Men, trans/masculine, and non-binary people negotiating conception: Normative resistance and inventive pragmatism.

BACKGROUND: Growing numbers of men, trans/masculine, and non-binary people are undertaking pregnancies, yet relatively little is known about the experiences of this diverse population in regard to conception. AIMS: This study sought to examine men's, trans/masculine, and non-binary people's experiences of pregnancy, including conception. METHODS: Interviews were conducted with 51 men, trans/masculine, and non-binary people who were gestational parents living in Australia, Canada, the European Union (including the United Kingdom), and the United States. Thematic analysis was undertaken, focusing on accounts of conception. Pfeffer's conceptual frameworks of normative resistance and inventive pragmatism were used as an analytic tool. RESULTS: Themes developed focused on: 1) choosing a clinic donor, 2) kinship with donors, 3) conceiving via intercourse with a partner, 4) negotiating receipt of donor sperm, 5) challenges associated with known donors, 6) challenges associated with fertility clinics, and 7) experiences of conception. DISCUSSION: The forms of normative resistance and inventive pragmatism identified suggest that men, trans/masculine, and non-binary people who are gestational parents seek to normalize their experiences of conception, while also acknowledging the specific challenges they face.

Altered collagen chemical compositional structure in osteopenic women with past fractures: A case-control Raman spectroscopic study.

Incidences of low-trauma fractures among osteopenic women may be related to changes in bone quality. In this blinded, prospective-controlled study, compositional and heterogeneity contributors of bone quality to fracture risk were examined. We hypothesize that Raman spectroscopy can differentiate between osteopenic women with one or more fractures (cases) from women without fractures (controls). This study involved the Raman spectroscopic analysis of cortical and cancellous bone composition using iliac crest biopsies obtained from 59-cases and 59-controls, matched for age (62.0 ± 7.5 and 61.7 ± 7.3 years, respectively, p = 0.38) and hip bone mineral density (BMD, 0.827 ± 0.083 and 0.823 ± 0.072 g/cm3, respectively, p = 0.57). Based on aggregate univariate case-control and odds ratio based logistic regression analyses, we discovered two Raman ratiometric parameters that were predictive of past fracture risk. Specifically, 1244/1268 and 1044/959 cm-1 ratios, were identified as the most differential aspects of bone quality in cortical cases with odds ratios of 0.617 (0.406-0.938 95% CI, p = 0.024) and 1.656 (1.083-2.534 95% CI, p = 0.020), respectively. Both 1244/1268 and 1044/959 cm-1 ratios exhibited moderate sensitivity (59.3-64.4%) but low specificity (49.2-52.5%). These results suggest that the organization of mineralized collagen fibrils were significantly altered in cortical cases compared to controls. In contrast, compositional and heterogeneity parameters related to mineral/matrix ratios, B-type carbonate substitutions, and mineral crystallinity, were not significantly different between cases and controls. In conclusion, a key outcome of this study is the significant odds ratios obtained for two Raman parameters (1244/1268 and 1044/959 cm-1 ratios), which from a diagnostic perspective, may assist in the screening of osteopenic women with suspected low-trauma fractures. One important implication of these findings includes considering the possibility that changes in the organization of collagen compositional structure plays a far greater role in postmenopausal women with osteopenic fractures.

Exploration of Principal Component Analysis: Deriving Principal Component Analysis Visually Using Spectra.

Spectroscopy rapidly captures a large amount of data that is not directly interpretable. Principal component analysis is widely used to simplify complex spectral datasets into comprehensible information by identifying recurring patterns in the data with minimal loss of information. The linear algebra underpinning principal component analysis is not well understood by many applied analytical scientists and spectroscopists who use principal component analysis. The meaning of features identified through principal component analysis is often unclear. This manuscript traces the journey of the spectra themselves through the operations behind principal component analysis, with each step illustrated by simulated spectra. Principal component analysis relies solely on the information within the spectra, consequently the mathematical model is dependent on the nature of the data itself. The direct links between model and spectra allow concrete spectroscopic explanation of principal component analysis , such as the scores representing "concentration" or "weights". The principal components (loadings) are by definition hidden, repeated and uncorrelated spectral shapes that linearly combine to generate the observed spectra. They can be visualized as subtraction spectra between extreme differences within the dataset. Each PC is shown to be a successive refinement of the estimated spectra, improving the fit between PC reconstructed data and the original data. Understanding the data-led development of a principal component analysis model shows how to interpret application specific chemical meaning of the principal component analysis loadings and how to analyze scores. A critical benefit of principal component analysis is its simplicity and the succinctness of its description of a dataset, making it powerful and flexible.

