Persistence exponents and the statistics of crossings and occupation times for Gaussian stationary processes.

We consider the persistence probability, the occupation-time distribution, and the distribution of the number of zero crossings for discrete or (equivalently) discretely sampled Gaussian stationary processes (GSPs) of zero mean. We first consider the Ornstein-Uhlenbeck process, finding expressions for the mean and variance of the number of crossings and the "partial survival" probability. We then elaborate on the correlator expansion developed in an earlier paper [G. C. M. A. Ehrhardt and A. J. Bray, Phys. Rev. Lett. 88, 070602 (2002)] to calculate discretely sampled persistence exponents of GSPs of known correlator by means of a series expansion in the correlator. We apply this method to the processes d(n)x/dt(n)=eta(t) with n>/=3, incorporating an extrapolation of the series to the limit of continuous sampling. We then extend the correlator method to calculate the occupation-time and crossing-number distributions, as well as their partial-survival distributions and the means and variances of the occupation time and number of crossings. We apply these general methods to the d(n)x/dt(n)=eta(t) processes for n=1 (random walk), n=2 (random acceleration), and larger n, and to simple diffusion from random initial conditions in one to three dimensions. The results for discrete sampling are extrapolated to the continuum limit where possible.

Production and supply of high specific activity radioisotopes for radiotherapy applications

High specific activity radioisotopes such as Lu-177, Pm-149, Ho-166 and Rh-105 can be produced by indirect methods involving neutron irradiation of isotopically enriched (e.g. Ru-104) targets producing parent radioisotopes that beta decay to form the desired daughter radioisotopes. For example, Lu-177 can be produced by direct (n, gamma) irradiation of Lu-176. However, only about 20 percent of the Lu-176 atoms are converted to Lu-177 and the long-lived impurity Lu-177m (half-life = 160 days) is also produced in small quantities. Direct irradiation of Yb-176 results in the production of Yb-177 (half-life = 1.9 hr) that beta decays to form Lu-177, with the further advantage that this route of production avoids long-lived Lu-177m. Chemical separation of the Lu-177 from the Yb target results in a high specific activity Lu-177 that can then be used for radiotherapy. Separation of Rh-105 from irradiated Ru-104 targets is also being investigated by volatilization of the Ru

Persistence of a continuous stochastic process with discrete-time sampling.

We introduce the concept of "discrete-time persistence," which deals with zero-crossings of a continuous stochastic process, X(T), measured at discrete times, T=n Delta T. For a Gaussian Markov process with relaxation rate mu, we show that the persistence (no crossing) probability decays as [rho(a)](n) for large n, where a = exp(-mu Delta T), and we compute rho(a) to high precision. We also define the concept of "alternating persistence," which corresponds to a<0. For a>1, corresponding to motion in an unstable potential (mu<0), there is a nonzero probability of having no zero-crossings in infinite time, and we show how to calculate it.

A novel potential effector of M-Ras and p21 Ras negatively regulates p21 Ras-mediated gene induction and cell growth.

Here, we report the identification and characterization of a new member of the RalGDS-family, which is widely expressed and interacts strongly and selectively with the GTP-bound forms of M-Ras and p21 Ras. This Ras pathway modulator (RPM), also termed RGL3, exhibited Ras-binding and catalytic domains typical of the RalGDS-family of guanine nucleotide exchange factors, and was most similar to Rlf (RalGDS-like factor), but was distinguished by a unique proline-rich region with multiple candidate SH3-domain binding sites. RPM/RGL3 resembled AF-6 and Nore1 in interacting strongly with constitutively active M-Ras and p21 Ras. In contrast to Rlf, transiently expressed RPM/RGL3 did not activate an Elk-1-inducible reporter gene alone or in combination with activated p21 Ras, but strongly inhibited induction of this reporter gene by co-expression of activated H-Ras or MEKK-1. This inhibitory effect was independent of the Ras binding domain and required a second signal provided by p21 Ras or MEKK-1, but not Raf-1 or M-Ras. Expression of RPM/RGL3 also strongly inhibited cell growth of fibroblasts transformed by an activated Src Y527F. Thus, RPM/RGL3 is a novel potential effector of both p21 Ras and M-Ras with the novel function of negatively regulating Elk-1-dependent gene induction downstream of p21 Ras or MEKK-1.

