Behaviour of Arctic charr Salvelinus alpinus during an induced mating season in captivity: how male relative size influences male behavioural investment and female preference over time.

The behaviour of sexually mature Arctic charr Salvelinus alpinus specimens (fifth farm generation) was observed in captivity for four consecutive days. Only agonistic interactions between males of different size were facilitated on the first 2 days, while both agonistic and courtship interactions were possible from the third day up to the end of the experiment. The reliability of behavioural analysis was assessed in order to reduce the possibility of observer errors within the generated datasets. The behavioural investment of big males, small males and females was analysed using general linear models (two-way repeated measures ANOVAs with time and male size as factors). A peak in the agonistic interactions between males occurred during the first day of interactions, where the agonistic investment of big males was significantly higher than that of small males. This resulted in an increased investment in submissive behaviour by the small males, who consistently performed submissive behaviours from the second day of interactions up to the end of the trial. Big males were found to invest significantly more than small males in courtship behaviours for the duration of the trial. Even though females performed inter-sexual behaviours towards both big and small males for the entire observation period, female interaction rate towards big males was higher than towards small males. This study suggests that both male investment in mating behaviour and female preference might be related to male characteristics such as body length and that S. alpinus behavioural patterns and mate choice cues might be strongly context-related and characterized by high levels of behavioural plasticity (i.e. presence-absence of certain behavioural units or potential reversal of a mate choice cue) within the same species. Finally, in light of this, some conservation measures are discussed. In particular, effective management plans should take into account the high level of behavioural plasticity likely to be occurring in this species.

A Toll-like receptor-1 variant and its characteristic cellular phenotype is associated with severe malaria in Papua New Guinean children.

Genetic factors are likely to contribute to low severe malaria case fatality rates in Melanesian populations, but association studies can be underpowered and may not provide plausible mechanistic explanations if significant associations are detected. In preparation for a genome-wide association study, 29 candidate single-nucleotide polymorphisms (SNPs) with minor allele frequencies >5% were examined in a case-control study of 504 Papua New Guinean children with severe malaria. In parallel, an immunological substudy was performed on convalescent peripheral blood mononuclear cells (PBMCs) from cases and controls. Following stimulation with a Toll-like receptor (TLR) 1/2 agonist, effector cytokines and chemokines were assayed. The only significant genetic association observed involved a nonsynonymous SNP (TLR1rs4833095) in the TLR1 gene. A recessive (TT) genotype was associated with reduced odds of severe malaria of 0.52 (95% confidence interval (0.29-0.90), P=0.006). Concentrations of pro-inflammatory cytokines interleukin-1ß and tumour necrosis factor α were significantly higher in severe malaria cases compared with healthy controls, but lower in children with the protective recessive (TT) genotype. A genetic variant in TLR1 may contribute to the low severe malaria case fatality rates in this region through a reduced pro-inflammatory cellular phenotype.

Tigecycline use in the outpatient parenteral antibiotic therapy setting.

In the context of globally increasing antimicrobial resistance, tigecycline appears to be a useful therapeutic option. The need for prolonged courses for complex infections has prompted consideration of its use via outpatient parenteral antibiotic therapy (OPAT) programmes, although clinical outcomes when used in this setting remain unknown. We retrospectively reviewed the patient characteristics and outcomes of 11 patients who received tigecycline, most commonly delivered as 100 mg once daily, via OPAT at three tertiary Australian hospitals. Rates of co-morbidity and prior antibiotic use were high. Patients had a wide range of infections including bone and/or joint (n = 5), intra-abdominal (n = 3), lower respiratory tract (n = 2) and parapharyngeal abscess (n = 1). Mycobacterial species (n = 5) were the most frequent pathogen, and multi-resistant organisms were common (n = 4). The median OPAT duration was 14 days (IQR 6-30). Nausea was encountered in 45 % of cases. At completion of OPAT, 1 patient (9 %) was cured, 2 (18 %) had improved and 8 (73 %) failed therapy. Failure occurred due to either progression or non-response of infection (n = 4), re-admission (n = 3), premature cessation of tigecycline due to nausea (n = 3) or death (n = 1). Whilst OPAT delivery of tigecycline is a therapeutic option, when used as second-line therapy for complex, often multi-resistant infections in patients with multiple comorbidities, high rates of clinical failure, readmissions and adverse effects, especially nausea, should be anticipated.

