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Importance: The prevalence of e-cigarette use among US adults, especially young adults, is rising. Many would like to quit vaping nicotine but are unable to do so. Cytisinicline, a plant-based alkaloid, targets nicotinic acetylcholine receptors, reduces nicotine dependence, and helps adults to stop smoking cigarettes. Cytisinicline may also help e-cigarette users to quit vaping. Objective: To determine the efficacy and safety of cytisinicline vs placebo to produce abstinence from e-cigarette use in adults seeking to quit vaping nicotine. Design, Setting, and Participants: This double-blind placebo-controlled randomized clinical trial compared 12 weeks of treatment with cytisinicline vs placebo, with follow-up to 16 weeks. It was conducted from July 2022 to February 2023 across 5 US clinical trial sites. A total of 160 adults who vaped nicotine daily, sought to quit, and did not currently smoke cigarettes were enrolled, and 131 (81.9%) completed the trial. Intervention: Participants were randomized (2:1) to cytisinicline, 3 mg, taken 3 times daily (n = 107) or placebo (n = 53) for 12 weeks. All participants received weekly behavioral support. Main Outcomes and Measures: Biochemically verified continuous e-cigarette abstinence during the last 4 weeks of treatment (weeks 9-12; primary outcome) and through 4 weeks posttreatment (weeks 9-16; secondary outcome). Missing outcomes were counted as nonabstinence. Results: Of 160 randomized participants (mean [SD] age, 33.6 [11.1] years; 83 [51.9%] female), 115 (71.9%) formerly smoked (≥100 lifetime cigarettes). Continuous e-cigarette abstinence in cytisinicline and placebo groups occurred in 34 of 107 participants (31.8%) vs 8 of 53 participants (15.1%) (odds ratio, 2.64; 95% CI, 1.06-7.10; P = .04) at end of treatment (weeks 9-12) and in 25 of 107 participants (23.4%) vs 7 of 53 participants (13.2%) during weeks 9 to 16 (odds ratio, 2.00; 95% CI, 0.82-5.32; P = .15). There was no evidence, based on nonsignificant interactions, that cytisinicline efficacy differed in subgroups defined by demographic characteristics, vaping pattern, e-cigarette dependence, or smoking history. Cytisinicline was well tolerated, with 4 participants (3.8%) discontinuing cytisinicline due to an adverse event. Conclusions and Relevance: In this randomized clinical trial, cytisinicline for 12 weeks, with behavioral support, demonstrated efficacy for cessation of e-cigarette use at end of treatment and was well tolerated by adults, offering a potential pharmacotherapy option for treating nicotine e-cigarette use in adults who seek to quit vaping. These results need confirmation in a larger trial with longer follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT05431387.
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Sistemas Eletrônicos de Liberação de Nicotina , Vaping , Humanos , Vaping/efeitos adversos , Masculino , Feminino , Adulto , Método Duplo-Cego , Azocinas/uso terapêutico , Pessoa de Meia-Idade , Abandono do Hábito de Fumar/métodos , Tabagismo/terapia , Tabagismo/tratamento farmacológico , Agonistas Nicotínicos/uso terapêutico , Agonistas Nicotínicos/administração & dosagemRESUMO
Primary hepatic angiosarcoma (PHA) is an exceedingly rare and aggressive neoplasm of mesenchymal origin. PHA makes a very small portion of primary liver tumors and conveys a poor prognosis. Symptomatology can be vague and often mimics primary hepatocellular carcinoma upon presentation. Diagnosis requires careful immunohistopathologic confirmation. We present a case of PHA in a patient with abdominal pain and suspected underlying cryptogenic cirrhosis.
