The effects and pharmacokinetics of rhG-CSF on the treatment of neutropenia in patients with renal failure]

rhG-CSF (recombinant human granulocyte colony stimulating factor) promotes production and release of neutrophil from bone marrow, and it enhances neutrophil function. In this study, the pharmacokinetics, effects on neutrophil and immune functions and efficacy and safety of rhG-CSF were studied in patients with end-stage renal failure (CRF). To 9 patients with CRF; 2 patients on conservative therapy and 7 patients under regular hemodialysis, 50 micrograms/m2 rhG-CSF were administered intravenously under the schedule of single or 2 week consecutive injection. In single injection study, serial changes in plasma rhG-CSF concentration and peripheral blood cell count were examined following the administration. In consecutive injection study, plasma rhG-CSF concentration, anti-rhG-CSF antibody, peripheral blood cell counts, blood chemistry and coagulation factors, and neutrophil and immune functions were examined. As the results, 1) Half life of rhG-CSF, 2.87 +/- 0.65 hr, was about 2 times longer than that in healthy subjects, and it was not affected by hemodialysis treatment. 2) Marked increase in leukocyte and neutrophil counts and mild increase in lymphocyte count were observed during single and consecutive administration of rhG-CSF. There was no significant change in other leukocyte differentiations, RBC, or platelet count. 3) Neutrophil alkaline phosphatase score increased significantly during single and consecutive administration, and other neutrophil function also improved in several patients with impaired neutrophil function. 4) Slight bone pain and increase in serum alkaline phosphatase were observed in about a half of patients during consecutive injection study. Neither antibody nor accumulation of rhG-CSF was noted.(ABSTRACT TRUNCATED AT 250 WORDS)     

In-vivo enhancement of neutrophil function by administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in cyclophosphamide (CPA) treated mice]

The in-vivo effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on the number and function (phagocytosis and superoxide production) of peripheral neutrophils were studied in time sequence in cyclophosphamide (CPA) treated mice. The neutrophil function was evaluated by the phagocytosis of fluorescent particles, analyzing the number of fluorescence-positive cells and the fluorescence intensity of each neutrophil by flow cytometry and also by the superoxide production, measuring chemiluminescence of the leukocyte suspension by a photometer. In CPA-treated (100 mg/kg) mice, the neutrophil function including both the phagocytosis and the superoxide production declined significantly (p less than 0.01) as the peripheral neutrophil count (PNC) decreased, reached the nadir on the same day as PNC and returned to the normal level 8 days after first CPA treated day (day 0). When rhG-CSF (100 micrograms/kg) was administered subcutaneously daily for 5 consecutive days initiating at day 1, a decrease in PNC and a decline in the neutrophil function were prevented and a significant (p less than 0.05-p less than 0.01) increase of PNC was observed after day 4. In addition, the function of increased neutrophils was significantly (p less than 0.05-p less than 0.01) enhanced after day 4 and even at day 3, when an increase in PNC was not observed yet. The study shows that rhG-CSF appears to enhance neutrophil function by a direct effect on mature neutrophils, which have been impaired by CPA at the phase of progenitor cells in the bone marrow and subsequently have appeared in the peripheral blood and that rhG-CSF is effective on the impaired host defense mechanism in CPA-treated mice, improving not only drug-induced neutropenia but also the deteriorated function of neutrophils.     

Effect of L-NAME on decreased ileal muscle contractility induced by peritonitis in rats

Background/Purpose: It is now well established that intestinal inflammation is associated with disturbed contractility. The aim of this study was to determine the effects of peritonitis on longitudinal ileum smooth muscle responses to KCl, carbachol and substance P (SP) and to examine the role of nitric oxide (NO) and N_omega-nitro-L-arginine methylester (L-NAME) on ileal contractility in this peritonitis model. Methods: Peritonitis was induced by cecal ligation and puncture (CLP) in 20 rats. While 10 of these received 1 mL distilled water as placebo, the other 10 received 5 mg/kg (subcutaneously) L-NAME before the operation. Another group of 10 rats underwent a sham operation. Twenty-four hours after the operation, the rats were killed, and their ileum was excised. Ileum segments were placed in longitudinal direction in a 10-mL organ bath; concentration-response relationship for KCl, carbachol, and SP were obtained by adding the reagent cumulatively to the bath. Results: The KCl-, carbachol-, and SP-induced contractions were decreased markedly, with no change in the pD₂ values in the peritonitis group compared with controls. Peritonitis-induced changes in the contractile responses were restored significantly by in vivo L-NAME pretreatment. Conclusions: The model of CLP-induced peritonitis in rats showed that KCl-induced nonreceptor-mediated, carbachol- and SP-induced receptor-mediated contractions are significantly decreased by inflammation in the longitudinal ileum muscle. Increased synthesis of NO may be responsible for these decreases in contractile responses because they were restored significantly by in vivo L-NAME injection. Inhibition of NOS with L-NAME injection may afford a new therapeutic approach to the treatment of gastrointestinal stasis in septic patients. J Pediatr Surg 37:901-905.     

