Migration of radiocesium in two forest soils as obtained from field and column investigations.

Depth profiles of radiocesium were measured in a podsolic parabrown earth of a spruce stand and in a podsol of a pine stand up to 3 years after the Chernobyl accident. At the same sites undisturbed soil columns of 20 cm diameter and 40 cm length were taken, transferred to the laboratory and irrigated intermittently with synthetic rainwater containing initially a known amount of radiocesium. The resulting migration of radiocesium in the columns under unsaturated conditions was determined as a function of time up to 3 years with a scanner technique. The depth profiles of radiocesium observed in the field and in the columns were evaluated with a compartment model to obtain the residence half-times of this radionuclide in the various soil horizons. The field observations yielded a residence half-time in the organic layer of both soils of approximately 4-6 years for Chernobyl-derived cesium, and of 10-15 years for cesium from the global fallout of weapons testing. In the mineral soil (0-5 cm), under spruce the residence time of Chernobyl-derived cesium was 15 years, that of cesium from the global fallout (present in the soil since approximately 30 years) was 50 years. Under pine, the residence time in the mineral soil was 4 years for Chernobyl-derived cesium and 11 years for global fallout cesium. Obviously, in each layer of both soils cesium becomes less available for migration with time. The residence times of radiocesium evaluated from the column experiments were in good agreement with those obtained from the field observations. Due to the comparatively short duration of the column experiments, however, the long-term increase of the residence time of radiocesium in the soil was not yet unambiguously observable.


Weighing naked proteins: practical, high-accuracy mass measurement of peptides and proteins.

Two new technologies have made the study of proteins by mass spectrometry straight-forward. Proteins with molecular masses of up to more than 100 kilodaltons can be analyzed at picomole sensitivities to give simple mass spectra corresponding to the intact molecule. This development has allowed unprecedented accuracy in the determination of the molecular weights of proteins. A number of "case studies" are used to present the revolutionary impact that these powerful new ways of looking at proteins are having on biological research.


From molecules to cells: imaging soft samples with the atomic force microscope.

Since its invention a few years ago, the atomic force microscope has become one of the most widely used near-field microscopes. Surfaces of hard sample are imaged routinely with atomic resolution. Soft samples, however, remain challenging. An overview is presented on the application of atomic force microscopy to organic samples ranging from thin ordered films at molecular resolution to living cells. Fundamental mechanisms of the image formation are discussed, and novel imaging modes are introduced that exploit different aspects of the tip-sample interaction for local measurements of the micromechanical properties of the sample. As examples, images of Langmuir-Blodgett films, which map the local viscoelasticity as well as the friction coefficient, are presented.


Interactions of small nuclear RNA's with precursor messenger RNA during in vitro splicing.

Precursor messenger RNA splicing requires multiple factors including U1, U2, U4, U5, and U6 small nuclear RNA's. The crosslinking reagent psoralen was used to analyze the interactions of these RNA's with an adenovirus precursor messenger RNA in HeLa nuclear extract. An endogenous U2-U4-U6 crosslinkable complex dissociated upon incubation with precursor messenger RNA. During splicing, U1, U2, U5, and U6 became crosslinked to precursor messenger RNA and U2, U5, and U6 became crosslinked to excised lariat intron. U2 also formed a doubly crosslinked complex with U6 and precursor messenger RNA. The U1, U5, and U6 crosslinks to the precursor messenger RNA mapped to intron sequences near the 5' splice site, whereas the U2 crosslink mapped to the branch site. The kinetics of crosslink formation and disappearance delineates a temporal pathway for the action of small RNA's in the spliceosome. Potential base pairing interactions between conserved sequences in the small nuclear RNA's and precursor messenger RNA at the sites of crosslinking suggest that the 5' splice site is defined in several steps prior to the first cleavage event.


Miocene fossil hominids and the chimp-human clade.

Miocene hominoids from Europe are among the earliest members of the great ape and human clade (the Hominidae). One of these forms, represented by well-preserved cranial remains from Rudabánya, Hungary, sheds new light on the question of the evolutionary relations among living hominids. This new evidence supports the view that humans have a specific evolutionary relation with chimpanzees, to the exclusion of all other apes.


DNA sequences from a fossil termite in Oligo-Miocene amber and their phylogenetic implications.

DNA was extracted from the fossil termite Mastotermes electrodominicus preserved in Oligo-Miocene amber (25 million to 30 million years old). Fragments of mitochondrial [16S ribosomal DNA (rDNA)] and nuclear (18S rDNA) genes were amplified by polymerase chain reaction. Phylogenetic analysis of fossil and extant 18S rDNA confirmed morphological cladistic analyses of living dictyopterans (termites, cockroaches, and mantids). The fossil termite shares several sequence attributes with Mastotermes darwiniensis. Addition of this fossil to living-species phylogeny is required to substantiate Mastotermes monophyly and affects molecular phylogenetic hypotheses of termites in this, the oldest DNA yet characterized.


Measurement of quantum tunneling between chiral isomers of the cyclic water trimer.

A detailed experimental study of the water trimer is reported. A vibration-rotation-tunneling band of the perdeuterated cluster has been measured near 89.6 wave numbers by tunable far infrared laser absorption spectroscopy. The data indicate a chiral six-membered ring structure with rapid quantum tunneling occurring between the enantiomers. The observed vibration involves torsional motion of the water subunits about each hydrogen bond axis. It is speculated that larger water clusters would also exhibit transient chirality and that similar effects may be found in liquid water.


Discovery of a peptide-based renin inhibitor with oral bioavailability and efficacy.

Peptidic renin inhibitors have been poorly absorbed across the intestine or rapidly eliminated by the liver and have been reported to have oral bioavailabilities of less than 2%. A peptide-based renin inhibitor, A-72517 (molecular mass of 706 daltons), was devised that has oral bioavailabilities of 8, 24, 32, and 53% in the monkey, rat, ferret, and dog, respectively. Dose-related reductions in blood pressure, plasma renin activity, and plasma angiotensin II in parallel with increased plasma drug concentrations were observed after oral administration of A-72517 to conscious, salt-depleted dogs. Thus, peptide-based molecules of sizable molecular mass can be absorbed intact into the systemic circulation of animals. These findings support the potential of peptide-based drugs for oral administration.


Actin filament dynamics in living glial cells imaged by atomic force microscopy.

Observation of filamentous actin (F-actin) in living cells is currently limited to the resolution of the light microscope. Higher resolution procedures require sample fixation and preclude dynamic studies. The atomic force microscope (AFM) can image and manipulate samples at very high, sometimes atomic resolution by scanning a fine tip over the surface of interest and detecting physical interactions between the tip and sample. This study demonstrates that F-actin can be readily resolved in living cells with the AFM and that the dynamic properties of F-actin are easily observed.


Multiple zinc finger forms resulting from developmentally regulated alternative splicing of a transcription factor gene.

Transcripts encoding the Drosophila putative transcription factor CF2 are subject to developmentally regulated alternative splicing, and they encode protein isoforms that differ in the number of zinc fingers. One testis-specific RNA encodes an isoform that includes three zinc fingers and a frame-shifted segment. Two other transcripts encode isoforms with six and seven zinc fingers which bind to distinct promoters and DNA target sequences. Thus, because of alternative splicing, a single gene appears to encode distinct DNA-binding proteins, each capable of regulating different gene sets in different tissues and developmental periods.


Rodent carcinogens: setting priorities.

The human diet contains an enormous background of natural chemicals, such as plant pesticides and the products of cooking, that have not been a focus of carcinogenicity testing. A broadened perspective that includes these natural chemicals is necessary. A comparison of possible hazards for 80 daily exposures to rodent carcinogens from a variety of sources is presented, using an index (HERP) that relates human exposure to carcinogenic potency in rodents. A similar ordering would be expected with the use of standard risk assessment methodology for the same human exposure values. Results indicate that, when viewed against the large background of naturally occurring carcinogens in typical portions of common foods, the residues of synthetic pesticides or environmental pollutants rank low. A similar result is obtained in a separate comparison of 32 average daily exposures to natural pesticides and synthetic pesticide residues in the diet. Although the findings do not indicate that these natural dietary carcinogens are important in human cancer, they cast doubt on the relative importance for human cancer of low-dose exposures to synthetic chemicals.


X-ray laser microscopy of rat sperm nuclei.

The development of high brightness and short pulse width (< 200 picoseconds) x-ray lasers now offers biologists the possibility of high-resolution imaging of specimens in an aqueous environment without the blurring effects associated with natural motions and chemical erosion. As a step toward developing the capabilities of this type of x-ray microscopy, a tantalum x-ray laser at 44.83 angstrom wavelength was used together with an x-ray zone plate lens to image both unlabeled and selectively gold-labeled dried rat sperm nuclei. The observed images show approximately 500 angstrom features, illustrate the importance of x-ray microscopy in determining chemical composition, and provide information about the uniformity of sperm chromatin organization and the extent of sperm chromatin hydration.


Intercellular propagation of calcium waves mediated by inositol trisphosphate.

Two types of calcium (Ca2+) signaling-propagating intercellular Ca2+ waves of increasing intracellular Ca2+ concentration ([Ca2+]i) and nonpropagating oscillations in [Ca2+]i-co-exist in a variety of cell types. To investigate this difference in Ca2+ signaling, airway epithelial cells were loaded with heparin, an inositol 1,4,5-triphosphate (IP3) receptor antagonist, by pulsed, high-frequency electroporation. Heparin inhibited propagation of intercellular Ca2+ waves but not oscillations of [Ca2+]i. In heparin-free cells, Ca2+ waves propagated through cells displaying [Ca2+]i oscillations. Depletion of intracellular Ca2+ pools with the Ca2+-pump inhibitor thapsigargin also inhibited the propagation of Ca2+ waves. These studies demonstrate that the release of Ca2+ by IP3 is necessary for the propagation of intercellular Ca2+ waves and suggest that IP3 moves through gap junctions to communicate intercellular Ca2+ waves.


Diverse migratory pathways in the developing cerebral cortex.

