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Susceptibility of two strains of rainbow trout (one with suspected resistance to whirling disease) to Myxobolus cerebralis infection.

The susceptibility of 2 strains of rainbow trout Oncorhynchus mykiss, 1 from North America (TL) and 1 from Germany (GR), to Myxobolus cerebralis (the cause of salmonid whirling disease) was assessed following exposure to the infectious stages (triactinomyxons). Two laboratory experiments were conducted with age-matched rainbow trout of each strain. At the beginning of the study, the 2 trout strains were aged ca. 570 degree-days in Expt 1, and ca. 999 degree-days in Expt 2. In both experiments, replicate groups of each trout strain were exposed to 10, 100, 1000 or 10000 triactinomyxons (TAMs) fish(-1) for 2 h. The fish were then held in aquaria receiving 15 degrees C well-water. Severity of infection was evaluated 5 mo after exposure by presence of clinical signs (whirling and/or black tail), prevalence of infection, severity of microscopic lesions, and spore counts. Clinical signs of whirling disease were evident only in the younger fish exposed in Expt 1: These occurred first among TL rainbow trout at the highest dose at 6 to 7 wk post exposure and then 2 wk later in fish at the 1000 TAMs dose. Black tail was also observed among GR rainbow trout at the 10000 TAMs dose only, but in fewer fish. The prevalence of infection, spore numbers, and severity of microscopic lesions due to M. cerebralis among GR rainbow trout were less at all doses compared to TL rainbow trout. Risk of infection analyses showed that TL rainbow trout were more prone to infection at the lower doses than GR trout. Mean spore counts were consistently (10- to 100-fold) less in GR than TL trout at doses of 1000 TAMs or lower. Microscopic lesions increased with increasing dose in both strains of rainbow trout. The mechanisms underlying the greater resistance of the GR strain to M. cerebralis infections are unknown, but are under investigation as part of a long-term project to determine the basis for resistance and susceptibility of salmonid fishes to whirling disease.

Age Factors↗

The effect of tamoxifen on semen fertilization capacity in White Leghorn male chicks.

Tamoxifen (TAM) is an antiestrogen that advances sexual puberty in cockerels, turkey toms, and Muscovy drakes. The effect of TAM on semen-fertilization capacity in White Leghorn (WL) male chicks was assayed in the present study. Sixty, 2-wk-old, male chicks were divided into two equal groups. The chicks from one group were injected im with 1 mg of TAM per kg of BW every other day; those from the second group were vehicle-treated (with corn oil) and served as controls. Each chick was paired with a virgin, WL laying hen. When semen was produced, the paired female was inseminated twice a week. The results revealed that TAM administration caused the early production of fertile semen, which resulted in the first normal descendants as early as 8 wk of age and brought about 100% of parenthood by the age of 88 days.

Animals↗

Effects of tamoxifen dose and nutrition scheme during growth on stimulation of the reproductive system in cornish breed cocks.

The effects of tamoxifen (TAM) antiestrogen dose as well as protein and energy content in feed on stimulation of the reproductive system development in meat type cocks were studied. The experiment was conducted on males of the Dominant White Cornish chicken breed. The optimum TAM dose for stimulation of reproductive system development was at the level of 5 mg per kg body weight. The effects of TAM administration on the following traits were investigated: body weight, breast muscle thickness, age at sexual maturity, egg fertilization and hatchability. No effect of TAM on breast muscle thickness was found. It was also noted that semen obtained from 11 to 12 week old males of the Dominant White Cornish breed could be used successfully in the insemination of females.

Animal Feed↗

The duration of 3-d form analysis in transformational apparent motion.

