Showing papers by "University of Medicine and Dentistry of New Jersey published in 1994"

Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II

Abstract: THE RNA polymerase II general transcription factor TFIIH is composed of several polypeptides. The observation that the largest subunit of TFIIH is the excision-repair protein XPB/ERCC3 (ref. 1), a helicase implicated in the human DNA-repair disorders xeroderma pigmentosum (XP) and Cockayne's syndrome2,3, suggests a functional link between transcription and DNA repair4,5. To understand the connection between these two cellular processes, we have extensively purified and functionally analysed TFIIH. We find that TFIIH has a dual role, being required for basal transcription of class II genes and for participation in DNA-excision repair. TFIIH is shown to complement three different cell extracts deficient in excision repair: XPB/ERCC3, XPC and XPD/ ERCC2. The complementation of XPB and XPD is a consequence of ERCC3 and ERCC2 being integral subunits of TFIIH, whereas complementation of XPC is due to an association of this polypeptide with TFIIH. We found that the general transcription factor IIE negatively modulates the helicase activity of TFIIH through a direct interaction between TFIIE and the ERCC3 subunit of TFIIH.

The Cold-Shock Response--A Hot Topic

Abstract: The cold-shock response of Escherichia coli describes a specific pattern of gene expression in response to abrupt shifts to lower temperatures. This pattern includes the induction of cold-shock proteins, synthesis of proteins involved in transcription and translation, and repression of heat-shock proteins. The identified cold-shock proteins are involved in various cellular functions from supercoiling of DNA to initiation of translation. The major cold-shock protein, CspA, has high sequence similarity with three other E. coli proteins--CspB, CspC, and CspD. Using translational lacZ fusions, cspB was found to be cold-shock inducible at the level of transcription like cspA, while cspC and cspD were not. The Csp proteins, which share sequence similarity with other prokaryotic proteins and with the 'cold-shock domain' of eukaryotic Y-box proteins, may have a function in activating transcription or unwinding or masking RNA molecules. Because the cold-shock response can also be induced by the addition of certain inhibitors of translation, it has been proposed that the state of the ribosome is the physiological sensor for the induction. In addition to E. coli, cold-shock proteins have also been found in other prokaryotic and eukaryotic organisms.

Self-report assessment of female sexual function: psychometric evaluation of the Brief Index of Sexual Functioning for Women.

Abstract: Previous self-report measures of female sexual function have been either overly restrictive or inappropriate for use in large-scale clinical trials. Accordingly, we have developed the Brief Index of Sexual Functioning for Women (BISF-W), a 22-item, self-report instrument for the assessment of current levels of female sexual functioning and satisfaction. The BISF-W was administered at monthly intervals to a standardization sample of 269 women, ages 20–73 years. A principal components analysis yielded a three-factor solution—interest/desire, sexual activity, and satisfaction—which accounted for 51.2% of the variance. Concurrent validity was demonstrated by means of a comparison with the Derogatis Sexual Function Inventory. In addition, the BISF-W was compared to the Brief Sexual Function Questionnaire, a similar self-report measure of sexual functioning for men. Major advantages of the BISF-W are its ease of administration and scoring, suitability for use in both clinical and nonclinical samples, and assessment of key dimensions of female sexuality. However, based on its moderate test—retest reliability and internal consistency, further development of the instrument is indicated.

Co-evolution of ligand-receptor pairs

Abstract: Specific receptors for lutropin (luteinizing hormone; LH) and follitropin (follicle-stimulating hormone; FSH) mediate the actions of human chorionic gonadotropin (hCG) and FSH5 on the gonads. Here we report that short independent sequences of the beta-subunit enable hCG to distinguish between the receptors for FSH and LH. Residues between the 11th and 12th cysteines restrict FSH receptor binding; residues between the 10th and 11th cysteines and, to a much lesser extent, residues carboxy-terminal to the 12th cysteine also affect LH receptor binding. CF101-109, an hCG analogue containing hFSH beta residues between the 11th and 12th cysteines, had high affinity for both LH and FSH receptors. Modifications to CF101-109 that reduce binding to either LH or FSH receptors yield gonadotropin analogues having differing ratios of LH:FSH activity. Ligand-binding specificity of the LH receptor is determined by residues encoded by parts of exons 2-4 and 7-9 which prevent hFSH binding but have little effect on hCG binding. FSH receptor specificity is controlled primarily by residues encoded by exons 5 and 6 that prevent hCG binding but have little effect on hFSH binding. These determinants can be interchanged to create receptor analogues that bind hCG and hFSH. Our observations support a model in which distinct negative determinants restrict ligand-receptor interaction. This explains coevolution of binding specificity in families of homologous ligands and their receptors. Natural or designed manipulation of these determinants leads to the 'evolution' of new, specific protein-protein interactions.