Cyclosporin A-induced tolerance is not amplified by the addition of a steroid therapy

The effect of adding steroids to a cyclosporin A (CyA) schedule designed to induce tolerance to heart allografts in rats was investigated. CyA treatment alone, at a dose of 15 mg/kg per day for 2 weeks, resulted in the successful induction of tolerance (graft survival>100 days) in 70% of the rats. The inclusion of 5 mg/kg of steroids (Solumedrone), administered IM for 40 or 60 days, not only failed to improve this long-term survival (LTS) rate achieved with CyA alone but reduced it from 70% to 50% after 40 days of steroid treatment and to 30% after 60 days of steroid treatment. The administration of 5 mg/kg and 40 mg/kg of steroids during the high-risk period for graft rejection (days 30–50 or 40–60) was shown to delay but not prevent subsequent rejections from occurring. Steroid treatment alone (5 mg/kg per day) was found to be only weakly immunosuppressive. Thus, we have demonstrated that the addition of steroids to a CyA tolerizing schedule was detrimental to the induction of tolerance.     

Suppression of T cells results in long-term survival of mouse heart xenografts in C6-deficient rats

Abstract: The present study aimed to investigate the role of cellular immune response in the absence of membrane attack complex (MAC) formation in the concordant mouse‐to‐rat heart xenografting. Hearts from BALB/c mice were transplanted into the neck vessels of C6‐competent (C6⁺) and C6‐deficient (C6^?) PVG rats. Liposome‐encapsulated dichloro‐methylene diphosphonate (Lip‐Cl₂MDP) was administered at a dose of 10 ml/kg 2 days before transplantation and every 5 days thereafter. Cyclosporine (CsA) was administered intramuscularly (i.m.) at a dose of 15 mg/kg per day. The heart xenografts were harvested for immuno‐histological analysis at the time of rejection and the functioning grafts were removed at 70 days after transplantation. In untreated C6⁺ rats, xeno‐grafts survived for 2.3 ± 0.5 days. Treatment with CsA or Lip‐Cl₂MDP in C6⁺ rats did not significantly affect graft survival (2.5 ± 0.6 and 2.3 ± 0.4 days, respectively). In untreated C6^? rats, xenografts survived for 5.0 ± 0.6 days. However, Lip‐Cl₂MDP in C6^? rats resulted in a prolongation of graft survival to 11 ± 2.3 days (P < 0.05 vs. untreated C6^? rats), while treatment with CsA alone in these rats led to more than 70 days' survival in four out of six grafts (61 ± 16 days). In untreated C6⁺ rats, immunohistology showed a severe myocardial necrosis and thrombosis with a scarce cellular infiltrate in the rejected xenografts. By contrast, in untreated C6^? rats, xenografts were heavily infiltrated by macrophages and T cells. The number of macrophages, but not T cells, was markedly reduced in Lip‐Cl₂MDP‐treated rats. In CsA‐treated C6^? rats, the grafts harvested at 70 days after transplantation had a normal morphology, with a minimal cellular infiltrate. Our data indicate that MAC‐mediated injury plays an essential role in concordant xenograft rejection. Once this mechanism has been prevented, suppression of T cells allows for long‐term xenograft survival.     