During early development of the mammalian cerebral cortex, young neurons migrate outward from the site of their final mitosis in the ventricular zone into the cortical plate, where they form the adult cortex. Time-lapse confocal microscopy was used to observe directly the dynamic behaviors of migrating cells in living slices of developing cortex. The majority of cells migrated along a radial pathway, consistent with the view that cortical neurons migrate along radial glial fibers. A fraction of cells, however, turned within the intermediate zone and migrated orthogonal to the radial fibers. This orthogonal migration may contribute to the tangential dispersion of clonally related cortical neurons.


Prevention of programmed cell death of sympathetic neurons by the bcl-2 proto-oncogene.

Approximately half of the neurons produced during embryogenesis normally die before adulthood. Although target-derived neurotrophic factors are known to be major determinants of programmed cell death--apoptosis--the molecular mechanisms by which trophic factors interfere with cell death regulation are largely unknown. Overexpression of the bcl-2 proto-oncogene in cultured sympathetic neurons has now been shown to prevent apoptosis normally induced by deprivation of nerve growth factor. This finding, together with the previous demonstration of bcl-2 expression in the nervous system, suggests that the Bcl-2 protein may be a major mediator of the effects of neurotrophic factors on neuronal survival.


Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors.

Altered processing of the amyloid precursor protein (APP) is a central event in the formation of amyloid deposits in the brains of individuals with Alzheimer's disease. To investigate whether cellular APP processing is controlled by cell-surface neurotransmitter receptors, human embryonic kidney (293) cell lines were transfected with the genes for human brain muscarinic acetylcholine receptors. Stimulation of m1 and m3 receptor subtypes with carbachol increased the basal release of APP derivatives within minutes of treatment, indicating that preexisting APP is released in response to receptor activation. Receptor-activated APP release was blocked by staurosporine, suggesting that protein kinases mediate neurotransmitter receptor-controlled APP processing.


E2F: a link between the Rb tumor suppressor protein and viral oncoproteins.

The cellular transcription factor E2F, previously identified as a component of early adenovirus transcription, has now been shown to be important in cell proliferation control. E2F appears to be a functional target for the action of the tumor suppressor protein Rb that is encoded by the retinoblastoma susceptibility gene. The disruption of this E2F-Rb interaction, as well as a complex involving E2F in association with the cell cycle-regulated cyclin A-cdk2 kinase complex, may be a common mechanism of action for the oncoproteins encoded by the DNA tumor viruses.


Atomic structure of the DNA repair [4Fe-4S] enzyme endonuclease III.

The crystal structure of the DNA repair enzyme endonuclease III, which recognizes and cleaves DNA at damaged bases, has been solved to 2.0 angstrom resolution with an R factor of 0.185. This iron-sulfur [4Fe-4S] enzyme is elongated and bilobal with a deep cleft separating two similarly sized domains: a novel, sequence-continuous, six-helix domain (residues 22 to 132) and a Greek-key, four-helix domain formed by the amino-terminal and three carboxyl-terminal helices (residues 1 to 21 and 133 to 211) together with the [4Fe-4S] cluster. The cluster is bound entirely within the carboxyl-terminal loop with a ligation pattern (Cys-X6-Cys-X2-Cys-X5-Cys) distinct from all other known [4Fe-4S] proteins. Sequence conservation and the positive electrostatic potential of conserved regions identify a surface suitable for binding duplex B-DNA across the long axis of the enzyme, matching a 46 angstrom length of protected DNA. The primary role of the [4Fe-4S] cluster appears to involve positioning conserved basic residues for interaction with the DNA phosphate backbone. The crystallographically identified inhibitor binding region, which recognizes the damaged base thymine glycol, is a seven-residue beta-hairpin (residues 113 to 119). Location and side chain orientation at the base of the inhibitor binding site implicate Glu112 in the N-glycosylase mechanism and Lys120 in the beta-elimination mechanism. Overall, the structure reveals an unusual fold and a new biological function for [4Fe-4S] clusters and provides a structural basis for studying recognition of damaged DNA and the N-glycosylase and apurinic/apyrimidinic-lyase mechanisms.


Small-angle synchrotron x-ray scattering reveals distinct shape changes of the myosin head during hydrolysis of ATP.

In the energy transduction of muscle contraction, it is important to know the nature and extent of conformational changes of the head portion of the myosin molecules. In the presence of magnesium adenosine triphosphate (MgATP), fairly large conformational changes of the myosin head [subfragment-1 (S1)] in solution were observed by small-angle x-ray scattering with the use of synchrotron radiation as an intense and stable x-ray source. The presence of MgATP reduced the radius of gyration of the molecule by about 3 angstrom units and the maximum chord length by about 10 angstroms, showing that the shape of S1 becomes more compact or round during hydrolysis of MgATP. Comparison with various nucleotide-bound S1 complexes that correspond to the known intermediate states during ATP hydrolysis indicates that the shape of S1 in a key intermediate state, S1-bound adenosine diphosphate (ADP) and phosphate [S1**.ADP.P(i)], differs significantly from the shape in the other intermediate states of the S1 adenosine triphosphatase cycle as well as that of nucleotide-free S1.


Neural computing in cancer drug development: predicting mechanism of action.

Described here are neural networks capable of predicting a drug's mechanism of action from its pattern of activity against a panel of 60 malignant cell lines in the National Cancer Institute's drug screening program. Given six possible classes of mechanism, the network misses the correct category for only 12 out of 141 agents (8.5 percent), whereas linear discriminant analysis, a standard statistical technique, misses 20 out of 141 (14.2 percent). The success of the neural net indicates several things. (i) The cell line response patterns are rich in information about mechanism. (ii) Appropriately designed neural networks can make effective use of that information. (iii) Trained networks can be used to classify prospectively the more than 10,000 agents per year tested by the screening program. Related networks, in combination with classical statistical tools, will help in a variety of ways to move new anticancer agents through the pipeline from in vitro studies to clinical application.


Some anthropological aspects of the prehistoric Tyrolean ice man.

The corpse of a Late Neolithic individual found in a glacier in Oetztal is unusual because of the intact nature of all body parts that resulted from the characteristics of its mummification process and its protected geographical position with regard to glacier flow. Anthropological data indicate that the man was 25 to 40 years old, was between 156 and 160 centimeters in stature, had a cranial capacity of between 1500 and 1560 cubic centimeters, and likely died of exhaustion.


Slowing of mortality rates at older ages in large medfly cohorts.

It is generally assumed for most species that mortality rates increase monotonically at advanced ages. Mortality rates were found to level off and decrease at older ages in a population of 1.2 million medflies maintained in cages of 7,200 and in a group of approximately 48,000 adults maintained in solitary confinement. Thus, life expectancy in older individuals increased rather than decreased with age. These results cast doubt on several central concepts in gerontology and the biology of aging: (i) that senescence can be characterized by an increase in age-specific mortality, (ii) that the basic pattern of mortality in nearly all species follows the same unitary pattern at older ages, and (iii) that species have absolute life-span limits.


Demography of genotypes: failure of the limited life-span paradigm in Drosophila melanogaster.

Experimental systems that are amenable to genetic manipulation can be used to address fundamental questions about genetic and nongenetic determinants of longevity. Analysis of large cohorts of ten genotypes of Drosophila melanogaster raised under conditions that favored extended survival has revealed variation between genotypes in both the slope and location of age-specific mortality curves. More detailed examination of a single genotype showed that the mortality trajectory was best fit by a two-stage Gompertz model, with no age-specific increase in mortality rates beyond 30 days after emergence. These results are contrary to the limited life-span paradigm, which postulates well-defined, genotype-specific limits on life-span and brief periods of intense and rapidly accelerating mortality rates at the oldest age.


Absorption spectra of the hybrid pigments responsible for anomalous color vision.

Unequal homologous recombination events between green and red cone pigment genes produce the red-green or green-red hybrid pigment genes found in many individuals with variant color vision. Photobleaching difference absorption spectroscopy of hybrid pigments produced in cultured cells shows that the spectral sensitivity of each hybrid pigment is intermediate between the parental green and red pigment sensitivities. Amino acids encoded by exons 2, 3, 4, and 5 produce spectral shifts at the wavelength of maximal absorbance of 0 to 4, 0 to 4, 3 to 4, and 15 to 21 nanometers, respectively, the exact value depending on the identities of amino acids elsewhere in the hybrid.


Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.

Apolipoprotein E (apoE) is a ligand for receptors that clear remnants of chylomicrons and very low density lipoproteins. Lack of apoE is, therefore, expected to cause accumulation in plasma of cholesterol-rich remnants whose prolonged circulation should be atherogenic. ApoE-deficient mice generated by gene targeting were used to test this hypothesis and to make a mouse model for spontaneous atherosclerosis. The mutant mice had five times normal plasma cholesterol, and developed foam cell-rich depositions in their proximal aortas by age 3 months. These spontaneous lesions progressed and caused severe occlusion of the coronary artery ostium by 8 months. The severe yet viable phenotype of the mutants should make them valuable for investigating genetic and environmental factors that modify the atherogenic process.


Formation of a gated channel by a ligand-specific transport protein in the bacterial outer membrane.

The ferric enterobactin receptor (FepA) is a high-affinity ligand-specific transport protein in the outer membrane of Gram-negative bacteria. Deletion of the cell-surface ligand-binding peptides of FepA generated mutant proteins that were incapable of high-affinity uptake but that instead formed nonspecific, passive channels in the outer membrane. Unlike native FepA, these pores acted independently of the accessory protein TonB, which suggests that FepA is a gated porin and that TonB acts as its gatekeeper by facilitating the entry of ligands into the FepA channel. The sequence homology among TonB-dependent proteins suggests that all ligand-specific outer membrane receptors may function by this gated-porin mechanism.


DNA polymerase beta and DNA synthesis in Xenopus oocytes and in a nuclear extract.

The identities of the DNA polymerases required for conversion of single-strand (ss) M13 DNA to double-strand (ds) M13 DNA were examined both in injected Xenopus laevis oocytes and in an oocyte nuclear extract. Inhibitors and antibodies specific to DNA polymerases alpha and beta were used. In nuclear extracts, inhibition by the antibody to polymerase beta could be reversed by purified polymerase beta. The polymerase beta inhibitors, dideoxythymidine triphosphate (ddTTP) and dideoxycytidine triphosphate (ddCTP), also blocked DNA synthesis and indicated that polymerase beta is involved in the conversion of ssDNA to dsDNA. These results also may have particular significance for emerging evidence of an ssDNA replication mode in eukaryotic cells.


