Variability of T2-Relaxation Times of Healthy Lumbar Intervertebral Discs is More Homogeneous within an Individual Than across Healthy Individuals.

BACKGROUND AND PURPOSE: When one uses T2 relaxometry to classify lumbar intervertebral discs as degenerated, it is unclear whether the normative data should be based on other intervertebral discs from the same individual or from a pool of extraneous controls. This study aimed to explore the extent of intra- versus intersubject variation in the T2 times of healthy intervertebral discs. MATERIALS AND METHODS: Using prospectively acquired T2-relaxometry data from 606 intervertebral discs in 101 volunteers without back pain (47 men, 54 women) in a narrow age range (25-35 years), we calculated intra- and intersubject variation in T2 times of intervertebral discs graded by 2 neuroradiologists on the Pfirrmann scale. Intrasubject variation of intervertebral discs was assessed relative to other healthy intervertebral discs (Pfirrmann grade, ≤2) in the same individual. Multiple intersubject variability measures were calculated using healthy extraneous references ranging from a single randomly selected intervertebral disc to all healthy extraneous intervertebral discs, without and with segmental stratification. These variability measures were compared for healthy and degenerated (Pfirrmann grade ≥3) intervertebral discs. RESULTS: The mean T2 values of healthy (493/606, 81.3%) and degenerated intervertebral discs were 121.1 ± 22.5 ms and 91.5 ± 18.6 ms, respectively (P < .001). The mean intrasubject variability for healthy intervertebral discs was 9.8 ± 10.7 ms, lower than all intersubject variability measures (P < .001), and provided the most pronounced separation for healthy and degenerated intervertebral discs. Among intersubject variability measures, using all segment-matched healthy discs as references provided the lowest variability (P < .001). CONCLUSIONS: Normative measures based on the T2 times of healthy intervertebral discs from the same individual are likely to provide the most discriminating means of identifying degenerated intervertebral discs on the basis of T2 relaxometry.

The importance of level stratification for quantitative MR studies of lumbar intervertebral discs: a cross-sectional analysis in 101 healthy adults.

PURPOSE: To investigate whether quantitative T2-times depend on lumbar intervertebral disc (IVD) level. METHODS: The lumbar spine (Th12/L1-L5/S1) of 101 participants (53.5% female, 30.0[± 3.6]years, 173.5[± 9.6]cm and 69.9[± 13.4]kg), without history of back pain, was examined on a 3T scanner with sagittal T2-mapping. All IVDs were stratified according to Pfirrmann grade and lumbar level, with mean T2-time determined for the entire IVD volume and in five subregions of interests. RESULTS: Significant level-dependent T2-time differences were detected, both for the entire IVD volume and its subregions. For the entire IVD volume, Pfirrmann grade 2 IVDs displayed 9-18% higher T2-times in Th12/L1 IVDs compared to L2/L3-L5/S1 IVDs (0.001 > p < 0.004) and significantly different T2-times in L1/L2-L2/L3 IVDs compared to most of the IVDs in the lower lumbar spine. In Pfirrmann grades 1, 3 and 4 IVDs, no significant level-dependent T2-time differences were observed for the entire IVD. More pronounced results were observed when comparing IVD subregions, with significant level-dependent differences also within Pfirrmann grade 1 and grade 3 IVDs. For example, in posterior IVD subregions mean T2-time was 80-82% higher in Th12/L1 compared to L3/L4-L4/L5 Pfirrmann grade 1 IVDs (p < 0.05) and 10-14% higher in L5/S1 compared to L3/L4-L4/L5 Pfirrmann grade 3 IVDs (0.02 > p < 0.001). DISCUSSION: Significant level-dependent T2-time differences within several Pfirrmann grades, both for the entire IVD volume and for multiple IVD subregions, were shown in this large cohort study. The T2-time differences between levels existed in both non-degenerated and degenerated IVDs. These findings show the importance of stratifying for lumbar level when quantitative IVD studies are performed using T2-mapping. These slides can be retrieved under Electronic Supplementary Material.