Men, trans/masculine, and non-binary people's experiences of pregnancy loss: an international qualitative study.

BACKGROUND: Growing numbers of men, trans/masculine, and non-binary people are becoming gestational parents, yet very little is known about experiences of pregnancy loss among this diverse population. METHODS: The study employed a cross sectional design. Interviews were undertaken with a convenience sample of 51 trans/masculine and non-binary people who had undertaken at least one pregnancy, living in either Australia, the United States, Canada, or the European Union (including the United Kingdom). Participants were recruited by posts on Facebook and Twitter, via researcher networks, and by community members. 16 (31.2%) of the participants had experienced a pregnancy loss and are the focus of this paper. Thematic analysis was used to analyse interview responses given by these 16 participants to a specific question asking about becoming pregnant and a follow up probe question about pregnancy loss. RESULTS: Thematic analysis of interview responses given by the 16 participants led to the development of 10 themes: (1) pregnancy losses count as children, (2) minimizing pregnancy loss, (3) accounting for causes of pregnancy loss, (4) pregnancy loss as devastating, (5) pregnancy loss as having positive meaning, (6) fears arising from a pregnancy loss, (7) experiences of hospitals enacting inclusion, (8) lack of formal support offered, (9) lack of understanding from family, and (10) importance of friends. CONCLUSIONS: The paper concludes by outlining specific recommendations for clinical practice. These include the importance of focusing on the emotions attached to pregnancy loss, the need for targeted support services for men, trans/masculine, and non-binary people who undertake a pregnancy (including for their partners), and the need for ongoing training for hospital staff so as to ensure the provision of trans-affirming medical care.

Transnormativity in the psy disciplines: Constructing pathology in the Diagnostic and Statistical Manual of Mental Disorders and Standards of Care.

The psy disciplines (i.e., psychiatry, psychology, psychoanalysis, and psychotherapy) have played a significant role in shaping understandings of transgender people's lives in ways that are transnormative (i.e., by emphasizing one particular account of what it means to be transgender). This article documents (a) how the rise of the psy disciplines created opportunities for transgender people to access treatment (but that such access often required tacit acceptance of transnormativity), and (b) how transgender people have resisted transnormative accounts within the psy disciplines. More specifically, this article explores how both the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, and what is now the World Professional Association for Transgender Health's Standards of Care, have often enshrined highly regulatory accounts of transgender people's lives, while also changing over time, in part as a result of the contributions of transgender people. The article concludes by considering recent contributions by transgender people in terms of the use of informed consent models of care and clinical research, and highlights the ongoing marginalization of transgender people in terms of access to ethical, transcompetent care. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Inflammation, Active Fibroplasia, and End-stage Fibrosis in 172 Biliary Atresia Remnants Correlate Poorly With Age at Kasai Portoenterostomy, Visceral Heterotaxy, and Outcome.

Published histologic studies of the hilar plate or entire biliary remnant at the time of Kasai portoenterostomy (KHPE) have not provided deep insight into the pathogenesis of biliary atresia, relation to age at surgery, prognosis or the basis for successful drainage. We report detailed histologic findings in 172 centrally reviewed biliary remnants with an average of 6 sections per subject. Active lesions were classified as either necroinflammatory (rare/clustered in a few subjects) or active concentric fibroplasia with or without inflammation (common). Inactive lesions showed bland replacement by collagen and fibrous cords with little or no inflammation. Heterogeneity was common within a given remnant; however, relatively homogenous histologic patterns, defined as 3 or more inactive or active levels in the hepatic ducts levels, characterized most remnants. Homogeneity did not correlate with age at KHPE, presence/absence of congenital anomalies at laparotomy indicative of heterotaxy and outcome. Remnants from youngest subjects were more likely than older subjects to be homogenously inactive suggesting significantly earlier onset in the youngest subset. Conversely remnants from the oldest subjects were often homogenously active suggesting later onset or slower progression. More data are needed in remnants from subjects <30 days old at KHPE and in those with visceral anomalies. Prevalence of partially preserved epithelium in active fibroplastic biliary atresia lesions at all ages suggests that epithelial regression or injury may not be a primary event or that reepithelialization is already underway at the time of KHPE. We hypothesize that outcome after KHPE results from competition between active fibroplasia and reepithelialization of retained, collapsed but not obliterated lumens. The driver of active fibroplasia is unknown.