Reversal of cyclosporine-induced mortality with a synthetic polymeric immunostimulant in a murine model of fecal peritonitis

We have been investigating the effects of a synthetic immunostimulative polymer known as copovithane (Cpv). This agent appears to enhance humoral immunity in untreated and cyclosporine-immunosuppressed mice and is nontoxic in rodents and man. The purpose of this study was to determine whether cyclosporine (CsA) is deleterious to survival in a murine cecal ligation, puncture, and excision (CLPE) model of fecal peritonitis, and--if so--whether this effect could be ameliorated by Cpv without interfering with skin allograft acceptance. Cpv significantly prolongs survival in the CLPE model; the optimal dose for this effect was found to be 100 mg/kg. CsA was found to have a significant and deleterious effect on survival at several dosage levels when administrated 48 and 24 hr before cecal ligation, and immediately before and 16 hr after cecal ligation. Using a dose of CsA sufficient for skin allograft acceptance and the same schedule of administration outlined above, Cpv 100 mg/kg was administered 48 hr prior to cecal ligation. Mice treated with CsA plus Cpv had significantly longer survival than mice treated with CsA alone; furthermore, the survival of CsA-plus-Cpv-treated animals was not significantly different from that of saline-treated controls. Acceptance and survival of H-2 incompatible skin allografts in mice treated with CsA were not affected by Cpv 100 mg/kg/week. We conclude that CsA-induced mortality in the CLPE model can be abrogated by Cpv without adversely affecting skin allograft survival. It may eventually be possible to reduce the incidence of septic complications in clinical allotransplantation by prophylactically administering Cpv to patients on CsA immunosuppression.     

The platelet activating factor as a pivotal mediator of shock after liver ischemia

Liver failure is often accompanied by shock, which is usually refractory to conventional vasopressive therapy, and it is believed that some potent chemical mediators are involved in this process. The platelet activating factor (PAF) is a newly discovered inflammatory mediator that has a remarkable hypotensive action. In the present study, the possible role of PAF in shock after ischemic liver failure was investigated. Partial hepatic ischemia was induced in Wistar rats by clamping the hepatic afferent vessels to almost 70% of the whole liver for 90 min. One group of rats was pretreated with 10 g/kg of TCV-309, a PAF antagonist. Pretreatment with TCV-309 inhibited the shock that ultimately occurred in the untreated rats; the survival rate 16h after hepatic ischemia was 20% in the untreated control group but 100% in the group pretreated with TCV-309. The level of PAF in the plasma after hepatic ischemia was 2,939±2,412 pg/ml, which was significantly higher than that of the surgical control (920±188 pg/ml). These findings strongly suggest that anoxical disintegration of the liver derives PAF which causes shock. Thus, a PAF antagonist is expected to be an effective prophylactic treatment for patients who are at risk of developing shock from an ischemic liver.     

The ability of polymorphonuclear leukocytes to produce active oxygen in a model of peritonitis in rats

To elucidate the mechanism of enhancing survival in peritonitis rats treated with lentinan, a fully purified beta-1,3-glucan, we measured the active oxygen-producing ability of polymorphonuclear leukocytes (PMNs). Four groups of rats (group I, fecal peritonitis control; II, rats receiving 3 mg/kg lentinan intraperitoneally at the same time as peritonitis induction; III, rats receiving 1 mg/kg gentamicin intramuscularly; and IV, rats receiving combined lentinan-gentamicin treatment) were used. The survival period was significantly longer in group IV than in the other three groups. The ability of ascitic PMNs to produce active oxygen (superoxide, H₂O₂, myeloperoxidase) was significantly more than that of blood PMNs in each group at 20 h after peritonitis induction. The increase in active oxygen production in ascitic PMNs was higher in group IV compared with that in the other three groups. The concentration of lentinan in the blood was high at 24 h after administering lentinan intraperitoneally to both the normal and peritonitis rats. In the in vitro study, the superoxide production in normal rat blood PMNs was significantly higher in the presence of cytokines (IL-1 beta, IL-6, TNF-alpha) without dose-dependence but was not higher for the lentinan group than in the control. This study therefore suggests that lentinan activated the peritoneal macrophage secretory activity and produced cytokines which thus enhanced the ability of PMNs to produce active oxygen, which possesses a bactericidal ability in PMNs.     

