Longitudinal-transverse separations of deep-inelastic structure functions at low Q2 for hydrogen and deuterium.

We report on a study of the longitudinal to transverse cross section ratio, R=sigmaL/sigmaT, at low values of x and Q2, as determined from inclusive inelastic electron-hydrogen and electron-deuterium scattering data from Jefferson Laboratory Hall C spanning the four-momentum transfer range 0.06

Pulmonary metastasectomy for pediatric solid tumors.

Most pediatric thoracic malignancy is pulmonary disease secondary to solid tumors of childhood. The management of isolated pulmonary metastases in adulthood is well documented. Little has been published to document the long-term outcome of pulmonary metastasectomy in childhood. A retrospective study was undertaken to assess the results of surgery for isolated pulmonary metastases. Twenty children underwent surgery over 12 years (mean follow-up 8 years). Five had Wilms' tumor (mean age 51 months), eight had osteogenic sarcoma (mean age 141 months), three had rhabdomyosarcoma (mean age 92 months), two had hepatoblastoma (mean age 30 months) and two had teratoma (mean age 72 months). Four had bilateral synchronous metastases and thoracotomies, and one had bilateral metachronous metastases and thoracotomies. Nineteen children were discharged well within 10 days of surgery. There was one early complication: a death due to pneumonia. Four children subsequently died postoperatively with cranial metastases (mean 29 months postoperatively). The remaining 16 children remain alive and well. As part of the combined therapy, these results would support an aggressive surgical approach to this disease. Preoperative assessment should include contrast enhanced computed tomogram of the head and chest as well as chest X-ray taken immediately preoperatively to exclude metastases. Bilateral synchronous and metachronous thoracotomy is well tolerated in childhood.

Effects of hypophysectomy and growth hormone administration on the mRNA levels of collagen I, III and insulin-like growth factor-I in rat skeletal muscle.

The effect of short-term treatment of normal or hypophysectomized rats with biosynthetic growth hormone (GH) was studied in extensor digitorum longus and soleus muscles. In situ hybridization revealed that in normal rats, mRNA for collagen I, collagen III and insulin-like growth factor-I (IGF-I) are expressed by fibroblasts between the muscle fibre areas and that the specificity of this location was not altered by GH administration. Hypophysectomy appeared to cause a decrease in IGF-I and decreased collagen I and III gene expression (P < 0.001, P < 0.001, respectively). GH administration seemed to increase IGF-I mRNA levels in all the animals studied. Quantitative image analysis that GH administration to hypophysectomized rats caused an increase in collagen I gene expression after 2 days (P < 0.05) and an increase in collagen III gene expression after 4 days (P < 0.05). The results indicate that the fibroblast cells are an important target for the action of GH on skeletal muscle and that the fibroblasts respond to GH by increases in the expression of mRNA for collagen I and collagen III.

Growth hormone increases IGF-I, collagen I and collagen III gene expression in dwarf rat skeletal muscle.

The effect of short-term treatment with biosynthetic growth hormone (GH) of male dwarf rats was studied in EDL and soleus muscles. In situ hybridisation revealed that in the untreated dwarf rat collagen I, collagen III and insulin-like growth factor-I (IGF-I) mRNA is mainly expressed by fibroblasts between the muscle fibre areas. Quantitative image analysis showed that, 8 h after a single GH injection, the level of mRNA for all three genes increased compared to the untreated dwarf animal. IGF-I mRNA levels were similar in normals and untreated dwarf rats but significantly increased 8 h after a single GH injection in EDL (P < 0.01) and soleus (P < 0.001). In untreated dwarf rats, collagen I and III gene expression was significantly less than in normal animals (P < 0.001). Collagen III gene expression also increased significantly 8 h after a single GH injection, in both muscles (P < 0.01). Collagen I gene expression showed significant increases 8 and 24 h after GH treatment in EDL (P < 0.01), although the increases seen in soleus did not reach significance. The effects of multiple GH injections (one, two or four) did not appear to be additive. The results of the time course studies are consistent with an intermediary role for IGF-I in the production of collagen in muscle.

Outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer.

