Platelet-activating factor receptor deficiency delays elimination of adult worms but reduces fecundity in Strongyloides venezuelensis-infected mice

We describe the parasitological kinetics and histopathological and immunological alterations in platelet-activating factor receptor-deficient (PAFR(-/-)) and wild-type mice after a single Strongyloides venezuelensis infection (subcutaneous inoculation of 500 L3 larvae). There was no difference in the numbers of worms that reached and became established in the small intestines of PAFR(-/-) and wild-type mice. However, at 12 days after infection, significantly more worms were recovered from PAFR(-/-) mice. Although PAFR(-/-) infected mice showed a delay in elimination of adult worms, worms established in the small intestine of these mice produced a significantly lower number of eggs due to a reduction in worm fecundity. There were also significant reductions in the number of circulating and tissue eosinophils and tumor necrosis factor levels in the small intestines of PAFR(-/-) mice infected for 7 days compared to the number and level in wild-type mice. Histological analysis confirmed the reduced inflammatory process and revealed that the PAFR(-/-) mice had a smaller number of goblet cells. The concentrations of the type 2 cytokines interleukin-4 (IL-4), IL-5, and IL-10 were lower in small intestine homogenates and in supernatants of antigen-stimulated lymphocytes from spleens or mesenteric lymph nodes of PAFR(-/-) mice than in the corresponding preparations from wild-type mice. Thus, in S. venezuelensis-infected PAFR(-/-) mice, decreased intestinal inflammation is associated with enhanced worm survival but decreased fecundity. We suggest that although a Th2-predominant inflammatory response decreases worm survival, the worm may use factors produced during this response to facilitate egg output and reproduction. PAFR-mediated responses appear to modulate these host-derived signals that are important for worm fecundity.     

Annexin A1 modulates natural and glucocorticoid-induced resolution of inflammation by enhancing neutrophil apoptosis

This study aimed at assessing whether AnxA1, a downstream mediator for the anti-inflammatory effects of GCs, could affect the fate of immune cells in tissue exudates, using LPS-induced pleurisy in BALB/c mice. AnxA1 protein expression in exudates was increased during natural resolution, as seen at 48-72 h post-LPS, an effect augmented by treatment with GC and associated with marked presence of apoptotic neutrophils in the pleural exudates. The functional relevance of AnxA1 was determined using a neutralizing antibody or a nonspecific antagonist at FPR/ALXRs: either treatment inhibited both spontaneous and GC-induced resolution of inflammation. Injection of Ac2-26 (100 μg, given 4 h into the LPS response), an AnxA1-active N-terminal peptide, promoted active resolution and augmented the extent of neutrophil apoptosis. Such an effect was prevented by the pan-caspase inhibitor zVAD-fmk. Mechanistically, resolution of neutrophilic inflammation was linked to cell apoptosis with activation of Bax and caspase-3 and inhibition of survival pathways Mcl-1, ERK1/2, and NF-κB. These novel in vivo data, using a dynamic model of acute inflammation, provide evidence that AnxA1 is a mediator of natural and GC-induced resolution of inflammation with profound effects on neutrophil apoptosis.     

Thermographic evaluation of hind paw skin temperature and functional recovery of locomotion after sciatic nerve crush in rats

INTRODUCTION:

Peripheral nerves are often damaged by direct mechanical injury, diseases, and tumors. The peripheral nerve injuries that result from these conditions can lead to a partial or complete loss of motor, sensory, and autonomic functions, which in turn are related to changes in skin temperature, in the involved segments of the body. The aim of this study was to evaluate the changes in hind paw skin temperature after sciatic nerve crush in rats in an attempt to determine whether changes in skin temperature correlate with the functional recovery of locomotion.

METHODS:

Wistar rats were divided into three groups: control (n = 7), sham (n = 25), and crush (n = 25). All groups were subjected to thermographic, functional, and histological assessments.

RESULTS:

ΔT in the crush group was different from the control and sham groups at the 1^st, 3^rd and 7^rd postoperative days (p<0.05). The functional recovery from the crush group returned to normal values between the 3^rd and 4^th week post-injury, and morphological analysis of the nerve revealed incomplete regeneration at the 4^th week after injury.