Transformational apparent motion (TAM) occurs when a figure changes discretely from one configuration to another overlapping configuration. Rather than an abrupt shape change, the initial shape is perceived to transform smoothly into the final shape as if animated by a series of intermediate shapes. We find that TAM follows an analysis of form that takes 80-140 msec. Form analysis can function both at and away from equiluminance and can occur over contours defined by uniform regions as well as outlines. Moreover, the forms analyzed can be 3-D, resulting in motion paths that appear to smoothly project out from or into the stimulus plane. The perceived transformation is generally the one that involves the least change in the shape or location of the initial figure in a 3-D sense. We conclude that perception of TAM follows an analysis of 3-D form that takes approximately 100 msec. This stage of form analysis may be common to both TAM and second-order motion.

Color Perception↗

Combined in vitro anti-tumoral action of tamoxifen and retinoic acid derivatives in hepatoma cells.

Chemotherapy does not have a prominent role in the treatment of hepatoma. However, an acyclic retinoid prevented tumor recurrence post-hepatectomy, and tamoxifen (TAM) induced apoptosis in tumor cells. Combination therapy of these agents on proliferation and apoptosis of hepatoma cells has not been explored. HepG2, Hep1B, Hepa1-6 and MH1C1 hepatoma cells were incubated with TAM, 9-cis- and all-trans retinoic acid (CRA, ATRA, respectively) alone or in combination. Proliferation rate was assessed and apoptosis was analyzed by flow cytometry, immunostaining, caspase activity assays and the expression of apoptosis- and/or cell cycle-related molecules. CRA and TAM, but not ATRA monotherapy were moderately effective. Apoptosis was accompanied by upregulation of caspase 3 and 8 activity, and increased p27, bax, caspase 3 expression, while the levels of p21cip/waf and bcl-2 were unchanged or decreased. Combination therapy enhanced apoptosis from a maximum of 60% after monotherapy to more than 90% after 96 h in all cell types. Pro-apoptotic effects were paralleled by inhibition of proliferation. Combination of TAM and CRA, but not ATRA, have an additive to synergistic anti-proliferative and pro-apoptotic effect on HCC cells. This justifies trials for HCC using combinations of these biological response modifiers.

Animals↗

Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma.

Monocyte chemotactic protein-1 (MCP-1, CCL2) is an important determinant of macrophage infiltration in tumors, ovarian carcinoma in particular. MCP-1 binds the chemokine receptor CCR2. Recent results indicate that proinflammatory and anti-inflammatory signals regulate chemokine receptor expression in monocytes. The present study was designed to investigate the expression of CCR2 in tumor-associated macrophages (TAM) from ovarian cancer patients. TAM isolated from ascitic or solid ovarian carcinoma displayed defective CCR2 mRNA (Northern blot and PCR) and surface expression and did not migrate in response to MCP-1. The defect was selective for CCR2 in that CCR1 and CCR5 were expressed normally in TAM. CCR2 gene expression and chemotactic response to MCP-1 were decreased to a lesser extent in blood monocytes from cancer patients. CCR2 mRNA levels and the chemotactic response to MCP-1 were drastically reduced in fresh monocytes cultured in the presence of tumor ascites from cancer patients. Ab against TNF-alpha restored the CCR2 mRNA level in monocytes cultured in the presence of ascitic fluid. The finding of defective CCR2 expression in TAM, largely dependent on local TNF production, is consistent with previous in vitro data on down-regulation of chemokine receptors by proinflammatory molecules. Receptor inhibition may serve as a mechanism to arrest and retain recruited macrophages and to prevent chemokine scavenging by mononuclear phagocytes at sites of inflammation and tumor growth. In the presence of advanced tumors or chronic inflammation, systemic down-regulation of receptor expression by proinflammatory molecules leaking in the systemic circulation may account for defective chemotaxis and a defective capacity to mount inflammatory responses associated with advanced neoplasia.

Ascites↗

Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages.