The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product.

Mitogen-activated protein (MAP) kinases, also known as extracellular signal-regulated kinases (ERKs), are thought to act at an integration point for multiple biochemical signals because they are activated by a wide variety of extracellular signals, rapidly phosphorylated on threonine and tyrosine, and highly conserved. A critical protein kinase lies upstream of MAP kinase and stimulates the enzymatic activity of MAP kinase. The structure of this protein kinase, denoted MEK1, for MAP kinase or ERK kinase, was elucidated from a complementary DNA sequence and shown to be a protein of 393 amino acids (43,500 daltons) that is related most closely in size and sequence to the product encoded by the Schizosaccharomyces pombe byr1 gene. The MEK gene was highly expressed in murine brain, and the product expressed in bacteria phosphorylated the ERK gene product.


Removal of nonhomologous DNA ends in double-strand break recombination: the role of the yeast ultraviolet repair gene RAD1.

Double-strand breaks (DSBs) in Saccharomyces cerevisiae can be repaired by gene conversions or by deletions resulting from single-strand annealing between direct repeats of homologous sequences. Although rad1 mutants are resistant to x-rays and can complete DSB-mediated mating-type switching, they could not complete recombination when the ends of the break contained approximately 60 base pairs of nonhomology. Recombination was restored when the ends of the break were made homologous to donor sequences. Additionally, the absence of RAD1 led to the frequent appearance of a previously unobserved type of recombination product. These data suggest RAD1 is required to remove nonhomologous DNA from the 3' ends of recombining DNA, a process analogous to the excision of photodimers during repair of ultraviolet-damaged DNA.


Interaction of the immunosuppressant deoxyspergualin with a member of the Hsp70 family of heat shock proteins.

Deoxyspergualin (DSG) is a potent immunosuppressant whose mechanism of action remains unknown. To elucidate its mechanism of action, an intracellular DSG binding protein was identified. DSG has now been shown to bind specifically to Hsc70, the constitutive or cognate member of the heat shock protein 70 (Hsp70) protein family. The members of the Hsp70 family of heat shock proteins are important for many cellular processes, including immune responses, and this finding suggests that heat shock proteins may represent a class of immunosuppressant binding proteins, or immunophilins, distinct from the previously identified cis-trans proline isomerases. DSG may provide a tool for understanding the function of heat shock proteins in immunological processes.


Profiles. Diversity flourishes in Japan's research labs.

Japan may look homogenous but the pace of change has actually created a people of extraordinary diversity. Scientists educated before the war at the elite "Imperial" universities are different from those born a few years later; those who experienced postwar poverty are not the same as those born into riches a little later; researchers in wealthy industrial labs see the world differently from their poorer colleagues at the universities; and scientists who have lived abroad for a long while change their perceptions for ever. Below, Science talks to Japanese scientists of different ages and different experiences in a wide variety of disciplines: Among them are a Nobel Prize--winner, an ex-student radical, one of Japan's most powerful scientific leaders, an eccentric genius--and some older people who remember Japan's problems and younger people who see Japan's opportunities.


Interleukin-6 and its receptor: a paradigm for cytokines.

Many cytokines and cytokine receptors involved in the regulation of hematopoiesis, immune responses, and inflammation have been identified and characterized at the molecular level. Several characteristic features of cytokines, such as pleiotropy and redundancy, are now more clearly understood on the basis of their molecular structures. Accumulating evidence has demonstrated an intimate link between cytokines and various diseases such as allergy, autoimmune diseases, and cancer. The pathogenesis of these diseases and therapies to treat them will be discussed based on insights derived from cytokine research.


Multistep carcinogenesis: a 1992 perspective.

Cancer is the leading cause of death in Japan. Recent changes in cancer incidence patterns may reflect the trend toward a more Western diet and life-style. Among the dietary factors that contribute to carcinogenesis are the heterocyclic amines, a group of mutagenic compounds present in cooked meat and fish. Carcinogenesis is a multistep process in which cells accumulate multiple genetic alterations as they progress to a more malignant phenotype. Recognition of the growing number of interacting factors that contribute to carcinogenesis may force reconsideration of current methods of risk assessment.


Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C.

Hydrolysis of inositol phospholipids by phospholipase C is initiated by either receptor stimulation or opening of Ca2+ channels. This was once thought to be the sole mechanism to produce the diacylglycerol that links extracellular signals to intracellular events through activation of protein kinase C. It is becoming clear that agonist-induced hydrolysis of other membrane phospholipids, particularly choline phospholipids, by phospholipase D and phospholipase A2 may also take part in cell signaling. The products of hydrolysis of these phospholipids may enhance and prolong the activation of protein kinase C. Such prolonged activation of protein kinase C is essential for long-term cellular responses such as cell proliferation and differentiation.


The economics of health care in Japan.

Japan's health care system balances universal coverage at reasonable cost. The government has taken on the responsibility of acting as insurer and subsidizing health care spending for the employees of small enterprises and the self-employed. Despite the fee-for-service form of payment, costs have been contained by the use of a nationally uniform fee schedule that is mandatory for all providers. However, the increasingly affluent and aging population is making new demands on the system that can only be met by a major restructuring.


A priori evaluation of aqueous polarization effects through Monte Carlo QM-MM simulations.

A Monte Carlo quantum mechanical-molecular mechanical (QM-MM) simulation method was used to determine the contributions of the solvent polarization effect to the total interaction energies between solute and solvent for amino acid side chains and nucleotide bases in aqueous solution. In the present AM1-TIP3P approach, the solute molecule is characterized by valence electrons and nucleus cores with Hartree-Fock theory incorporating explicit solvent effects into the total Hamiltonian, while the solvent is approximated by the three-point charge TIP3P model. The polarization energy contributes 10 to 20 percent of the total electrostatic energy in these systems. The performance of the hybrid AM1-TIP3P model was further validated by consideration of bimolecular complexes with water and by computation of the free energies of solvation of organic molecules using statistical perturbation theory. Excellent agreement with ab initio 6-31G(d) results and experimental solvation free energies was obtained.


Hemoglobin-AGE: a circulating marker of advanced glycosylation.

Advanced glycosylation end products (AGEs) form spontaneously from glucose-derived Amadori products and accumulate on long-lived tissue proteins. AGEs have been implicated in the pathogenesis of several of the complications of aging and diabetes, including atherosclerosis and renal disease. With the use of recently developed AGE-specific antibodies, an AGE-modified form of human hemoglobin has been identified. Termed hemoglobin-AGE (Hb-AGE), this modified species accounts for 0.42 percent of circulating hemoglobin in normal individuals but increases to 0.75 percent in patients with diabetes-induced hyperglycemia. In a group of diabetic patients treated with the advanced glycosylation inhibitor aminoguanidine, Hb-AGE levels decreased significantly over a 1-month period. Hemoglobin-AGE measurements may provide an index of long-term tissue modification by AGEs and prove useful in assessing the contribution of advanced glycosylation to a variety of diabetic and age-related complications.


Phase coupling by synaptic spread in chains of coupled neuronal oscillators.

Many neural systems behave as arrays of coupled oscillators, with characteristic phase coupling. For example, the rhythmic activation patterns giving rise to swimming in fish are characterized by a rostral-to-caudal phase delay in ventral root activity that is independent of the cycle duration. This produces a traveling wave of curvature along the body of the animal with a wavelength approximately equal to the body length. Here a simple mechanism for phase coupling in chains of equally activated oscillators is postulated: the synapses between the cells making up a "unit oscillator" are simply repeated in neighboring segments, with a reduced synaptic strength. If such coupling is asymmetric in the rostral and caudal directions, traveling waves of activity are produced. The intersegmental phase lag that develops is independent of the coupling strength over at least a tenfold range. Furthermore, for the unit oscillator believed to underlie central pattern generation in the lamprey spinal cord, such coupling can result in a phase lag that is independent of frequency.


Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14.

Linkage analysis was used to search the genome for chromosomal regions harboring familial Alzheimer's disease genes. Markers on chromosome 14 gave highly significant positive lod scores in early-onset non-Volga German kindreds; a Zmax of 9.15 (theta = 0.01) was obtained with the marker D14S43 at 14q24.3. One early-onset family yielded a lod score of 4.89 (theta = 0.0). When no assumptions were made about age-dependent penetrance, significant results were still obtained (Zmax = 5.94, theta = 0.0), despite the loss of power to detect linkage under these conditions. Results for the Volga German families were either negative or nonsignificant for markers in this region. Thus, evidence indicates a familial Alzheimer's disease locus on chromosome 14.


Sarcoidosis in autoimmune disease.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Sarcoidosis coexisting with connective tissue diseases, once considered rare, complicates various such disorders, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome, and the spondyloarthropathies. Symptoms common to sarcoidosis and autoimmune disease include keratoconjunctivitis sicca, weight loss, fever, lymphadenopathy, pulmonary complaints, and cutaneous lesions. Consequently, the diagnosis of sarcoidosis in association with connective tissue disease is often difficult and may require biopsy of the lung, liver, skin, lymph node, muscle, or bone marrow for pathological confirmation. Abnormalities of immune function as well as autoantibody production, including rheumatoid factor and antinuclear antibodies, are seen in sarcoidosis and in connective tissue diseases, suggesting a common immunopathogenic mechanism. The severity and course of sarcoidosis associated with autoimmune disease is variable. The incidence of sarcoidosis in association with rheumatic disease may be underestimated if new symptoms of sarcoidosis are attributed to the primary rheumatic disease and a secondary diagnosis is not pursued.


Cryptococcal meningitis in systemic lupus erythematosus.

Two cases of cryptococcal meningitis occurring in patients with systemic lupus erythematosus (SLE) are presented, and 24 additional cases from the literature are reviewed. The insidious onset of this infrequent complication is emphasized. The nonspecific neurological findings associated with this infection are often mistakenly diagnosed as a central nervous system manifestation of SLE. Earlier diagnosis and effective antifungal therapy have improved the prognosis of cryptococcal meningitis in SLE patients in recent years. Strategies for the treatment of patients with this complication are discussed.


Septic subdeltoid bursitis.