Design and microfabrication of a miniature fiber optic probe with integrated lenses and mirrors for Raman and fluorescence measurements.

Fiber optics coupled to components such as lenses and mirrors have seen extensive use as probes for Raman and fluorescence measurements. Probes can be placed directly on or into a sample to allow for simplified and remote application of these optical techniques. The size and complexity of such probes however limits their application. We have used microfabrication in polydimethylsiloxane (PDMS) to create compact probes that are 0.5 mm thick by 1 mm wide. The miniature probes incorporate pre-aligned mirrors, lenses, and two fiber optic guides to allow separate input and output optical paths suitable for Raman and fluorescence spectroscopy measurements. The fabricated probe has 70 % unidirectional optical throughput and generates no spectral artifacts in the wavelength range of 200 to 800 nm. The probe is demonstrated for measurement of fluorescence within microfluidic devices and collection of Raman spectra from a pharmaceutical tablet. The fluorescence limit of detection was 6 nM when using the probe to measure resorufin inside a 150-µm inner diameter glass capillary, 100 nM for resorufin in a 60-µm-deep × 100-µm-wide PDMS channel, and 11 nM for fluorescein in a 25-µm-deep × 80-µm-wide glass channel. It is demonstrated that the same probe can be used on different sample types, e.g., microfluidic chips and tablets. Compared to existing Raman and fluorescence probes, the microfabricated probes enable measurement in smaller spaces and have lower fabrication cost. Graphical abstract A microfabricated spectroscopic probe with integrated optics was developed for chemical detection in small spaces and in remote applications.

Congenital Acute Myeloid Leukemia with Unique Translocation t(11;19)(q23;p13.3).

Congenital leukemia is rarely encountered in clinical practice, even in tertiary children's hospitals. Leukemia may cause significant coagulopathy, putting the patient at risk of intracranial hemorrhage. In this case, the authors present a female infant with a unique mixed phenotypic congenital acute myeloid leukemia showing mixed-lineage leukemia (MLL) rearrangement and severe coagulopathy resulting in a large subdural hematoma. Despite the fatal outcome in this case, neurosurgical treatment of patients with acute myeloid leukemia should be considered if coagulopathy and the clinical scenario allow.

Next-generation Raman tomography instrument for non-invasive in vivo bone imaging.

Combining diffuse optical tomography methods with Raman spectroscopy of tissue provides the ability for in vivo measurements of chemical and molecular characteristics, which have the potential for being useful in diagnostic imaging. In this study a system for Raman tomography was developed and tested. A third generation microCT coupled system was developed to combine 10 detection fibers and 5 excitation fibers with laser line filtering and a Cytop reference signal. Phantom measurements of hydroxyapatite concentrations from 50 to 300 mg/ml had a linear response. Fiber placement and experiment design was optimized using cadaver animals with live animal measurements acquired to validate the systems capabilities. Promising results from the initial animal experiments presented here, pave the way for a study of longitudinal measurements during fracture healing and the scaling of the Raman tomography system towards human measurements.

Tissue phantoms to compare spatial and temporal offset modes of deep Raman spectroscopy.

Time-resolved and spatially offset Raman spectroscopies have previously been demonstrated for depth analysis through strongly scattering, non-transparent materials. In this study, several series of tissue phantoms were created with varied compositions and thicknesses to compare the potential of these different Raman techniques for biomedical applications. Polydimethylsiloxane (PDMS) phantoms were made with TiO2 particles suspended as a scattering agent, mimicking the scattering properties of biological tissues. The phantom layers contained embedded biomineral simulating inclusions (sphere or layer-shaped) with varied carbonate to phosphate ratios. The tissue phantoms were studied using Time Resolved Raman Spectroscopy (TRRS), Spatially Offset Raman Spectroscopy (SORS), and their combination, using a single instrumental setup with picosecond pulsed excitation at 720 nm and two different detectors. A comparison is made of the efficiency of these techniques to resolve chemical information from these heterogeneous scattering phantom samples. Measurements with continuous wave detection were found to offer a better signal-to-noise ratio than with TRRS, and in SORS measurements ratios of target to matrix signal were found to vary depending on the structural geometry and optical properties of the phantoms. Anomalous SORS behaviour, in which the relative contribution from the target decreases with offset, was observed in cases where the target was highly scattering and the top layer was relatively transparent. Time gating with an intensified charge-coupled device (ICCD) detector can yield more direct information on the depth of the hidden material.