Current and potential therapeutic uses of lanthanide radioisotopes.

In the last 25 years, diagnostic nuclear medicine has come to depend on the versatile chemistry of a single radioisotope, technetium-99m (Tc-99m). Different chelating molecules can be used to guide Tc-99m through various physiological pathways in the body to gain information about disease states. No single radioisotope similarly dominates therapeutic applications. In the field of radioisotope therapy, much discussion and debate have focused on what radioisotope might be "ideal" for treatment of malignant tumors. The ideal may not be a single radioisotope, but rather the class of very closely related radiolanthanides and lanthanide-like radioisotopes. These radioisotopes possess strikingly similar chemistries and thus all may be conjugated to biomolecules using a single chelate, the DOTA moiety (and its chemical analogs). They also provide a wide range of physical characteristics, such as half-lives and beta energies, that can be chosen to match the biological properties of the conjugated biomolecule and the malignant tumor. Thus, the radiolanthanide-DOTA bioconjugate model provides a set of physically diverse, but chemically very similar, therapeutic radiopharmaceutical agents, the individual members of which can be tailored to treat specific types of cancers.

Investigation of recoil collection method for production of high specific activity nuclear medicine isotopes.

High specific activity radiopharmaceuticals cannot readily be produced by (n, gamma) reactions in nuclear reactors, because the great abundance of parent atoms remaining have the same chemical characteristics as the produced isotope. We have investigated the effectiveness of using recoil atom collection methods for separating the produced radioisotope. Gold-198, produced from isotopically pure (natural) gold-197, was chosen for these experiments, which were run in the high flux (approximately 10(14) n/cm2 s thermal flux) of the reflector of the University of Missouri Research Reactor. Seven separate experiments were run, with a 2 mm separation between the emitter and the collector. Collection efficiencies were only a few percent of the radioisotope atoms produced in the top atomic layer of the emitter, instead of the 30% range anticipated. Furthermore, the collected radioisotope, instead of being nearly pure, contained a large quantity of the parent. Unless the reason for the "contamination" of product with the parent can be reduced by several orders of magnitude, this "surface hot atom recoil" method appears to offer no practical application for nuclear medicine isotope production.

M-Ras, a widely expressed 29-kD homologue of p21 Ras: expression of a constitutively active mutant results in factor-independent growth of an interleukin-3-dependent cell line.

M-Ras, a recently identified homologue of p21 Ras, is widely expressed, with levels of the 29-kD protein in spleen, thymus, and NIH 3T3 fibroblasts equaling or exceeding those of p21 Ras. A G22V mutant of M-Ras was constitutively active and its expression in an interleukin-3 (IL-3)-dependent mast cell/megakaryocyte cell line resulted in increased survival in the absence of IL-3, increased growth in IL-4, and, at high expression levels, in factor-independent growth. Expression of M-Ras G22V, however, had a negative effect on growth in the presence of IL-3, suggesting that M-Ras has both positive and negative effects on growth. Expression of M-Ras G22V in NIH-3T3 fibroblasts resulted in morphological transformation and growth to higher cell densities. M-Ras G22V induced activation of the c-fos promoter, and bound weakly to the Ras-binding domains of Raf-1 and RalGDS. Expression of a mutant of M-Ras G22V that was no longer membrane-bound partially inhibited (40%) activation of the c-fos promoter by N-Ras Q61K, suggesting that M-Ras shared some, but not all, of the effectors of N-Ras. An S27N mutant of M-Ras, like the analogous H-Ras S17N mutant, was a dominant inhibitor of activation of the c-fos promoter by constitutively active Src Y527F, suggesting that M-Ras and p21 Ras shared guanine nucleotide exchange factors and are likely to be activated in parallel. Moreover, M-Ras was recognized by the monoclonal anti-Ras antibody Y13-259, commonly used to study the function and activity of p21 Ras. Mammalian M-Ras and a Caenorhabditis elegans orthologue exhibit conserved structural features, and these are likely to mediate activation of distinctive signaling paths that function in parallel to those downstream of p21 Ras.