Cytoplasmic dynein is involved in nuclear migration in Aspergillus nidulans

Abstract: Nuclear migration plays an important role in the growth and development of many organisms including the multinuclear fungus Aspergillus nidulans. We have identified four genes, nudA, nudC, nudF, and nudG, in which temperature-sensitive mutations affect nuclear distribution. In this report, we describe the cloning of the nudA gene by complementation of the mutant phenotype by using a chromosome VIII-specific cosmid library. A genomic fragment of nudA hybridized to an mRNA of approximately 14 kb. Sequencing analysis of nudA revealed four ATP-binding sites that are characteristic of the cytoplasmic dynein heavy chain. The amino acid sequence of the nudA gene product shows 52% overall identity with the rat brain cytoplasmic dynein heavy chain. Our study provides in vivo evidence that dynein, a microtubule motor molecule, plays a role in the nuclear migration process.

Mammalian toxicology of organophosphorus pesticides

Abstract: Organophosphorus compounds have been utilized as pesticides for almost five decades. They continue to be used as insecticides, helminthicides, ascaricides, nematocides, and to a lesser degree as fungicides and herbicides. While they have been and continue to be extremely useful in agricultural pest control throughout the world, their extensive use has led to numerous poisonings of nontarget species, including many human fatalities. The primary acute mammalian toxicity associated with exposure to organophosphorus pesticides results from inhibition of the enzyme acetylcholinesterase. However, other toxicities, some of which are life-threatening but not related to acetylcholinesterase inhibition, have been observed following exposure to certain organophosphorus compounds. The focus of the current review is to summarize the known effects, both cholinergic and noncholinergic, of organophosphorus pesticides in mammals. Included in this summary is a discussion of the metabolic activation of organophosphorus pesticides, since this process plays a critical role in mediating the acute toxicities of many of these pesticides.

Epigenetic lesions at the H19 locus in Wilms' tumour patients.

Abstract: To test the potential role of H19 as a tumour suppressor gene we have examined its expression and DNA methylation in Wilms' tumours (WTs). In most WTs (18/25), H19 RNA was reduced at least 20–fold from fetal kidney levels. Of the expression–negative tumours ten retained 11p15.5 heterozygosity: in nine of these, H19 DNA was biallelically hypermethylated and in two cases hypermethylation locally restricted to H19 sequences was also present in the non–neoplastic kidney parenchyma. IGF2 mRNA was expressed in most but not all WTs and expression patterns were consistent with IGF2/H19 enhancer competition without obligate inverse coupling. These observations implicate genetic and epigenetic inactivation of H19 in Wilms' tumorigenesis.

The nature of memory impairments in multiple sclerosis: Acquisition versus retrieval

Abstract: The present study was designed to examine whether verbal memory impairment in multiple sclerosis (MS) is attributable to impaired information acquisition or compromised retrieval. Twenty-three MS and 23 control subjects were administered a 10-item verbal list-learning task. Subjects were trained to a specific criterion on the verbal test in order to assure equal information acquisition. Following a 30-min delay, retrieval and recognition performance was evaluated. MS subjects required significantly more trials to reach criterion on the task relative to controls, but the groups did not differ on tests of recall and recognition. Performance was correlated with rate of information processing speed. These results suggest that verbal memory impairment among MS subjects is a consequence of inadequate initial learning and not a function of impaired retrieval.

