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Experimental design for the surgical relocation of the ovary into the vaginal fornix.

After translocation into the vaginal vault while attached to a pedicle consisting of the infundibulo-pelvic ligament, the ovary was found to maintain its function in laboratory primates. In the majority of the baboons the ovulatory pattern returned within a few weeks after the surgical procedure. The only significant complication was a transitory, and self-limited, infection which was evident on inspection and on the biopsy specimens, but caused no clinical symptoms. By comparing the surgical outcome in two primate species, namely Papio Cynocephalus and Macaca Arctoides, it could be deduced that the Homo Sapiens would be a more suitable experimental model than either of the laboratory primates used in this research. Because there are potentially effective methods for reducing the likelihood of postoperative infection in the relocated ovary, the experience gained by this new method suggests the possibility that it could be utilized in the future for the purpose of collecting ova for in vitro fertilization in carefully selected, and otherwise untreatable, cases of female sterility.

Animals

The effect of repeated phlebotomy on bilirubin turnover, bilirubin clearance and unconjugated hyperbilirubinaemia in the Crigler-Najjar syndrome and the jaundiced Gunn rat: application of computers to experimental design.

1. A multicompartmental model of erythrokinetics and bilirubin production has been developed to predict the consequences of chronic phlebotomy on daily bilirubin turnover. 2. Control values for four physiological variables including bilirubin turnover were determined in a 20-year-old woman with type I congenital nonhaemolytic jaundice (Crigler-Najjar syndrome). With these base-line data, the model predicted the following changes during phlebotomy: a 34% fall in bilirubin turnover; a 240% increase in the haemoglobin content of bone-marrow erythroid precursors; a 25% fall in the half-life of 51Cr-labelled erythrocytes; a characteristic alteration of the erythrocyte survival curve after labelling with [2-14C]glycine. 3. On the assumption, previously validated in normal volunteer subjects and patients with Gilbert's syndrome, that hepatic bilirubin clearance was independent of turnover and would therefore remain unchanged, a fall in plasma unconjugated bilirubin concentration during phlebotomy from 436 to 282 mumol/1 was expected. 4. Accordingly, the patient underwent phlebotomy 350 ml/week for 2 months, and 500 ml/week during an additional 3 months. Appropriate studies during phlebotomy confirmed each of the predictions in paragraph 2 above. In particular, turnover fell by 31%. Unexpectedly, plasma unconjugated bilirubin remained essentially unchanged. Analogous results were observed in phlebotomized jaundiced Gunn rats. 5. Kinetic studies in both the patient and the rats demonstrated that the failure of plasma unconjugated bilirubin to fall in parallel with bilirubin turnover resulted from a prolongation of the terminal half-life of radioactively labelled bilirubin and a fall in bilirubin clearance in every instance. 6. These studies indicate that (a) in congenital non-haemolytic jaundice, bilirubin clearance is uniquely influenced by bilirubin turnover and (b) compartmental modelling and kinetic studies are useful for predicting and interpreting the results of both physiological experiments and experimental therapeutic regimens.

Adult

Operative staging of apparently localized adenocarcinoma of the prostate: results in fifty unselected patients. I. Experimental design and preliminary results.

The design and details of a prospective, randomized study protocol involving bipedal lymphography, and exploratory laparotomy with selective node biopsy in patients with apparently localized adenocarcinoma of the prostate are presented. The analysis includes the results of selected diagnostic tests, and an assessment of the accuracy of clinical vs. surgical staging in 50 unselected patients. Lymphatic metastases were found at the time of diagnostic laparotomy in 18 of the 50 patients (36%). Both increasing size (advanced T stage) and decreasing differentiation of the primary tumor were associated with an increased incidence of lymph node metastases. Of 25 patients with T1 and T2 tumors (Stage B), and 25 patients with T3 tumors (Stage C), lymphatic dissemination was found in 20 and 52%, respectively. Eleven of 20 patients (55%) with poorly differentiated tumors had lymph node metastasis, compared with only 2 or 11 patients (18%) with well-differentiated tumors. Twelve patients had a change in their clinical stage following exploratory laparotomy; in eight the stage was increased and in four it was decreased. Of 18 patients with lymphatic metastases, some of which were extensive and most of which were associated with increased serum acid phosphatase values, no evidence of concurrent bony or visceral dissemination was found. Although preliminary, this finding should stimulate the search for effective treatment in these patients who were previously thought to be incurable on the basis of probable vascular dissemination.

Acid Phosphatase

Anatomical substages of stage III Hodgkin's disease: implications for staging, therapy, and experimental design.

Twenty-three patients with pathologic stage III Hodgkin's disease were classified with respect to the presence or absence of symptoms (III-A, III-B), the presence or absence of splenic involvement (IIIS+, IIIS-) and anatomic substage--the extent of disease within the abdomen (III1, III2). Stage III1 disease included disease limited to the upper abdomen, i.e., spleen, splenic node, celiac node, and/or portal node. All other more extensive disease was classified as stage III2. Symptoms and splenic involvement did not predict either disease-free survival or survival. However, 5 year actuarial disease-free survival was significantly better in III1 patients as compared to III2 patients (77% vs. 13%, p less than .001). Eight of nine stage III2 patients receiving total nodal radiotherapy alone relapsed. When considered along the previous studies of anatomic substage, these findings suggest that patients in stage III1 and III2 should receive different therapeutic approaches. Analysis of therapeutic results in stage III patients must consider anatomic substage.

Abdomen

Drug concentrations in neuropsychiatry. Methodological pitfalls: the influence of experimental design on results.

The valid study of relationships between pharmacokinetic measurements and clinical effects of psychotropic drugs depends on: (i) analytical methods for the drugs; (ii) the fluid assessed and pharmacokinetic derivations; (iii) clinical assessments and the nature of psychiatric illness; and (iv) statistical work. Standard problems with analytical methods include lack of specificity, unjustified claims for sensitivity, and failure to recognize metabolites as potential analytical contaminants and compounds for separate study. Problems with pharmacokinetic derivations include inappropriate calculations and incorrect assignment of terms such as 'half-life'. Clinical difficulties mostly relate to variations between patient groups, selection procedures and rating methods, and to timing of samples. Statistical controversies concern the calculation of metabolite ratios, pooling of data from drugs and their metabolites, and abuse of statistical techniques. These methodological problems are illustrated by reference to work with phenothiazines, tricyclic antidepressants, lithium, benzodiazepines and anticonvulsants.

Body Fluids

Importance of interactions between nutrients and environmental contaminants as a factor in experimental design in toxicological research: with emphasis on selenium and ascorbic acid.

Interactions between dietary components and environmental contaminants may influence the outcome of toxicological testing. A comparison was made between the vitamin and mineral content of laboratory animal basal diets as supplied by two major feed companies. Striking differences in nutrient content of Guinea pig, rat, and primate diets, as supplied by these companies are cited. Attention is drawn to the lack of data on selenium content of these feeds. The importance of Vitamin C in regards to ameliorating toxic effects of heavy metals is discussed.

Animal Feed

A controlled prospective study of the effect of endurance training on the recurrence rate of myocardial infarction. A description of the experimental design.

A multicenter prospective study has been designed to determine whether participation in an exercise program which produces a significant training effect will affect the recurrence rate in men who have survived an initial myocardial infarction. The control group consists of subjects who participate in a program involving low intensity activities designed to avoid a significant training effect. The subjects will be followed for a period of 4 years and a reduction of 50 per cent in the risk of recurrence will be considered clinically significant. The criteria for entry, the method of allocation, the structure of the exercise program and method of assessing cardiorespiratory fitness are described.

Angina Pectoris