IL-12 is a central cytokine in the activation of inflammation and immunity and in the generation of Th1-type responses. Tumor-associated macrophages (TAM) from mouse and human tumors showed defective production of IL-12. Defective IL-12 production was associated with lack of p50/p65 NF-kappa B activation. TAM produced increased amounts of the immunosuppressive cytokine IL-10. Abs against IL-10 restored the defective capacity of TAM to produce IL-12. Our data suggest that during tumor growth an IL-10-dependent pathway of diversion of macrophage function can be activated into the tumor microenvironment and results in the promotion of the IL-10+ IL-12- phenotype of TAM. Blocking IL-10, as well as other immunosuppressive cytokines present in the tumor microenvironment, such as TGF-beta, may complement therapeutic strategies aimed at activating type I antitumor immune responses.

Animals↗

STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion.

It is well established that tumor progression is associated with the accumulation of myeloid suppressive cells, which in mice include Gr-1+ immature myeloid cells and F4/80+ macrophages. The paradox is that with the exception of terminal stages of the disease or chemotherapy treatment, tumor-bearing mice or cancer patients do not display a profound systemic immune suppression. We therefore raised the question as to whether myeloid cell-mediated T cell suppression is controlled at a local level at the site of the tumor. We have demonstrated that after adoptive transfer to tumor-bearing recipients, Gr-1+ (immature myeloid cells) freshly isolated from spleens of tumor-bearing mice become F4/80+ tumor-associated macrophages (TAM). These TAM, but not F4/80+ macrophages or Gr-1+ cells freshly isolated from spleens of tumor-bearing or naive mice were able to inhibit T cell-mediated immune response in vitro via induction of T cell apoptosis. Arginase and NO were both responsible for the apoptotic mechanism, and were seen only in TAM, but not in freshly isolated Gr1+ cells. Using the analysis of STAT activity in combination with STAT knockout mice, we have determined that STAT1, but not STAT3 or STAT6, was responsible for TAM-suppressive activity.

Animals↗

Management of skin tears and stage II skin ulcers with two topical regimens: a study of cost minimization.

A health-economic study of newly formed skin tears and stage II ulcers used an unblinded, comparative, parallel-group design to evaluate two topical regimens as to time required for complete healing and assessment of cost minimization. Thirty-six elderly patients, at risk for developing indolent wounds of the skin and underlying tissues, were assigned to receive either a saline spray and a topical antibiotic ointment (TAM, n = 14) or Dermagran Spray and Dermagran Ointment (DSO, n = 22). The 76 wounds that appeared in these patients had comparable pretreatment surface areas of 3.73 +/- 0.96 cm2 in the DSO group versus 5.57 +/- 1.13 cm2 in the TAM group (P = NS). All wounds were treated twice daily, starting within 24 hours of their appearance, until complete healing. The 19 wounds in the TAM group healed within 48.0 +/- 25.3 days versus 15.4 +/- 1.9 days for the 57 wounds in the DSO group (P < .05). The cost of wound management for a given patient was calculated by adding the costs of nursing labor and the amount of product consumed to effect complete healing. To this end, the cost of the TAM regimen was $323.23 +/- 171.70 versus $104.75 +/- 12.92 for the DSO regimen (P < .05). Results are presented in light of the increasing pressure on long-term care facilities to provide effective and affordable treatment.

Administration, Topical↗

[Zone I and II flexor tendon laceration in children].