Autobiographical memory in multiple sclerosis patients: assessment and cognitive facilitation.

The multifocal nature of lesions in multiple sclerosis hints at the occurrence of autobiographical memory (AbM) impairment. However, the dearth of studies on AbM in multiple sclerosis is noticeable, notwithstanding the importance of AbM in everyday life. In the first section of this study, 25 multiple sclerosis patients and 35 controls underwent a detailed episodic AbM assessment. Results obtained by means of ANOVA suggested an AbM retrieval deficit in every patient. That pattern of performance paved the way for the second section of the study, in which we followed up 10 out of the 25 patients. Our objective was to assess the effectiveness of a cognitive facilitation programme designed to alleviate AbM retrieval deficits, based on the key role of mental visual imagery on AbM. Statistical group analyses by means of ANOVA and individual analyses using the χ(2) test showed significant differences in AbM test results, in post-facilitation relative to pre-facilitation training, in all 10 patients. Moreover, the patients' comments showed that the positive effects were transferred in their daily life functioning. We would like to suggest that the facilitation programme efficiently enhanced the process of self-centred mental visual imagery, which might have compensated for poor retrieval of personal memories by providing better access to visual details and detailed visual scenes of personal recollections.

Subjective Cognitive Decline in a Registry Sample: Relation to Psychiatric History, Loneliness, and Personality.

BACKGROUND: With the increasing focus on prevention of Alzheimer's disease, there is need for characterization of preclinical populations. Local participant registries offer an opportunity to facilitate research engagement via remote data collection, inform recruitment, and characterize preclinical samples, including individuals with subjective cognitive decline. OBJECTIVES: We sought to characterize subjective cognitive decline in a registry sample, as related to psychiatric history and related variables, including personality and loneliness, quality of life, and factors related to dementia risk (e.g., family history of dementia). DESIGN, SETTING, PARTICIPANTS: Participants were 366 individuals (mean age=67.2 (range 50-88), 65% female, 94% white, 97% non-Hispanic or Latino, 82% with at least a bachelor's degree) with no reported history of mild cognitive impairment or dementia. All participants had expressed interest in research, primarily via community outreach events and prior research involvement. Data was collected via electronic surveys, distributed using REDCap. Electronic questionnaires included questions on demographic variables, subjective cognitive decline, quality of life, loneliness, and personality. RESULTS: There was a high prevalence of risk factors for dementia in the registry sample (68% with family history of dementia, 31% with subjective cognitive decline). Subjective cognitive decline was more common in women and associated with history of depression, but not with family history of dementia. Subjective cognitive decline was also associated with lower conscientiousness and lower emotional stability, as well as higher loneliness and lower quality of life. Among participants who endorsed a psychiatric history, most reported onset more than 10 years prior, rather than within the last 10 years. CONCLUSIONS: Subjective cognitive decline in a registry sample may be more strongly associated with longstanding psychiatric and personality variables, rather than family history of dementia, adding to the literature on characterization of subjective cognitive decline across different settings. These findings highlight the acceptability of remote data collection and the potential of registries to inform recruitment by characterizing registrants, which may help to stratify dementia risk and match participants to eligible trials.

Marc Dax and the discovery of the lateralisation of language in the left cerebral hemisphere.

In 1836, Marc Dax presented a revolutionary conclusion based on both his clinical observations and reports from the literature: the localisation of language in the left hemisphere. Twenty-seven years later, his son, Gustave Dax, extended and enriched his work. Their involvement in 19th century neuropsychology is impressive and recognition should have been considerable. However, according to the vast majority of historians of neurology, neuropsychology and aphasiology, the priority in establishing the dominance of the left brain hemisphere for speech goes to Paul Broca in an undivided way. Is it possible that Marc Dax's and his son, Gustave Dax's works were entirely unknown? Were they known and utterly forgotten? Were they ignored? How did we get to know that they existed? The aim of the present paper is to try to answer those and other questions and to demonstrate that there is abundance of data pointing out that the priority of the discovery of left hemisphere dominance for speech ought to be, at least, shared by Dax and Broca.