Characterization of biofluids prepared by sessile drop formation.

Sessile drop formation, also called drop deposition, has been studied as a potential medical diagnostic, but the effects of complex biofluid rheology on the final deposition pattern are not well understood. We studied two model biofluids, blood plasma and synovial fluid, when deposited onto slightly hydrophilic substrates forming a contact angle of 50-90°. Drops were imaged during the evaporation process and geometric properties of the drop, such as contact angle and drop height, were calculated from the images. The resulting dried biofluid drops were then examined using light microscopy and Raman spectroscopy to assess morphological and chemical composition of the dried drop. The effect of substrate contact angle (surface wetting) and fluid concentration was examined. We found that when biofluids are deposited onto slightly hydrophilic surfaces, with a contact angle of 50-90°, a ring-shaped deposit was formed. Analysis of the drying drop's geometric properties indicates that biofluid dynamics follow the piling model of drop formation, as proposed by Deegan et al. The final deposition pattern varied with substrate surface and concentration, as shown by light microscopy photos of dried drops. The chemical composition of the outer ring was minimally affected by substrate surface, but the spatial heterogeneity of protein distribution within the ring varied with concentration. These results indicate that biofluid drop deposition produces ring-shaped deposits which can be examined by multiple analytical techniques.

Liver cirrhosis in Fontan patients does not affect 1-year post-heart transplant mortality or markers of liver function.

BACKGROUND: Liver cirrhosis is recognized with long-term follow-up of patients after the Fontan procedure. The effect of liver cirrhosis on the use of heart transplant (HT) and on post-HT outcomes is unknown. METHODS: We reviewed Fontan patients evaluated for HT from 2004 to 2012 with hepatic computed tomography (CT) imaging, classified as normal, non-cirrhotic changes, or cirrhosis. The primary outcome was 1-year all-cause mortality, and the secondary outcome was differences in serial post-HT liver evaluation. RESULTS: CT imaging in 32 Fontan patients evaluated for HT revealed 20 (63%) with evidence of liver disease, including 13 (41%) with cirrhosis. Twenty underwent HT, including 5 non-cirrhotic and 7 cirrhosis patients. Characteristics at listing between normal or non-cirrhotic (n = 13) and cirrhosis (n = 7) groups were similar, except cirrhosis patients were older (median 17.6 vs 9.6 years, p = 0.002) and further from Fontan (median 180 vs 50 months, p < 0.05). Serial liver evaluation was similar, including aspartate aminotransferase, alanine aminotransferase, bilirubin, albumin, and tacrolimus dose at 1, 3, 6, 9, and 12 months. Overall patient survival was 80% at 1 year, with no difference between cirrhosis and non-cirrhosis patients (86% vs 77%, p = 0.681). Liver biopsies were performed in 7 patients before HT, and all specimens showed architectural changes with bridging fibrosis. CONCLUSIONS: Most patients evaluated for HT had abnormal liver findings by CT, with cirrhosis in 41%. One-year mortality and serial liver evaluation were similar between groups after HT. Liver cirrhosis identified by CT imaging may not be an absolute contraindication to HT alone in this population.

Alterations to bone mineral composition as an early indication of osteomyelitis in the diabetic foot.

OBJECTIVE: Osteomyelitis in the diabetic foot is a major risk factor for amputation, but there is a limited understanding of early-stage infection, impeding limb-preserving diagnoses. We hypothesized that bone composition measurements provide insight into the early pathophysiology of diabetic osteomyelitis. RESEARCH DESIGN AND METHODS: Compositional analysis by Raman spectroscopy was performed on bone specimens from patients with a clinical diagnosis of osteomyelitis in the foot requiring surgical intervention as either a biopsy (n = 6) or an amputation (n = 11). RESULTS: An unexpected result was the discovery of pathological calcium phosphate minerals in addition to normal bone mineral. Dicalcium phosphate dihydrate, also called brushite, and uncarbonated apatite were found to be exclusively associated with infected bone. CONCLUSIONS: Compositional measurements provided a unique insight into the pathophysiology of osteomyelitis in diabetic foot ulcers. At-patient identification of pathological minerals by Raman spectroscopy may serve as an early-stage diagnostic approach.

Effects of pathology dyes on Raman bone spectra.