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An insulinoma is a rare neuroendocrine tumor characterized by inappropriate secretion of insulin with resultant hypoglycemia and concomitant symptoms. Symptoms include diaphoresis, tremor, palpitations, tachycardia, visual disturbances, weakness, confusion, syncope, seizures, and even coma. Enteropancreatic neoplasms are rare in general but among them, insulinomas are among the more common neuroendocrine tumors though they still have a very low incidence. They can be benign or malignant, however, the latter is exceptionally rare. In the case of malignancy, such spread usually includes metastasis to the liver and surrounding nodes. They can also be sporadic or occur in association with other inherited conditions. Herein, we present a case of insulinoma in a 51-year-old female.
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Importance: Cytisinicline (cytisine) is a plant-based alkaloid that, like varenicline, binds selectively to α4ß2 nicotinic acetylcholine receptors, which mediate nicotine dependence. Although not licensed in the US, cytisinicline is used in some European countries to aid smoking cessation, but its traditional dosing regimen and treatment duration may not be optimal. Objective: To evaluate the efficacy and tolerability of cytisinicline for smoking cessation when administered in a novel pharmacokinetically based dosing regimen for 6 or 12 weeks vs placebo. Design, Setting, and Participants: A 3-group, double-blind, placebo-controlled, randomized trial (ORCA-2) compared 2 durations of cytisinicline treatment (6 or 12 weeks) vs placebo, with follow-up to 24 weeks, among 810 adults who smoked cigarettes daily and wanted to quit. It was conducted at 17 US sites from October 2020 to December 2021. Interventions: Participants were randomized (1:1:1) to cytisinicline, 3 mg, 3 times daily for 12 weeks (n = 270); cytisinicline, 3 mg, 3 times daily for 6 weeks then placebo 3 times daily for 6 weeks (n = 269); or placebo 3 times daily for 12 weeks (n = 271). All participants received behavioral support. Main Outcomes and Measures: Biochemically verified continuous smoking abstinence for the last 4 weeks of cytisinicline treatment vs placebo (primary) and from end of treatment to 24 weeks (secondary). Results: Of 810 randomized participants (mean age, 52.5 years; 54.6% female; mean of 19.4 cigarettes smoked daily), 618 (76.3%) completed the trial. For the 6-week course of cytisinicline vs placebo, continuous abstinence rates were 25.3% vs 4.4% during weeks 3 to 6 (odds ratio [OR], 8.0 [95% CI, 3.9-16.3]; P < .001) and 8.9% vs 2.6% during weeks 3 to 24 (OR, 3.7 [95% CI, 1.5-10.2]; P = .002). For the 12-week course of cytisinicline vs placebo, continuous abstinence rates were 32.6% vs 7.0% for weeks 9 to 12 (OR, 6.3 [95% CI, 3.7-11.6]; P < .001) and 21.1% vs 4.8% during weeks 9 to 24 (OR, 5.3 [95% CI, 2.8-11.1]; P < .001). Nausea, abnormal dreams, and insomnia occurred in less than 10% of each group. Sixteen participants (2.9%) discontinued cytisinicline due to an adverse event. No drug-related serious adverse events occurred. Conclusions and Relevance: Both 6- and 12-week cytisinicline schedules, with behavioral support, demonstrated smoking cessation efficacy and excellent tolerability, offering new nicotine dependence treatment options. Trial Registration: ClinicalTrials.gov Identifier: NCT04576949.