Lifestyle guidelines for managing adverse effects on bone health and body composition in men treated with androgen deprivation therapy for prostate cancer: an update.

BACKGROUND: Men treated with androgen deprivation therapy (ADT) for prostate cancer are prone to multiple treatment-induced adverse effects, particularly with regard to a deterioration in bone health and altered body composition including decreased lean tissue mass and increased fat mass. These alterations may partially explain the marked increased risk in osteoporosis, falls, fracture and cardiometabolic risk that has been observed in this population. METHODS: A review was conducted that assessed standard clinical guidelines for the management of ADT-induced adverse effects on bone health and body composition in men with prostate cancer. RESULTS: Currently, standard clinical guidelines exist for the management of various bone and metabolic ADT-induced adverse effects in men with prostate cancer. However, an evaluation of the effectiveness of these guidelines into routine practice revealed that men continued to experience increased central adiposity, and, unless pharmacotherapy was instituted, accelerated bone loss and worsening glycaemia occurred. CONCLUSIONS: This review discusses the current guidelines and some of the limitations, and proposes new recommendations based on emerging evidence regarding the efficacy of lifestyle interventions, particularly with regard to exercise and nutritional factors, to manage ADT-related adverse effects on bone health and body composition in men with prostate cancer.

Prophylactic radiotherapy against heterotopic ossification following internal fixation of acetabular fractures: a comparative estimate of risk.

OBJECTIVE: Radiotherapy (RT) is effective in preventing heterotopic ossification (HO) around acetabular fractures requiring surgical reconstruction. We audited outcomes and estimated risks from RT prophylaxis, and alternatives of indometacin or no prophylaxis. METHODS: 34 patients underwent reconstruction of acetabular fractures through a posterior approach, followed by a 8-Gy single fraction. The mean age was 44 years. The mean time from surgery to RT was 1.1 days. The major RT risk is radiation-induced fatal cancer. The International Commission on Radiological Protection (ICRP) method was used to estimate risk, and compared with a method (Trott and Kemprad) specifically for estimating RT risk for benign disease. These were compared with risks associated with indometacin and no prophylaxis. RESULTS: 28 patients (82%) developed no HO; 6 developed Brooker Class I; and none developed Class II-IV HO. The ICRP method suggests a risk of fatal cancer in the range of 1 in 1000 to 1 in 10,000; the Trott and Kemprad method suggests 1 in 3000. For younger patients, this may rise to 1 in 2000; and for elderly patients, it may fall to 1 in 6000. The risk of death from gastric bleeding or perforation from indometacin is 1 in 180 to 1 in 900 in older patients. Without prophylaxis risk of death from reoperation to remove HO is 1 in 4000 to 1 in 30,000. CONCLUSION: These results are encouraging, consistent with much larger series and endorse our multidisciplinary management. Risk estimates can be used in discussion with patients. ADVANCES IN KNOWLEDGE: The risk from RT prophylaxis is small, it is safer than indometacin and substantially overlaps with the range for no prophylaxis.

Detection of a noble gas molecular ion, 36ArH+, in the Crab Nebula.

Noble gas molecules have not hitherto been detected in space. From spectra obtained with the Herschel Space Observatory, we report the detection of emission in the 617.5- and 1234.6-gigahertz J = 1-0 and 2-1 rotational lines of (36)ArH(+) at several positions in the Crab Nebula, a supernova remnant known to contain both molecular hydrogen and regions of enhanced ionized argon emission. Argon-36 is believed to have originated from explosive nucleosynthesis in massive stars during core-collapse supernova events. Its detection in the Crab Nebula, the product of such a supernova event, confirms this expectation. The likely excitation mechanism for the observed (36)ArH(+) emission lines is electron collisions in partially ionized regions with electron densities of a few hundred per centimeter cubed.

Augmentation index in resistance to thyroid hormone (RTH).