DISCUSSION:

This study is the first demonstration that sciatic nerve crush in rats induces an increase in hind paw skin temperature and that skin temperature changes do not correlate closely with functional recovery     

Lactobacillus plantarum culture supernatants improve intestinal tissue exposed to deoxynivalenol

In the present study, histological, morphometrical and ultrastructural analysis were performed to investigate intestinal mucosa changes in piglets exposed to deoxynivalenol alone or associated with two strains of Lactobacillus plantarum and the respective culture supernatants. Jejunal explants were incubated for 4 h in culture medium with a) only culture medium (DMEM, control group), b) deoxynivalenol (DON, 10 μM), c) heat-inactivated Lactobacillus plantarum strain1 ? LP1 (1.1 × 10⁸ CFU/ml) plus DON, d) heat-inactivated Lactobacillus plantarum strain2–LP2 (2.0 × 10⁹ CFU/ml) plus DON, e) heat-inactivated Lactobacillus plantarum strain1 culture supernatant (CS1) plus DON, and f) heat-inactivated Lactobacillus plantarum strain1 culture supernatant (CS1) plus DON. Explants exposed to DON and DON plus LP1 and LP2 showed a significant increase in histological changes (mainly villi atrophy and apical necrosis) and a significant decrease in villi height when compared to unexposed explants. However, explants treated with CS1 + DON and CS2 + DON remained similar to the control group both in histological and morphometrical aspects. DON also induced a significant decrease in goblet cell density compared to control whereas CS1 + DON treatment induced an increase in the number of goblet cells in comparison to DON explants. In addition, ultrastructural assessment showed control, CS1 + DON and CS2 + DON explants with well delineated finger shape villi, meanwhile DON-treated, LP1 + DON and LP2 + DON explants showed a severe villi atrophy with leukocytes exudation on the intestinal surface. Taken together, our results indicate that the culture supernatant treatment reduced the toxic effects induced by DON on intestinal tissue and may contribute as an alternative strategy to reduce mycotoxin toxicity.     

Myxovirus resistance,osteopontin and suppressor of cytokine signaling 3 polymorphisms predict hepatitis C virus therapy response in an admixed patient population: comparison with IL28B

OBJECTIVES:

Suppressor of cytokine signaling 3, myxovirus resistance protein and osteopontin gene polymorphisms may influence the therapeutic response in patients with chronic hepatitis C, and an association with IL28 might increase the power to predict sustained virologic response. Our aims were to evaluate the association between myxovirus resistance protein, osteopontin and suppressor of cytokine signaling 3 gene polymorphisms in combination with IL28B and to assess the therapy response in hepatitis C patients treated with pegylated-interferon plus ribavirin.

METHOD:

Myxovirus resistance protein, osteopontin, suppressor of cytokine signaling 3 and IL28B polymorphisms were analyzed by PCR-restriction fragment length polymorphism, direct sequencing and real-time PCR. Ancestry was determined using genetic markers.

RESULTS:

We analyzed 181 individuals, including 52 who were sustained virologic responders. The protective genotype frequencies among the sustained virologic response group were as follows: the G/G suppressor of cytokine signaling 3 (rs4969170) (62.2%); T/T osteopontin (rs2853744) (60%); T/T osteopontin (rs11730582) (64.3%); and the G/T myxovirus resistance protein (rs2071430) genotype (54%). The patients who had ≥3 of the protective genotypes from the myxovirus resistance protein, the suppressor of cytokine signaling 3 and osteopontin had a greater than 90% probability of achieving a sustained response (p<0.0001). The C/C IL28B genotype was present in 58.8% of the subjects in this group. The sustained virological response rates increased to 85.7% and 91.7% by analyzing C/C IL28B with the T/T osteopontin genotype at rs11730582 and the G/G suppressor of cytokine signaling 3 genotype, respectively. Genetic ancestry analysis revealed an admixed population.

CONCLUSION:

Hepatitis C genotype 1 patients who were responders to interferon-based therapy had a high frequency of multiple protective polymorphisms in the myxovirus resistance protein, osteopontin and suppressor of cytokine signaling 3 genes. The combined analysis of the suppressor of cytokine signaling 3 and IL28B genotypes more effectively predicted sustained virologic response than IL28B analysis alone.     

Effect of hepatic dysfunction on oral cyclosporin pharmacokinetics in marrow transplant patients

The effect of hepatic dysfunction, defined as abnormal serum bilirubin level, on oral cyclosporin (CSP) pharmacokinetics was examined in 28 marrow transplant patients who received CSP for prophylaxis of graft-v- host disease. Serum CSP concentrations were measured by radioimmunoassay. Forty-one concentration-time courses were studied, divided among patients with no (less than 1.2 mg/dL), mild (1.2 to 2.0 mg/dL), and moderate (2.0 to 5.0 mg/dL) hepatic dysfunction. CSP elimination, as determined by elimination rate constant and clearance, was delayed in patients with moderate hepatic dysfunction compared to those with no hepatic dysfunction (P less than .05). The volume of distribution, lag time for absorption, maximum serum concentration, and time at which the maximum concentration was achieved was not affected by hepatic function. These data indicate that patients with moderate hepatic dysfunction have delayed CSP or CSP metabolite elimination and may be at higher risk for developing CSP-related toxicity.     

