Imaging P-glycoprotein function in rats using [11C]-N-desmethyl-loperamide

Objective

One mechanism that may be responsible for drug resistance in epilepsy is the upregulation of P-glycoprotein (P-gp), a drug efflux pump, at the epileptogenic focus. In this study, we sought to evaluate the potential of a recently developed P-gp PET radiotracer, [¹¹C]N-desmethyl-loperamide ([¹¹C]dLop), for measuring P-gp function in the rat brain.

Methods

The precursor to [¹¹C]dLop was synthesized in two steps from commercially available starting materials and subsequently radiolabeled in one step using [¹¹C]methyl iodide. [¹¹C]dLop was then administered to two groups of rats, controls (n = 4) and those treated with a P-gp inhibitor (n = 8). Cyclosporin A (CsA, 50 mg/kg, n = 3) and tariquidar (TQ, 20 mg/kg, n = 5) were both used as P-gp inhibitors. MicroPET brain scans were performed for 120 min with arterial blood sampling. A one-tissue compartment model was used to estimate the distribution volume of radiotracer as the outcome measure of P-gp function.

Results

Plasma levels of parent [¹¹C]dLop decreased rapidly to <0.1 mean standardized uptake value (SUV) at 60 min. In controls, brain uptake of [¹¹C]dLop was very low (<0.1 mean SUV). In contrast, the mean SUVs were significantly higher in rats treated with CsA (0.51) or TQ (0.22). Estimation of distribution volumes was stable by 70 min. Estimated distribution volumes were significantly larger after P-gp inhibition (CsA = 7.3, TQ = 4.7) compared to controls (no inhibitor = 2.1).

Conclusions

The rat brain demonstrates significantly increased uptake of [¹¹C]dLop after P-gp inhibition. [¹¹C]dLop is a substrate of P-gp, and will serve as a promising radiotracer for studying P-gp function in the future.     

Sexual function and psychological characteristics of penile paraffinoma

Aim:To identify the sexual, emotional and psychological status of men who augmented their penis with mineral oil injection for their small penis. Methods: Men who had penile paraffin were asked to answer the semi-structured questionnaire. The questionnaire was designed to assess the motivation, method of penile injection, changes in erectile function and satisfaction after penile injection. SCL (Symptom checklist)-90-R, STAI (State and Trait Anxiety Inventory) and Zung SDS (Self-rating depression scale) were also included in the questionnaire for psycho-logical evaluation. Results: A total of 357 men completed the questionnaire. The first-ranked motivation of the injection was recommendation by their acquaintances (48.9 %). The majority of the respondents had the procedure by non-medical person (78.0 %). Before injection, 17.2 % had a sense of inferiority in their penis and 32 % worried about their weak erectile function. After injection, 33.0 % have found relief from their sense of inferiority and 17.8 % wish to feel improvement in their cr~tile function. Most of the respondents (91%) were not satisfied with their penis and 74 % of them replied that they want to remove the injected material. Only 15.6 % did not experience side effects.Most of the subjects have suffered from various side effects such as inflammation, skin necrosis, pain, etc. No evidence of psychiatric pathology was found in psychological evaluation. Conclusion: The motivations of mineral oil injection were recommendation by their acquaintances or desire to be more mannish. Most of them had suffered from various side effects and only a small number of them felt improvement in their sense of inferiority, in their penis and erectile function. Increased public awareness is needed for the prevention of this physically and psychologically debilitating problem. (Asian J Andro12003 Sep; 5:191-194 )     

Effects of anesthetic agents on cellular <Superscript>123</Superscript>I-MIBG transport and in vivo <Superscript>123</Superscript>I-MIBG biodistribution

Objectives Small animal imaging with meta-iodobenzylguanidine (MIBG) allows characterization of animal models, optimization of tumor treatment strategies, and monitoring of gene expression. Anesthetic agents, however, can affect norepinephrine (NE) transport and systemic sympathetic activity. We thus elucidated the effects of anesthetic agents on MIBG transport and biodistribution. Methods SK-N-SH neuroblastoma and PC-12 pheochromocytoma cells were measured for ¹²³I-MIBG uptake after treatment with ketamine (Ke), xylazine (Xy), Ke/Xy, or pentobarbital (Pb). NE transporters were assessed by Western blots. Normal ICR mice and PC-12 tumor-bearing mice were injected with ¹²³I-MIBG 10 min after anesthesia with Ke/Xy, Ke, Xy, or Pb. Plasma NE levels and MIBG biodistribution were assessed. Results Cellular ¹²³I-MIBG uptake was dose-dependently inhibited by Ke and Xy but not by Pb. Treatment for 2 h with 300 μM Ke, Xy, and Ke/Xy decreased uptake to 46.0 ± 1.6, 24.8 ± 1.5, and 18.3 ± 1.6% of controls. This effect was completely reversed by fresh media, and there was no change in NE transporter levels. In contrast, mice anesthetized with Ke/Xy showed no decrease of MIBG uptake in target organs. Instead, uptakes and organ-to-blood ratios were increased in the heart, lung, liver, and adrenals. Plasma NE was notably reduced in the animals with corresponding decreases in blood MIBG, which partly contributed to the increase in target organ uptake. Conclusion In spite of their inhibitory effect at the transporter level, Ke/Xy anesthesia is a satisfactory method for MIBG imaging that allows favorable target tissue uptake and contrast by reducing circulating NE and MIBG. Bong-Ho Ko and Jin-Young Paik equally contributed to this work. This work was supported by the Korea Research Foundation Grant KRF-2005-202-E00116. Presented in part at the fifth Annual Meeting of the Society for Molecular Imaging, Hawaii, August 30–September 2, 2006.     

