect of rokitamycin on human polymorphonuclear leukocyte (PMNL) chemotaxis was studied in vitro and in vivo. It was found that rokitamycin in vitro at a concentration of 20 micrograms/ml caused a diminution of PMNL migration, while at lower concentrations no significant effects on migration was observed. In in-vivo studies before and after the ingestion of rokitamycin by six healthy individuals, no change on PMNL chemotaxis was found.

Temporal arteritis in seropositive rheumatoid arthritis with rheumatoid nodule.

A 61-year-old woman, suffering from classic seropositive rheumatoid arthritis with rheumatoid nodule histologically documented, developed temporal arteritis. HLA-DR typing revealed the presence of DR3 and DR4 antigens. The findings from previous studies support the association of HLA-DR antigens, giant cell arteritis-polymyalgia rheumatica and rheumatoid arthritis, and suggest the participation of a common immunogenetic mechanism in their pathogenesis.

Flurbiprofen versus ASA in influenza symptomatology: a double-blind study.

The effectiveness and safety of flurbiprofen 100 mg b.i.d. vs acetylsalicylic acid (ASA) 500 mg b.i.d. were evaluated in a 4-day double-blind study in 30 patients suffering from influenza. The antipyretic effect of flurbiprofen was similar to that of ASA. Upper and lower respiratory symptoms, gastrointestinal symptoms, articular and muscular pain and asthenia were improved by both drugs. Only one patient on ASA discontinued the treatment.