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Fumar Cigarros , Alcaloides Quinolizidínicos , Agentes de Cessação do Hábito de Fumar , Abandono do Hábito de Fumar , Tabagismo , Humanos , Pessoa de Meia-Idade , Alcaloides , Azocinas , Duração da Terapia , Quinolizinas , Abandono do Hábito de Fumar/métodos , Tabagismo/tratamento farmacológico , Agentes de Cessação do Hábito de Fumar/administração & dosagem , Agentes de Cessação do Hábito de Fumar/efeitos adversos , Agentes de Cessação do Hábito de Fumar/uso terapêutico , Método Duplo-Cego , Resultado do Tratamento , Masculino , Feminino , Alcaloides Quinolizidínicos/administração & dosagem , Alcaloides Quinolizidínicos/efeitos adversos , Alcaloides Quinolizidínicos/farmacocinética , Alcaloides Quinolizidínicos/uso terapêutico , Nicotina/antagonistas & inibidores , Receptores Nicotínicos/efeitos dos fármacos , Fumar Cigarros/tratamento farmacológicoRESUMO
Invasive lobular carcinoma (ILC) is the second most common subclass of breast cancer and adds to the breast malignancy burden in women. Studies focused on metastatic patterns of ILC have reported bone, gynecologic organs, the peritoneum, and the gastrointestinal tract as potential sites of metastasis. Metastatic spread to the stomach has been reported, but generally remains an infrequent finding. Due to vague symptomatology and the visual limitations of endoscopic examination, metastatic lesions can often mimic a primary gastric malignancy. Metastasis in the stomach can be challenging to diagnose and requires a multimodal, thorough endoscopic and immunohistochemical evaluation. It is important to distinguish the primary origin of malignant lesions as treatment can range from systemic chemotherapy to surgical resection based on the diagnosis. We present a case of an underlying ILC metastatic lesion mimicking a primary gastric adenocarcinoma.
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Gastrointestinal stromal tumors (GISTs) are one of the most common, potentially malignant, subepithelial lesions identified in the gastrointestinal tract. Hypothesized to derive from the interstitial cells of Cajal (ICC), GISTs commonly demonstrate gain of function mutations in proto-oncogenic receptor tyrosine kinase CD117 (KIT). Depending on mitotic activity and tumor size characteristics, GISTs may transform from benign to malignant neoplasms. Increasing evidence suggests that early identification of a GIST is paramount for optimal prognostic outcomes. We present a rare case of a GIST located in the uncinate pancreas identified via endoscopic ultrasound (EUS) and diagnosed with an EUS-guided fine needle aspiration (EUS-FNA) biopsy.
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Rectal tonsils are an abnormal reactive proliferation of lymphoid tissue in the rectum. Typical lymphoid tissue of the colon and rectum can proliferate with an increased number of germinal centers in response to exposure to an antigen in the GI tract. This response, in rare cases, escalates to the proliferation of a lymphoid mass known as a rectal tonsil. Here, we present a case of a 46-year-old woman with iron deficiency anemia who underwent colonoscopy with incidental finding of a rectal tonsil. This report discusses initial clinical workup, colonoscopy findings, pathological analysis, subsequent testing, and surgical removal of the identified mass and this rare finding.
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Several types of contraception methods exist, and among these are hormonal and non-hormonal intrauterine devices (IUDs). Cases have been reported of fractured IUD pieces and retention of copper fragments upon attempted removal in office. These findings suggest the importance of careful removal of an IUD by providers. A 38-year-old Caucasian woman, gravida 2, para 2, presented for a colposcopy and endometrial biopsy (EMB). She had had a copper IUD (ParaGard) placed 10 years prior. She now requested to have it removed. After completion of the colposcopy and EMB, the provider located the IUD strings for removal. During careful removal of the IUD, a piece was broken off and remained in the uterine cavity. Upon visual inspection of the removed IUD, the right wing was missing and presumed to be still in the patient. Transabdominal and transvaginal ultrasound (TVUS) confirmed presence of a portion of the IUD in the uterine wall near the cervix. The patient was scheduled for surgical removal of the IUD by robot-assisted total laparoscopic hysterectomy with bilateral salpingectomy. This case highlights the importance of thorough evaluation of an IUD upon removal. Practitioners who work with IUD insertion and removal should remain informed about this rare complication. Risk of fracture during IUD removal should be better communicated between physicians and patients. This case study underlines the importance of careful IUD planning, from insertion to removal. Further research considering improved stepwise removal should be considered.