Second-generation cementless total hip arthroplasty in patients with osteonecrosis of the femoral head

The results of cementless total hip arthroplasties in patients with osteonecrosis have been inferior to those in patients with other diagnoses. Fifty-eight primary total hip arthroplasties with insertion of a femoral stem with a circumferentially proximal porous coating and a cementless acetabular component were followed for a mean of 11.1 years. Fifty-seven (98%) of 58 stems were biologically stable, and one stem was loose. There were acetabular revisions in 18 hips (31%) because of polyethylene wear and osteolysis. One hip (1.7%) underwent revision of both acetabular and femoral components. Osteolysis around the acetabular component was seen on radiographs in 22 hips (37.9%). Femoral osteolysis was seen in 9 hips (15.5%), and there was no osteolysis below the lesser trochanter in any hip. Second-generation femoral prostheses provide excellent fixation in patients with osteonecrosis of the femoral head. However, a high rate of polyethylene wear and osteolysis in these high-risk patients remains a challenging problem.     

Proteomic analysis to identify biomarker proteins in pancreatic ductal adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is the fifth most common cause of death from cancer in Korea. PDAC is difficult to diagnose at an early stage and even more difficult to cure. Thus, there is an urgent need to identify molecular targets for early diagnosis and effective treatment. The objectives of this study were to identify differentially expressed biomarker proteins of PDAC using proteomic analysis, to validate the identified biomarker proteins associated with carcinogenesis using western blot analysis and to evaluate clinical factors influencing expression of candidate biomarker proteins. Methods: In the present study, we carried out proteomic analysis in 10 pairs of PDAC specimens with matching adjacent normal tissues to clarify the different patterns of protein expression. The proteins were separated by high‐resolution 2‐D polyacrylamide gel electrophoresis (2D PAGE) and the differentially expressed proteins were identified by matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS). Differential expression of candidate biomarker proteins associated with carcinogenesis was further validated using western blot analysis. Standard statistical analysis was carried out in an attempt to establish a correlation between clinical variables and expression of candidate biomarker proteins. Results: Analysis of PDAC and the adjacent normal tissues showed reproducibly similar proteomic patterns for each group. Approximately 700 spots each were seen by silver‐stained gels from both PDAC and normal tissues. Differentially expressed protein spots were gel digested and identified by MALDI‐TOF MS. Twenty‐five proteins were identified, of which five proteins (galectin‐1, enolase‐2, α‐1‐antitrypsin, N‐myc interactor, peroxiredoxin‐4) were previously reported as being differentially expressed either at the mRNA level or protein level in human cancer. The five proteins were selected for candidate biomarker proteins related to carcinogenesis. These proteins were further validated by western blot analysis. Among the candidate biomarker proteins, galectin‐1 expression was highly correlated to histology (P = 0.019), T stage (P = 0.047), N stage (P = 0.033) and American Joint Committee on Cancer stage (P = 0.011). Conclusion: Differentially expressed 25 proteins in PDAC were identified using proteomic analysis and five proteins related to carcinogenesis were validated by western blot analysis. galectin‐1 expression was highly correlated to tumour histology and stage.     