AIM OF THE STUDY: The goals of this study is to determine the effect of post-operative management as optimun period of post-operative immobilization, type of immobilization and importance of early mobilization program in zone I and II flexor tendon laceration in children. MATERIAL: Thirty-seven patients who had sustained flexor tendon lacerations of 42 digits in zone I or II were available for critical evaluation. Inclusion criteria were primary flexor tendon repairs in children under 15 years: lesions of flexor pollicis longus, digits with crush injuries, skin loss or revascularization were omitted from this study. The average post-operative follow-up was 3 years (range 12-89 months). Flexor tendon repair had been performed on 9 index, 14 middle, 9 ring and 10 small fingers. Tendon laceration occurred in zone I in 16 fingers, zone II in 26. Patients were divided into three groups: 0 to 5 years, 5 to 10 years and 11 to 15 years. METHODS: Immediate primary suture with modified Kessler technique was performed on the day of injury. Post-operative treatment included the use of an early passive motion program in 11 digits. The remaining 31 digits were managed by immobilization in a cast or splint for 4-6 weeks without early mobilization. The percentage of normal digital function that was recovered following flexor tendon repair was determined by a computation of total active motion (TAM) as described by Glogovac and Strickland (TAM = PIP active flexion + DIP active flexion-extension deficit/175). Data were analysed to determine the effect of age, the effect of early passive motion program, the effect of varying periods of post repair immobilization and the effect of the type of immobilization. RESULTS: Tendon ruptures were identified in four digits. One was in a non cooperative patient who removed splint immobilization after two weeks post-repair. The three remaining patients were immobilized with a short splint. Isolated or combined profundus and superficialis repairs achieved comparable results when managed with an early passive motion or with simple immobilization without early motion program. Immobilization for 5 or 6 weeks resulted in an appreciable deterioration of function (TAM = 86 p. 100) in comparison with 4 weeks immobilization (TAM = 93 p. 100) (p > 0.05). Complication rate as rupture is higher in the group immobilized with a short splint, especially when children is under five. DISCUSSION: Primary flexor tendon repairs in children in this series achieved satisfactory functional results in comparison with adults. There is however, in the very young, some widely differing results since the necessity of post operative care was not fully appreciated. Immobilization with a short splint should be avoided because of greater complication rate as rupture, especially in very young. We found no benefit of early passive mobilization protocols. Immobilization should not be extend beyond 4 weeks because of deterioration of final functional result.

Adolescent↗

Tamoxifen chemoprevention of a hormone-independent tumor in the proto-neu transgenic mice model.

We evaluated the effect of tamoxifen (TAM) on tumor development in proto-neu transgenic mice that spontaneously develop mammary carcinomas overexpressing the neu protein. These mammary carcinomas are hormone independent because superimposable growth of transplants was observed in females and males. Virgin transgenic mice treated with TAM from 24 weeks of age, ie., when subclinical mammary tumors are already present, showed a slightly accelerated tumor development. In contrast, transgenic mice treated with TAM starting at 12 weeks of age, when subclinical tumors are not yet present, showed a 50% reduction of tumor incidence. Light microscopy analysis of the mammary gland of these mice revealed an apparently normal ductal branching but a complete regression of the acini. In conclusion, TAM can prevent the occurrence of hormone-independent breast carcinoma if given early enough to inhibit normal cells.

Animals↗

Comparative effects of estrogen and antiestrogens on differentiation of osteoblasts in mouse bone marrow culture.

Estrogens as well as some antiestrogens have been shown to prevent bone loss in postmenopausal women. These compounds seem to inhibit bone resorption, but their anabolic effects have been less explored. In this study, bone marrow cultures were used to compare the effect of 17beta-estradiol (E2), and two triphenylethylene derivatives, tamoxifen (TAM), and FC1271a, and a benzothiophene derivative raloxifene (RAL) on differentiation of osteoblasts. All enhanced osteoblastic differentiation of 21-day cultures as indicated by increased mineralization and bone nodule formation. All, except RAL, stimulated cell proliferation during the first 6 days of the culture. However, in the presence of RAL the content of total protein was increased in 13-day cultures. SDS-PAGE and autoradiography of [14C]-proline labeled proteins revealed elevated level of the newly synthesized collagen type I. The pure antiestrogen ICI 182,780 abolished the increase of the specific activity of alkaline phosphatase by E2, TAM, and FC1271a but not the effect of RAL on protein synthesis. Our results show that E2 as well as TAM, FC1271a, and RAL stimulate bone formation in vitro but the mechanism of the anabolic action of RAL in bone clearly differs from that of E2, TAM, and FC1271a.

Animals↗

Long-term tamoxifen treatment: a possible aetiological factor in the development of uterine carcinosarcoma: two case-reports and review of the literature.