Four cases of septic subdeltoid bursitis are described. Clinical presentations, microbiology, and therapies are reviewed for these cases as well as for the six previously reported cases in the literature. The etiology of septic subdeltoid bursitis was related to bacteremia, trauma, or immune incompetence. Compared with septic oelcranon and prepatellar bursitis, septic subdeltoid bursitis was associated with a more profound inflammatory reaction in the bursa, required more sophisticated diagnostic imaging, and necessitated more aggressive therapy. Appropriate therapy generally resulted in favorable outcomes.


Cyclosporine in rheumatoid arthritis.

The efficacy and toxicity of cyclosporine in the treatment of patients with rheumatoid arthritis (RA) are reviewed. Most of the early trials were restricted to patients with intractable RA. The initial daily dose of cyclosporine was 5 to 10 mg/kg, which is now considered high. Of 283 cyclosporine-treated patients in nine studies, 8% discontinued the drug prematurely because of inefficacy and 17% because of adverse reactions. Cyclosporine improves clinical parameters but does not influence the erythrocyte sedimentation rate. The most important side effects are gastrointestinal intolerance and nephrotoxicity. The former is of minor importance with the present dosage schedule (starting daily dose, 2.5 mg/kg), and increments should follow the principle "go low, go slow." Guidelines are given to avoid or reduce nephrotoxicity. It may be beneficial to administer cyclosporine early in the course of RA.


Collagenase in synovitis of rheumatoid arthritis.

There are two types of collagenases, products of two distinct genes, called MMP-1 (matrix metalloproteinase 1 or "fibroblast-type collagenase") and MMP-8 ("neutrophil collagenase"). In synovial fluid, MMP-8 is stored as latent proenzyme in polymorphonuclear neutrophils. MMP-8 is activated by hypochlorous acid produced by myeloperoxidase from hydrogen peroxide and chloride ion and by the hydroxyl radical produced in Haber Weiss reaction fed by superoxide produced by, eg, NADPH (reduced nicotinamide adenine dinucleotide) oxidase and xanthine oxidase. In addition to activation upon secretion, oxidatively modified MMP-8 is susceptible to a subsequent proteolytic attack and activation by cathepsin G. The authors suggest that activation of neutrophil-derived MMP-8 involves oxidative, nonproteolytic activation upon secretion and a more slowly progressive proteolytic activation by cathepsin G (or chymases and tryptases), and that these oxidative and proteolytic activation mechanisms act in concert. In contrast to MMP-8, MMP-1 is synthesized de novo and secreted immediately after synthesis by fibroblasts, macrophages, and some epithelial cells. Human rheumatoid synovial tissue contains mainly fibroblast-type MMP-1 collagenase as assessed by collagenase extracted from synovial tissue and by MMP-1 and MMP-8 immunostaining. It is suggested that in vivo, MMP-1 in synovitis tissue is activated by a plasminogen activator/plasminogen/prostromelysin (alternatively tryptases)/proMMP-1 cascade. In conclusion, MMP-8 and MMP-1 show type-specific compartmentalization and modes of activation in rheumatoid synovial fluid and tissue.


Light and electron microscopic observations on the synovitis of ankylosing spondylitis.

Light microscopic studies on synovium obtained from seven knees and three hips of patients with ankylosing spondylitis and peripheral arthritis showed surface fibrin, proliferation of synovial lining cells, moderate infiltration with lymphocytes, and sometimes striking numbers of plasma cells. There was some vascular congestion and obliteration, occasional bone and cartilage debris, and a tendency toward increased fibrous tissue. Although the intensity of some findings varies from those in rheumatoid arthritis, there were no consistent distinguishing features. Electron microscopy of eight synovial tissue specimens showed increased type B or synthetic lining cells. Structures that could possibly have been organisms were seen among synovial cells in two patients. Immune complex-like deposits were not seen in vessel walls, although there were other vascular alterations. Synovial fluid studies showed 2,200 to 16,500 white blood cells/mm3 (mean, 8,236), 29% to 93% polymorphonuclear leukocytes (mean, 66%), and 0.5 to 32% lymphocytes (mean, 18%). The presence of at least some activated lymphocytes (lymphoblasts) in seven of nine patients in addition to the above findings in synovium suggest an immunological component to the driven process. No more than 32% lymphocytes was found in any synovial fluid despite the use of nonsteroidal antiinflammatory drugs. Thus no support for synovial fluid lymphocytosis, such as has been described in rheumatoid arthritis patients treated with nonsteroidal antiinflammatory drugs alone, is provided.


[Defects in canalization of seminal pathways].

We assessed the value of ultra sonography in diagnosis and grading the alterations in canalization of seminal pathways. After clinical examination and semen analysis, we studied 4100 patients by scrotal US with sector mechanical (7.5 MHz) probe with water bag and by transrectal US for prostatic vesicular region evaluation with 5-6.5 MHz linear probe (lately we used biplanar probe). In three cases, we performed us guided aspiration and contrast media injection of prostatic cavity. In 63 cases (1.53%) we found developmental malformations of seminal vesicles. The abnormality was bilaterally in 33% and it was associated with malformations of urinary tract in 17.46%. Other malformations were found in 0.12% cases. Ultrasonography was always able to establish obstruction level and type, and the possible associated abnormalities. US permitted to avoid or to restrict testis biopsy or vasoseminal vesiculogram. Ultrasonography is eventually able to guide second level diagnostic examination (aspiration biopsy and contrast media injection of prostatic cysts) and endourethral approach to drainage.


[Ultrasound-color Doppler in the study of sexual impotence].

Male impotence is a relatively frequency disease. To define the correct aetiology of this disorder is important to plan a right diagnosis to difference organic, psychological and psycho-organic causes. From June 90 to June 91 fifty-four patients with male impotence of different degree were observed and went through diagnostic investigations. The patients were classified in four groups (A, B, C, D) as clinical results of the pharmacological test (intracavernous injection of PGE1 alpha 15 micrograms). A and B groups showed normal and nearly normal hemogenic finding. C group showed either low arterial flow increase after FIC or venous leakage. D group showed very low haemodynamic increase. The analysis of Eco-doppler studies was performed 5'-10'-20' after intracavernous injection of PGE1 alpha obtaining three haemodynamic markers: the systolic top flow (Vs) the diastolic ending flow (Vd) resistance flow index. The Authors discuss the results obtained considering the Eco-color-doppler the most important stage in the haemodynamic evaluation of sexual impotence.


[Extrarenal ultrasound and color Doppler: renal artery stenosis].

There is a long term interest in noninvasive Doppler (Duplex Doppler, Color Doppler) methods to screen patients with reno-vascular hypertension resistant to medical therapy. Doppler criteria for the diagnosis of renal artery stenosis in native kidneys vary (peak systolic velocity exceeding 100 cm/sec; RAR (Renal Aortic Ratio) exceeding 3.5; Doppler shift frequency exceeding 6-8 KHz; dampened peripheral waveform; lack of signal in complete occlusion). When the vessels are adequately visualized (about 40% of cases) sensitivity and specificity are quite good (80-90%). In the transplanted kidney Doppler diagnosis of renal artery is easier (diagnostic accuracy about 90%). The diagnostic criteria have been well codified (Doppler shift of 7.5 KHz at an insonating frequency of 3 MHz).


[Ultrasound and color Doppler control of percutaneous angioplasty (PTA) of the renal artery].

The Authors report their experience about fifty patients affected with renovascular hypertension, treated by percutaneous transluminal angioplasty (PTA) for stenosis of main renal artery and now studied by Duplex-Scan and Color-doppler. Results, compared with arterial pressure measurements, renography and laboratory renal function evaluation, showed a sensibility of 84%, specificity of 90% and an accuracy of 87.5%. Advantages and limits of Duplex-scan in patients treated by PTA are briefly discussed.


[The role of nuclear medicine in renovascular pathology of urologic significance].

The diagnostic contribution of the radiological techniques (intravenous urography, angiography, sonography, computer tomography) is well-known. On the contrary, in this field, the possibilities of the Nuclear Medicine are underestimated. Radiological methods have high detail recognition but are only suitable for assessing the functional significance of morphological changes in a restricted sense; in the last 25 years, nuclear medical renal diagnosis has achieved a differentiated development stage which permits new qualitative and quantitative tests. The radioisotopic methods offer morphological informations which surely are less exact than those given by radiological techniques, on the other hand they add irreplaceable parameters of functional significance; these parameters concern the perfusion and the accumulation and excretion constants of selected areas of interest in renal districts. This is made possible by a wide choice of radiopharmaceuticals, having a different dynamic pattern and biodistribution. The Authors consider scintigraphic imaging of different renal pathologies: trauma, characterized by hypoperfusion; hematoma and/or urinoma; pseudotumor and carcinoma. Nuclear medical techniques allow in nearly all the cases a rapid and exact diagnostic guidance. The AA. emphasize the absence of invasiveness, the simplicity and the good compliance of these methods in all patients, even if seriously ill, and the usefulness in follow-up and diagnosis of several pathological conditions. Finally, they underline the absence of an appreciable radiobiological hazard.


[Intra-renal ultrasound and color Doppler: pathology or nephrologic significance].

Us-Doppler examination of the native kidney gives more detailed information on nephrological vascular disease. Since there is a close connection between renal functional units (nephrons) and vascular and interstitial compartments, alterations in intrarenal flow will obviously occur in all types of medical nephropathy, irrespective of the origin of the anatomopathological damage. Altered intrarenal flow occur with increased vascular impedance, in turn related to an increased resistance index (RI). In nephropathy with dilatation, the RI can distinguish obstructive from non-obstructive dilatation (high and normal RI, respectively). Personal experience of 80 kidneys with nonobstructive medical nephropathy has shown a good correlation between increased RI and deterioration of renal function, demonstrating that, renal function being equal, RI is higher in Vascular than Tubulo-interstitial and Glomerular nephropathies. For medical nephropathy of transplanted kidneys, Us-Doppler evaluation can be combined with conventional Doppler for diagnosing acute rejection. In this series, an elevated RI (0.90) is highly predictive of acute rejection (92% specificity) but has low sensitivity (30%). At the threshold value of RI = 0.80, sensitivity is 66% and specificity is 78%. However, it is considered that far more reliable information is obtained if Doppler examination is combined with conventional U.S. morphology.


[Integration of diagnostic methods in renal vascular pathology].