The in vivo effect of a new,in vitro,extremely potent vitamin D3 analog KH1060 on the suppression of renal allograft rejection in the rat

KH1060 is a new 20-epi-vitamin D₃ analog, which has exerted a considerable immunosuppressive potency in vitro. We have tested in vivo the effect of KH1060 on the suppression of renal allograft rejection in the rat. Allogenic kidney transplantation from DA donor rats to Lewis recipient rats treated intraperitoneally with KH1060 in doses from 0.2 to 6 g/kg/day, or saline (placebo group), or CyA 10 mg/kg/day for 10 days (positive control group), was performed. Median graft survival time in KH1060-treated groups was 7–9 days, in the placebo group 6 days, whereas CyA led to long-term graft survival, 34 days in 50% of rats and >100 days in 50% of rats. In vivo, KH1060 failed to prolong renal allograft survival considerably, and led to development of hypercalcemia. Our results stress the existence of a large discrepancy between the in vitro and in vivo immunoregulatory effects of this vitamin D analog.     

Effect of prenatal glucocorticoids and postnatal nitric oxide inhalation on survival of newborn rats with nitrofen-induced congenital diaphragmatic hernia

Background/Purpose: Pulmonary hypertension and pulmonary hypoplasia account for the high mortality rate associated with congenital diaphragmatic hernia (CDH). In animal models of CDH, postnatal nitric oxide (NO) inhalation resulted in significantly better survival rates and antenatal glucocorticoid administration in improved lung compliance. The objective of this study was to evaluate the combined effect of prenatal glucocorticoid administration and postnatal NO inhalation on the survival rate of newborn rats with nitrofen-induced CDH. Methods: Right-sided CDH was induced by maternal administration of a single oral dose (100 mg, intraperitoneally) of nitrofen on day 11.5 of pregnancy. Dexamethasone (DEX, 0.25 mg/kg) was given in groups III and IV by maternal intraperitoneal injection on day 18.5 and 19.5 of pregnancy. Control animals (groups I and II) received vehicle alone. After spontaneous delivery, the newborn animals were exposed to either NO (80 ppm; groups II and IV) or room air (groups I and III). Vitality (Rat-Score), sO₂ and survival were monitored continuously for 12 hours until animals were killed. Hernia size was estimated as percentage of total thoracic content. Results: Right-sided CDH was observed in 392 of 491 newborn rats (81%). Animals with large hernias ([gt ]50%) died within 4 hours after birth, irrespective of treatment. Hernias with less than 50% of the thoracic volume were considered clinically relevant hernias. In this category, 12.5% of animals without treatment (group I) survived compared with 63.6% after NO treatment alone (group II; P [lt ] .01). Survival rate after DEX treatment alone (group III) was 69.4% (group III v I; P [lt ] .01). In group IV (DEX and NO) 95.2% of the animals survived (group IV v I; P [lt ] .001). In contrast to DEX alone, NO administration resulted in significantly better sO₂(group II and IV) compared with group I (P [lt ] .05). Conclusion: Combination of prenatal maternal glucocorticoids and postnatal NO inhalation significantly improved survival rate of newborn rats with nitrofen-induced CDH.     

Additive effect of an immunomodulator and broad-spectrum antibiotic in fecal peritonitis

We examined the effect of muramyl dipeptide (3 micrograms/g body weight) and a broad-spectrum antibiotic cefoxitin (15 mg/kg) on survival and systemic bacteremia in rats with peritonitis. When muramyl dipeptide given 24 hours prior to placement of the bacterial inoculum was combined with a single prophylactic dose of cefoxitin, survival was 100 percent (p less than 0.001) and systemic bacteremia at 4 hours postinoculation was significantly decreased. Twenty-four hour pretreatment with either muramyl dipeptide alone or cefoxitin alone was associated with survival rates of 43 percent and 56 percent, respectively. When muramyl dipeptide was given with cefoxitin at the time of administration of the bacterial inoculum, no survival advantage was seen over the use of cefoxitin alone. There were no significant differences among groups in quantitative bacteremia at 24 hours postinoculation or in the number of intraabdominal abscesses. This study clearly demonstrates an additive effect of muramyl dipeptide pretreatment given with a prophylactic dose of cefoxitin in a human fecal peritonitis rat model.     

Effects of combined treatment of tadalafil and tamsulosin on bladder dysfunction via the inhibition of afferent nerve activities in a rat model of bladder outlet obstruction

Purpose

To investigate the effects of combined treatment of tadalafil (a phosphodiesterase-5 inhibitor) and tamsulosin (an α₁-adrenoceptor antagonist) on bladder dysfunction in a rat model of bladder outlet obstruction (BOO).