A Significant Correlation between Nuclear CXCR4 Expression and Axillary Lymph Node Metastasis in Hormonal Receptor Negative Breast Cancer

Background and objectives In breast cancer, the expression pattern of CXCR4 may be correlated with the degree of axillary lymph node involvement. The aim of this study was to evaluate the contributing factors that contribute to the correlation between CXCR4 expression and axillary lymph node metastasis in breast cancer. Methods Between August 1997 and August 2002, sections of paraffin-embedded tissue were obtained from 107 patients who received optimal treatment for breast cancer. The expression of CXCR4 was evaluated by immunohistochemical staining. Results A significant correlation was found in the expression of nuclear CXCR4 and lymph node metastasis (P = 0.03). We found a significant correlation between a high nuclear expression of CXCR4 and axillary lymphatic metastasis in estrogen and progesterone receptor negative breast cancer (P = 0.01 and P = 0.01). There was a significant correlation between the high expression of nuclear CXCR4 and axillary lymphatic metastasis in comparisons between positive estrogen and/or progesterone receptor expression and negative expression (P = 0.02). Conclusions Our results showed that high expression of nuclear CXCR4 was significantly correlated with lymph node metastasis in breast cancer. The high expression of nuclear CXCR4 in hormone receptor negative breast cancer was associated with a high possibility of lymph node metastasis.     

Challenges in Pulmonary Risk Assessment and Perioperative Management in Bariatric Surgery Patients

Bariatric surgery has serious associated medical comorbidity and procedure-related risks and is, thus, considered an intermediate-to-high-risk non-cardiac surgery. Altered respiratory mechanics, obstructive sleep apnea (OSA), and less often, pulmonary hypertension and postoperative pulmonary embolism are the major contributors to poor pulmonary outcomes in obese patients. Attention to posture and positioning is critical in patients with OSA. Suspected OSA patients requiring intravenous narcotics should be kept in a monitored setting with frequent assessments and naloxone kept at the bedside. Use of reverse Tredelenburg position, preinduction, maintenance of positive end-expiratory pressure, and use of continuous positive airway pressure can help improve oxygenation in the perioperative period.     

Crossed screws versus dorsomedial locking plate with compression screw for first metatarsocuneiform arthrodesis: a cadaver study

BACKGROUND: We hypothesized that a dorsomedial locking plate with adjunct screw compression would provide superior rigidity compared to crossed screws for first metatarsocuneiform (MTC) arthrodesis. MATERIALS AND METHODS: In ten matched lower extremity pairs, specimens in each pair were randomly assigned to receive screw fixation or plate with screw fixation. Bone mineral density (BMD) was measured. For the crossed-screw construct, two 4.0-mm cannulated screws were used. One screw was inserted dorsal to plantar beginning from the first metatarsal 10 to 15 mm distal to the joint, and the second was inserted from the cuneiform 8 to10 mm proximal to the joint, medial to the first screw, into the first metatarsal. For the plate construct, a 4.0-mm cannulated compression screw was inserted from the dorsal cortex of the first metatarsal to the plantar aspect of the medial cuneiform. A locking plate was inserted dorsomedially across the MTC joint. Specimens were loaded in four-point bend configuration (displacement rate, 5 mm/min) until failure of the fixation or 3-mm deformation. An extensometer was used to measure deformation. RESULTS: There was no difference in load to failure or stiffness between the two groups. BMD was positively correlated with load to failure in the screw (r = 0.893, p = 0.001) and the plate (r = 0.858, p = 0.001) construct. CONCLUSION: The plate construct with compression screw did not show different rigidity as compared with the screw construct with the numbers available. CLINICAL RELEVANCE: Further investigation of a dorsomedial plate with adjunct screw compression may be warranted for first MTC arthrodesis.     

External rotation humeral osteotomy for brachial plexus birth palsy

In patients with brachial plexus birth palsy, persistent muscular imbalance across the developing shoulder results in progressive glenohumeral dysplasia, characterized by increased glenoid retroversion, humeral head flattening, and posterior subluxation of the humeral head. Soft-tissue procedures-such as tendon transfers and musculotendinous lengthenings--will provide limited functional improvements in the setting of advanced glenohumeral deformity. For patients with internal rotation contracture and external rotation weakness associated with severe glenohumeral dysplasia, external rotation osteotomy of the humerus may be used to improve global shoulder function. The purpose of this article is to review the history, indications, and surgical technique of external rotation humeral osteotomy for patients with brachial plexus birth palsy.     

Comparative study of the extent of palatal lengthening by different methods

Palatal lengthening is often emphasized in performing palatoplasty. However, definitive data regarding the method of measuring palatal length and the extent of palatal lengthening expressed quantitatively have not been reported. The authors have devised an easy method of measuring palatal length that can be expressed quantitatively, and they examined the characteristics of various methods of palatoplasty that are presently used commonly. A paper ruler was used to measure both a straight-line and a curved distance while the patient was under general anesthesia before and immediately after the palatoplasty. According to this study, the straight-line distance was lengthened to a significantly greater degree than the curved distance was after pushback palatoplasty for incomplete types of cleft palate and two-flap palatoplasty for complete types. Furlow double-opposing Z-palatoplasty and two-flap palatoplasty appeared to allow for greater palatal lengthening than the pushback palatoplasty. Further investigations will be undertaken to determine the correlation between the extent of palatal lengthening and speech development.