Preparation and properties of radioactive rhenium glass microspheres intended for in vivo radioembolization therapy.

Rhenium glass microspheres composed of metallic rhenium particles dispersed within a magnesium alumino borate glass matrix were produced by sintering ReO2 powder and glass frit at 1050 degrees C. The in vitro chemical durability of radioactive and nonradioactive microspheres was determined from chemical corrosion tests on microspheres immersed in phosphate-buffered saline (PBS) solution at 37 degrees C. The dosimetric properties of these microspheres also were calculated. The rhenium glass microspheres are chemically durable in body fluids and release < 1.2% of radioactive rhenium after being immersed in PBS solution for 32 days at 37 degrees C. Therapeutic radioactive rhenium activities can be obtained in < 10 h by neutron activation of these microspheres in a thermal neutron flux of 8 x 10(13) cm(-2)s(-1). A 50 mg injection of radioactive rhenium glass microspheres containing 3.7 GBq of 186Re and 8.5 GBq of 188Re could deliver a 100 Gy dose to a cancerous liver while limiting the total body dose from rhenium dissolution in vivo to approximately 1 mGy.

Rhenium-188(Sn)HEDP for treatment of osseous metastases.

UNLABELLED: Rhenium-188 (tin) hydroxyethylidine diphosphonate [188Re(Sn)HEDP] is a new radiopharmaceutical that localizes in skeletal metastases and emits beta particles that may be therapeutically beneficial. METHODS: It was evaluated by in vitro and in vivo testing in the laboratory, in animals and in humans using 188Re from a variety of sources. It may be produced by a desk-top method developed previously for 186Re(Sn)HEDP using 188Re produced through neutron irradiation of either enriched 187Re or naturally occurring rhenium targets or the use of a 188W/188Re generator. RESULTS: So long as the mass of rhenium in the 188Re-perrhenate to be processed into 188Re(Sn)HEDP is at least 100 microg, satisfactory radiochemical yields and purity may be obtained by all methods. The 188Re(Sn)HEDP has biodistribution and radiation dosimetry characteristics that are similar to those noted previously for 186Re(Sn)HEDP and appears to result in similar benefits and toxicities in patients with skeletal metastases. External radiation exposure monitoring indicates that, only 4 hr after a therapeutic administration of 1110 MBq (30 mCi) of 188Re(Sn)HEDP, average exposure rates at 1 meter from the patient would be only 0.5 mR/hr. CONCLUSION: Same-day, on-demand, outpatient therapy of disseminated skeletal metastases appears to be feasible with 188Re(Sn)HEDP.

Reactor-produced radionuclides at the University of Missouri Research Reactor.

A revolution in radiotherapy has been developing in recent years, based on more sophisticated targeting methods including radioactive intra-arterial microspheres, chemically-guided bone agents, labeled monoclonal antibodies, and isotopically-tagged polypeptide receptor-binding agents. The isotopes of choice for these applications are reactor-produced beta emitters such as Sm-153, Re-186, Re-188, Ho-166, Lu-177, and Rh-105. The University of Missouri Research Reactor (MURR) has been in the forefront of research into means of preparing, handling, and supplying these high specific activity isotopes in quantities appropriate not only for research, but also for patient trials in the U.S. and around the world. Considerable effort has been expended to develop techniques for irradiation, handling, and shipping isotopes worldwide. The MURR has also served as a highly reliable production source for isotopes, with one of the best operating histories of any isotope production reactor in the world.