[Memory improvement in patients with temporal lobe epilepsy at one-year postoperative]. / Amélioration mnésique postopératoire un an après traitement chirurgical de l'épilepsie du lobe temporal.

INTRODUCTION: Several studies have assessed the impact of surgery on both anterograde and remote memory in patients with temporal lobe epilepsy (TLE). The majority of results have shown an extensive memory deficit in patients after temporal resection (TL). However, few protocols have used a prospective longitudinal design. Moreover, the postoperative delays were variable from one study to the next, instead of regular monitoring to identify the potential effect of time elapsed after surgery on memory performance. In addition, some studies have not used strict inclusion criteria to establish homogeneous patient groups. Finally, the impact of surgery on memory has been often assessed by comparing memory skills between epileptic patients and healthy controls. Our aim was to examine the impact of TL on memory in patients with TLE, recruited according to clear-cut clinical criteria. Moreover, we focused on memory performance progression per se in epileptic patients pre- and postoperatively, rather than on memory performance analysis expressed as "deficient" or "normal". METHODS: We assessed 30 patients with unilateral TLE (17 right TLE and 13 left TLE) on four anterograde memory tests and six remote memory tasks. Patients completed all tests preoperatively, and 5 and 12 months after TL. RESULTS: Five months after surgery, performance was equivalent to the preoperative scores for both groups in anterograde memory tasks and remote memory tests. One year after TL, patients with right TLE showed enhanced performance in the verbal anterograde memory tests and in retrieving recent autobiographical memories. Results for left TL showed improved scores only in a recognition memory test of faces. CONCLUSIONS: In the present study, surgical patients were "double winners" gaining seizure freedom and potential of memory stability or recovery. The gain was observed only 12 months after surgery and following temporal resection lateralisation. Our data showed postoperative memory improvement in patients with temporal lobe epilepsy presenting with specific clinical characteristics.

Perceptive eating as part of the journey in inflammatory bowel disease: Lessons learned from lived experience.

BACKGROUND: Inflammatory bowel diseases (IBD) include ulcerative colitis (UC) and Crohn's disease (CD), incurable remitting-relapsing conditions that impact more than 3 million people in the United States alone. A diagnosis of IBD can be life-altering; patients must make significant adjustments to manage their symptoms, and this may include dietary changes. While diet may impact IBD symptoms and disease progression, there is currently no one diet recommendation for IBD patients to follow. Few studies explored patient beliefs and practices around their dietary intake. OBJECTIVE: Our objective was to identify patient beliefs, attitudes, and behaviors around diet in management of symptoms and flares in patients with IBD. METHODS: We conducted semi-structured interviews with patients N = 16 patients with UC or Crohn's colitis, recruited from an IBD center in a large metropolitan medical center. All patients were referred by their behavioral health provider. Interviews were transcribed verbatim; two analysts coded the transcripts using NVivo software. This analysis examines the themes derived from the questions about diet. RESULTS: The sample of participants in this study (N = 16) was adult patients of the IBD clinic with either UC or Crohn's disease in the colon. Three main themes emerged from our analysis: evolving attempts at controlling symptoms through diet (subthemes: initial attempts to modify diet to control symptoms, and food avoidance was commonly reported but safe foods were not), beliefs about how food affects IBD (subthemes: liquid nutrition rests the bowels, diet for general health is all that is needed for IBD management, and diet is part of IBD management), and perceptive eating. DISCUSSION: Our findings confirmed those from previous studies that patients with IBD do notice that eating certain foods induces symptoms, and controlling dietary intake is one way that they choose to manage symptoms of IBD. Some patients had beliefs about how food affects their IBD, whether by reducing inflammation, or giving the gut rest. We also noted that patients used perceptive eating in their approach to diet by using a combination of experience and knowledge.

Neuronal inclusions resembling Negri bodies in the thalamus of a red kangaroo (Macropus rufus).

Eosinophilic intracytoplasmic neuronal inclusions resembling Negri bodies, but not associated with lyssaviral infection, were detected in the ventrolateral thalamus of a young-adult, male red kangaroo (Macropus rufus). Similar neuronal inclusions, also with a regional distribution in the brain, have been reported as an incidental, possibly age-related finding in other animal species.

Encephalomyocarditis virus infection in alpacas.