BACKGROUND: Hospitalization and intravenous (IV) broad-spectrum antibiotics are the standard of care for all febrile neutropenic patients with cancer. Recent work suggests that a low-risk population exists who might benefit from an alternate approach. METHODS: A prospective randomized clinical trial was performed comparing oral ciprofloxacin 750 mg plus clindamycin 600 mg every 8 hours with IV aztreonam 2 g plus clindamycin 600 mg every 8 hours for the empiric outpatient treatment of febrile episodes in low-risk neutropenic patients with cancer. RESULTS: The oral regimen cured 35 of 40 episodes (88% response rate), whereas the IV regimen cured 41 of 43 episodes (95% response rate, P = 0.19). Although the cost of the oral regimen was significantly less than that of the IV regimen (P < 0.0001), it was associated with significant renal toxicity (P < 0.05), which led to early termination of the study. Overall, combining its safety and efficacy, the IV regimen was superior (P = 0.03). CONCLUSIONS: This prospective study suggested that outpatient antibiotic therapy for febrile episodes in low-risk neutropenic patients with cancer is safe and effective. Better oral regimens are needed.

Human growth hormone treatment of hypophysectomized rats increases the proportion of type-1 fibres in skeletal muscle.

The studies describe alterations after hypophysectomy in the proportion of the type-1 and type-2 fibres in rat skeletal muscles, and the effects of replacement treatment with pituitary human (h) GH. Cytochemical analysis of myosin ATPase, succinate dehydrogenase and lactate dehydrogenase activities in sections of rat hind limb muscles were used as markers of fibre type and revealed that hypophysectomy reduced the proportion of type-1 fibres by 50% in soleus and in extensor digitorum longus muscles. This reduction in the proportion of type-1 fibres was accompanied by the appearance of transitional fibres (type 2C/1B). Following seven daily injections of hGH (60 mIU/day) to hypophysectomized rats, the proportion of type-1 fibres in both soleus and in extensor digitorum longus was increased with a concomitant reduction in the number of transitional fibres. After 11 days of treatment, all these transitional fibres had reverted back to type-1 fibres. Only hGH was observed to elicit this effect; injections of other pituitary hormones had no effect on the proportions of these transitional fibres. These alterations in fibre type occurred more rapidly than the changes reported after prolonged electrical stimulation of muscle or following extended exercise. These findings suggest that hypophysectomy and GH injection can result in a rapid alteration in the fibre composition of skeletal muscle, which may have important implications in terms of the resistance to fatigue and speed of contraction of the muscle.

Enhancement of the autocatalytic activation of trypsinogen to trypsin by bile and bile acids.

The activation of trypsinogen to trypsin in the small intestine can occur by the action of enterokinase or, alternatively, as an autocatalytic process catalysed by trypsin itself. We have found that bile salts and human bile cause a significant enhancement of the autocatalytic activation of trypsinogen. This effect is dependent on the calcium ion concentration and is most marked around pH 5.4 and 7.8. An optimum concentration exists for each bile salt at which the greatest enhancement occurs. At this concentration, certain bile salts have been shown to produce activation effects of up to 55-fold. It is suggested that this activation of the autocatalytic process by bile plays an important role in protein digestion in the small intestine, since it has been shown previously that duodenal trypsin levels are abnormally low in patients with an impairment of bile secretion.

The use of arginine analogues for investigating the functional organization of the arginine-binding site in lobster muscle arginine kinase. Role of the 'essential' thiol group.