Two cases of uterine carcinosarcoma developing after long-term tamoxifen (TAM) treatment are presented. The patients, 67 and 72 years old, were treated with TAM for 6 and 7 years, continuously. They both developed an heterologous malignant mixed Mullerian tumor (mmMt). At laparotomy, an advanced stage of disease was found with peritoneal spread. In spite of the surgical and the postoperative treatment, they both died of disease, 3 and 10 months later. There are only 10, well documented, similar cases reported. Another 7 were identified in series of uterine malignancies developing after TAM treatment. Considerable evidence suggests that mmMt represents an epithelial cancer with sarcomatous dedifferentiation. Prolonged (> 5 years) TAM treatment may represent a causative factor in the development of this highly lethal disease (80% of the reported patients had a dismal prognosis). Large uterine polyps with special histological features, may represent an intermediate step in the tumor formation. Close follow-up of the patients is warranted.

Adenocarcinoma↗

Mechanisms mediating the effects of IL-3 gene expression on tumor growth.

IL-3 gene expression within tumors leads to host-cell infiltration, particularly by macrophages, slower tumor growth, and enhanced immunogenicity. Surprisingly, tumor-associated macrophages (TAMs) from within FSAN-JmIL3 tumors had decreased expression of TNF-alpha and iNOS. On short-term culture, TAMs from FSAN-JmIL3 tumors regained their capacity to produce TNF-alpha and NO, indicating that they were primed in vivo. In vitro experiments were unable to demonstrate differences between FSAN-JmIL3 and FSAN tumor cells in their ability to stimulate TNF-alpha production by TAMs. In the absence of evidence that TAM activation was responsible for the slower growth of FSAN-JmIL3 tumors, the response of tumor cells to these effector molecules was studied. TNF-alpha and NO were cytotoxic for FSAN-JmIL3 cells but growth stimulatory for FSAN. These tumor-related phenotypic changes may contribute as much if not more than functional changes in host infiltrating cells to the slower growth of FSAN-JmIL3 tumors in vivo.

Animals↗

Endometrial cancer in patients with breast carcinoma treated with tamoxifen: report of two cases and the literature overview.

Tamoxifen (TAM) is the endocrine treatment of choice in the first-line therapy for all stages of breast cancer, in both pre- and postmenopausal women. Some clinical studies indicated a small but significant increase in the risk of subsequent endometrial carcinoma in breast cancer women who take TAM as an adjuvant therapy. In this study, we present two cases of breast cancer patients in whom endometrial cancer was diagnosed during TAM treatment; the current status of knowledge on the relationship between TAM use and the risk of endometrial cancer is reviewed.

Aged↗

Effects of short term treatment with pentagastrin, proglumide, tamoxifen given separately or together with 5-fluorouracil on the growth in the murine transplantable Colon 38 cancer.

It is well known that 5-fluorouracil (5-FU) is the most effective drug in the treatment of colon cancer, however the positive response is small, only about 20%. On the other hand, it has been postulated that the growth of colon cancer depends on many growth factors, such as gastrin and estrogens. The search for new substances increasing the antitumor effect of 5-FU has lasted for many years. The aim of the present study was to examine the effects of pentagastrin (PEN, syntetic gastrin analogue), proglumide (PRO, a blocker of gastrin receptor) and tamoxifen (TAM, a partial estrogen antagonist) given separately or together with 5-FU on proliferation, apoptosis, necrosis and proliferation/apoptosis (P/A) ratio in the murine transplantable Colon 38 cancer. The male mice were implanted with a suspension of Colon 38 cells. After 7 days, the animals were treated with PEN (250 microg/kg b.w., twice daily), PRO (100 mg/kg. b.w., twice daily), TAM (10 microg/animal) separately or together with 5-FU (60 mg/kg b.w., once) for 2 days. The incorporation of bromodeoxyuridine (BrdU) into cell nuclei was used as an index of cell proliferation (labeling index--LI). The in situ labeling of nuclear DNA fragmentation according to TUNEL method was considered as an apoptotic index (AI). It was found that 5-FU increased the apoptosis, unexpectedly increased the LI and decreased the P/A ratio when compared to control. Both PEN and PRO increased the apoptosis and in the case of PRO decreased P/A ratio when compared to control. TAM did not affect any of the examined parameters. All of the investigated substances modify the 5-FU action: PEN and PRO on AI and LI and TAM on AI and P/A ratio. Necrosis was observed in 3 tumors treated with PEN + 5-FU, in 2 tumors of PRO + 5-FU group and in 1 tumor of group with 5-FU and with PEN. Further studies are needed to elucidate if those modification of 5-FU action by the examined substances will be useful in the inhibition of the growth of Colon 38 cancer.