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BACKGROUND: Glutathione S-transferase 1 (GSTP1) expression is inactivated in >90% of all prostate cancers in association with aberrant DNA methylation. Detection of serum free methylated GSTP1 (mGSTP1) DNA is associated with overall survival (OS) and response to docetaxel in metastatic castration-resistant prostate cancer (mCRPC) in test and internal validation cohorts. OBJECTIVE: To assess the relationship between serum free mGSTP1 and treatment outcomes in SYNERGY, a phase 3 multicentre randomised trial testing the addition of custirsen to first-line chemotherapy with docetaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Serum free mGSTP1 DNA was measured by a sensitive methylation-specific polymerase chain reaction assay in paired samples (baseline and after two cycles of docetaxel) from 600 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between serum free mGSTP1 at baseline, change in mGSTP1 after docetaxel, OS, and time to prostate-specific antigen (PSA) progression were examined using Cox proportional hazards models and Kaplan-Meier methods. RESULTS AND LIMITATIONS: Serum free mGSTP1 was detectable at baseline in 458 (81%) patients. Of those with detectable mGSTP1 at baseline, mGSTP1 became undetectable after two cycles in 243 (53%). Undetectable mGSTP1 at baseline was associated with longer OS (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.29-0.55; p<0.00001). The event of mGSTP1 becoming undetectable after two cycles of chemotherapy was associated with longer OS (HR 0.36, 95% CI 0.29-0.46; p<0.00001) and longer time to PSA progression (HR 0.44, 95% CI 0.35-0.56; p<0.00001). Associations between mGSTP1 and clinical outcomes were independent of other established prognostic variables. Analysis was limited by the lack of radiographic progression-free survival data. CONCLUSIONS: This is the first study to externally validate the prognostic role of a circulating epigenetic biomarker in mCRPC. Further studies are needed to validate serum free mGSTP1 as a surrogate endpoint for clinical trials and as a potential clinical decision tool. PATIENT SUMMARY: In this study, we confirmed that a blood marker predicted outcomes after chemotherapy for metastatic prostate cancer. This marker may accelerate future clinical trials of new therapies and be useful in the clinic to guide treatment decisions.
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Antineoplásicos/uso terapêutico , DNA/sangue , Docetaxel/uso terapêutico , Glutationa Transferase/genética , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Metilação de DNA , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do TratamentoRESUMO
Whereas feeding inhibition caused by exposure to contaminants has been extensively documented, the underlying mechanism(s) are less well understood. For this study, the behavior of several key feeding processes, including ingestion rate and assimilation efficiency, that affect the dietary uptake of Cu were evaluated in the benthic grazer Lymnaea stagnalis following 4-5 h exposures to Cu adsorbed to synthetic hydrous ferric oxide (Cu-HFO). The particles were mixed with a cultured alga to create algal mats with Cu exposures spanning nearly 3 orders of magnitude at variable or constant Fe concentrations, thereby allowing first order and interactive effects of Cu and Fe to be evaluated. Results showed that Cu influx rates and ingestion rates decreased as Cu exposures of the algal mat mixture exceeded 10(4) nmol/g. Ingestion rate appeared to exert primary control on the Cu influx rate. Lysosomal destabilization rates increased directly with Cu influx rates. At the highest Cu exposure where the incidence of lysosomal membrane damage was greatest (51%), the ingestion rate was suppressed 80%. The findings suggested that feeding inhibition was a stress response emanating from excessive uptake of dietary Cu and cellular toxicity.
