Chemotherapeutic treatment of the diencephalic syndrome. A case report

Tumors of the hypothalamus present with a variety of clinical syndromes. Such syndromes appear to be both age and histology dependent. The diencephalic syndrome, an entity classically seen in infancy, presents as failure to thrive. In essentially all cases the pathologic substrate is a tumor with a predominance of gliomas. The traditional approach to treatment of the diencephalic syndrome has been surgery both for decompression and pathologic diagnosis followed by irradiation. Because of the tumor location, surgery is often confined to biopsy rather than radical extirpation. Furthermore, in infancy focal brain irradiation is not without significant morbidity. Within this context, we would like to present a case discussion regarding a 27-month-old boy with a hypothalamic-midbrain protoplasmic glioma treated with primary chemotherapy after surgical biopsy and pathologic documentation. The schedule of drugs utilized was based on the hypothesis of biochemical modulation of nitrosourea chemotherapy. Successful response to therapy was documented by sequential computed tomography (CT) studies and serial neurologic examinations beginning at age 5 months and every 2 months thereafter. The response of a single patient with the diencephalic syndrome treated primarily with chemotherapy makes extrapolation premature. Rather, the authors suggest chemotherapy as an alternative to focal brain irradiation. Such therapy could be utilized either in the event of recurrent tumor or as late consolidation after primary treatment with chemotherapy. The latter approach would allow a patient to have radiation therapy deferred until a later age at which time morbidity attending brain irradiation may be minimized.     

A critical period for functional vestibular development in zebrafish.

We have determined a critical period for vestibular development in zebrafish by using a bioreactor designed by NASA to simulate microgravity for cells in culture. A critical period is defined as the briefest period of time during development when stimulus deprivation results in long lasting or permanent sensory deficits. Zebrafish eggs were collected within 3 hours of being laid and fertilized. In experiment 1, eggs were placed in the bioreactor at 3, 24, 30, 36, 48, or 72 hours postfertilization (hPF) and maintained in the bioreactor until 96 hPF. In experiment 2, eggs were placed in the bioreactor immediately after they were collected and maintained in the bioreactor until 24, 36, 48, 60, 66, 72, or 96 hPF. Beginning at 96 hPF, all larvae had their vestibulo-ocular reflexes (VOR) evaluated once each day for 5 days. Only larvae that hatched from eggs that were placed in the bioreactor before 30 hPF in experiment 1 or removed from the bioreactor later than 66 hPF in experiment 2 had VOR deficits that persisted for at least 5 days. These data suggest a critical period for vestibular development in the zebrafish that begins before 30 hPF and ends after 66 hPF. To confirm this, zebrafish eggs were placed in the bioreactor at 24 hPF and removed at 72 hPF. VORs were evaluated in these larvae once each day for 5 days beginning at 96 hPF. These larvae had VOR deficits that persisted for at least 5 days. In addition, larvae that had been maintained in the bioreactor from 24 to 66 hPF or from 30 to 72 hPF, had only temporary VOR deficits. In a final experiment, zebrafish eggs were placed in the bioreactor at 3 hPF and removed at 96 hPF but the bioreactor was turned off from 24 hPF to 72 hPF. These larvae had normal VORs when they were removed from the bioreactor at 96 hPF. Taken as a whole, these data support the idea that there is a critical period for functional maturation of the zebrafish vestibular system. The developmental period identified includes the timeframe during which the vestibular primary afferent neurons are born, innervate their central and peripheral targets, and remodel their central projections.     