Production of nitric oxide and peroxynitrite in the lung during acute endotoxemia

Abstract: Nitric oxide is a short-lived cytotoxic mediator that has been implicated in the pathogenesis of endotoxin-induced tissue injury and septic shock. In the present studies we determined whether this mediator is produced in the lung during acute endotoxemia. We found that intravenous injection of rats with bacterially derived lipopolysaccharide (LPS), a condition that induces acute endotoxemia, caused a time-dependent increase in inducible nitric oxide synthase (iNOS) mRNA expression in the lung, which reached a maximum after 24 h. This was correlated with nitric oxide production in the lung as measured by electron paramagnetic spin trapping, which was detectable within 6 h. Alveolar macrophages (AMs) and interstitial macrophages (IMs) isolated from rats 6-12 h after induction of acute endotoxemia were also found to exhibit increased nitric oxide production in response to in vitro stimulation with interferon-gamma (IFN-gamma) and LPS measured by nitrite accumulation in the culture medium. The effects of acute endotoxemia on nitric oxide production by these cells were, however, transient and returned to control levels by 24 h in AMs and 36 h in IMs. Interestingly, although nitrite accumulation in the culture medium of IMs isolated 48 h after induction of acute endotoxemia and stimulated with low concentrations of IFN-gamma and LPS was reduced, when compared with cells from control animals, these cells, as well as AMs, continued to express high levels of iNOS protein and mRNA. This was correlated with increased peroxynitrite production by the cells. Peroxynitrite has been shown to act as a nitrating agent and can generate nitrotyrosine residues in proteins. Using a specific antibody and immunohistochemistry, we found evidence of nitrotyrosine residues in sections of lungs 48 h after treatment of rats with endotoxin. These data suggest that nitric oxide produced by IMs and AMs can react with superoxide anion to form peroxynitrite. Taken together, the present studies demonstrate that AMs and IMs are activated following acute endotoxemia to produce reactive nitrogen intermediates and that both cell types contribute to inflammatory responses in the lung.

Parathyroid Hormone-Related Protein as a Prohormone: Posttranslational Processing and Receptor Interactions

Abstract: PARATHYROID hormone-related protein (PTHrP) bioactivity was identified in 1983 in tumors associated with humoral hypercalcemia of malignancy (HHM). The N-terminal amino acid and complementary DNA (cDNA) sequences were identified in 1987. The search for the causative agent of HHM was fueled by the frequency with which HHM occurs, by the severe complications of hypercalcemia (coma, renal failure, death), and by the identification in clinical and laboratory studies of a novel calcium-regulating hormone that could be postulated as the cause of HHM. It was expected at the time that this search would lead to the purification of the responsible “humor,” and that that “humor,” when identified, would prove to have some normal physiological role. It was not anticipated that the “humor” would prove to be produced by almost every type of cell in the body at some stage of development, or that the search for the novel “humor” would lead to the identification of an unusually large, complicated, and interesting family of...

Pain, Hurt, and Harm -- The Ethics of Pain Control in Infants and Children

Abstract: It has long been recognized that patients receive less relief from pain than they should1,2. A recent review concluded that pain can be relieved effectively in 90 percent of patients but is not relieved effectively in 80 percent of patients3. The tendency toward undermedication for pain is even more pronounced in children than in adults4. There are large discrepancies between the amounts of postoperative analgesia ordered for and administered to adults and those ordered for and administered to children who have the same diagnoses and have undergone the same procedures5,6. Interest in pain control . . .

The recombination signal sequence-binding protein RBP-2N functions as a transcriptional repressor.

Abstract: We have identified a cellular protein, RBP-2N, a presumed recombinase, as a repressor of transcription. Inhibition of transcription by RBP-2N was dependent on its DNA recognition site and was demonstrated in vitro and in vivo. This repression appears to be general, as transcription mediated by SP1 and Gal4/VP16 was inhibited by RBP-2N. The protein was purified to near homogeneity from human cells on the basis of its binding to a site present in the promoter of the adenovirus pIX gene. The DNA recognition sequence is 5'-TGGGAAAGAA, which is markedly different from the recombination signal sequence originally identified as the target site for this protein. The sequence of the purified protein is 97% identical with that published for the mouse RBP-2N protein. The reported homolog in Drosophila is Suppressor of Hairless. RBP-2N binding sites are present in a number of cellular and viral promoters, so RBP-2N may have a general role in transcriptional repression.

Reappraisal of partial lateral internal sphincterotomy.