Animals↗

Low-rate emergence of thymidine analogue mutations and multi-drug resistance mutations in the HIV-1 reverse transcriptase gene in therapy-naive patients receiving stavudine plus lamivudine combination therapy.

OBJECTIVES: Mutations usually associated with zidovudine exposure have been observed in zidovudine-naive patients treated by stavudine in combination. These mutations were named thymidine analogue mutations (TAMs). This fact, combined with phenotypical and biochemical findings provided additional evidence for cross-resistance between zidovudine and stavudine. A recent genotypic study in naive patients receiving stavudine/didanosine combination showed emergence of TAMs and a multidrug-resistance mutation (MDR), Q151M, in 36 and 10% of cases, respectively. Stavudine plus lamivudine is one of the most used binucleoside associations in the antiretroviral combinations. The objective of this study was to assess the genotypic changes in the HIV-1 reverse transcriptase (RT) gene in antiretroviral-naive patients treated by stavudine plus lamivudine. METHODS: We analysed the RT gene of 44 HIV-1 patients, naive of antiretroviral therapy, who were treated for 24 or 48 weeks with stavudine/lamivudine. RESULTS: At the end of the follow-up, all patients acquired the lamivudine-associated mutation M184V. Only two subjects (4.5%) developed a TAM (T215Y; M41L), one subject developed a V75T/A mutation and one subject developed the particular MDR pattern F116Y, Q151M. CONCLUSIONS: Our study clearly demonstrated that naive subjects treated with stavudine/lamivudine for 24-48 weeks selected a low rate of TAMs and MDR Q151M. One hypothesis explaining these results could be the development of the M184V mutation.

Acquired Immunodeficiency Syndrome↗

[Assessment of complications in a randomized controlled study on multimodality therapy for patients following breast-conserving surgery: Kansai Breast Cancer Radiotherapy Research Group (5'-KBR)].

PURPOSE: We conducted a randomized controlled study to evaluate the safety and usefulness of a combined treatment of radiotherapy and chemotherapy with doxifluridine (5'-DFUR) plus tamoxifen (TAM) as an adjuvant therapy for breast cancer patients after conservative surgery. The complications observed in this trial are reported herein. METHODS: A total of 550 patients were registered and randomized (based on factors such as T, N, with/without radiotherapy) to groups A and B. Drug regimens were: group A, 5'-DFUR 600 mg/body/day for 6 months and TAM 20 mg/body/day for 2 years; group B, 5'-DFUR 600 mg/body/day for 2 years and TAM 20 mg/body/day for 2 years. Radiotherapy (2 Gy x 5 times/week, for 5 weeks) was administered to 88.6% of evaluable patients (481/543). Radiation-related acute adverse reactions occurred in 28.5% of the 481 patients and moderate to severe reactions occurred in 1.5% of the patients. Delayed radiation-related adverse reactions occurred in 23.8% of the patients but none were severe. Chemo-endocrine therapy-related adverse reactions occurred in 17.9% of group A patients and 25.6% of group B patients. Grade 3 reactions occurred in 6 of the group A patients (2.4%) and in 5 of the group B patients (1.9%); all adverse reactions subsided after dose reduction or discontinuation. These findings suggest that the combination therapy of irradiation and 5'-DFUR with TAM is safe for patients after breast conserving surgery.

Antineoplastic Combined Chemotherapy Protocols↗