OBJECTIVE: Resistance to thyroid hormone (RTH) is associated with a varied clinical presentation. The cardiac effects of RTH have been described but vascular function has yet to be fully evaluated in this condition. We have measured the arterial function of those with RTH to assess any vascular changes. DESIGN: An observational study. PATIENTS: Twelve RTH patients were recruited from the thyroid clinic (mean value +/- SD), age 40.8 +/- 18.7 years; BMI 27.2 +/- 4.2 kg/m(2) and compared with 12 healthy, euthyroid, age-matched controls (age 41.4 +/- 19.3; BMI 24.8 +/- 4.4 kg/m(2)) with no history of cardiovascular disease. No interventional measures were instituted. MEASUREMENTS: Arterial stiffness was measured using pulse wave analysis at the radial artery. Thyroid function, fasting lipids and glucose were also measured on the same occasion in both patients and controls. Results The corrected augmentation index, a surrogate marker of arterial stiffness was significantly higher in patients compared with controls (21.0% +/- 14.1%vs. 5.4% +/- 18.2%, P < 0.03). Low density lipoprotein cholesterol (LDL-cholesterol) levels were also significantly elevated in patients compared with controls (3.0 +/- 0.6 vs. 2.1 +/- 0.5 mmol/l; P < 0.002). CONCLUSION: RTH patients show evidence in this study of increased augmentation index consistent with an increase in arterial stiffness compared with euthyroid controls. They also demonstrate elevated LDL-cholesterol levels. Both these measures may lead to increased cardiovascular risk.

Less invasive stabilisation system plating for distal femoral fractures.

PURPOSE: To review the outcome of less invasive stabilisation system (LISS) plating for complex distal femoral fractures. METHODS: Records of 6 men and 11 women who underwent LISS plating for complex distal femoral fractures from September 2001 to August 2005 were reviewed. One patient who died 12 months after surgery due to a cardiac problem was excluded. The mean age of the remaining patients was 61 years and the mean follow-up period was 12 months. Four patients, 3 of whom had open fractures, had sustained high-energy trauma. According to the AO classification, 8 fractures were type 33A and 9 type 33C. RESULTS: The mean time to union was 17 weeks. Two patients with non-union underwent a second LISS plating and bone grafting, resulting in a satisfactory final outcome. Delayed radiographic union was observed in one patient, but clinically he was asymptomatic and mobile. The fracture finally united at 9 months. CONCLUSION: LISS plating is useful in treating complex distal femoral fractures, resulting in reduced blood loss and low infection rates, while achieving early mobility due to primary stability of the construct.

Endothelial dysfunction in a murine model of thyroid hormone resistance.

BACKGROUND: The development of a knockin mouse model of resistance to thyroid hormone (RTH) has led to a greater understanding of both the molecular and clinical behaviour of this syndrome. We have investigated the vascular response in RTH using a specific (TRbeta PV) knockin mouse model targeting the PV mutation to the thyroid hormone receptor beta gene locus. MATERIALS AND METHODS: Ring segments of the thoracic aorta were used to assess the response of homozygous, heterozygous and wild-type controls to contractile agents, potassium chloride and phenylephrine. Each genotype after maximal contraction was exposed to increasing concentrations of relaxing agents, acetylcholine (ACh) and sodium nitroprusside (SNP). RESULTS: The response of these aortic ring segments to ACh and SNP demonstrates that endothelium-dependent relaxation to ACh was significantly impaired in both heterozygous and homozygous mice compared to controls (69.8 +/- 2.0%, 59.7 +/- 1.4% and 75.0 +/- 1.7%, respectively; P < 0.001). However, endothelium independent responses to SNP showed no difference between genotypes (114.4 +/- 3.2%, 116.8 +/- 2.6% and 106.9 +/- 4.9%; P = NS). CONCLUSION: These data suggest that endothelial function is impaired in the RTH mouse aorta. The respective roles of elevated thyroid stimulating hormone (TSH), elevated thyroid hormone concentrations and the mutated thyroid hormone beta receptor require further elucidation.

Subclinical hypothyroidism, arterial stiffness, and myocardial reserve.