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Cobre/toxicidade , Compostos Férricos/toxicidade , Lymnaea/efeitos dos fármacos , Adsorção , Animais , Dieta , Comportamento Alimentar/efeitos dos fármacos , Lisossomos/efeitos dos fármacosRESUMO
Tuberculosis (TB) remains uncontrolled in many parts of the world and the development of an effective vaccine against TB represents a high priority unmet medical need. Healthy PPD (tuberculin purified protein derivative)-negative adult volunteers, aged 18-40 years received three doses of the candidate Mtb72F/AS02A vaccine according to a 0-1-2 months schedule in an open-label Phase I study (NCT00730795). Solicited, unsolicited and serious adverse events (AEs), hematological and biochemical laboratory parameters were assessed. Mtb72F-specific humoral responses were assessed by ELISA and cell-mediated immune (CMI) responses by intracellular cytokine staining (ICS) and short-term ELISPOT assays. CMI responses to the component peptides (Mtb39a and the Mtb32a C- and N-terminal antigen domains, Mtb32C and Mtb32N) were also assessed by ICS. The Mtb72F/AS02A vaccine appeared to be mainly locally reactogenic but this was considered acceptable, since these AEs were usually transient and resolved within 1-2 days. Most AEs reported were mild in intensity, no serious AEs occurred, no medically significant biochemical or hematological abnormalities related to vaccination were measured and all AEs resolved without sequelae. The vaccine induced statistically significant changes in humoral and CMI response measures. The Mtb72F antigen induced good production of IL-2 and IFNgamma in the ELISPOT assay and CD4(+) T cells expressing at least two activation markers (mainly CD40-L and IL-2) were observed with ICS. A similar CMI profile was observed with Mtb39a and Mtb32N. The induced CMI responses persisted for at least 6 months post-vaccination. All subjects were seropositive for anti-Mtb72F antibodies one month post-dose 2 and 6 months post-dose 3. This first trial in humans found Mtb72F/AS02A to have an acceptable tolerability, to be immunogenic in healthy adults and warrants further development of the vaccine.
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Vacinas contra a Tuberculose/efeitos adversos , Vacinas contra a Tuberculose/imunologia , Adulto , Anticorpos Antibacterianos/sangue , Linfócitos T CD4-Positivos/química , Linfócitos T CD4-Positivos/imunologia , Antígenos CD40/análise , Citocinas/biossíntese , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Experimentação Humana , Humanos , Imunização Secundária/métodos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Dermatopatias/induzido quimicamente , Vacinas contra a Tuberculose/administração & dosagem , Adulto JovemRESUMO
We used a phylogenetically based comparative approach to evaluate the potential for physiological studies to reveal patterns of diversity in traits related to susceptibility to an environmental stressor, the trace metal cadmium (Cd). Physiological traits related to Cd bioaccumulation, compartmentalization, and ultimately susceptibility were measured in 21 aquatic insect species representing the orders Ephemeroptera, Plecoptera, and Trichoptera. We mapped these experimentally derived physiological traits onto a phylogeny and quantified the tendency for related species to be similar (phylogenetic signal). All traits related to Cd bioaccumulation and susceptibility exhibited statistically significant phylogenetic signal, although the signal strength varied among traits. Conventional and phylogenetically based regression models were compared, revealing great variability within orders but consistent, strong differences among insect families. Uptake and elimination rate constants were positively correlated among species, but only when effects of body size and phylogeny were incorporated in the analysis. Together, uptake and elimination rates predicted dramatic Cd bioaccumulation differences among species that agreed with field-based measurements. We discovered a potential tradeoff between the ability to eliminate Cd and the ability to detoxify it across species, particularly mayflies. The best-fit regression models were driven by phylogenetic parameters (especially differences among families) rather than functional traits, suggesting that it may eventually be possible to predict a taxon's physiological performance based on its phylogenetic position, provided adequate physiological information is available for close relatives. There appears to be great potential for evolutionary physiological approaches to augment our understanding of insect responses to environmental stressors in nature.