Methods

Cystometry was performed in conscious female BOO rats 6 weeks after partially ligation of the urethra. Either tadalafil (0.03, 0.1 and 0.3 mg/kg) or tamsulosin (0.001, 0.003 and 0.01 mg/kg) was cumulatively applied intravenously at 30-min intervals to examine changes in cystometric parameters and blood pressures. Changes in cystometric parameters and blood pressures were also checked when tadalafil (0.3 mg/kg), tamsulosin (0.003 mg/kg) or both were intravenously applied.

Results

In BOO rats, application of either tadalafil (0.3 mg/kg) or tamsulosin (0.003, 0.01 mg/kg) alone significantly increased threshold pressures and intercontraction intervals whereas there were no significant changes in other cystometric parameters. In addition, because a significant reduction in blood pressures was detected after the administration of tamsulosin (0.01 mg/kg), tamsulosin at a lower dose (0.003 mg/kg) was used for the combined treatment. The combination therapy of tadalafil and tamsulosin induced a significantly larger rate of increase in intercontraction intervals (1.7 times) compared with monotherapy of either drug (1.3 times each) although the combined therapy did not affect blood pressures.

Conclusions

These results suggest that the combination therapy of tadalafil and tamsulosin can induce the additive inhibitory effects on urinary frequency compared with monotherapy, more likely via inhibition of the afferent limb of micturition reflex rather than the efferent function as evidenced by the increases in threshold pressures and intercontraction intervals without affecting bladder contractile function.

     

Effect of 1α-vitamin D3 on bone strength and composition in growing rats with and without corticosteroid treatment

The effects of 1-vitamin D₃ were studied for 6 months in 2-month-old male and female rats on a moderately low calcium diet with or without low-dose prednisolone treatment. Both cortical bone mechanical and biochemical properties were examined. Femoral bone specimens were subjected to torsional loading tests. With age, bone strength and stiffness increased in both sexes, accompanied by an increased degree of mineralization (bone ash and calcium concentrations). During growth, strength and stiffness increased more in male than in female rats. When 1-vitamin D₃ (0.5 g/kg/day) was given alone, bone mechanical competence improved significantly whereas insulin-like growth factor-I (IGF-I) and calcium concentrations in the bone matrix were significantly reduced. Treatment with low-dose prednisolone (0.5 mg/kg/day) alone did not influence bone mechanical properties compared with intact control rats (without prednisolone) although a significant reduction in calcium concentration and an increased phosphorus concentration were measured. A combined therapy with prednisolone and 1-vitamin D₃ significantly increased bone strength, toughness, and stiffness compared with control bones. Both mineralization degree (ash and calcium concentration) and IGF-I concentration were decreased.We conclude that (1) mechanical properties of rat cortical bones improve relatively more in males compared with agematched females during growth which is related to increased bone mass and size, (2) low-dose prednisolone treatment does not change mechanical properties in males, and altered them only nonsignificantly in females despite a change in mineralization degree in both sexes; (3) treatment with 1-vitamin D₃ results in a consistent increase in mechanical competence of the bone accompanied by a significant decrease in IGF-I concentration in the bone matrix.     

Effect of parathyroid hormone on hypogonadism induced bone loss of proximal femur of orchiectomized rat

Purpose

Management of hypogonadism-induced osteoporosis in elderly men is still a challenge. We investigated the short-term effects of parathyroid hormone (PTH) treatments on strength, micro-architecture, and mineral density of trochanteric region of orchiectomized rat femur.

Methods

Eight-month-old male Sprague?CDawley rats (n?=?44) were divided into two groups: (1) orchiectomized (ORX) and (2) sham group. Twelve weeks after orchiectomy, half of the orchiectomized animals were treated with daily subcutaneously injected PTH (0.040?mg/kg/BW) (ORX-PTH) for 5?weeks. The other half remained untreated (ORX). The sham-operated group was divided and treated in the same way (sham, sham-PTH). After 5?weeks, both femurs were excised for biomechanical and histomorphometric analysis, trabecular measurements, mineral content assessment, and immunofluorescence analysis.