Encephalomyocarditis virus (EMCV) infection was detected by real-time reverse transcription PCR (qRT-PCR) in four adult alpacas (Vicugna pacos) from two properties on the Far North Coast of New South Wales (NSW) in April and May 2018 and in two adult alpacas from a third property on the Central Coast of NSW in October 2018. Viral RNA was detected in a range of samples, including blood, fresh body organs and mucosal swabs. EMCV was isolated from the blood and body organs of five of these alpacas. These animals displayed a range of clinical signs, including inappetence, colic, recumbency and death. Necropsy findings included multifocal to coalescing areas of myocardial pallor, pulmonary congestion and oedema, hepatic congestion and serosal effusion. Histopathological changes comprised acute, multifocal myocardial degeneration and necrosis, with mild, neutrophilic and lymphocytic inflammation (5/5 hearts) and mild, perivascular neutrophilic meningoencephalitis (1/3 brains). This is the first report of disease due to EMCV in alpacas under farm conditions, and it identifies EMCV infection as a differential diagnosis for acute disease and death in this camelid species. In addition to the samples traditionally preferred for EMCV isolation (fresh heart, brain and spleen), blood samples are also appropriate for EMCV detection by qRT-PCR assay.

Attraction of New Zealand flower thrips, Thrips obscuratus, to cis-jasmone, a volatile identified from Japanese honeysuckle flowers.

This work was undertaken to identify floral compound(s) produced by honeysuckle flowers, Lonicera japonica (Thunberg), that mediate the attraction of New Zealand flower thrips Thrips obscuratus (Crawford). Volatiles were collected during the day and night and analyzed by gas chromatography-mass spectrometry (GC-MS) to determine their emission over these two periods. Nine compounds were identified in the headspace; the main compound was linalool, and the other compounds were germacrene D, E,E-alpha-farnesene, nerolidol, cis-jasmone, cis-3-hexenyl acetate, hexyl acetate, cis-hexenyl tiglate, and indole. There was a quantitative difference between day and night volatiles, with cis-3-hexenyl acetate, hexyl acetate, cis-hexenyl tiglate, and cis-jasmone emitted in higher amounts during the day compared to the night. When the compounds were tested individually in field trapping experiments, only cis-jasmone attracted New Zealand flower thrips in a significant number. In another field trapping experiment, cis-jasmone caught similar numbers of New Zealand flower thrips compared to a floral blend formulated to mimic the ratios of the compounds emitted during the day, while catch with the night-emitted floral blend was not significantly different from the control. Subsequently, two field trapping experiments were conducted to determine the optimal attraction dose for cis-jasmone, a range of 1-100 mg loaded onto a red rubber stopper was tested, and the highest catches were in traps baited with 100 mg loading. A higher range of 100-1000 mg loaded into polyethylene vials was tested, and the highest catch was in traps baited with 500 mg. In another experiment aimed at comparing the attraction efficacy of cis-jasmone with the two other known thrips attractants (ethyl nicotinate and p-anisaldehyde), ethyl nicotinate showed the highest trap catch followed by cis-jasmone. A smaller number of Thrips tabaci (Lindeman) was attracted to traps baited with cis-jasmone. These results suggest that cis-jasmone might act as a kairomone that mediates the attraction of New Zealand flower thrips to the flowers of the Japanese honeysuckle.

Pathology of highly pathogenic avian influenza virus (H5N1) infection in Canada geese (Branta canadensis): preliminary studies.

Susceptibility of Canada geese (Branta canadensis) to highly pathogenic avian influenza (HPAI) virus (H5N1) infection was studied by inoculating 10 naïve (antibody-negative) animals (5 adults and 5 juveniles) with A/chicken/Vietnam/14/05 (H5N1) virus. In the adults, 1 of 5 became infected, and 4 of 5 remained normal; in the juvenile group, 5 of 5 became infected. The pathology observed in the affected animals was similar to that reported in natural occurrences. Peripheral and parasympathetic nervous systems were examined and found infected, as well as cerebrospinal fluid-contacting neurons. In some locations with significant virus infection in cells, the expected inflammatory reaction was absent or very mild. Immunohistochemistry was used to locate influenza A virus nucleoprotein in brain, spinal cord, respiratory and digestive systems, pancreas, heart, and peripheral and parasympathetic nervous systems. Further studies are needed to explain age-related differences in susceptibility.