1. The nature of arginine binding to lobster arginine kinase and the extent of its possible involvement with the ;essential' thiol group of the enzyme has been investigated with some inhibitory analogues of arginine. 2. Most of the analogues inhibit competitively, although mixed inhibition may occur if the alpha-carboxy group or alpha-amino group is absent. 3. The K(i) values indicate that strength of binding depends on the length of the carbon chain (l-isoleucine>l-valine>l- alpha-aminobutyrate>l-alanine) and the integrity of the substituents on the alpha-carbon atom (l-arginine>agmatine and l-ornithine>putrescine). The guanidino group probably contributes little to substrate binding, but a positive charge near the delta-nitrogen atom appears to be important (l-ornithine>l -citrulline>l-alpha-aminobutyrate). A cyclic analogue, 2-carboxymethyl-3-oxo-2,3,5,6,7,8-hexahydro-1H-imidazo [1,2-a][1,3]diazepine-8-carboxylic acid, has a low K(i) value similar to that of an equivalent straight-chain form, suggesting that arginine probably binds in a folded configuration. 4. The aliphatic l-amino acids give enzyme difference spectra similar to that with l-arginine and the integrity of the alpha-carboxy and alpha-amino groups appears to be a minimal but not sufficient requirement for this, as l-ornithine gives an atypical difference spectrum. A difference spectrum is interpreted as indicating an enzyme conformational change. No difference spectrum was observed with methylguanidine. 5. The ability of aliphatic alpha-l-amino acids to protect against inhibition by 5,5'-dithiobis-(2-nitrobenzoic acid) is proportional to the number of atoms in the carbon chain and inversely proportional to K(i). Ornithine gives greater protection than citrulline; analogues lacking the alpha-amino groups also protect. Agmatine, lacking the alpha-carboxy group, did not protect. 6. It is concluded that it is unlikely that the ;essential' thiol group in the enzyme interacts with any part of the arginine molecule during catalysis except, possibly, the alpha-carboxyl group.

Evolutionary variation between a monomer and a dimer arginine kinase. Purification of the enzyme from Holothuria forskali and a comparison of some properties with that from Homarus vulgaris.

1. A purification procedure for the dimeric arginine kinase of the sea cucumber Holothuria forskali is described. 2. The enzyme has a mean molecular weight of 77250 and is composed of two equal, dissociable subunits. 3. It also shows co-operativity between substrate binding at one catalytic site to a much greater extent than the nomomeric lobster arginine kinase for which such co-operativity could not be detected unambiguously. The constants for substrate binding are reported assuming that the enzyme follows rapid-equilibrium random kinetics. From a comparison with other species, the development of co-operativity between the nucleotide- and guanidine-binding sites on one subunit is suggested to have occurred more than once in the evolution of the phosphagen kinases and is not dependent on subunit aggregation. 4. Both enzymes show similar pH profiles for thermal inactivation at 22 degrees C and have very similar stabilities. Above 40 degrees C the dimeric enzyme is much more stable than the monomer. Rate constants for heat inactivation and Arrhenius activation energies are reported. 5. The dimeric enzyme is also more stable to urea inactivation. Substrates and argininic acid all improve the stability of both enzymes. The effects of individual substrates are more distincitive with the dimeric enzymes and increase its stability to an extent that makes it about as stable as dogfish creatine kinase. In the physiological range dimerization does not seem to confer any particular advantage with respect to stability over the monomer form.

Properties and reaction with iodoacetamide of adenosine 5'-triphosphate-creatine phosphotransferase from human skeletal muscle. Further evidence about the role of the essential thiol group in relation to the mechanism of action.

1. The purification of creatine kinase from human and monkey skeletal muscle by horizontal electrophoresis on Sephadex blocks is described. 2. The purified enzymes are shown to have similar chemical and kinetic properties to the rabbit muscle enzyme and a common mechanism is inferred. 3. Iodoacetamide has a similar apparent second-order inhibition constant with the human and rabbit enzymes, but the inhibition does not go to completion with the former. This is even more marked with the monkey enzyme, which has more reactive thiol groups, but inhibition is only about 50%. 4. Single substrates have little effect on the inhibition by iodoacetamide, but with the primate enzymes, in contrast with the rabbit enzyme, high concentrations of ADP-Mg(2+) plus creatine convert the essential thiol group from being pH-independent into one with a normal ionization. Low concentrations of ADP-Mg(2+) plus creatine first enhance the rate of inactivation, but cause protection as the reaction proceeds. These results are interpreted to indicate an activation of the thiol group on the subunit to which the substrates bind and a co-operatively induced decrease in the activity of the thiol group on the other subunit which lacks substrates. 5. The effects of a substrate equilibrium mixture on the rate of inhibition are essentially those of ADP-Mg(2+) plus creatine. 6. Since no substrate combination affords significant protection to the thiol group associated with the catalytic site to which the substrates are bound, it is concluded that any mechanism involving the thiol group in a direct participation in the transition-state complex of the catalytic reaction must be abandoned unless the transition state is only a small part of the time taken for one catalytic cycle.