Results

The femoral trochanteric strength after PTH treatment was enhanced in the breaking test (ORX-F_max?=?158.7?N vs. ORX?+?PTH-F_max?=?202?N). Stiffness of treated ORX animals reached nearly the levels observed in untreated sham rats. PTH therapy improved the trabecular connectivity, width, and area (ORX-Tb.Ar?=?47.79% vs. ORX?+?PTH-Tb.Ar?=?68.47%, P?<?0.05) in the proximal femur. The treated rats showed significantly improved mineral content in ashed femurs (ORX-mineral content?=?43.73% vs. ORX?+?PTH-mineral content?=?49.49%) when compared to the untreated animals. A comparison of widths of fluorescence bands in cortical bone of the subtrochanteric cross-sections showed a significant increase in oppositions after the PTH therapy.

Conclusions

Our finding supports the hypothesis that PTH therapy seems to be a rational therapy in patients with hypogonadism induced bone loss and improves the bone strength of trochanteric region of rat femur.     

Oxychlorine species suppress postsurgical adhesions in rats

Background

Surgically induced adhesions complicate up to 100% of abdominal surgeries. Food and Drug Administration–approved treatments are generally not only less effective than desired but they also have major contraindications. Oxychlorine species, including chlorine dioxide (ClO₂), suppress scar formation in infected wounds without affecting keratinocytes while reducing fibroblast proliferation. The aim of the present study was to evaluate the effect of oxychlorine solutions containing ClO₂ on adhesion formation.

Methods

Male Wistar rats were subjected to Buckenmaier model of surgical adhesions and treated with either oxychlorine solutions containing ClO₂ (40–150 ppm) or isotonic saline solution. To increase the severity of adhesions, peritonitis was produced by intraperitoneal administration of a diluted nonlethal dose of feces (50 mg/kg). Wound strength of the healed wound was measured to evaluate the effects of oxychlorine solutions. In addition, an oxychlorine solution of lesser efficacy (at 100 ppm) was compared with three available anti-adhesion materials.

Results

Reproducibility of the model was validated in 26 rats. Oxychlorine solutions containing ClO₂ (40–110 ppm) significantly reduced postsurgical adhesion formation without affecting the strength of the healed wound. Higher concentrations (120 and 150 ppm) had no effect. Fecal peritonitis significantly increased, and solutions with ClO₂ at 110 ppm significantly reduced adhesion formation. The effect of the oxychlorine solution was significantly greater than that of Interceed, Guardix, Seprafilm, and isotonic saline solution.

Conclusions

ClO₂-containing oxychlorine solutions could be an innovative strategy for the suppression of surgical adhesion formation, with the additional advantage of contributing antiseptic properties.     

Clinical significance of preoperative peripheral blood neutrophil count in patients with non-metastatic upper urinary tract carcinoma

Purpose

Preoperative elevation of markers of systemic inflammation is associated with a poor outcome in several cancers. The purpose of this study was to evaluate the prognostic significance of preoperative systemic inflammatory markers in patients with non-metastatic upper urinary tract cancer (UUTC).

Methods

The records of 84 patients with non-metastatic UUTC who had undergone nephroureterectomy were reviewed, and the associations between preoperative clinical variables and recurrence-free survival (RFS) were analyzed by univariate and multivariate analyses.

Results

Clinical tumor stage, neutrophil count, and neutrophil-to-lymphocyte ratio were significantly associated with RFS in univariate analysis. Multivariate analysis showed that clinical T stage (hazard ratio [HR], 3.009; 95 % confidence interval [CI], 1.149–9.321; p = 0.024) and neutrophil count (HR, 3.521; 95 % CI, 1.423–9.108; p = 0.007) were independent predictors of RFS. The 3-year RFS in patients with a neutrophil count <4,000/μL was significantly higher than that in patients with a neutrophil count ≥4,000/μL (82.9 vs. 51.0 %, p = 0.004). Based on clinical T stage (T2 or less vs. T3 or greater) and neutrophil count (<4,000 vs. ≥4,000/μL), patients were stratified into 3 groups: low, intermediate, and high risk groups. RFS rates were significantly different between the 3 groups (p = 0.0005).

Conclusions

Preoperative neutrophil count was an independent predictor of RFS in patients with non-metastatic UUTC. Stratification of patients based on neutrophil count and clinical T stage may be valuable for preoperative patient counseling and identifying patients with poor prognosis who may be candidates for neoadjuvant chemotherapy.     