CONTEXT: Subclinical hypothyroidism (SCH) is associated with increased risk of cardiac disease; its impact on arterial function is less clear. OBJECTIVE: The objective of the study was the assessment of arterial and cardiac function. DESIGN: The study was a 6-month controlled observational study using pulse wave analysis and tissue Doppler dobutamine stress echocardiography. SETTING: The study was conducted at a thyroid clinic. PATIENTS: Nineteen female SCH patients with raised TSH, normal free T(4), and no cardiovascular disease [aged 49.2 +/- 3.8 yr; body mass index (BMI) 29.9 +/- 6.7 kg/m(2)] were recruited from the thyroid clinic, and 10 female controls (aged 50.2 +/- 3.4 yr; BMI 29.7 +/- 7.2 kg/m(2)) also participated in the study. INTERVENTIONS: Incremental doses of l-thyroxine were used. MAIN OUTCOME MEASURES: Indices of vascular stiffness and left ventricular echocardiographic function were measured. RESULTS: Baseline augmentation gradient was elevated in SCH, compared with controls [10.3 +/- 5.1 (sd) mm Hg vs. 8.0 +/- 4.2, P < 0.05]; when euthyroid (mean T(4) dose 114 mug/d), it fell to 8.8 +/- 5.3 mm Hg (P < 0.05). Heart rate-corrected augmentation index was 26.7 +/- 9.9 vs. 18.8 +/- 9.9% (P < 0.02), falling to 19.7 +/- 9.6% (P < 0.001) after treatment. Time of travel of the reflected wave was 139.3 +/- 11.7 msec, compared with 141.5 +/- 8.8 msec in controls (P < 0.05), increasing to 144.9 +/- 11.9 msec (P < 0.05). There were no differences in resting global, regional left ventricular function, or regional myocardial velocities during maximal dobutamine stress between SCH patients and controls, or in treated patients, compared with baseline. CONCLUSIONS: Arterial stiffness was increased in SCH and improved with l-thyroxine, which may be beneficial, whereas myocardial functional reserve was similar to controls and remained unaltered after treatment.

Unusual complications of thyroid carcinoma.

Thyroid carcinomas are the most frequent endocrine malignancies. Complications may arise from an established malignancy and these may lead to the initial clinical presentation or cause subsequent problems. In this case report two elderly patients with differentiated and undifferentiated thyroid carcinomas who suffered unusual medical complications are described. The incidence and treatment of thyroid carcinoma is discussed and the importance of fine needle aspiration of thyroid nodules and the recognition of iodine containing radiographic contrast media in the causation of iodine induced thyrotoxicosis is highlighted.

Fracture stiffness in callotasis determined by dual-energy X-ray absorptiometry scanning.

Assessing healing after distraction limb lengthening is essential to manage patients undergoing callotasis for leg lengthening or bone transport. Direct measurement of fracture stiffness can assess healing but the equipment may not be available. In addition, it requires removal of the fixator, which may be complicated for ring fixators. The present study investigates whether an equivalent measure of healing can be based on the mineral density pattern from dual-energy X-ray absorptiometry (DXA) scans. Nine consecutive patients undergoing callotasis were studied. Bending stiffness of the distraction segment was measured and DXA scans were performed regularly starting 6 weeks after completing distraction. In all, 23 simultaneous readings of bending stiffness and DXA scans were obtained. All density patterns showed a distinct minimum value of bone mineral density. We found a high and significant correlation between fracture bending stiffness and the square of the total mineral content at the location of minimum bone density (r2 = 0.77, P < 0.001). We conclude that DXA scans can be used reliably and effectively to determine fracture bending stiffness, valuable for determining both time of frame removal and delay in union.

Trefoil factor expression in normal and diseased human salivary glands.