Management of severe musculoskeletal injuries of the upper extremity

Limb salvage was successful in 25 patients treated for severe grade III upper extremity injuries. In a retrospective review of 20 men and five women, follow-up time averaged 26 months. These high-energy injuries were characterized by massive soft-tissue injury, highly comminuted fractures, and significant neurovascular injury. Farm, industrial, and vehicular accidents accounted for 80% of the cases. Over 50% of the patients had concomitant systemic and/or other significant extremity injuries. Initial treatment consisted of irrigation and debridement and fracture stabilization using external and/or internal fixation. An average of four additional surgical procedures was required to provide soft-tissue coverage and maximum possible functional recovery. Forty-eight percent of the extremities underwent free vascularized or pedicular flaps for coverage or reconstruction. At final follow-up observation, 12% of the extremities rated excellent, 20% rated good, 52% fair, and 16% were poor. Experience gained in managing these severe upper extremity fractures supports the following observations. (a) Grade III open fractures of the upper extremities are frequently associated with significant neural, vascular, and musculotendon injuries. (b) External fixation plays an important role in the stabilization of grossly contaminated fractures. (c) Residual functional disability is common, and most patients do not return to their previous occupation. (d) Staged reconstruction directed toward maximum functional return may take several years.     

Synthesis and release of 5-fluorouracil from poly(N-vinylpyrrolidinone) bearing 5-fluorouracil derivatives.

1-beta-allyloxycarbonyloxymethyl-5-fluorouracil (4) and 1,3-bis(beta-allyloxycarbonyloxymethyl)-5-fluorouracil (5) were synthesised by reacting 5-fluorouracil with formaldehyde followed by treating the product with isopropenyl chloroformate. The monomers 4 and 5 were copolymerized separately with N-vinylpyrrolidinone to form linear copolymers and cross-linked polymer networks, respectively. The monomer reactivity ratios in the copolymerization of 4 with NVP were evaluated by both linear and non-linear methods and the effect of monomer feed composition on copolymer molecular weight was examined. The degradation of the polymer networks in phosphate buffer (pH 7.4) was investigated. The hydrolytic scission of the carbonate groups resulted in release of 5-fluorouracil and a decrease in cross-linking density. The time-dependent fractional release of the 5-FU could be fitted by a power relationship with exponents between 0.10 and 0.25.     

Cellular and molecular basis of age-related sarcopenia.

Sarcopenia, the decline in muscle bulk and performance associated with normal aging, is an important component of frailty in the elderly. The gradual loss of both motor nerves and muscle fibers during senescence appears to be the major problem. Atrophy (especially in fast-twitch fibers) and impaired function of the surviving cells also contribute to sarcopenia. Although skeletal muscle has the capacity to regenerate itself, this process is not activated by the gradual age-related loss of muscle fibers. The endocrine, autocrine, and paracrine environment in old muscle is less supportive of protein synthesis, reinnervation of muscle fibers, and satellite cell activation, proliferation, and differentiation. Lifelong exposure of DNA to free radical damage results in accumulation of somatic mutations in nerves and muscle fibers. Reduced protein synthesis leads to atrophy, and slower fractional protein turnover contributes to longer retention of proteins that may have been damaged by free radicals. Many genes are differentially expressed in young and old muscle, but additional research is needed to determine which of these genes have a significant role in the pathogenesis or adaptation to sarcopenia.     

A new immune-competent animal model of mucosally derived squamous cell carcinoma.

OBJECTIVES: To develop an immune-competent animal model for mucosally derived squamous cell carcinoma (SCCA). STUDY DESIGN: Fifteen Fischer 344 rats were inoculated with 1, 2, 5, 10, or 20 x 10(6) FAT7 cells in their flanks. The animals were observed for tumor growth and metastasis. RESULTS: All animals developed tumors that grew exponentially. Pulmonary metastases developed in all animals and 13% developed lymph node metastases. CONCLUSION: The FAT7 flank tumor in Fischer 344 rats is a new animal model that closely resembles the behavior of human mucosal head and neck cancer. SIGNIFICANCE: The existence of an immune-competent, mucosally derived, and reliable animal model of SCCA that somewhat resembles human head and neck SCCA gives the opportunity to perform immune-modulating experiments on head and neck cancer in these animals. EBM rating: B-3.