The application of population pharmacokinetic analysis to large scale clinical efficacy trials

Summary Results have been presented that demonstrate the ability to conduct population pharmacokinetic analysis as a component of clinical efficacy and safety trials. This method of analysis offers the potential to determine the pharmacokinetics of a drug in the actual patients receiving medication and to evaluate relationships between pharmacokinetics and drug action. However, active involvement in the protocol design, and data collection process are required to ensure the quality of the resultant data set.     

Weight change in depression: influence of "disinhibition" is mediated by body mass and other variables.

The direction of weight change (gain or loss) in depression has recently been found to be a stable characteristic of patients across depressive episodes. A search for determinants of the direction of weight change revealed two candidates: the body mass index (BMI) (weight in kilograms/height in meters squared) and a psychological variable, "disinhibition" of dietary restraint. The present study, of 68 patients with a history of recurrent depression, found a significant correlation between BMI and weight change; in other words, heavier persons were more likely to gain weight if depressed. There was also a correlation between "disinhibition" and weight change. "Disinhibition" correlated with BMI and, when controlled for BMI, age and sex, the correlation between "disinhibition" and weight change fell to insignificance. We conclude that BMI along with age and sex mediated the correlation between "disinhibition" and weight change.     

Anaesthetic anagement of Miller’s syndrome

Miller's syndrome is a rare congenital disorder with facial features similar to that of Treacher-Collins syndrome. This report details the anaesthetic management of an infant during multiple surgical procedures, beginning with pylormyotomy at one month of age. Airway management was difficult because of severe micrognathia and was accomplished using an awake intubation with a conventional straight blade modified for continuous administration of oxygen ("oxyscope"). Due to recurrent upper airway obstruction and the anticipated need for multiple surgical procedures in the first years of life, a tracheostomy was placed. Because of the multiple airway, orthopaedic, and nutritional difficulties, it is important that a prospective, multidisciplinary approach be used in these patients' care. Consideration should be given to early tracheostomy for airway maintenance.     

Routine application of the omental pedicle graft in 50 consecutive patients at risk for sternal wound infection

After cardiac surgery, healing can be delayed by sternal wound infection, particularly if mediastinitis develops. Because of the technical simplicity of omentopexy, we recommend the use during open-heart surgery of an omental pedicle graft in selected cases to prevent postoperative complications. This article describes our experience over a 4-month period (from 30 March 1989 through 2 August 1989) with this technique in 50 consecutive patients at moderate-to-high risk for postoperative sternal and mediastinal problems. The patients included 39 men (78%) and 11 women (22%), whose ages ranged from 22 to 83 years (mean, 55 years). Preoperative risk factors included extreme obesity, 13 patients (26%); chronic obstructive pulmonary disease, 13 patients (26%); diabetes mellitus, 6 patients (12%); obesity and diabetes, 8 patients (16%); and obesity, diabetes, and chronic obstructive pulmonary disease, 3 patients (6%). Operative risk factors included cardiac reoperation involving prolonged surgery, 6 patients (12%); bilateral mammary grafting, 17 patients (34%); and the need for prolonged (greater than 72-hour) mechanical respiratory assistance, 2 patients (4%). Three of the 50 patients (6%) were considered to be at moderate risk due to an increase in nosocomial infections at the time of their surgical procedures. Although the omentopexy itself caused no complications, 5 patients had major complications related to the cardiac procedure. Two of these patients died, for an operative mortality of 4%; death was caused by progressive peritonitis in 1 case and by cardiac tamponade in the other case. At least 2 of the remaining 3 patients withstood localized mediastinal infection and had thereafter an extremely benign postoperative course. We conclude that an omental pedicle graft, placed prophylactically in patients at risk for sternal wound infection, can serve as a valuable adjunct to healing after cardiac surgery.     

Cytomegalovirus cecal erosion causing massive hemorrhage in a bone marrow transplant recipient

A 24-year-old male underwent bone marrow transplantation for severe aplastic anemia. Posttransplantation complications included severe graft-versus-host disease and cytomegalovirus (CMV) infection manifested by gastrointestinal bleeding and apparent pneumonitis. Massive rectal bleeding necessitated exploratory laparotomy at which time a right colon resection was performed. Fifteen cecal ulcers were present which on histologixc examination revealed numerous cells containing characteristic intranuclear inclusions. Life-threatening gastrointestinal lesions associated with CMV infection will be seen with increasing frequency as more patients undergo the severe immunosuppression associated with bone marrow and organ transplantation. Prompt recognition and expeditious surgical management will result in improved survival in this high-risk population.

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Résumé Chez un sujet de 24 ans qui avait subi une transplantation de moelle osseuse sort survenues des complications de rejet et une infection à cytomégalovirus qui s'est manifestée par une hémorragie digestive et une atteinte pulmonaire. L'abondance de l'hémorragie a imposé une laparotomie exploratrice qui a conduit à une hémicolectomie droite. Sur la pièce de résection on a découvert quinze ulcérations. L'examen histologique a montré qu'elles contenaient de nombreuses cellules dont le noyau présentait de nombreuses inclusions caractéristiques.Ce type de lésions digestives allant de pair avec une infection a cytomégalovirus devrait devenir de plus en plus fréquent chez les malades qui présentent des phénomènes immuno-dépressifs après transplantation d'organes ou de moelle osseuse. Il sera nécessaire de les reconnaitre rapidement pour les traiter chirurgicalement sans retard. C'est à ce prix que le risque d'évolution fatale pourra être réduit chez ces sujets à haut risque.

