Effect of menstrual cycle phase on dopamine D2 receptor availability in female cynomolgus monkeys

Sex differences have been reported in a variety of affective and neurodegenerative disorders that involve dysfunctional dopamine (DA) neurotransmission. In addition, there is evidence for differences in sensitivity to the abuse-related effects of psychostimulants across the menstrual cycle which may result from effects of ovarian hormones on DA function. The goal of the present study was to extend previous work examining menstrual cycle-related changes in DA D2 receptor availability in humans to drug-naive female cynomolgus monkeys (n=7) using the selective D2-like receptor ligand [(18)F]fluoroclebopride (FCP) and a high-resolution microPET P4 scanner. Menstrual cycle phase was characterized by daily vaginal swabs and measurements of serum progesterone levels. PET studies were conducted once during the luteal phase and once during the follicular phase. Regions of interest in the caudate nucleus, putamen, and cerebellum were defined on coregistered MRIs. Distribution volumes were calculated for FCP in each structure and the distribution volume ratio (DVR) for both brain regions relative to the cerebellum was used as a measure of D2 receptor availability. FCP DVRs were significantly higher in the luteal phase compared to the follicular phase in both the caudate nucleus (11.7% difference, p=0.02) and putamen (11.6% difference, p=0.03). These findings extend earlier work in humans and suggest that changes in DA receptor availability may be involved in the variation in symptoms of various neuropsychiatric disorders across the menstrual cycle, including differences in sensitivity to the abuse-related effects of stimulants.     

An MR-compatible device for delivering smoked marijuana during functional imaging

Smoking is the preferred method of administration for two of the most frequently abused drugs, marijuana and nicotine. The high temporal and spatial resolution of functional magnetic resonance imaging (fMRI) make it a natural choice for studying the neurobiological effects of smoked drugs if the challenges of smoking in a magnetic resonance (MR) scanner can be overcome. We report on a design for an MR-compatible smoking device that can be used for smoking marijuana (or tobacco) during fMRI examinations. Nine volunteers smoked marijuana cigarettes (3.51% Delta9-THC) on two occasions: with and without the device. The device allowed subjects to smoke while they lay in the scanner, while containing all smoke and odors. Plasma Delta9-THC, subjective reports of intoxication, and heart rate increases are reported, and were all similar in individuals smoking marijuana either with or without the device. The use of this device will help advance research studies on smoked drugs including marijuana, tobacco and crack cocaine.     

Origin, fate, and properties of multinucleated giant cells and their association with milk-synthesizing tissues of the bovine mammary gland

Histological study of multinucleated giant cells (MGC) in bovine mammary glands demonstrated that the cells predominated during mammary involution. Concentrations of MGC increased from the early to later stages of involution, and were more prevalent in older cows. There was no association between infection status and prevalence of MGC. A study of the relationship between MGC and other components of the mammary parenchyma indicated that these cells formed in response to substances that accumulated in mammary secretions during involution. MGC appeared to play a role in resorption of insoluble milk constituents, and removal of amyloid and effete macrophages.     

Detection of Clinical and Subclinical Tubulo‐Interstitial Inflammation by the Urinary CXCL10 Chemokine in a Real‐Life Setting

Urinary CXCL10 is a promising noninvasive biomarker for tubulo‐interstitial allograft inflammation, but its diagnostic characteristics have not been assessed in a real‐life setting. We investigated urinary CXCL10 in 213 consecutive renal allograft recipients having 362 surveillance biopsies at 3/6 months and 80 indication biopsies within the first year posttransplant. Allograft histology results were classified as (i) acute Banff score zero, (ii) interstitial infiltrates only, (iii) tubulitis t1, (iv) tubulitis t2–3 and (v) isolated vascular compartment inflammation. For clinical and subclinical pathologies, urinary CXCL10 correlated well with the extent of tubulo‐interstitial inflammation. To determine diagnostic characteristics of urinary CXCL10, histological groups were separated into two categories: no relevant inflammation (i.e. acute Banff score zero and interstitial infiltrates only) versus all other pathologies (i.e. tubulitis t1–3 and isolated vascular compartment inflammation). For subclinical pathologies, AUC was 0.69 (sensitivity 61%, specificity 72%); for clinical pathologies, AUC was 0.74 (sensitivity 63%, specificity 80%). A urinary CXCL10‐guided biopsy strategy would have reduced performance of surveillance and indication biopsies by 61% and 64%, respectively. Missed (sub)clinical pathologies were mostly tubulitis t1 and isolated vascular compartment lesions. In real life, urinary CXCL10 had clinically useful diagnostic properties making it a candidate biomarker to guide allograft biopsies.     