Modern technology allows us to study the renal vascular diseases by means of many diagnostic procedures. In the past the main diagnostic technique was Urography, whereas Angiography were performed only in few selected cases. The new Imaging Techniques totally changed the diagnostic approach to this kind of diseases. Today in fact Echo-Color-Doppler and Nuclear Medicine are the early diagnostic techniques to be performed. Actually only few selected patients undergo Angiography, not the conventional one but the Digital; this new technique, in fact, in case of renovascular Hypertension is not only of diagnostic value but is often the definitive therapy.


[Diagnostic imaging in renal vascular diseases: old and new ways. Role of nuclear medicine].

Using the nuclear medicine procedures it is possible to evaluate the renovascular hypertension via the captopril test. Decreased renal blood flow due to stenotic vessel may produce a variety of findings on the renogram using both OIH-I131 and DTPA-Tc99m. Delayed transit time and excretion also may be detected. In this situation the sensitivity and specificity of Nuclear Medicine for RAS detection is very low. Using Captopril test is possible to detect enhanced modification on the shape of renogram due to Angiotensin Converting enzyme inhibition.


[Vascular pathology of urologic significance: Doppler and color Doppler].

The combined use of B-mode ultrasonography and doppler (p.w. and/or color doppler) provides a more accurate and detailed study of vascular pathology than B-mode ultrasonography alone. In fact, besides to document the presence of blood flow and to assess its direction, doppler US provides a quantitative evaluation of blood flow. Chromatic codification of blood flow (usually red if flowing towards the probe, blue if flowing away from the probe and yellow or green in the case of turbulence) permits to assess the presence of blood flow even in areas where a vessel cannot be depicted by B-mode ultrasonography. In fact in the study of blood flow to the kidney it's possible with color-doppler to visualize not only the main renal arteries but segmental-intraparenchymal arteries too; that is very useful in the detection of rejection of allograft. In renal artery, blood flow presents a pattern of low resistance: a brief systolic phase followed by a longer diastolic one, without inversion of flow. In renal vein, blood flow is, on the contrary, continuous. The main disorders of the kidney and urinary tract, which can be detected by color doppler are the following: renal-vascular hypertension, rejection of allograft, renal vein thrombosis, portal hypertension with spleno-renal collateral channels, disorders of ureteral motility, space occupying lesions, medical nephropathies and obstructive uropathies. Sophisticated analysis of the flow pattern to the kidney with color doppler, by some doppler sonographic parameters (resistance index RI, pulsatility index PI), in these disorders adds a functional element to the traditional ultrasonographic imaging with a better characterization of the disease.


[Ultrasonography in the follow-up of patients after extracorporeal shockwave lithotripsy].

Extracorporeal shock wave lithotripsy (ESWL) has revolutionized treatment of urinary stones, but created new clinical situations and problems in the interpretation of which x-rays and ultrasonography have proved invaluable. This paper defined the role of ultrasound in the follow-up of patients who had undergone ESWL and assessed its advantages and limitations in evaluating the efficacy of this form of therapy and in monitoring the elimination of stone fragments. The utility of ultrasound in the diagnosis and monitoring of the complications due to ESWL has been emphasized. Finally ultrasound is a valid tool when performing those echo-guided procedures which are essential for the treatment of obstructive complications secondary to ESWL.


[Role of ultrasonography in the follow-up of surgically treated patients. Upper urinary tract. Complications after conservative surgery].

The Authors describe the purposes of ultrasonographic follow-up after both conservative surgery and endoscopic or endourological operations of the upper urinary tract. In these cases ultrasonography evaluates the results of normal surgery, the presence of early or late complications, and of iatrogenic lesions. The echo-patterns of deformations in the outline of the kidneys, of hematic, urinary or lymphatic collections (both retroperitoneal and intraperitoneal), of fistulas, of sclero-lipomatosis and of post-cicatrization hydronephrosis are described. The importance of evaluating the degree of obstruction by a dynamic ultrasonographic study with furosemide-test is emphasized. The ultrasonographic monitoring of urethral and pyelostomy setting of catheters is also described. The echo-patterns of retroperitoneal and intraperitoneal fluid collections and renal hematomas, in relation also the kind of fluid contained are widely discussed.


[Radical prostatectomy: role of ultrasonography in the follow-up].

After a brief summary about surgical technique of radical prostatectomy and its indications in the different stages of prostatic cancer, the Authors describe complications and surgical sequelae of this operation. The Authors report a brief series. It is composed with 13 patients. Their have been submitted to radical prostatectomy for prostatic cancer between January 1989 and September 1991. Pathological stage was B1 in 6 patients, B2 in 2 patients, C1 in 4 cases and C2 in 1. Particularly the role of ultrasonography in detection and follow-up of early complications such as lymphocele, pelvic hematoma and anastomotic urine leakage is stressed. Transrectal ultrasound is especially useful in the detection of urine leakage from vesico-urethral anastomosis. This technique is compared with traditional cystourethrography and advantages and disadvantages of the two techniques are discussed. Later complications of radical prostatectomy are anastomotic stenosis, pelvic recurrences, nodal or parenchymal metastasis, urinary incontinence. The role of transrectal ultrasound in the detection of anastomotic strictures is stressed, especially when the study is done during micturition. Transrectal ultrasound is not so satisfying in the detection of pelvic recurrences, especially if they are smaller than 1 cm. In case of large masses digital examination is diagnostic itself. At last the Authors describe urinary incontinence and its etiology as a complication of radical prostatectomy. Particularly a surgical technique for vesico-urethral anastomosis proposed by Rocca Rossetti and its value in post-operative continence is described. The Authors show the results of transrectal ultrasound in the detection of striated urethral sphincter and its function after radical prostatectomy.


[Use of ultrasonography in morphofunctional evaluation of orthotopic neo-bladder].

Seventeen patients submitted to radical cystectomy and orthotopic bladder replacement according to Reddy's technique were studied at the 1, 3, 6 and 12-month, then annually follow-up by physical examination, intravenous pyelogram, cystourethrography, suprapubic and transrectal ultrasonography and complete urodynamics. Sixteen patients (94%) reported day-time urinary continence and twelve patients (70%) day-time and nocturnal continence. Cysto-manometry showed a mean bladder capacity of 450 cc with a maximal endocavitary pressure of 40 cm. H2O and satisfactory peak flow rate. Vesico-ureteral reflux was never detected at roentgenography. Ultrasonography may be useful in the study of a possible reflux or stenosis of the neovesico-ureteral junction by detecting renal scars or dilatation of the renal cavities. Sovrapubic ultrasonography can quantify the capacity of the neo-bladder (300-600 cc), study its shape, walls and contractions that do not cause the involuntary opening of the neo-bladder neck. Transrectal ultrasonography studies the bladder neck shape and its dynamic function. Residual urine volume never exceeded 50 cc. Ultrasonography demonstrated its effectiveness and reliability and limited the application of more invasive roentgenographic procedures.


[Circumvallate nephro-cystostomy].

Circumvallate nephro-cystostomy (CNC) provides a subcutaneous connection of a nephrostomy and a cystostomy catheter thus allowing spontaneous micturition. This procedure is suitable for those patients affected by an obstructive nephropathy where it was not possible to insert a double "J" stent or where surgical treatment was not allowed. Patients affected by debilitating disease benefit from these procedure by avoiding problems connected with daily handling of catheter, examples are medications at the insertion site or possible dislodgement of a nephrostomy catheter added to the psychological problems related to carry the urine collection bag. A number of 13 patients have been treated with this method, 5 had monolateral CNC, 8 had bilateral CNC for a total of 21 procedures. All but one cause of ureteral obstruction were neoplastic, the exception being a patient with necrosis of the ureter subsequent to major vascular surgery. CNC had a residence time ranging from 1, 5 to 25 months with an average of 9.8 months. Only in 2 cases it was necessary to remove CNC due to recurrent cystitis and orchitis due to bladder irritation by a cystostomy catheter and for an obstruction which could not be remedied in a patient with necrosis of the ureter. The most important complication, i.e. obstruction, occurred in 4 cases. In the above mentioned case CNC was removed after 9 months of proper performance. In the other 3 cases obstruction occurred after 2, 3, 18 months and in all this cases obstruction was easily removed. Besides obstruction only minor malfunctions were experienced and the procedure was very well tolerated by all patients.(ABSTRACT TRUNCATED AT 250 WORDS)


[Use of ultrasound-guided percutaneous nephrostomy before and after ESWL: 4 years of experience].

We evaluated the usefulness of percutaneous nephrostomy in 1700 patients treated for reno-ureteral stones by extracorporeal shock wave lithotripsy (SWL). Out of this group 81 patients (5.8%) underwent echo-guided percutaneous nephrostomy (EPCN): the procedure has been performed in local anesthesia in 38% of the cases (31 pts) before SWL and in 62% (50 pts) after. The majority of EPCN were carried out for the presence of acute or chronic ureteral obstruction with echographic evaluable dilation of pyelocaliceal system when retrograde ureteral manipulations failed or were considered unsuitable. EPCN before SWL was performed because of ureteral stone and uncomplicated pyelocalyceal dilation (19 pts); ureteral stone, pyelocaliceal dilation and fever > 38 degrees C (3 pts); ureteral stone, pyelocalyceal dilation and functional IVP exclusion (5 pts); pyelic stone in solitary kidney (1 pts); ureteral stones in pregnancy (2 pts). EPCN after SWL was performed because of uncomplicated, persistent pile-up (31 pts); ureteral pile-up complicated by fever and colics (9 pts); ureteral obstructing fragments (2 pts); double J obstruction by stone dust (3 pts); persistent ureteral pile-up around double J (3 pts); anuria in solitary kidney (1 pt). Out of the patients who underwent EPCN before SWL 13% were stone free and without drainage at discharge, 77% had passable stone fragments at discharge and drainage has been taken out at 15-30 days check up, 10% had unbroken stone and underwent with drainage to ureterolithotripsy.(ABSTRACT TRUNCATED AT 250 WORDS)


[Endoscopic compression of bladder diverticula].

The authors refer on the pathogenesis, diagnosis and therapy of bladder diverticula, with particular reference to the endoscopic compression technique performed in 35 patients. The authors stress the usefulness of bladder ultrasonography in the follow-up of operated patients. Results are comparable to those obtained cystography.


[Bladder neoplasms].