The treatment of experimental peritonitis with intraperitoneal betadine solution

Betadine (polyvinylpyrrolidone-iodine) antiseptic solution was evaluated as to safety and efficacy on intraperitoneal application in 220 rat experiments, and compared with cephalothin and kanamycin solutions as intraperitoneal antimicrobial agents. We found that intraperitoneal Betadine solution is apparently safe to rats at doses of 2.5 ml/kg or less as regards acute and chronic toxicity. In experimental peritonitis, intraperitoneal Betadine solution produced significantly increased survival (P < 0.0001) over untreated controls, and was as effective as intraperitoneal cephalothin or kanamycin in a monomicrobial peritonitis. Intraperitoneal Betadine solution is well absorbed. Our results suggest that further studies of this application of Betadine solution are indicated.     

Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic renal cell carcinoma treated with first-line and subsequent second-line targeted therapy: A proposal of the modified-IMDC risk model

Purpose

The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model has been designed for prognostification in patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy. One factor is neutrophil count; however, increasing evidence has suggested the superiority of neutrophil-to-lymphocyte ratio (NLR) for predicting outcome. In this study, we evaluate the prognostic effect of NLR levels on patients with mRCC treated with targeted therapy, and then we compare the predictive accuracy of the IMDC risk model and its modified one by using NLR, instead of neutrophil count.

Enhanced survival in antibiotic-treated murine fecal peritonitis by administration of copovithane, a selective immunostimulative polymer

The purpose of this study was to determine the effect of an immunostimulative polymer, Copovithane (Cpv), plus antibiotics (netilmicin and clindamycin) in a murine model of fecal peritonitis. Cpv augments humoral immunity with little effect on T cells and is nontoxic. Cpv 100 mg/kg iv administered at the onset of sepsis increased median survival time (MST) by 40-55% over untreated controls. Four experiments were performed. Cpv in combination with antibiotics when given at the time of onset of sepsis was significantly more effective than antibiotics alone (MST 235 vs 105 hr, P less than 0.05 at 144, 168, 192, 216 hr). In the second and third experiments Cpv alone and with antibiotics was administered 15 hr after the onset of sepsis. Cpv significantly augmented survival over controls in the second experiment (MST 87 vs 60 hr, P less than 0.025 at 96 hr). Cpv plus antibiotics was significantly better than antibiotics alone in the third experiment (MST 111 vs 64 hr, P less than 0.05 at 72 hr, P less than 0.005 at 120 hr). In the final experiment, Cpv did not inhibit growth of 20 bacterial species in agar and liquid media. Cpv significantly enhances survival in murine fecal peritonitis even when administered after the onset of sepsis; furthermore Cpv plus antibiotics in established peritonitis produces longer survival than antibiotics alone. Synthetic immunomodulators such as Cpv could eventually play a significant role in the management of peritoneal infection in humans.     

Hematological Diagnostic Markers of Acute Appendicitis in Children

Background

White blood cell (WBC) and platelet indices are useful biomarkers in many inflammatory diseases. A study was made of possible WBC and platelet indices in children with acute appendicitis.

Methods

We reviewed the results of the complete blood count tests made on admission of 150 children with acute appendicitis (94 boys, 56 girls) and those of 74 healthy children (46 boys, 28 girls). We compared the WBC and platelet indices between the children with acute appendicitis and healthy children and between the complicated and uncomplicated cases of appendicitis.

Results

The children with acute appendicitis had higher WBC, neutrophil count, neutrophil percentage and neutrophil/ lymphocyte ratio and lower lymphocyte count and lymphocyte percentage than the healthy children. Cases of appendicitis with complications had lower lymphocyte count, lymphocyte percentage and higher neutrophil to lymphocyte ratio than those without complications. In girls WBC, neutrophil count and neutrophil percentage were higher in complicated acute appendicitis. WBC, neutrophil count, neutrophil percentage, lymphocyte percentage and a neutrophil/lymphocyte ratio >2.5 were accurate markers for acute appendicitis in children, but not for detecting complicated cases. Girls with acute appendicitis had lower platelet distribution width than healthy girls, with high sensitivity and positive predictive value at platelet distribution width <12.4%, but moderate specificity and negative predictive value.

Conclusions

The Neutrophil/lymphocyte ratio can be used as an additional diagnostic marker of acute appendicitis in children, but cannot detect complications, and platelet distribution width can be an additional marker for confirming, but not excluding, acute appendicitis in girls.