Assessing the impact of mailing self-sampling kits for human papillomavirus testing to unscreened non-responder women in Manitoba.

Background: CervixCheck, Manitoba's cervical cancer screening program, conducted a pilot study to assess whether screening participation could be improved in unscreened women by offering a mailed self-sampling kit for human papillomavirus (hpv) testing instead of a Pap test. Methods: In a prospective cohort study design, a sample of unscreened women (n = 1052) who had been sent an invitation letter from CervixCheck in the past but who did not respond were randomized to either an intervention group or a control group. The intervention group received a mailed hpv self-sampling kit; the control group received no additional communication. Returned hpv self-sampling swabs were analyzed by a provincial laboratory. After 6 months, screening participation in the two study groups was compared using a logistic regression model adjusted for age and area of residence (urban or rural). Secondary outcomes included hpv positivity, specimen inadequacy, compliance with follow-up, and time to colposcopy. Results: Screening participation was significantly higher in the intervention group than in the control group (n = 51, 9.6%, vs. n = 13, 2.5%; odds ratio: 4.7; 95% confidence interval: 2.56 to 8.77). Geographic area of residence (urban or rural) and age were not statistically significant. Conclusions: The study demonstrated that hpv self-sampling kits can enhance screening participation in unscreened non-responder women in the setting of an organized screening program. Next steps should include additional research to determine the best implementation strategy for hpv self-sampling in Manitoba.

Floral scent of Canada thistle and its potential as a generic insect attractant.

The flowers of Canada thistle, Cirsium arvense (L.), attract a wide range of insects, including pollinators and herbivorous species. This attraction is primarily mediated by floral odor, which offers potential for developing generic insect attractants based on odor. In this study, we have analyzed the chemical composition of the volatiles produced by Canada thistle flowers. Nineteen floral compounds were identified in the headspace, including phenylacetaldehyde (55%), methyl salicylate (14%), dimethyl salicylate (8%), pyranoid linalool oxide (4.5%), and benzaldehyde (3.5%). Other minor compounds include benzyl alcohol, methylbenzoate, linalool, phenylethyl alcohol, furanoid linalool oxide, p-anisaldehyde, 2,6-dimethyl-1,3,5,7-octatetraene, benzylacetate, benzyl tiglate, (E,E)-alpha-farnesene, benzyl benzoate, isopropyl myristate, and 2-phenylethyl ester benzoic acid. The relative attractiveness of various doses of the main floral volatile compound phenylacetaldehyde (i.e., 10, 100, 200, and 400 mg) was tested for insect attraction. Both the total catch and the biodiversity of insect species trapped increased as the loading of phenylacetaldehyde increased. Volatiles were chosen from the odors from the flowers of Canada thistle and formulated and tested in the field. An 11-component blend was the most attractive of several floral blends tested. These findings indicate that chemical components of flower odors of Canada thistle can serve as a generic insect attractant for monitoring of invasive pest species.

Epidemiology and risk factors for recurrent severe lower limb cellulitis: a longitudinal cohort study.

OBJECTIVE: To describe the epidemiology and risk factors for recurrence of severe lower leg cellulitis (LLC). METHODS: A longitudinal cohort study using state-wide data of adults presenting with recurrent LLC following a primary episode occurring between January 2002 and December 2013. The incidence of recurrent LLC was estimated using the cumulative incidence function, accounting for mortality. Independent risk factors for recurrence were identified using Fine-Gray sub-distribution and Cox proportional hazards models. RESULTS: Of 36 276 patients presenting with their first episode of LLC, 4598 had at least one recurrence during the follow-up period. The cumulative incidence of first, second, and third recurrences at 12 months since previous infection was 6.3% (95% CI 6.0-6.5), 17.2% (95% CI 16.1-18.4), and 29.4% (95% CI 26.8-31.9), respectively, and at 5 years was 13.9% (95% CI 13.5-14.3), 35.9% (95% CI 34.2-37.5), and 52.9% (95% CI 49.5-56.2), respectively. The length of hospitalization increased from 3 days for the primary episode to 4 and 5 days for first and all subsequent recurrences, respectively. Independent risk factors for recurrent LLC included age, ethnicity (Indigenous Australian), local factors relating to lower leg pathology, conditions that commonly result in peripheral oedema, and systemic conditions that may be associated with increased leg size. CONCLUSIONS: LLC recurrences are frequent, and each episode increases the likelihood of subsequent recurrence and length of hospitalization. These data provide context and scope to develop workable and effective strategies to prevent secondary episodes for all cases of primary LLC.