The authors underline the diagnostic accuracy of transurethral bladder ultrasonography in the estimation of local infiltration of bladder tumors. The study was conducted on 21 patients who underwent either endoscopic resection or cystectomy. The clinical staging obtained by transurethral echography was compared with the pathological one. The results obtained by either method were comparable in all cases.


[Pathology of the spermatic cord].

The purpose of this study has been to establish the role of spermatic cord in the etiopathogenesis of fertility. We describe herein the anatomy and pathology of the spermatic cord and objective method for diagnosing the disorder and evaluating the therapeutic results. The most pathological conditions affecting the cord there was a complete resolution, this condition it isn't the same for the vas deferens or varicocele. A variety of diagnostic modalities including thermography, Doppler, and particularly ultrasonography may be used to study satisfactorily. Ultrasonography technique may provide a simple but accurate non-invasive method for accurately determined pathological conditions of the scrotum. It has a limited role in the management of the normal vas deferens or in congenital malformations including agenesis of vas deferens.


[Duplex scanner in the diagnosis of vasculogenic impotence].

This paper is reporting the experience of the Authors in the use of Duplex-scanner and eco-color-doppler in the diagnosis of the erectile dysfunctions and particularly in the importance of vascular (arterious and venous) origin. For this purpose, we selected a sample constituted of 41 patients: 22 with psychogenic, 8 with arterial, 5 with venous impotence, 5 patients with Peyronie's disease and 1 patient with posttraumatic arterio-venous fistula. The Authors, while underlining the remarkable accuracy and diagnostic reliability of eco-doppler, emphasize the indication of the method up to consider it "investigation of prime choice", not only in the patients with the dysfunction of vis erigendi but, in the cases in which a morphological evaluation, besides hemodynamical one, become necessary.


[Selective arteriography in the study of arterial vasculogenic impotence].

According to the fundamental circulatory nature of penile erection, insufficiency of the arterial blood supply to the corpora cavernosa caused by an organic arterial disease is found in a large fraction of case, overall among the patients aged more than 40. It is possible to evaluate arterial origin of erectile dysfunction by using of noninvasive methods, but to obtain the necessary panoramicity and the characterization of the lesions it needs the use of angiography. Performance of standard arteriography leads to insufficient visualization of pudendal and penile vessels and risks false positive results. Because of penile hemodynamic variability in its different states is necessary the use of pharmacologic devices to perform a diagnostic arteriography. For the selective study of the pudenda and peniena vascularization we perform a selective arteriography bilaterally, with the catheter tip placed in the proximal part of the internal iliac artery. We use a contrast medium particularly diluted and mixed with xylocaine. We perform angiographic sequences after intracavernous injection of 8-10 mgr of papaverine to obtain the maximum blood flow and to prevent spasm of the terminal arterioles. Arteriography gives a complete study of the pudenda arterial tree and its terminal ramifications, and it is able to supply all the necessary informations regarding the planning of revascularization procedures. Treatment of arterial lesions is possible with surgical and radiologic methods. As in other arteries, percutaneous transluminal angioplasty (P.T.A.) can be applied in the therapy of impotence caused by arterial insufficiency. P.T.A. is the election treatment in the stenosis of the common iliac and internal iliac arteries.(ABSTRACT TRUNCATED AT 250 WORDS)


[The Rigiscan system in the diagnosis of male sexual impotence].

The article reviews historical basis of Nocturnal Penile Tumescence (NPT) test and the evolution of techniques to perform it. From complex and time-consuming instruments, modern technology has brought us to the use of the Rigiscan system. This is a transportable (home or office usable), computerized method to detect change of penile rigidity and circumference during sleep-related spontaneous-or daytime induced-erections. While the instrument was mainly developed to perform NPT tests, it is nowadays used to record penile rigidity in realtime after the intracavernous injection of vasoactive drugs. In our experience, normal parameters to refer for a NPT evaluation are: number of erectile episodes: 4-5 per night; mean duration od episodes: > 30 minutes; increase of penile circumference: > 3 cm (base loop) and > 2 cm (tip loop); maximal rigidity: > 70% (both base and tip). Reference parameters for realtime monitoring after intracavernous injection of PGEI are: latency of response: < 12 minutes; duration (with a stable plateau): > 30 minutes; constant plateau: > 70%; increase of penile circumference: > 3 cm (base) and > 2 cm (tip). The use of these reference parameters, together with the data coming from other procedures (e.g. penile arterial flow with the Doppler), allows a better diagnostic accuracy in the approach to sexual impotence.


[Impotence: introductory notes].

If we define erectile impotence as the inability to achieve and maintain a firm erection we can distinguish several pathogens of impotence: psychologic disorders, neurogenic sinusoidal disorders, arterial disorders, venous & sinusoidal disorders and systemic diseases and other disorders can cause erectile impotence. An etiologic screening of impotence must be carried out by Urologists in order to adopt the best surgical approach. Especially when surgery has to be planned, a complete, often invasive screening associated with a super-specialist diagnostic study is necessary at the beginning of any procedure. Different approaches to impotence can be adopted on the basis of patient's age, etiology and failure of other devices. The main methods of surgical correction of impotence may be divided as follows: a) percutaneous transluminal angioplasty (P.T.A.); b) revascularization; c) surgical treatment of "venous leakage", d) trans-luminal veno-occlusion (T.L.V.O.); e) correction of penile curvature; f) prostheses placement. The diagnosis of arteriogenic impotence depends upon the arteriographic demonstration of bilateral hemodynamically significant obstruction. In our experience the injection of papaverine during the test has provided a better visualization of cavernous arteries and helicine branches. Reduction of luminal diameter by more than 50% suggest a hemodynamically significant stenosis. Intracavernous injection of vasoactive agents has provided an attractive alternative to surgery. We have employed papaverine alone or with phentolamine or phenoxybenzamine. After short term treatment, some patients have achieved good erections without further injections. For P.T.A. of the distal internal pudendal arteries our approach has been via the ipsilateral or contralateral femoral arteries. Under local anesthesia a penile arteriographic catheter is placed in the internal pudendal artery.(ABSTRACT TRUNCATED AT 250 WORDS)


[Role of penile ultrasonography in erection deficit].

The presence of penile nodule, curvature, disorders in blood flow to and from the corpora cavernosa is often correlated with organic sexual impotence. Echography allows to obtain a clear imaging of penile structures: diameters of corpora cavernosa can be measured before and after injection of vasoactive drugs. In our study penile structure were evaluated using a Combison 310 and a Toshiba with 7.5 MHz probe. In a lot of cases echography was repeated after intracavernous injection of PGE 1 or papaverine. The equipment needed for this evaluation is expensive but echography is undoubtedly less invasive than other equivalent examinations like cavernosography. Although the sensitivity and specificity of penile echography have not yet been clearly established this test is generally considered to be an useful and objective one. Penile echography is particularly usefull in discriminating between echogenic and not-echogenic nodules in case of Peyronie disease.


[Ultrasound and color Doppler in the diagnosis of vasculogenic impotence].

Echo-color-doppler is a non invasive diagnostic technique which can provide data about arterial and venous vascular circle of the penis with greater precision than Doppler CW. In the tumescent phase after a PGE1 injection the systolic velocity (SV) reaches a rate higher than 25 cm/sec and the diastolic velocity (DV) higher than 2 cm/sec, resistance index (RI) > to 0.70 with evident colour marked from 1 to 3 KHz. In erection arterial flow decrease and SV is lower than 25 cm/sec with DV lower than 2 cm/sec or with negative values; RI < to 0.70 or negative. The data are confirmed by clinical investigation and traditional diagnostic exams in normal and pathological patients. Echo-color-doppler reduces invasive exams and acquires a primary position on the diagnostic scale of impotence.


[Can post-traumatic renal failure be modified therapeutically?].

Acute renal failure in the late phase after severe trauma is particularly dangerous, since it is resistant to therapy and contributes to the development of post-traumatic multiple organ failure. We have studied different treatment regimes in order to establish whether late renal failure can be prevented (study A: colloidal and crystalloid solutions; study B greater than: crystalloid solutions and dopamine; continuous infusion 3 micrograms/kg body weight). Renal function was assessed by means of the score by Goris as well as by creatinine clearance over a period of 14 days. Haemodynamics and cardiac function were determined on a daily basis. The demographic parameters were comparable in both groups. In group A 37 of 61 patients died (60.6%), and in group B 17 of 38 patients (44.7%) (P less than 0.05). The incidence of impairment of renal function was comparable; in group A there was significantly more severe damage (18%) compared to group B (2.6%). This coincided with significantly higher mortality in group A (group A: 60.65%; group B: 44.7%). In group A a lesser volume was given during the preclinical and clinical course, even after correcting for the volume-saving effect of colloidal solutions. In addition, cardiac index was higher in group B (day 9: 5.9 +/- 0.61 l/min) than in group A (day 9: 4.4 +/- 0.5 l/min) and pulmonary capillary wedge pressure (PCWP) was lower and systemic vascular resistance (SVR) higher over the whole period. Also, the arterio-venous oxygen difference (AvDO2) was higher following day 9 in patients in group A, but creatinine clearance was better in group B patients.(ABSTRACT TRUNCATED AT 250 WORDS)


[Differences of acute and chronic epidural hematoma].

Standard neurosurgical management demands prompt evacuation of all extradural hematomas to obtain a low incidence of mortality and morbidity. In selected cases some authors have suggested that moderate hematomas can be managed conservatively without risk to the patient and with a normal outcome. The goal of this study was to analyze the differences in preoperative clinical parameters between a group of acute and a group of chronic extradural hematomas (chronic extradural hematoma was defined as a delay of more than 72 h from the accident to diagnosis). One hundred fifteen (115) patients with extradural hematomas underwent a standard evaluation, documentation and neurosurgical management (prompt evacuation of all extradural hematomas through a craniotomy). Ninety-five patients (83%) had an acute extradural hematoma. Twenty patients (17%) had a chronic extradural hematoma. We analyzed the following parameters: age, cause of accident, clinical findings, Glasgow Coma Score, morphology of hematoma, location of hematoma, cause of bleeding and clinical outcome. The mean age (chronic 30/acute 32) and age distribution were not significantly different between groups. There were no differences in the cause of accident. All patients in both groups had skull fractures. There was no difference between groups regarding hematoma location, most of there being located in the temporal fossa. In the group of acute extradural hematomas, 62% of patients had a Glasgow Coma Score of less than 8 and 47% had pupillary dilation. In the group of chronic extradural hematomas, moderate clinical symptoms were found, with headache and discrete psychological changes most common. Eighty percent (80%) of the patients had a Glasgow Coma Score of greater than 13 and no patients had pupillary dilation.(ABSTRACT TRUNCATED AT 250 WORDS)


[Surgical treatment of fractures in tropical countries].