     

"Freedom of choice" laws: empirical evidence of their contribution to competition in mental health care delivery

Freedom of Choice laws have been forwarded as laws which enhance consumer choice and efficient functioning of markets for mental health services. The name of these laws constitute a misnomer, because they serve to force consumers to buy a specific type of insurance coverage. Nevertheless, under a specific set of markets conditions, the implementation of Freedom of Choice laws may increase competition and improve efficiency in the market. Empirical estimates are reported of the effect on prices of this legislation.     

Iodine-125 labeled phenylphosphonic acid: A new radiopharmaceutical for long-term investigations of the skeleton

A skeletal seeking radiopharmaceutical labeled with a long-lived radionuclide was developed to evaluate regional bone formation and its subsequent resorption. The agent is [phosphonate (phenylmethylene hydroxy) bis]-I-125 or I-125 PA. Tissue distribution studies in mice (N=16) showed approximately 40% of the administered dose to be retained by the skeleton up to 336 hours post IV injection. The percentage of the dose accumulated by the thyroid gland remained at less than 0.5%, indicating minimal deiodination of the I-125 PA. Whole body retention studies in the same species revealed a triexponential release pattern with the longest component comprising 33% of the dose with a biologic half-life of 962 days. A fractured rat tibia model was studied with I-125 PA and Tc-99^m MDP. Chronic loss of the I-125 PA relative to normal tibia was quantitated: five days (62.8%); 30 days (47.4%). Concomitant increased uptake of the Tc-99^m MDP was observed at the fracture site relative to normal: five days (186%); 30 days (1,041%). The above data suggest that I-125 PA can be utilized to measure acute bone formation and chronic resorption.     

Surgical management of recurring or metastatic thyroid cancer

The surgical oncologist is sometimes confronted with a patient who was surgically treated for cancer of the thyroid gland and now has recurrent disease. In most instances, additional surgical treatment is indicated. The magnitude of surgery is primarily determined by the amount of tissue removed at the original operation. Surgery for recurrent disease may include completion of total thyroidectomy with dissection of lymphatic tissues in the thyroid compartment or/and neck dissection, preferably modified. Several clinical situations are outlined and discussed.     

In vitro proliferation of endothelial cells from kitten retinal capillaries

When microvessel (predominantly capillary) fragments freshly isolated from the retinas of young kittens are incubated in tissue culture medium, we observe the slow outgrowth of cells that appear to be derived from the capillary endothelium. The cells grow as a monolayer with a tightly packed, mosaic-like array. Electron microscopy of these cells reveals "tight junctions" (zonulae occludentes) resembling those found in the endothelium of intact capillaries. The availability of in vitro preparations of retinal capillary endothelial cells should facilitate investigations of the causes of abnormal endothelial cell proliferation in various diseases and of factors that modify cell junctions and capillary permeability in the retina. Since we have previously demonstrated proliferation in culture of intramural pericytes ("mural cells") from retinal capillaries, it should now be possible to carry out compratative studies of biochemical and functional properties of retinal capillary pericytes and endothelial cells.     

Preoperative Evaluation of Pancreatic Masses with Positron Emission Tomography Using 18F-fluorodeoxyglucose: Diagnostic Limitations

Identification of pancreatic cancer in patients presenting with an enlarged pancreatic mass is a major diagnostic problem. Positron emission tomography (PET) using the radiolabeled glucose analogue ¹⁸F-fluorodeoxyglucose (FDG) has been suggested to provide excellent accuracy for noninvasive determination of suspicious pancreatic masses. We conducted a prospective study to verify these results. Forty-two patients admitted for pancreatic surgery underwent PET scanning. Image analysis was based on visual film evaluation and quantification of regional tracer uptake. PET imaging was visually analyzed by three observers blinded for the results of other diagnostic tests; they qualitatively graded the scans using a five-point scale (I = low to V = high) for the presence and intensity of focal FDG uptake. Diagnosis was proven by histology (n= 38) or follow-up (n= 4). Furthermore, the results of PET were compared with helical computed tomography (CT) and conventional ultrasonography (US), done during the routine diagnostic workup before pancreatic cancer surgery. Regarding only the results with scores of IV and V as positive for representing definite malignancy yielded a sensitivity of 71% and a specificity of 64% for film reading. Quantification of regional tracer uptake contributed no significant diagnostic advantage for differentiation between benign and malignant tumors. Helical CT revealed a sensitivity of 74% and a specificity of 45.5% and abdominal US 56% and 50%, respectively. We concluded that PET imaging provides only fair diagnostic accuracy (69%) for characterizing enlarged pancreatic masses. PET does not allow exclusion of malignant tumors. In doubtful cases, the method must be combined with other imaging modalities, such as helical CT. The results indicate that the number of invasive procedures is not significantly reduced by PET imaging.