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Cádmio/metabolismo , Ecologia , Insetos/classificação , Insetos/fisiologia , Rios , Poluentes Químicos da Água/metabolismo , Absorção , Animais , Cádmio/toxicidade , Variação Genética , Insetos/genética , Filogenia , Poluentes Químicos da Água/toxicidadeRESUMO
It has become increasingly apparent that diet can be a major source of trace metal bioaccumulation in aquatic organisms. In this study, we examined cadmium uptake, efflux, and subcellular compartmentalization dynamics in the freshwater oligochaete Lumbriculus variegatus. L. variegatus is an important component of freshwater food webs in Europe and North America and is potentially useful as a standard food source for laboratory-based trophic transfer studies. Cadmium accumulation and depuration were each followed for 10 days. Rate constants of uptake (k(u)) and efflux (k(e)) were estimated and subcellular Cd compartmentalization was followed over the course of uptake and efflux. The partitioning of Cd into operationally-defined subcellular compartments was relatively consistent throughout the 20-day experiment, with the majority of Cd accumulating in the cytosol. No major changes in Cd compartmentalization were observed over uptake or depuration, but there appeared to be some exchange between heat-stable and heat-labile cytosolic protein fractions. Cadmium accumulation from solution was strongly affected by ambient calcium concentrations, suggesting competition between Cd and Ca for uptake sites. Finally, we demonstrate the ability to manipulate the whole body calcium content of L. variegatus as a potential tool for examining calcium influences on dietary Cd dynamics. The potential for this species to be an important conduit of Cd to higher trophic levels is discussed, along with its potential as a standardized food source in metal trophic transfer studies.
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Cádmio/metabolismo , Cadeia Alimentar , Oligoquetos/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Cádmio/análise , Cálcio/análise , Carbonato de Cálcio/química , Água Doce/química , Oligoquetos/química , Oligoquetos/efeitos dos fármacos , Fatores de Tempo , Distribuição Tecidual , Poluentes Químicos da Água/análiseRESUMO
A major challenge in ecotoxicology lies in generating data under experimental conditions that are relevant to understanding contaminant effects in nature. Biodynamic modeling combines species-specific physiological traits to make predictions of metal bioaccumulation that fare well when tested in the field. We generated biodynamic models for seven predatory stonefly (Plecoptera) species representing the families Perlidae (5) and Perlodidae (2). Each taxon was exposed to cadmium independently via diet and via solution. Species varied approximately 2.6 fold in predicted steady-state cadmium concentrations. Diet was the predominant source of accumulated cadmium in five of the seven species and averaged 53.2 +/- 9.6% and 90.2 +/- 3.7% of net Cd accumulation in perlids and perlodids, respectively. Differences in Cd bioaccumulation between the two families were largely driven by differences in dissolved accumulation rates, which were considerably slower in perlodidsthan in perlids. We further examined the subcellular compartmentalization of Cd accumulated from independent aqueous and dietary exposures. Predicted steady-state concentrations were modified to only consider Cd accumulated in metal-sensitive subcellular compartments. These values ranged 5.3 fold. We discuss this variability within a phylogenetic context and its implications for bioassessment.
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Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Insetos/efeitos dos fármacos , Animais , Cádmio/farmacocinética , Poluentes Ambientais/farmacocinética , Insetos/fisiologia , Modelos Biológicos , Especificidade da Espécie , Frações Subcelulares/metabolismoRESUMO
The influence of metal exposure history on rates of aqueous Cd accumulation, elimination, and subcellular distribution was examined in the aquatic insect Hydropsyche californica. Specimens were obtained from a reference site and a metal-contaminated site and returned to the laboratory where they were continuously exposed to aqueous Cd (518 ng/L, nominal) for 6 d, followed by 9 d of depuration. Rates of Cd accumulation and elimination were similar in insects from the two sites. Efflux rate constants, k((e), ranged from 0.20 to 0.24/d (t 1/2 approximately 3 d). Immediately following exposure, the cytosol accounted for 40% of the body burden in insects from both sites; however, 89 +/- 2% of the cytosolic Cd was associated with metallothionein-like proteins (MTLP) in insects from the contaminated site, compared to 60 +/- 0% in insects from the reference site. The concentration of Cd bound to non-MTLPs (representing potentially Cd-sensitive proteins) was significantly greater in the insects from the reference site (134 +/- 7 ng/g) than in those from the contaminated site (42 +/- 2 ng/g). At the end of the depuration period, 90% of the accumulated Cd body burden had been eliminated, and Cd concentrations in MTLPs and non-MTLPs were similar between the sites. Results suggested that differences in exposure history had no influence on the bioaccumulation of Cd, but did affect the concentrations of Cd bound to MTLP during Cd exposure in these insects.