In tropical countries, the indication for operative treatment of fractures treatment must be restrictive. Based on our own experience and the treatment results, the prerequisites for operative treatment are given and proposals concerning indication, preoperative preparation and operative tactics. The osteosyntheses recommended are the different forms of external fixation, in particular the external fixator (AO) and the transfixational plaster cast technique. The external fixator is the basic tool in tropical traumatology.


[Late results after lumbar vertebrae fracture with Lorenz Böhler conservative treatment].

We report on a clinical and radiological follow-up of patients who had sustained a fracture of their lumbar spine between 1982 and 1989 and were treated at our department by the method of Lorenz Böhler. 244 patients left our clinic with a plaster bodice after fracture reposition, 153 came to the follow-up (most of the cases are documented radiologically from the first to the follow-up x-ray). Our results are similar to the outcomes which are published after early functional treatment. We could not find a relationship between the radiological and clinical results and we saw, that it is impossible to fix the spine sufficiently in a plaster bodice without fracture redislocation.


[Indications, technique and results of monosegmental dorsal spondylodesis in wedge compression fractures (grade II) of the thoracolumbar spine].

The management of wedge compression fractures of the thoracolumbar spine remains a controversial subject. Although there is an increasing tendency for operative intervention of spinal injuries, non-operative treatment of compression fracture has been the method of choice. The compression fracture is a fracture occurring during compressive forces of the anterior column due to flexion mechanisms. The more severe the compressive fracture, the more likely it will be to present, in an addition to anterior wedging, a failure of the posterior column indicating tension forces at that level. These fractures, defined as mechanically unstable and classified as compression fractures Grade II, are concentrated in the thoracolumbar region. Between June 1987 and July 1990 14 patients with compression fractures Grade II were treated posteriorly with one level internal fixation. Of the 14 patients, 9 had stabilization with plates and cerclage wire, 5 with an internal fixator. All patients received a localized fusion. In order to permit a more reliable analysis of the results of our stabilizing procedures, a comparison was made with a series of 11 cases with equivalent fractures treated non-operatively between 1986 and 1989. At clinical and radiographic follow-up evaluation, the results in the operative group were much more favourable, both subjective and objective, than in the non-operative group. We derive from these results that in thoracolumbar compression fractures Grade II, posterior one level stabilization and fusion is a recommendable surgical procedure.


Surgical management of pelvic ring disruptions. Indications, techniques and functional results.

In a period of 30 months, we treated 44 pelvic ring fractures by early operative stabilization. The ratio of associated musculoskeletal and intrapelvic lesions was very high, with a mean ISS of 36.2. The perioperative mortality rate (3/44) was acceptable with 6.8%. A second osteosynthesis was performed in fast 8% of type-B and in fast 40% of type-C lesions. The average hospital stay was very short with 42.0 days. We were able to mobilize the patients very early after their admission, thanks to the quick operative stabilization of the pelvic ring and the other skeletal injuries. Of the 39 surviving patients, 35 were reviewed clinically, functionally and radiographically after a mean of 19.3 months. There was a statistically significant difference in the rate of walking difficulties, walking distance, hip mobility, muscle force and the functional end-results between patients with type-B and those with type-C lesions. Lesions of type B are benign and can be adequately treated by the application of an anterior external fixator frame alone. The functional results are excellent or good in the great majority of cases. The type-C lesions are much more difficult to deal with. The anterior external fixator provides insufficient stability in many cases. It must be supplemented by posterior fixation or exchanged for anterior and posterior internal fixation. Even then, many patients with type-C lesions have functional disabilities and subjective complaints after treatment.


[Arthroscopic technique for replacing the anterior cruciate ligament using a free patellar tendon transplant].

The replacement of the anterior cruciate ligament (ACL) by a free patellar tendon graft is a well-known procedure. The disadvantage is that the necessary arthrotomy destroys the nerve supply of the joint capsule. Therefore, we developed a procedure of ACL replacement that can be done by arthroscopy without opening the joint except for a small incision needed for the arthroscopy and working canal. The surgical technique is described.


Knee-ligament injuries associated with leg fractures. Prospective study.

It has been proved in 25-35% of the cases that knee-ligament injuries are associated with fracture of the femoral diaphysis. No such association has been confirmed between leg fractures and knee ligaments. In order to find out if this is a coincidence, a prospective study was conducted on 229 patients who had undergone operations for leg fractures at various locations and of variable intensity. It was established in 41 cases (17.34%) that the leg fracture was associated with knee-ligament injuries, resulting in joint instability. A significantly higher percentage of associated ligament lesions was found in open fractures as opposed to closed leg fractures. The examination was carried out with the patient under general or block anesthesia. On the basis of what was established it is recommended that the knee be examined clinically in all leg osteosynthesis cases.


Experience with ifosfamide in the EORTC Soft Tissue and Bone Sarcoma Group.

The Soft Tissue and Bone Sarcoma Group of the European Organization on Research and Treatment of Cancer has conducted a number of studies of chemotherapy in advanced disease over the past 15 years. Following the discovery that the CYVADIC regimen (cyclophosphamide/vincristine/doxorubicin/dimethyl imidazole carboxamide) was less active than had been reported originally, the individual components of CYVADIC were studied. This showed that doxorubicin had considerable activity and that ifosfamide 5 g/m2 given over 24 hours was at least as active as cyclophosphamide. Subsequent studies have therefore centered on a combination of doxorubicin and ifosfamide. A large randomized trial showed no significant benefit of doxorubicin/ifosfamide over single-agent doxorubicin, but the doses of doxorubicin were different. More recently, using bone marrow growth factors, it has been possible to increase the doxorubicin dose to that given as a single agent and also maintain the ifosfamide dose. This is now being tested in a randomized trial to determine whether improved response rates and other indicators of outcome will be seen.


The clinical management of soft tissue sarcomas.

Sarcomas are a relatively rare and heterogeneous group of malignant tumors of principally mesenchymal origin. The histologic grade and size (and possibly compartmental localization) are the main factors predicting local and distant biologic aggressiveness. Tumor localization and surgical margins are significant prognostic factors that relate to the adequacy of local-regional therapy. A general consensus management usually consists of an incisional biopsy for diagnosis and grade, staging of the primary tumor and lungs, and function-preserving surgery with margins free of tumor either followed by or preceded by tumor bed high-dose radiotherapy. Each of these concepts remains under active investigation. The role of adjuvant therapy is not yet established despite tantalizing biologic effects documented in their trials. Ifosfamide in addition to doxorubicin does appear to have major activity; however, further laboratory investigation of resistance and metastases mechanisms and new drug evaluations are necessary for further advance.


Ifosfamide in pediatric oncology.

Ifosfamide is an effective drug for the treatment of solid tumors in children and most blastomas and sarcomas react favorably. It is administered in combination chemotherapy protocols. In young children, nephrotoxicity is a serious side effect. In older boys, gonadal damage is the major late side effect.


Combination therapy with carboplatin/cisplatin/ifosfamide/etoposide in ovarian cancer.

In 1987 a phase II study of combined high-dose platinum (carboplatin 300/mg/m2 day 1, cisplatin 50 mg/m2 days 2 and 3 q4wk) was carried out in 42 previously untreated ovarian cancer patients with residual disease. Since then, another phase II study of combined high-dose platinum and ifosfamide (1,500 mg/m2 days 1 to 3) has been carried out in 37 patients, while a third study of combined high-dose platinum and etoposide (70 mg/m2 intravenously days 1 to 5) is ongoing. Pathologic complete response (CR) and partial response (PR) rates in the first two studies were 62% in 37 evaluable patients, and 58% in 36 patients, 22% and 42% of whom were CRs, respectively. The preliminary results from the third study were: CR plus PR, 56%; CR, 24%. Hematologic toxicity was the dose-limiting factor in all three studies. Myelosuppression became substantial, but manageable, if another drug was added to the platinum combination. The percentage of patients experiencing World Health Organization grades 3 and 4 toxicity during treatment were: white blood cells 44%, 92%, and 79%; platelets 81%, 100%, and 95%, respectively, in studies I, II, and III. Nonhematologic toxicity was modest in all studies. Dose-limiting neurotoxicity occurred in 7%, 6%, and 5%; nephrotoxicity in 22%, 6%, and 11% of the patients. The percentage of patients receiving the stipulated doses of all study drugs in the sixth cycle was 31 in the first study compared with none in the second study. Combined high-dose platinum given either alone or in combination with ifosfamide or etoposide is highly active in ovarian carcinoma. However, further follow-up and a randomized trial are needed to establish the superiority of any one regimen.


The role of ifosfamide in gynecologic cancer.

Ifosfamide exhibits promising activity in a variety of gynecologic neoplasms. In carcinoma of the ovary, the drug shows clear-cut activity, effecting responses in patients who have proven clinically resistant to cisplatin-based combination chemotherapy. In carcinoma of the cervix, the drug also appears to be highly active, both as a single agent and in combination with other agents, such as the platinum compounds. The drug is active in uterine sarcomas and appears to be the most active agent studied to date in mixed mesodermal sarcomas of the uterus. The drug's role in combination with other agents in the treatment of all of these neoplasms is under study, but cannot be determined from currently available data on combination therapy. Its activity in other gynecologic tumors, such as endometrial carcinoma and ovarian germ cell tumors, is also indeterminate at present. Although further studies are needed, current evidence supports the contention that ifosfamide is a major new active drug in the management of gynecologic cancers.


Carboplatin/cyclophosphamide combination chemotherapy for advanced ovarian cancer.