Technetium- and rhenium-labeled progestins: synthesis, receptor binding and in vivo distribution of an 11 beta-substituted progestin labeled with technetium-99 and rhenium-186.

In an effort to develop radiopharmaceuticals useful for the diagnostic imaging of steroid receptor-positive breast tumors, we have radiolabeled an analog of the antiprogestin RU486 (mifepristone), modified to incorporate an N2S2 chelate system in the 11 beta-position, with 99Tc, 99mTc, and 186Re. For the 99Tc-labeled analogs (3), a syn pair and two individual antidiastereomers (linker methylene versus metal-oxo, relative to the N2S2 plane) were isolated. In competitive radiometric binding assays, the syn pair (3syn1,2) had affinity for the progesterone receptor that was 25% that of (promegestone) R5020 (or 161% that of progesterone), and the individual anti-diastereomers had affinities of 47% (3anti1) and 7% (3anti2) that of R5020 (or 303% and 45% that of progesterone). The specific-to-nonspecific binding ratio of the 99mTc (4) and 186Re (5) 11 beta-linked syn systems are 75/25 and 54/46, respectively. In vivo, conjugates 4 and 5 showed progesterone receptor-mediated uptake in rat uterus, but also high uptake in non-target tissues, presumably because of the high lipophilicity of the metal complexes. Modified systems may be useful in vivo as receptor-directed agents for diagnostic imaging or treatment of steroid receptor-positive tumors.

Rhenium-186(Sn)HEDP for treatment of painful osseous metastases: results of a double-blind crossover comparison with placebo.

Rhenium-186 (tin) hydroxyethylidene diphosphonate (HEDP) is a new radiopharmaceutical that simultaneously localizes in multiple skeletal metastases in patients with advanced cancer. A single intravenous administration of 30-35 mCi (1110-1295 MBq) is associated with a prompt, significant relief of osseous pain in about 80% of such patients. The efficacy of this new compound was evaluated further by utilizing a double-blind crossover comparison with 99mTc-methylene diphosphonate (MDP) as a radioactive placebo. The new rhenium compound resulted in a significantly (p less than 0.05) greater decrease in pain than did treatment with the radioactive placebo. Rhenium-186(Sn)HEDP appears to be a useful new compound for the palliation of painful skeletal metastases.

Therapeutic radionuclides: production and decay property considerations.

The development of effective therapeutic radiopharmaceuticals requires careful consideration in the selection of the radionuclide. The in vivo targeting and clearance properties of the carrier molecule must be balanced with the decay properties of the attached radionuclide. Radionuclides for therapeutic applications fall into three general categories: beta-particle emitters, alpha-particle emitters, and Auger and Coster-Kronig-electron emitters following electron capture. Alpha particles and Auger electrons deposit their energy over short distances with a high LET that limits the ability of cells to repair damage to DNA. Despite their high levels of cytotoxicity, the relatively short range of alpha particles requires binding of the carrier molecule to most cancer cells within a tumor in order to be effective. Because of the extremely short range of Auger electrons, the radionuclide must be carried directly into the nucleus to elicit high radiotoxicity, making it necessary to deliver the radionuclide to every cell within a tumor cell population. These characteristics impose rigid restrictions on the nature of the carrier molecules for these types of particle emitters but successful targeting of these types of radionuclides could result in high therapeutic ratios. Most beta-emitting radionuclides are produced in nuclear rectors via neutron capture reactions; however, a few are produced in charged-particle accelerators. For radionuclides produced by direct neutron activation, the quantities and specific activities that can be produced are determined in large part by the cross-section of the target isotope and the flux of the reactor. Many applications (e.g., therapeutic bone agents, radiolabeled microspheres, radiocolloids) do not require high-specific activities and can therefore utilize the wide range of radionuclides that can be produced in sufficient quantity by direct neutron activation. Other applications (e.g., MAb labeling) require high-specific activity radionuclides in order to deliver a sufficient number of radionuclide atoms to the target site without saturating the target or compromising the integrity of the carrier molecule. Most radionuclides, produced at NCA levels in reactors, are produced via indirect reactions. High-specific activity beta emitters can also be obtained from radionuclide generator systems where the longer-lived parent radionuclide may be obtained from direct neutron activation, as a fission product, or from charged-particle accelerators. It is essential that the half-life of a radionuclide used in RNT be compatible with the rates of localization in target tissues and clearance of the carrier molecule from normal tissues. This consideration is especially important for the various MAbs and their fragments that are currently under investigation as carrier molecules to RIT.(ABSTRACT TRUNCATED AT 400 WORDS)