Severe lower limb cellulitis: defining the epidemiology and risk factors for primary episodes in a population-based case-control study.

OBJECTIVE: To describe the epidemiology and risk factors for primary episodes of severe lower leg cellulitis (LLC). METHODS: This was a longitudinal cohort study using state-wide data linkage of adults presenting to Western Australian (WA) hospitals with a first ever LLC from January 2002 to December 2013. The study aimed at determining risk factors, medical records from the index patient, together with comparable data from controls matched by age, sex, postcode, and month of admission. RESULTS: During the period, 36 276 patients presented with their first episode of LLC. The incidence increased by 4.7% per annum, reaching 204.8 (95% CI 198.6-211.1) per 100 000 population by December 2013. Analysis of 29 062 case-control pairs showed several conditions with lower limb pathology were independently associated with LLC, including varicose veins (AOR 2.95, 95% CI 2.50-3.48, p < 0.001), lymphoedema (AOR 2.65, 95% CI 1.71-4.10, p < 0.001), tinea pedis (AOR 3.05, 95% CI 1.45-6.42, p 0.003), and saphenous vein harvest during coronary artery bypass grafting (AOR 1.74, 95% CI 1.32-2.30, p < 0.001). Also associated with LLC was obesity (AOR 2.05, 95% CI 1.82-2.31, p < 0.001), renal disease (AOR 1.28, 95% CI 1.14-1.44, p < 0.001), rheumatologic conditions (AOR 2.12, 95% CI 1.72-2.60, p < 0.001), hemiplegia/paraplegia (AOR 1.31, 95% CI 1.13-1.52, p < 0.001), and liver disease (AOR 1.77, 95% CI 1.51-2.06, p < 0.001). CONCLUSIONS: LLC presents a major burden to the health sector and is increasing with an ageing population. Given the high rates of recurrence, long-term morbidity, and economic impact, efforts to reduce primary episodes should be incorporated into the infectious diseases and healthy ageing research agenda.

Effect of corticotropin-like intermediate lobe peptide on pancreatic exocrine function in isolated rat pancreatic lobules.

Naturally occurring derivatives of pro-opiomelanocortin (POMC) have been identified in various extra-pituitary sites, including the endocrine and exocrine pancreas. Corticotropin-like intermediate lobe peptide (CLIP = ACTH18-39), a naturally occurring derivative of POMC, has been suggested to be an insulin secretagogue. To determine whether CLIP might also affect the exocrine pancreas, we measured its effect on amylase secretion and protein synthesis and secretion in isolated rat pancreatic lobules. Lobules were dual-pulsed with trace amounts of 14C- and 3H-leucine, both in the presence and absence of CLIP (10(-9)-10(-6) M), using a technique that permitted the labeling of both the synthetic and secretory compartments. The effect of CLIP on protein synthesis was determined by comparing 3H-leucine incorporation into lobules with and without CLIP. The secretory effect of CLIP was determined by measuring (a) secreted 14C-labeled protein as a percent of total incorporated radiolabeled protein, and (b) amylase release into incubation medium. The effect of CLIP on amylase release was compared with that of secretin, cholecystokinin-octapeptide, and carbamylcholine. To localize the biologically active region of CLIP, we similarly studied synthetic ACTH25-39. We demonstrated that CLIP stimulates amylase and protein secretion in a dose-dependent manner and is of similar potency to secretin and carbamylcholine. This effect appears to require the ACTH18-24 region of CLIP and results from stimulus-secretion coupling rather than augmented protein synthesis. We also confirmed the presence of immunoreactive-adrenocorticotropic hormone (IR-ACTH) in rat pancreatic extract using a COOH-terminally directed antibody to ACTH1-39 and demonstrated that this IR-ACTH co-eluted with synthetic CLIP. These findings suggest that CLIP might be an endogenous modulator of pancreatic exocrine function.