The efficacy and toxicity of combination intravenous carboplatin (300 mg/m2) and cyclophosphamide (600 mg/m2) were evaluated in 70 newly diagnosed patients with advanced-stage epithelial ovarian cancer. Cycles were administered at 4-week intervals for a total of six cycles, and treatment was provided on an outpatient basis without prehydration or forced diuresis. During treatment, patients were assessed by physical, gynecologic, and radiologic examinations. Seventy patients with a median age of 58 years (range, 35 to 77 years) were entered into the study. Most patients had serious cystadenocarcinoma; 78% had stage III or IV disease and 91% had grade II or III histologic subtype. Optimal debulking surgery was performed in only 46% of patients. The overall response rate to carboplatin/cyclophosphamide combination chemotherapy was 81%, with 66% achieving a clinical complete response. The median survival for all patients was 19+ months. For patients who had undergone optimal debulking surgery, median survival was 26 months, compared with a median survival of 13+ months for those who had undergone suboptimal surgery. Treatment was well tolerated by most patients. Significant nausea and vomiting (World Health Organization grades 2 to 3) occurred in only 6% of 377 cycles of therapy. Myelosuppression was mild, with leukopenia (WBC count less than or equal to 2 x 10(9)/L) observed in only 11 of 295 cycles (4%) and thrombocytopenia (less than or equal to 100 x 10(9)/L) in 17 of 279 cycles (6%). Nadir levels generally occurred on day 21 of each cycle. Symptomatic anemia requiring transfusion occurred in 18 of 290 cycles (6%). Moderate alopecia, necessitating use of a hairpiece, occurred in six patients; no signs or symptoms of neurotoxicity, ototoxicity, or nephrotoxicity were observed in any patient. Renal function was normal on follow-up investigation, which was performed a median of 5 months after completion of treatment. This study demonstrates that carboplatin/cyclophosphamide combination chemotherapy is well tolerated in women with advanced-stage epithelial ovarian cancer, and produces overall response rates and median survival times similar to those obtained with cisplatin-containing regimens.


Intraperitoneal carboplatin: rationale and experience.

We conducted a phase I/II trial of intraperitoneal (IP) carboplatin in 27 patients with advanced gynecologic malignancies. This was based on the known activity of carboplatin in ovarian cancer and pharmacologic measurements that predict a favorable ratio of IP to plasma drug exposure when carboplatin is administered by the IP route. All patients had extensive prior therapy with cisplatin (mean dose, 554 mg/m2). Starting dose was 200 mg/m2, which was escalated to 500 mg/m2. Patients with compromised renal function (creatinine clearance 30 to 60 mL/min) had slower escalations than patients with creatinine clearances greater than 60 mL/min. Myelosuppression, especially thrombocytopenia, was the dose-limiting toxicity. In pretreated patients, we recommend a starting dose of 400 mg/m2. Patients with creatinine clearances of 30 to 60 mL/min should start at the lower dose of 200 mg/m2. This is in general agreement with the results of other trials of IP carboplatin. Measurements of IP carboplatin in preclinical studies predict less tissue penetration by carboplatin than the parent compound cisplatin. Nevertheless, in our series of heavily pretreated patients receiving IP carboplatin, eight patients remained free of disease progression for more than 2 years. Further trials of IP carboplatin are indicated.


Carboplatin in the treatment of carcinoma of the ovary: the National Cancer Institute of Canada experience. Ovarian Cancer Subcommittee.

The National Cancer Institute of Canada Clinical Trials Group has used carboplatin in two studies in women with ovarian carcinoma. In a phase II study, carboplatin produced a clinical response rate of 28% among patients with tumor persistence or recurrence following one prior cisplatin-containing regimen. Carboplatin was most efficacious in those with smaller tumors, in those who had the best responses to prior cisplatin therapy, and in those with longer intervals between the primary cisplatin treatment and the secondary carboplatin course. In this setting, a starting dose of 320 mg/m2 is suggested. A phase III randomized trial of first-line therapy compared the efficacy of cyclophosphamide/cisplatin with cyclophosphamide/carboplatin. Four hundred eighteen eligible patients were enrolled. The regimens demonstrated comparable efficacy; however, the carboplatin-based regimen was more easily administered and caused less symptomatic toxicity. The long-term results in this population with macroscopic residual disease remain disappointing.


Meta-analysis of the role of platinum compounds in advanced ovarian carcinoma. The Advanced Ovarian Cancer Trialists Group.

This paper presents a systematic overview or meta-analysis of 54 randomized clinical trials testing a variety of chemotherapeutic approaches in advanced ovarian carcinoma. Prolonged follow-up data are available for most patients and individual patient data were made available for all patients; analysis was made on the basis of "intention to treat." Our report concentrates on two comparisons: (1) platinum alone versus platinum in combination, which appears to show a long-term survival advantage for the combination (however, the platinum dose in the single-agent arm was relatively low); and (2) carboplatin versus cisplatin, which shows no obvious survival differences. It is striking that no single study to date has been large enough to detect the modest survival differences expected from current therapy. Consequently, a series of international studies have been initiated. The International Collaborative Ovarian Neoplasm (ICON) group will examine the role of adjuvant chemotherapy in early ovarian cancer (ICON 1) and will compare carboplatin with cisplatin, doxorubicin, and cyclophosphamide in more advanced disease (ICON 2).


Utility of individualized carboplatin dosing alone and in combination regimens.

Carboplatin represents an ideal candidate for dose optimization in individual patients. The excellent correlations between renal function and carboplatin total body clearance and between carboplatin area under the plasma concentration by time curve (AUC) and thrombocytopenia allow calculation of carboplatin dosages that simultaneously minimize the likelihood of toxicity and maximize the amount of drug that can be delivered. Current studies are defining the essential relationship between carboplatin AUC and the likelihood of achieving a therapeutic response in various tumor types. These quantitative relationships between carboplatin AUC and thrombocytopenia and AUC and response should be the foundation for the intelligent use of carboplatin as an individual agent and for the intelligent assessment of the beneficial or adverse effects of other agents when combined with carboplatin.


A dose-escalation study of carboplatin/cyclophosphamide/etoposide along with autologous bone marrow or peripheral blood stem cell rescue.

Twenty patients have received 21 courses of high-dose cyclophosphamide (6 g/m2 over 4 days), etoposide (1,800 mg/m2 over 3 days), and carboplatin (800 to 1,600 mg/m2 by continuous infusion over 96 hours) and autologous bone marrow or peripheral blood stem cell rescue. The maximum tolerated dose of this regimen included these doses of cyclophosphamide and etoposide with a total of 1,600 mg/m2 carboplatin. Acute renal failure was the dose-limiting toxicity and, at the maximum tolerated dose, was observed in two patients of 14 evaluable courses. Nonhematologic toxicity was otherwise modest, and the overall response rate was 70% in patients with a wide variety of solid hematologic neoplasms.


Current experience with high-dose carboplatin therapy.

Carboplatin is well suited to dose escalation because its major dose-limiting toxicity is myelosuppression when given in 1,200 mg/m2 doses without marrow support. Repeated 800 mg/m2 doses can be given in an investigational setting. With autologous bone marrow rescue the maximum tolerated single-agent dose is approximately 1.8 to 2 g/m2, with dose-limiting toxicities being hepatitis, renal dysfunction, and ototoxicity. Combinations of carboplatin with other agents plus bone marrow rescue are now being investigated in germ cell tumors, ovarian cancer, breast cancer, and small cell lung cancer. High-dose carboplatin plus etoposide combinations are being evaluated with colony-plus stimulating factors in an effort to ameliorate myelosuppression. Future high-dose carboplatin studies could be designed with more predictable toxicity, using an assessment of carboplatin renal clearance. Carboplatin is an important new drug warranting further investigation at escalated doses.


Future directions with carboplatin: can therapeutic monitoring, high-dose administration, and hematologic support with growth factors expand the spectrum compared with cisplatin?

This paper reviews the role of pharmacokinetic methods in the clinical use of carboplatin. Published data establish that pretreatment renal function is the most significant determinant of carboplatin pharmacokinetics. Evidence suggests that the area under the plasma concentration versus time curve (AUC) correlates well with hematologic toxicity. Published data also suggest that a relationship exists between the AUC and therapeutic outcome in testicular teratoma and in ovarian cancer, although in the latter case the data are not conclusive. It is suggested that pharmacokinetically based dosing schemes may be advantageous and that randomized trials should be performed to test this hypothesis. In some clinical situations where dose prediction is not feasible, a simple therapeutic drug-monitoring strategy may prove useful. Since the toxicities of carboplatin are mainly hematologic, it has been possible to study the use of high-dose carboplatin with various forms of hematologic support. Carboplatin doses have been increased fourfold to sixfold and high response rates have been reported in ovarian cancer. An overall therapeutic advantage for this strategy has not yet been demonstrated in a randomized setting. Published data on ovarian cancer cell lines suggest that the range of sensitivities encountered is very large (30- to 100-fold). If the range of sensitivities found in vivo is equally large, then a clinical dose escalation of 10- to 100-fold may be necessary to produce a curative therapy for this disease. The investigation of the use of hematopoietic growth factors in association with carboplatin has just begun. Early data suggest that some support of the WBC count may be achieved, but the toxicities of granulocyte-macrophage colony-stimulating factor have themselves been a problem. Our own studies will attempt to achieve a substantial escalation in the administered AUC of carboplatin by increasing the frequency of carboplatin dosing, while administering granulocyte colony-stimulating factor and platelet support.


Carboplatin in the treatment of squamous cell head and neck cancers.

Cancer of the head and neck, or aerodigestive tract, represents only a small percentage of all cancer cases in the United States, yet its variable presentations have wide-ranging implications that make it one of the most problematic cancers. Recent research has focused on treatment approaches for the patient with advanced disease. Encouraging results have been noted with combination cisplatin/5-fluorouracil (5-FU) and, more recently, with carboplatin/5-FU, particularly in previously untreated patients. The carboplatin-containing regimen has several important advantages over that with cisplatin, including outpatient administration and less severe nausea and vomiting, an important consideration in terms of nutritional support for head and neck cancer patients. The demonstration of possible synergistic activity between platinum compounds and radiation therapy also has prompted considerable interest, as such a combined-modality approach offers the potential for improved quality of life in patients with head and neck cancers. Carboplatin is an excellent agent for the treatment of squamous cell head and neck cancers, with recognized single-agent activity and a high degree of efficacy, when combined with 5-FU. Carboplatin can be combined effectively with concurrent radiotherapy and, with its advantages over cisplatin, is increasingly used as part of initial therapy for head and neck cancers.