Effects of Estrogen Deficiency and/or Caffeine Intake on Alveolar Bone Loss,Density, and Healing: A Study in Rats

Background: The aim of this study is to evaluate the effects of caffeine and/or estrogen deficiency on ligature‐induced bone loss (BL), trabecular bone area (TBA), and postextraction bone healing (BH). Methods: Rats were assigned into one of the following groups (15 each): 1) control = non‐ingestion of caffeine/sham surgery; 2) caffeine = ingestion of caffeine/sham surgery); 3) ovariectomized (OVX) = non‐ingestion of caffeine/ovariectomy; or 4) caffeine/OVX = ingestion of caffeine/ovariectomy. The rats were under caffeine administration for 65 days and/or estrogen deficiency for 51 days. On day 21 after ovariectomy, one first mandibular molar received a ligature and the contralateral tooth was not ligated. The first maxillary molars were extracted 8 days before sacrifice. BL, TBA, the positive cells for tartrate‐resistant acid phosphatase (TRAP), receptor activator of nuclear factor‐κB ligand (RANKL), and osteoprotegerin (OPG) were analyzed in the furcation area of mandibular molars. Histometric BH and gene expression of bone morphogenetic protein (BMP)‐2, BMP‐7, osteopontin, and bone sialoprotein were evaluated in alveolar sockets. Results: The caffeine group presented the greatest BL and the OVX group the highest number of TRAP‐positive (TRAP⁺) cells around ligated teeth (P <0.05). The control group presented higher TBA and BH than the other groups (P <0.05). All test groups presented higher RANKL/OPG⁺ cells than the control group around ligated/unligated teeth. The OVX and caffeine/OVX groups presented a greater number of TRAP⁺ cells around unligated teeth than the control group (P <0.05). There were no differences among groups for gene expression (P >0.05). Conclusions: Caffeine increased BL in ligated teeth. Caffeine and/or estrogen deficiency decreased TBA in the unligated teeth and reduced BH after tooth extraction.     

A Simplified Palatal Lift Prosthesis for Neurogenic Velopharyngeal Incompetence

Velopharyngeal incompetence is a contributing factor to speech disorders and implies the presence of hypernasality, inappropriate nasal escape, and decreased air pressure during speech. One prosthetic treatment is a rehabilitative procedure employing a palatal lift prosthesis (PLP), which reduces hypernasality by approximating the incompetent soft palate to the posterior pharyngeal wall and consists of two parts, the anterior denture base and the palatal lifting plate, which are connected with steel wires; however, it seems difficult to reproduce the mobility of the soft palate in speaking, and it is therefore likely that the palatal lifting plate stimulates or oppresses the tissue of the soft palate and hinders rather than assists articulatory function. To avoid these disturbances we devised an adjustable PLP with a flexible conjunction between the denture base and the palatal lifting plate to obtain the optimal vertical lifting angle. The palatal plate was adapted to conform in a passive manner to the soft palate with light‐cured resin. The designed PLP simplified the procedure and reduced the number of adjustments and visits.     

Long-term results of anorectal myectomy for chronic constipation

Anorectal myectomy has been shown to provide clinical benefit to patients with outlet obstruction. Long-term results of anorectal myectomy have been evaluated in 57 patients operated on between February 1984 and February 1988 with a median follow-up of 24 months. Overall improvement was recorded in only 31 percent of patients. Spontaneous evacuation without the need for laxatives was recorded in only 11 patients (19 percent), while 38 (67 percent) had no functional improvement. Results were independent of preoperative colonic transit or histologic evidence of aganglionosis. Anorectal myectomy identified aganglionosis in 23 percent of patients with chronic constipation, but there was minimal long-term benefit from the procedure.     

Videoproctographic assessment after restorative proctocolectomy

Videoproctography was performed in 40 patients after restorative proctocolectomy to evaluate pouch emptying, anopouch angle, and pelvic floor movement in relationship to functional outcome. Results were compared between the two different pouch designs tested and a control group of 26 patients who had an intact rectum. There was no difference in emptying between the two pouch designs or compared with the control subjects. Emptying did not influence either the frequency of defecation or patient soiling rate. The presence of an anal stricture was associated with poor emptying in each case in the pouch group. Anorectal angle was no different between the different pouch designs or compared with the control group at rest, during pelvic floor contraction, or attempted defecation. A similar finding was obtained with anorectal angle position and movement during pelvic floor contraction and attempted defecation in both pouch design groups and when compared with normal rectum. This study shows that the only factor that is consistently associated with poor pouch emptying is the presence of an anal stricture.Read at the meeting of The American Society of Colon and Rectal Surgeons, Toronto, Canada, June 11 to 16, 1989.