A system dynamics approach to model heat stress accumulation in dairy cows during a heatwave event.

Climate change is expected to increase the number of heat wave events, leading to prolonged exposures to severe heat stress (HS) and the corresponding adverse effects on dairy cattle productivity. Modelling dairy cattle productivity under HS conditions is complicated because it requires comprehending the complexity, non-linearity, dynamicity, and delays in animal response. In this paper, we applied the System Dynamics methodology to understand the dynamics of animal response and system delays of observed milk yield (MY) in dairy cows under HS. Data on MY and temperature-humidity index were collected from a dairy cattle farm. Model development involved: (i) articulation of the problem, identification of the feedback mechanisms, and development of the dynamic hypothesis through a causal loop diagram; (ii) formulation of the quantitative model through a stock-and-flow structure; (iii) calibration of the model parameters; and (iv) analysis of results for individual cows. The model was successively evaluated with 20 cows in the case study farm, and the relevant parameters of their HS response were quantified with calibration. According to the evaluation of the results, the proposed model structure was able to capture the effect of HS for 11 cows with high accuracy with mean absolute percent error <5%, concordance correlation coefficient >0.6, and R2 > 0.6, except for two cows (ID #13 and #20) with R2 less than 0.6, implying that the rest of the nine animals do not exhibit heat-sensitive behaviour for the defined parameter space. The presented HS model considered non-linear feedback mechanisms as an attempt to help farmers and decision makers quantify the animal response to HS, predict MY under HS conditions, and distinguish the heat-sensitive cows from heat-tolerant cows at the farm level.

Effect of vincristine on the bone marrow cells of patients with multiple myeloma: a cytomorphologic study.

The cytologic changes induced by vincristine (VCR) on the erythroblasts, the myeloid cells and the neoplastic plasma cells were studied on the bone marrow of 5 patients with plasma cell malignancies. Nine hours after the administration of the drug, the cytocidal effect on the 3 cell types was proportional to the magnitude of the stathmokinetic effect induced in them: marked on the erythroblasts (whose percentage incidence was sharply reduced), more modest on the myeloid cells, and still lower on the plasma cells. Nine days later the plasmocytomatous infiltrate was reduced as compared to before therapy, while the aliquot of hemopoietic cells was restored. At this time the mitotic index of plasma cells, but not that of the hemopoietic cells, was higher than before VCR administration. These findings suggest that the tumor mass reduction by VCR is followed by plasma cell recruitment, which is in progress 9 days after the drug administration. On the contrary, the regeneration of the hemopoietic cells has repopulated the bone marrow and is already exhausted in this lag time. It is hypothesized that VCR administrations given at about 9 day intervals are more and more effective on the recruited plasma cells, owing to the phase S-specificity of the drug. The regeneration of the hemopoietic cells is protected by this time interval.

Cytokinetic studies on circulating neoplastic cells of Hodgkin's disease.

In two patients with advanced Hodgkin's disease the DNA content, the mitotic index and the in vitro tritiated thymidine labeling index of the neoplastic cells found in peripheral blood, bone marrow and, in one case, in ascitic fluid have been determined. Cytologically the tumor cells were classified into three groups: atypical mononuclear cells, Hodgkin (H) cells and Reed-Sternberg (R-S) cells. Two populations with clearly different kinetic features were recognized. The first one was that of atypical mononuclear cells which exhibited diploid DNA content and proliferative activity of moderate degree: tetraploid cells were, however, observed more frequently than expected. The second population grouped together H and R-S cells, had tetraploid modal DNA content and very high proliferative activity. Hodgkin cells had tetraploid or slightly greater DNA content while R-S cells exhibited also DNA values as high as octoploid and sometimes greater. It can be postulated that by endomitosis some atypical mononuclear cells give origin to H cells and that these assume the monstrous features of R-S cells while increasing their DNA content during the DNA synthesis phase.

Cytokinetic changes in the peripheral blood of leukemic patients during cytostatic therapy. V. Effect of VP 16 213 studied with flow cytofluorometry and cytoautoradiography.

The cytokinetic effects induced by VP 16 213 (50-60 mg/sqm/12 hrs for 10 doses) on the peripheral blood and bone marrow blasts of two patients with acute myelomonocytic leukemia have been studied using DNA flow cytofluorometry and in vitro tritiated thymidine cytoautoradiography. Besides a striking cytocidal effect, the drug induced cell synchronization in the G2 phase of the cell cycle as evidenced by the building up of tetraploid nuclei without an increase in mitotic figures. The synchronizing effect was greater in the bone marrow than in peripheral blood. In one patient, the removal of the G2 block was observed which paralleled an increase in proliferative activity. The usefulness of flow cytofluorometry for rapidly detecting the cytokinetic changes induced in acute leukemia blasts by cytostatic drugs is affirmed.

Cytokinetic changes in the peripheral blood of leukemic patients during cytostatic therapy. VI. Effect of arabinosylcytosine.

Flow and conventional DNA-cytofluorometry and in vitro tritiated thymidine cytoautoradiography were employed in the study of the cytokinetic changes induced by Ara-c on the peripheral blood blast cells of six patients with acute non-lymphoblastic leukemias. Nine courses of therapy were studied, in 5 of which Ara-c was administered in low pulse doses (20-60 mg/sqm) repeated every 12 hrs and in the other 4 it was administered in continuous infusion (90-150 mg/sqm) lasting 24 hrs. Low repeated pulse doses have little cytocidal effect and increase the 2n-4n cell percentage and, less markedly, the LI, while the median grain count is reduced. Many U-like cells and accumulation of 3H-TdR labeled blasts in early S phase were observed during therapy. The continuous infusion of Ara-c induces striking cytoreduction and concomitantly decreases the 2n-4n percentage and LI. Progressive recovery of 2n-4n percentage and LI over pretreatment values was observed 24-48 hrs after stopping infusion in one case and was probably due to cell recruitment following tumor mass reduction. Our data agree with the literature, which is briefly reviewed, in that they indicate that Ara-c in a low intravenous pulse frequently dose synchronizes the blasts in S phase while higher doses of the drug are more often cytocidal in S phase and cell recruitment can follow cytoreduction.

Sequential vincristine, arabinosylcytosine and adriamycin in acute leukemia: cytologic and cytokinetic studies.

Cytokinetic and cytocidal effects exerted on peripheral blood blasts by sequential administration of vincristine (VCR) 2 mg on day 1, arabinosylcytosine (Ara-c) 50-60 mg/m2/12 hr from day 2-4), and Adriamycin (ADM, Farmitalia, Milan, Italy, 40-60 mg/m2 on day 5) have been examined in 22 courses of treatment performed on 12 patients with nonlymphoblastic and in 4 with lymphoblastic acute leukemia. In 4 patients, the bone marrow blasts wee examined before and also after VCR-Ara-c administration. In vitro tritiated thymidine autoradiography and propidium iodide-DNA flow cytometry were employed for kinetic studies. Blasts disappeared from blood with a median half time of 35 hr. After VCR-Ara-c administration, a significant increase in labeling index (LI) and in the aliquot of cells with DNA content between the diploid (2n) and the tetraploid (4n) values was observed in 80% of the courses in peripheral blood blasts and in all courses in bone marrow blasts. The median grain count over the labeled nuclei was decreased, and the 4n cell percentage and the bone marrow blast mitotic index did not increase. These findings suggest that the increase in the S phase fraction of blast population is due to cell synchronization. Increase in the S phase appears to heighten the cytocidal effect of ADM. The aliquot of the blasts cleared from blood after ADM were in fact related directly to the degree of labeling index increase observed during the previous administration of VCR and Ara-c.