Cell-Specific Proteins Synthesized by Salmonella typhimurium

Studies of the proteins synthesized by Salmonella typhimurium during growth within tissue culture cells have previously focused on a single cell type. In the present study we examine the different protein patterns exhibited by S. typhimurium during growth within three different cell types relevant to those it would encounter throughout the course of a natural infection, including intestinal epithelial cells (Intestine-407), macrophages (J774.A, rat bone marrow-derived macrophages, and mouse bone marrow-derived macrophages), and liver cells (NMuLi). Side-by-side comparisons reveal that S. typhimurium responds to these different cellular environments with specific patterns of protein synthesis unique to each cell type. The numbers of proteins detected in each cell line are as follows: 142 proteins in Intestine-407, of which 58 appear to be unique to growth within this cell line; 413 proteins in J774.A, of which 157 appear to be unique; 260 proteins in rat bone marrow-derived macrophages, of which 40 appear to be unique; 336 proteins in mouse bone marrow-derived macrophages, of which 113 appear to be unique; and 183 proteins in NMuLi, of which 91 appear to be unique.     

National Conference to Assess Antibody-Mediated Rejection in Solid Organ Transplantation

The process of humoral rejection is multifaceted and has different manifestations in the various types of organ transplants. Because this process is emerging as a leading cause of graft loss, a conference was held in April 2003 to comprehensively address issues regarding humoral rejection. Though humoral rejection may result from different factors, discussion focused on a paradigm caused by antibodies, typically against donor HLA antigens, leading to the term 'antibody-mediated rejection' (AMR). Conference deliberations were separated into four workgroups: The Profiling Workgroup evaluated strengths and limitations of different methods for detecting HLA reactive antibody, and created risk assessment guidelines for AMR; The Diagnosis Workgroup reviewed clinical, pathologic, and serologic criteria for assessing AMR in renal, heart and lung transplant recipients; The Treatment Workgroup discussed advantages, limitations and possible mechanisms of action for desensitization protocols that may reverse AMR; and The Basic Science Workgroup presented animal and human immunologic models for humoral rejection and proposed potential targets for future intervention. This work represents a comprehensive review with contributions from experts in the fields of Transplantation Surgery, Medicine, Pathology, Histocompatibility, Immunology, and clinical trial design. Immunologic barriers once considered insurmountable are now consistently overcome to enable more patients to undergo organ transplantation.     

Paediatric use of intensive care

OBJECTIVES--To determine the number of children from a defined population who use intensive care facilities, to analyse bed occupancy data for those children, and to estimate the number of intensive care beds required to satisfy this demand throughout the year. DESIGN--Examination of admission data books from intensive care units within the four Birmingham health authorities and the neighbouring health authorities. RESULTS--Two hundred and ninety seven children resident within the four Birmingham health authorities used intensive care facilities in a calendar year. One hundred and forty one (47%) of these were admitted for specialist paediatric services. Of the remaining 156, 106 (68%) were cared for in adult intensive care units, 46 (29%) in a paediatric intensive care unit and four (3%) in a special care baby unit. Use of intensive care varied from none to 11 patients each day, and was lowest in the summer and highest during the winter months. During periods of peak demand, one in 19,000 (5.3/100,000) children were using intensive care facilities. CONCLUSIONS--These data provide a population based minimum need for paediatric intensive care beds. They are higher than previous estimates and do not include provision for children from outside Birmingham, or for those denied intensive care due to bed shortages. These factors and the marked seasonal variation in demand need to be considered when planning intensive care services for children if bed shortages are to be avoided.