Experimental hydranencephaly in the ovine fetus

Hydranencephaly is defined as the replacement of a previously normal brain, in whole or in part, by membranous fluid-filled sacs. The etiology is not well understood, and the time course of development is unknown. Fifteen ovine fetuses were chronically cannulated and had both carotid arteries ligated at 100 days of gestation (term is 145–150 days). They were killed at 1 (n = 4), 2 (n = 6) and 4 (n = 5) weeks post-surgery, and the findings compared with those of 25 age-matched controls. By 2 weeks post-surgery the entire cerebral hemispheres and diencephalon had been replaced by fluid closely resembling cerebrospinal fluid. The choroid plexus, pituitary and brain stem remained outwardly normal, but the cerebellum showed signs of damage. Fetuses maintained normal values for blood gases and hematocrit up to 4 weeks post-surgery, and grew normally. Light microscopy of the brain stem showed significant losses of cell populations in the medulla by 4 weeks. Vascular casting and acute blood flow studies in an additional group of fetuses showed that the entire brain was perfused via the vertebral-occipital anastomosis immediately after acute bilateral carotid clamping, but that the blood flow rate was insufficient to maintain adequate oxygen delivery. Received: 4 August 1995 / Revised, accepted: 30 November 1995     

National Alliance for Oral Health Consensus Conference on Medically Necessary Oral Health Care: Legal issues

This paper examines medical malpractice law as it applies to medically necessary oral health care. The basic legal concepts and reported cases involving medically necessary oral health care are reviewed. It is concluded that dental professionals and consumer advocates must advance their educational and legislative advocacy efforts so that health professional colleagues and the public will become aware of the importance of these services and insurers will routinely include coverage of medically necessary oral health care in their medical and dental policies. While failure to provide medically necessary oral health care can be violative of patient rights and legally actionable, medical malpractice litigation should always be the behavior modifier of last resort.     

Radiologic search for embolized leaflets of prosthetic heart valves: A report of two cases

In a radiologic search for embolized leaflets of Edwards-Duromedics bileaflet valves in 2 patients, the embolized fragments were localized in the iliac vessels using computed tomography. Sonography was successful in one case and standard X-ray films of the abdomen were negative in both cases.In vitro investigations with Björk-Shiley and Edwards-Duromedics leaflets suggested that standard X-ray films of the abdomen and pelvis should be considered as the first investigational technique. If negative, computed tomography of the lower abdomen should be done.     

Gene therapy for sarcoma

Soft tissue sarcomas are mesenchymal tumors which respond poorly to systemic therapy. Recent studies suggest a higher response rate with an increased doxorubicin dosage. However, this was parallel with a profound hematotoxicity in 75% of patients. Transfer of the human multidrug resistance 1 (MDR1) gene to normal hematopoietic stem cells and transplantation may significantly reduce the hematotoxicity of anthracyclin-based chemotherapy. To test this concept of supportive gene therapy in advance of a clinical study, we transduced mobilized peripheral blood progenitor cells (PBPC) with the retroviral vector SF91m3 containing the human MDR1 gene, transplanted these cells to immune-deficient mice, allowed 6 weeks for engraftment to occur and treated the animals with MDR1-based chemotherapy. In the MDR1-transduced group the human leukocytes were significantly protected from the toxicity of chemotherapy (p < 0.05). While the gene transfer rate was in the range of 10% and thus comparable to recent clinical trials, the gene expression was 59% of transduced cells and thus significantly higher than previously reported for less-advanced vectors. On the other hand, ifosfamide, a drug which has been used successfully for stem cell mobilization, is active in soft tissue sarcoma. Due to these favorable characteristics sarcoma is an attractive target to test the efficacy of MDR1 gene therapy in a clinical setting. Gene therapeutic strategies may also be used to directly target sarcoma cells, e.g. by transfer of suicide genes. We found that adenoassociated virus 2 (AAV-2) vectors efficiently transduce human HS-1 and HT1080 sarcoma cells (>90%) while other tumor cell lines and primary human PBPC were less susceptible. The thymidine kinase (TK) suicide gene was cloned into an AAV-2 vector and a complete kill of TK-transduced HS-1 and HT1080 cells was observed following exposure to aciclovir or ganciclovir (GCV), while >90% of mock-transduced HS-1 cells survived at these dosages. Transplantation of those sarcoma cells to nonobese diabetic (NOD)/LtSz-severe-combined immunodeficient (scid)/scid (NOD/SCID) mice resulted in a survival of >5 months in the AAV-TK-transduced/GCV-treated group, while the mice in the mock-transduced/GCV-treated group had died after 3 weeks. These data show that soft tissue sarcomas are a particularly suitable model system for the development and clinical testing of new gene therapeutic concepts.