Exclusive binding of immunoglobulin to Fc gamma receptors on macrophages in 3-methylcholanthrene-induced murine tumors.

Immunogenic, chemically induced, murine tumors generally are infiltrated with large numbers of Fc gamma receptor (Fc gamma R)-positive cells, most of which are mononuclear phagocytes. This study demonstrates in inbred C3H/HeN mice that such immunogenic tumors contain large amounts of cell-bound immunoglobulin (Ig) and that, within the sensitivity limits of indirect immunofluorescence, the tumor-associated Ig is bound exclusively to host-derived Fc gamma R-positive cells. Depletion of Fc gamma R-positive cells from tumor cell suspensions removed all Ig-bearing cells. Specific competitive elution of the endogenous Ig with heterologous nonimmune IgG established that the endogenous Ig was bound through the Fc gamma R. Tumor-associated Fc gamma R-positive, Ig-bearing cells could be detected with soluble antigen-antibody complexes, and mononuclear phagocytes to which the exogenous complexes were bound expressed Fc gamma R at a level significantly above normal. The role of this macrophage-associated Ig in determining the level of interaction between host cells and the tumor remains to be determined.

Radiopharmaceutical therapy of 5T33 murine myeloma by sequential treatment with samarium-153 ethylenediaminetetramethylene phosphonate, melphalan, and bone marrow transplantation.

BACKGROUND: Total-body irradiation, followed by hematopoietic system rescue by bone marrow transplantation (BMT), has been found to improve the response of patients with multiple myeloma to treatment with melphalan. The problems of nonhematopoietic toxicity from whole-body irradiation might be circumvented by using a bone-seeking radiopharmaceutical, such as samarium-153 ethylenediaminetetramethylene phosphonate (153Sm-EDTMP), to ablate the bone marrow. PURPOSE: A mouse model system for multiple myeloma was used to evaluate the potential therapeutic efficacy of sequential therapy with 153Sm-EDTMP, melphalan, and BMT. METHODS: Female C57BL/KaLwRij mice were inoculated with 8 x 10(5) 5T33 murine myeloma cells. Treatment protocols were begun 3 or 10 days later, when the myeloma was either confined to bone marrow or disseminated in liver, spleen, and lymph nodes, simulating human multiple myeloma. 153Sm, a potent beta particle-emitting radioisotope of short half-life (46.7 hours), was linked to the bone-seeking chelate EDTMP. Animals in the first treatment group were each given 22.5 MBq 153Sm-EDTMP via the jugular vein (day 3 or 10), followed by 18.5 mg/kg melphalan (maximum tolerated dose) given intraperitoneally 5 days later (day 8 or 15) and syngeneic BMT another 2 days later (day 10 or 17). Survival in groups of six to 10 animals for each time series was compared with that in mice left untreated (control cohort), in mice treated with 153Sm-EDTMP alone (day 3 or 10), or in mice treated with melphalan alone (day 8 or 15). The hematopoietic systems of animals in the latter two treatment groups recovered full function, obviating the necessity of BMT. The end point was onset of paraparesis, at which time the animals were immediately killed by carbon dioxide asphyxiation. RESULTS: Median survival in untreated control animals was 23 days in those with localized disease and 24 days in those with disseminated myeloma. Treatment with 153Sm-EDTMP alone improved survival to a median of 29 days when commenced on day 3 and 30 days when begun on day 10. Melphalan treatment alone improved the median survival to 31 days for animals with localized myeloma and 34 days in animals with disseminated disease. Additional improvement in survival to a median of 42 days was achieved in animals treated 3 days after tumor inoculation with sequential 153Sm-EDTMP, melphalan, and BMT; median survival was 40 days using this regimen in animals with disseminated myeloma. CONCLUSIONS: Animals in all three treatment protocols survived longer than those left untreated after inoculation with myeloma cells (P < .001). Sequential treatment with 153Sm-EDTMP, melphalan, and BMT was significantly more effective than single-agent treatment (P < .01). No evidence of radiotoxicity was detected in nonhematopoietic organs. IMPLICATIONS: The survival advantage conferred by our sequential treatment protocol suggests its potential clinical usefulness in the treatment of multiple myeloma and other hematologic malignancies in humans.