Trefoil factors are wound-healing peptides important in protection and healing of the human gastrointestinal tract. Their potential for therapy of gastrointestinal ulcers has been established. This study investigated the hypothesis that trefoil factors are also present in human salivary gland. Tissues from surgical biopsy specimens were collected fresh into ice and stored in liquid nitrogen. Breast, stomach, and colon constituted positive controls. Trefoil factor mRNAs were detected by reverse transcription polymerase chain reaction (RT-PCR) or by in situ hybridization (ISH) with formalin-fixed, paraffin-embedded sections. Amplified DNA fragments were ligated into pGEM-T Easy vector and used to transform competent Escherichia coli JM109, allowing sequencing to confirm identity of cloned fragments. Generation of amplifiable cDNA was confirmed using primers specific to the ubiquitously expressed abl gene. By RT-PCR, TFF1 (pS2) mRNA was detected in 14 of 15 glands, TFF3 (hITF) mRNA in 13, and TFF2 (hSP) in only 1 gland. ISH of 15 glands (7 of which had been studied by RT-PCR) showed the same pattern of expression and indicated that TFF1 mRNA was usually expressed at low levels by a few mucous cells, whereas TFF3 was produced abundantly by most mucous cells. There was no difference in patterns of expression comparing parotid, submandibular, and minor mucous glands. Nor was there an obvious relationship between trefoil factor expression and pathology, but those glands not expressing TFF1 or TFF3 had evidence of chronic inflammation or atrophy. Trefoil factors are likely to be important in healing, predisposition to, and therapy of, oral diseases.

Expression of beta-defensin genes by human salivary glands.

This study investigated expression of genes encoding human beta-defensins 1 and 2 by human salivary glands. Tissues from surgical biopsies were collected fresh onto ice and stored in liquid nitrogen. Total RNA was extracted using Trizol reagent and human beta-defensin messenger RNA detected by reverse transcriptase polymerase chain reaction amplification. DNA sequencing of amplified fragments, after ligation into pGEM-T Easy vector and transformation of competent Escherichia coli, confirmed identities of cloned fragments. Human beta-defensin 1 messenger RNA was detected in all 25 samples that generated amplifiable cDNA, as assessed using abl-specific primers. Three of 13 submandibular gland samples (two normal, one chronically inflamed), and 2 of 2 minor salivary gland samples (one normal, one chronically inflamed) expressed human beta-defensin 2 messenger RNA. All six parotid gland samples studied were negative for human beta-defensin 2 messenger RNA. Thus, human beta-defensin 1 gene expression occurred in all human major and minor salivary glands studied, whereas human beta-defensin 2 expression occurred only in a small number of gland samples.

A homogeneous method to quantify mRNA levels: a hybridization of RNase protection and scintillation proximity assay technologies.

A novel method to measure mRNA levels has been developed by combining the detection capabilities of RNase protection (RPA) with the quantification advantages of scintillation proximity assay (SPA) technology. Sample processing is reduced to the addition of a single reagent post RNase digestion. As a model system, the inducible expression of rat apolipoprotein-A1 mRNA has been measured by both traditional gel-based RPAs and the SPA-based RPA assay. Results demonstrate that the ribonuclease protection proximity assay (RiPPA) faithfully reproduces the gel-based results and is at least as sensitive as many existing methods.

Protein kinase C-delta associates with vimentin intermediate filaments in differentiated HL60 cells.

The subcellular localization of protein kinase C (PKC)-delta was determined in HL60 cells differentiated toward monocytes/macrophages by treatment with TPA. PKC-delta was detected in the nucleus and cytoplasm of differentiated HL60 cells and, more specifically, associated with structures resembling intermediate filaments. Indirect immunostaining revealed that PKC-delta colocalized with vimentin in the cytosol and perinuclear region of these cells. Immunoprecipitation studies showed that PKC-delta was in an active (autophosphorylated) state in differentiated HL60 cells and that vimentin immunoprecipitated from these cells was also phosphorylated. Treatment of HL60 cells with the PKC-specific inhibitor chelerythrine decreased the phosphorylation of vimentin. These data suggest that vimentin is a substrate for PKC-delta and that this PKC isoenzyme may play a specific role in the regulation of shape change and cell adhesion during HL60 differentiation.