Abstract: PURPOSE: The aim of this study was to delineate the results, mortality, and morbidity of partial lateral internal sphincterotomy for the treatment of chronic anal fissure. METHOD: A retrospective review of 500 patients undergoing partial lateral internal sphincterotomy for chronic anal fissure between 1980 and 1990 was performed. Patients were identified by a review of an office surgical ledger and included all patients whose diagnosis was anal fissure and for whom a partial lateral internal sphincterotomy was performed as treatment. RESULTS: Over an average follow-up of 5.6 years, only 1 percent of patients failed to heal their fissures after performance of this operation. Minor complications included pain, pruritus, wound abscess, discharge, delayed healing, bleeding, fecal impaction, minor incontinence, and urgency and were present in 16 percent of patients, postoperatively. Two percent of patients who initially healed their fissures suffered a recurrence. Complication rates in openvs. closed sphincterotomy were 15 percentvs. 8 percent (P<0.01). Disorders of fecal continence occurred in 8 percent of patients over the long term. CONCLUSION: Extended follow-up after partial lateral internal sphincterotomy demonstrates a higher complication rate than was seen in patients being followed for shorter periods. However, the complication of impaired fecal continence only occurred in 8 percent of our patients, compared with 15 percent reported in the current literature, although using the same evaluative criteria. Patient satisfaction with the results of surgery was 98 percent. Careful patient selection, absence of preoperative continence problems, and meticulous surgical techniques are necessary to achieve this type of result.

Cellular Dosimetry: Absorbed Fractions for Monoenergetic Electron and Alpha Particle Sources and S-Values for Radionuclides Uniformly Distributed in Different Cell Compartments

Abstract: The importance of cellular dosimetry in both diagnostic and therapeutic nuclear medicine is becoming increasingly recognized. Methods: Experimental range-energy relations for electrons and alpha particles, along with derived geometric reduction factors, are used to calculate cellular absorbed fractions for these radiations. The resulting absorbed fractions are employed to calculate cellular S-values for several radionuclides. Results: Cellular absorbed fractions for monoenergetic electron sources with energies ranging from 0.1 keV to 1 MeV, distributed uniformly in the source region, are calculated for several target←source combinations including cell←cell, cell←cell surface, nucleus←nucleus, nucleus←cytoplasm and nucleus←cell surface. Similar data are also provided for monoenergetic alpha particle sources with energies ranging from 3 to 10 MeV. S-values are also conveniently tabulated for 32P, 86Rb, 89Sr, 90Y, 91Y, 114mIn, 131I. Auger-election-emitters 51Cr, 67Ga, 99mTc, 111In, 123I, 125I, 201Tl, 203Pb and the alpha emitter 210Po. In addition, S-values are given for radionuclides in the 212Pb, decay series, including 212Pb, 212Bi and 212Po. Both absorbed fractions and S-values are supplied for a number of different size cells and cell nuclei. Conclusions: With the absorbed fractions and S-values in hand, along with experimentally determined information on the biokinetics and subcellular distribution of the radionuclides, the cellular self-absorbed dose can be conveniently calculated.

Blood-Brain Barrier Abnormalities in Longstanding Multiple Sclerosis Lesions. An Immunohistochemical Study

Abstract: Thirty-five randomly selected plaques from five patients with longstanding multiple sclerosis were examined immunohistochemically for evidence of extravascular serum proteins. One lesion showed histological evidence of active demyelination and 34 were inactive. In the one active lesion and in 26 of the 34 inactive lesions, serum proteins were detected outside blood vessels in a distribution consistent with leakage during life. The findings suggest that the blood-brain barrier (BBB) is permanently damaged in many old plaques, although to a degree not often detectable by current gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced magnetic resonance imaging (MRI). The findings also suggest that in patients with multiple sclerosis, a breached BBB is not by itself sufficient to induce active demyelination. Continuous exposure of demyelinated axons and glia to cytokines, antibody or other factors present in the circulation might be important, however, in preventing oligodendrocyte regeneration and new myelin formation in longstanding lesions.