We report an overlooked source of artifacts for clinical specimens, where unexpected and normally negligible contaminants can skew the interpretation of results. During an ongoing study of bone fragments from diabetic osteomyelitis, strong Raman signatures were found, which did not correspond with normal bone mineral or matrix. In a bone biopsy from the calcaneus of a patient affected by diabetic osteomyelitis, Raman microspectroscopic analysis revealed regions with both abnormal mineral and degraded collagen in addition to normal bone. Additional bands indicated a pathological material. Stenotrophomonas maltophilia was identified in the wound culture by independent microbiologic examination. We initially assigned the unusual bands to xanthomonadin, a bacterial pigment from S. maltophilia. However, the same bands were also found more than a year later on a second specimen that had been noticeably contaminated with pathology marking dye. Drop deposition/Raman spectroscopy of commonly used pathology dyes revealed that a blue tissue-marking dye was responsible for the unusual bands in both specimens, even in the first specimen where there was no visible evidence of contamination.

Biomedical tissue phantoms with controlled geometric and optical properties for Raman spectroscopy and tomography.

To support the translation of Raman spectroscopy into clinical applications, synthetic models are needed to accurately test, optimize and validate prototype fiber optic instrumentation. Synthetic models (also called tissue phantoms) are widely used for developing and testing optical instrumentation for diffuse reflectance, fluorescence, and Raman spectroscopies. While existing tissue phantoms accurately model tissue optical scattering and absorption, they do not typically model the anatomic shapes and chemical composition of tissue. Because Raman spectroscopy is sensitive to molecular composition, Raman tissue phantoms should also approximate the bulk tissue composition. We describe the fabrication and characterization of tissue phantoms for Raman tomography and spectroscopy. These phantoms have controlled chemical and optical properties, and also multilayer morphologies which approximate the appropriate anatomic shapes. Tissue phantoms were fabricated to support on-going Raman studies by simulating the human wrist and rat leg. Surface meshes (triangle patch models) were generated from computed tomography (CT) images of a human arm and rat leg. Rapid prototyping was used to print mold templates with complex geometric patterns. Plastic casting techniques used for movie special effects were adapted to fabricate molds from the rapid prototypes, and finally to cast multilayer gelatin tissue phantoms. The gelatin base was enriched with additives to model the approximate chemistry and optical properties of individual tissue layers. Additional studies were performed to determine optimal casting conditions, phantom stability, layer delamination and chemical diffusion between layers. Recovery of diffuse reflectance and Raman spectra in tissue phantoms varied with probe placement. These phantoms enable optimization of probe placement for human or rat studies. These multilayer tissue phantoms with complex geometries are shown to be stable, with minimal layer delamination and chemical diffusion.

Intestinal adaptation after small bowel resection in human infants.

PURPOSE: In animal models, the small intestine responds to massive small bowel resection (SBR) through a compensatory process termed adaptation, characterized by increases in both villus height and crypt depth. This study seeks to determine whether similar morphologic alterations occur in humans after SBR. METHODS: Clinical data and pathologic specimens of infants who had both an SBR for necrotizing enterocolitis and an ostomy takedown from 1999 to 2009 were reviewed. Small intestine mucosal morphology was compared in the same patients at the time of SBR and at the time of ostomy takedown. RESULTS: For all samples, there was greater villus height (453.6 ± 20.4 vs 341.2 ± 12.4 µm, P < .0001) and crypt depth (178.6 ± 7.2 vs 152.6 ± 6 µm, P < .01) in the ostomy specimens compared with the SBR specimens. In infants with paired specimens, there was an increase of 31.7% ± 8.3% and 22.1% ± 10.0% in villus height and crypt depth, respectively. There was a significant correlation between the amount of intestine resected and the percent change in villus height (r = 0.36, P < .05). CONCLUSION: Mucosal adaptation after SBR in human infants is similar to what is observed in animal models. These findings validate the use of animal models of SBR used to understand the molecular mechanisms of this important response.

Fiber-optic Raman spectroscopy of joint tissues.