[Sicca syndrome in sarcoidosis--an overlap syndrome?]. / Sicca-Syndrom bei Sarkoidose--ein Overlap-Syndrom?

This is a case report on a 66-year old woman who suffered from chronic polyarthritis for 15 years and developed a sicca syndrome pattern for 2 years. 2 years later epithelioid cell granulomas were found from a submandibular lymph node as well as from a suspicious area at the epiglottis and the mucosa of the upper lip. Moreover, there was a chronic keratoconjunctivitis and discrete lung involvement. The sarcoidosis on the lip and at the epiglottis disappeared, and lung involvement and conjunctivitis improved under corticosteroid therapy. In spite of above therapy, the sicca syndrome pattern and the rheumatic complaints (osteoporosis) persisted.

Clinical and clinicopathologic response of canine bone tumor patients to treatment with samarium-153-EDTMP.

Forty dogs with spontaneous skeletal neoplasia were treated with 153Sm-EDTMP (ethylenediaminetetramethylene phosphonic acid). Both primary and metastatic lesions were treated. Two treatment regimes, a single (37 MBq (1.0 mCi)/kg dose or two 37 MBq (1.0 mCi)/kg doses separated by 1 wk) were tested. Response to treatment was varied. Large lesions with minimal tumor bone formation responded poorly, while primary lesions with substantial ossification usually exhibited a transient response. Small lesions with minimal lysis, metastatic lesions, and axial skeleton lesions generally responded well. The major adverse side effects of treatment were platelet and white blood cell count depression below baseline values for up to 4 wk (p less than 0.05). Minor depression of packed cell volume and transient elevation of serum alkaline phosphatase were also noted (p less than 0.05). No significant differences (p greater than 0.05) between the two treatment groups, either in treatment effect or undesirable side effects, were detected.

Clinical and clinicopathologic effects of samarium-153-EDTMP administered intravenously to normal beagle dogs.

A study was undertaken to determine the degree of acute bone marrow and vital organs injury sustained when dogs were administered doses of 153Sm-EDTMP calculated to irradiate an acute bone lesion arising from cancer metastasis to a dose considered palliative or even therapeutic (20-160 Gy). The study revealed significant (p less than 0.05) temporary depression of the bone marrow in all doses in the therapeutic (greater than 40 Gy) range. Palliative (20 Gy) doses caused significant leukocyte depression but insignificant (p greater than 0.05) depression of platelet and packed cell volumes when compared to control animals. A mild transient rise in the levels of serum alkaline phosphatase occurred immediately following radioisotope administration. All hematologic parameters had returned to normal by six weeks after the last injection of radioisotope. The study indicates potential for this compound as a safe, therapeutic radiopharmaceutical for treatment of cancer bone metastasis.

[Differential diagnosis problems in the assessment of pulmonary coin lesions]. / Differentialdiagnostische Probleme bei der Abklärung eines pulmonalen Rundherdes.

Cause for the publication was a primary hepatocellular carcinoma, the clarification of which was performed on an unusual diagnostic way. The consequence of a circular focus near the pleura were differential-diagnostic considerations. By an aimed biopsy and thoracoscopy a malignant tumour could be ascertained, in which case the histologic investigation resulted in the solitary metastasis of a hepatocellular carcinoma. The authors enter the problems of the diagnosis of pulmonary circular foci and of the hepatocellular carcinoma.