Family of the major cold‐shock protein, CspA (CS7.4), of Escherichia coli, whose members show a high sequence similarity with the eukaryotic Y‐box binding proteins

Abstract: Summary The cspA is a gene of Escherichia coli, whose expression is specifically induced at low temperatures to a level of 13% of total protein synthesis. The CspA protein consisting of 70 amino add residues has high sequence similarity with eukaryotic Y-box DNA-binding proteins. We found two independent clones from the Kohara miniset phage collection, which hybridized with a DNA fragment containing cspA. DNA sequencing of these clones confirmed that the two genes are highly homologous to cspA. One designated cspB is mapped at 35 min on the E. coli chromosome and encodes a 71-residue protein with 79% identity to CspA, while the other, cspC, is mapped at 40 min and encodes a 69-residue protein with 70% identity. In addition, a DNA sequence upstream of the clpA gene at 19 mm published elsewhere contains an open reading frame for a 74-residue protein with 45% identity to CspA. All csp genes were fused in the coding regions with the lacZ gene, and the expression of β-galactosidase was examined for these hybrid genes upon cold shock. A similar cold-shock induction to cspA was observed for cspB but not cspC and cspD. These results Indicate that E. coli has a family of the cspA gene, some of which are induced by cold shock.

The Effect of Gastric Bypass Surgery on Hypertension in Morbidly Obese Patients

Abstract: Background: Hypertension is the most common medical disorder associated with obesity. The relationship between dietary weight loss and the reduction of blood pressure is well established. However, the effect of gastric bypass surgery on blood pressure has not been well studied. Methods: We evaluated the relationship between weight loss and blood pressure in patients with diastolic hypertension who had gastric bypass surgery for morbid obesity. Patients were defined as hypertensive if taking antihypertensive medication or if both the preoperative office and mean hospital diastolic blood pressures were greater than 90 mm Hg. Two of the authors (J.L.C.,M.E.R.), blinded to all postoperative weights, classified the follow-up hypertensive status into one of four categories: resolved, improved, no change, or worse. The relationship between postoperative changes in blood pressure status and mean weight loss, percent excess weight loss, and body mass index were examined using a one-way analysis of variance. The relationship between postoperative weight loss and blood pressure was assessed in the baseline normotensive population using linear regression analysis. Results: There were 45 patients with diastolic hypertension; 91% were taking an antihypertensive medication. The mean follow-up was 39 months. The mean pre-operative weight was 137 kg and the mean weight loss at 1, 12, and 24 months following surgery was 13, 21, and 45 kg, respectively. Twelve months after surgery, hypertension had resolved in 22 patients (54%) and had improved in six patients (15%). These findings persisted through 48 months postoperatively. There was a significant relationship between the percentage of excess weight lost and improvement of hypertension at the 6-month and 12-month follow-up visits. There was also a significant relationship between the body mass index and improvement of hypertension at the 1-month, 12-month, 24-month, and 48-month follow-up visits. In the base-line normotensive patients there was not a significant relationship between our weight loss measures and changes in blood pressure. Conclusions: We conclude that postoperative weight loss in patients undergoing gastric bypass surgery was associated with resolution or improvement of diastolic hypertension in approximately 70% of cases. Resolution or improvement of hypertension occurred more often in patients with a lower postoperative body mass index. (Arch Intern Med. 1994;154:193-200)

Bicondylar tibial plateau fractures treated with a hybrid ring external fixator: a preliminary study.

Abstract: Twenty-three knees in 22 patients with Schatzker type VI tibial plateau fractures were treated with a hybrid ring external fixator using tensioned wires proximally and half-pins distally. All but two injuries were secondary to high-energy trauma. Six were open injuries, and eight patients had other major musculoskeletal trauma. Eight patients were treated with limited open reduction and internal fixation before application of the frame. The remainder received percutaneous cannulated screw fixation to stabilize the articular surface without opening the fracture site. Twenty-three fractures were followed to complete healing. Average time to healing was 4.4 months. Arc of motion averaged 107 degrees, and there were four flexion contractures of 5-15 degrees. Complications consisted of three deep wound infections, one deep venous thrombosis (DVT), one malunion, and one pin tract infection. The average knee score and patient function score were 84.7 and 80.5, respectively (Knee Society Clinical Rating System). There were 13 excellent, three good, one fair, and six poor results. The poor results were in patients who either developed deep wound infections or in those who sustained multiple musculoskeletal trauma compromising the patients' function score and ultimately the average score. This method provides good stabilization and allows early range of motion for complex tibial plateau fractures where extensive dissection and internal fixation are contraindicated due to traumatized soft tissue, osteopenia, and fracture comminution.