In this study, we report adaptation of Raman spectroscopy for arthroscopy of joint tissues using a custom-built fiber-optic probe. Differentiation of healthy and damaged tissue or examination of subsurface tissue, such as subchondral bone, is a challenge in arthroscopy because visual inspection may not provide sufficient contrast. Discrimination of healthy versus damaged tissue may be improved by incorporating point spectroscopy or hyperspectral imaging into arthroscopy where the contrast is based on the molecular structure or chemical composition. Articular joint surfaces of knee cadaveric human tissue and tissue phantoms were examined using a custom-designed Raman fiber-optic probe. Fiber-optic Raman spectra were compared against reference spectra of cartilage, subchondral bone and cancellous bone collected using Raman microspectroscopy. In fiber-optic Raman spectra of the articular surface, there was an effect of cartilage thickness on recovery of signal from subchondral bone. At sites with intact cartilage, the bone mineralization ratio decreased but there was a minimal effect in the bone mineral chemistry ratios. Tissue phantoms were prepared as experimental models of the osteochondral interface. Raman spectra of tissue phantoms suggested that optical scattering of cartilage has a large effect on the relative cartilage and bone signal. Finite element analysis modeling of light fluence in the osteochondral interface confirmed experimental findings in human cadaveric tissue and tissue phantoms. These first studies demonstrate the proof of principle for Raman arthroscopic measurement of joint tissues and provide a basis for future clinical or animal model studies.

Minor distortions with major consequences: correcting distortions in imaging spectrographs.

Projective transformation is a mathematical correction (implemented in software) used in the remote imaging field to produce distortion-free images. We present the application of projective transformation to correct minor alignment and astigmatism distortions that are inherent in dispersive spectrographs. Patterned white-light images and neon emission spectra were used to produce registration points for the transformation. Raman transects collected on microscopy and fiber-optic systems were corrected using established methods and compared with the same transects corrected using the projective transformation. Even minor distortions have a significant effect on reproducibility and apparent fluorescence background complexity. Simulated Raman spectra were used to optimize the projective transformation algorithm. We demonstrate that the projective transformation reduced the apparent fluorescent background complexity and improved reproducibility of measured parameters of Raman spectra. Distortion correction using a projective transformation provides a major advantage in reducing the background fluorescence complexity even in instrumentation where slit-image distortions and camera rotation were minimized using manual or mechanical means. We expect these advantages should be readily applicable to other spectroscopic modalities using dispersive imaging spectrographs.

Development of non-invasive Raman spectroscopy for in vivo evaluation of bone graft osseointegration in a rat model.

The use of bone structural allografts for reconstruction following tumor resection is widespread, although successful incorporation and regeneration remain uncertain. There are few non-invasive methods to fully assess the progress of graft incorporation. Computed tomography and MRI provide information on the morphology of the graft/host interface. Limited information is also available from DXA and ultrasound. Only few techniques can provide information on the metabolic status of the graft, such as the mineral and matrix composition of the regenerated tissue that may provide early indications of graft success or failure. To address this challenge, we discuss here the implementation of Raman spectroscopy for in vivo assessment of allograft implantation in a rat model. An array of optical fibers was developed to allow excitation and collection of Raman spectra through the skin of rat at various positions around the rat's tibia. The system is calibrated against locally constructed phantoms that mimic the morphology, optics and spectroscopy of the rat. The system was evaluated by carrying out transcutaneous Raman measurement on rat. Bone mineral and matrix Raman bands are successfully recovered. This new technology provides a non-invasive method for in vivo monitoring of bone graft osseointegration.

Individual differences in dopamine cell neuroadaptations following cocaine self-administration.

BACKGROUND: Addictive drugs produce neuroadaptations in dopamine neurons of the ventral tegmental area. It is unknown if individual differences in these neuroadaptive responses can account for naturally occurring differences in drug addiction liability. METHODS: To study this question, we took advantage of high-responder (HR) and low-responder (LR) rats, a population that exhibits spontaneous differences in several models of addiction. High-responder and LR rats were allowed to self-administer saline or a high dose of cocaine (500 microg/kg/infusion) over a brief period, to normalize drug intake across individuals. Drug-induced changes in the baseline activity of ventral tegmental area dopamine neurons were recorded after various periods of withdrawal. RESULTS: All rats developed self-administration behavior and showed similar levels of drug intake. Withdrawal from cocaine self-administration increased dopamine cell firing and bursting in all animals. However, these changes in firing rates and patterns were more persistent in HR than in LR rats. CONCLUSIONS: These results demonstrate individual differences in the duration of drug-induced neuroadaptations in dopamine neurons of the ventral tegmental area. More persistent elevation of dopamine cell activity and reduced capacity to return to baseline levels may be an important factor contributing to the development of addiction in "at-risk" individuals.