Dosimetry of Auger-electron-emitting radionuclides: report no. 3 of AAPM Nuclear Medicine Task Group No. 6.

Abstract: The biological effects of Auger-electron-emitting radionuclides can be as severe as those of alpha particles of high linear energy transfer. A great deal of effort has been expended in exploring the biological effects of Auger electron emitters. Much of this effort has been devoted to improving theoretical and experimental techniques required to calculate absorbed doses and correlate them with the observed biological effects. Given that the main purpose of dosimetry is to obtain a physical descriptor with which to correlate radiation toxicity, then nowhere is this challenge greater than when biological specimens are subject to Auger electron cascades. The dense shower of short-range Auger electrons released by radionuclides, which decay by electron capture or internal conversion, results in biological damage that is highly dependent on the location of the decay site within the cell. In this report, different approaches to Auger electron dosimetry are described and compared. Methods to calculate the absorbed dose from Auger electron emitters at the DNA, cellular, multicellular, and organ levels are described as they relate to the biological effects. The concept of a radiation weighting factor for Auger electrons to be used in the calculation of equivalent dose is reviewed. The importance of subcellular distribution of Auger emitters in determining the biological effects of these radionuclides is emphasized and incorporated into the equivalent dose formalism. The Task Group recommends that a preliminary radiation weighting factor of 10 be used for deterministic effects of Auger electrons, and a value of 20 for stochastic effects.

Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 1: Systemic administration.

Abstract: Several parameters necessary for the expression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity to dopaminergic neurons were examined in both mice and rats in order to determine if differences in these processes might underlie the marked differences in the sensitivity of the two species to the neurotoxic effects of MPTP. Monoamine oxidase-B activity was greater in brain tissues from rats than from mice. The kinetics of 1-methyl-4-phenylpyridinium (MPP+) uptake into neostriatal synaptosomal preparations from the two species were similar. Brain and neostriatal levels of MPP+ were 2-fold higher in rats after the administration of MPTP at 60 mg/kg and were 10 to 20 times higher in rats than in mice after MPTP treatment which produced similar decrements in the content of neostriatal dopamine. MPP+ concentrations in the extracellular fluid of the neostriatum of the two species were similar after the administration of the same dose of MPTP (40 mg/kg). However, this dose induced a 40-fold increase in neostriatal dopamine efflux in mice, whereas in rats only a 3-fold increase was observed. In addition, pretreatment of rats with guanethidine, a ganglionic blocking agent, permitted the use of high doses of MPTP which resulted in substantial damage to the striatal dopaminergic nerve terminals. It is concluded that nigrostriatal dopaminergic neurons in the rat require exposure to a much higher concentration of MPP+ than do those in mice for the induction of toxicity.

Multicellular dosimetry for micrometastases: dependence of self-dose versus cross-dose to cell nuclei on type and energy of radiation and subcellular distribution of radionuclides.

Abstract: UNLABELLED: In radioimmunotherapy, the treatment of bulk tumors by radionuclides that emit energetic beta particles is the preferred approach. However, for the eradication of small clusters of cancer cells, radionuclides that emit Auger electrons or alpha particles are considered to be advantageous because of their ability to deposit radiation energy locally. If such radionuclides are internalized by the cells, the total dose to the cell nuclei is thought to be primarily determined by the self-dose (dose to cell nucleus from activity within the cell) in comparison to the cross-dose (dose to the cell nucleus from activity in all other cells). METHODS AND RESULTS: The self-dose-to-cross-dose ratios to the cell nucleus were calculated for different cluster sizes (26-400 microns) with monoenergetic electron and alpha particle sources distributed uniformly in different cell compartments (cell surface, cytoplasm, nucleus). Model calculations were also performed for several radionuclides (Auger, beta and alpha emitters). Absorbed fractions for sources of monoenergetic electron and alpha particles, distributed uniformly in small spheres (26-5000 microns), were also calculated along with S-values for a number of radionuclides. CONCLUSIONS: When most of the cells in the cluster are labeled with beta or alpha emitters, the cross-dose component of the total dose is important irrespective of cluster size and subcellular source distribution and increases as the cluster size increases. The self-dose is always important for Auger emitters. When the self-dose is negligible, the mean absorbed dose to the cell nuclei is well represented by the mean dose to the micrometastasis.