The Effects of botulinum toxin A on muscle histology during distraction osteogenesis

Distraction osteogenesis is a highly successful method of bone formation, yet muscle fibrosis and contractures can result in significant morbidity. In the current study, we investigate the efficacy of botulinum toxin A in preventing fibrosis and potentially increasing muscle development in distracted muscles. Fifteen New Zealand White rabbits underwent tibial distraction at 1.5 mm/day until a 20% gain was achieved. Treatment groups were divided by drug (saline or botulinum toxin) and target muscle (gastrocnemius or tibialis anterior). Two additional control animals received no treatment. Bromeodeoxyuridine was delivered continuously throughout the 8‐week experiment, and following muscle harvest. Tissues were stained for BrdU, Pax‐7, vimentin, and haematoxylin and eosin staining. Mitotic activity increased in all distracted animals; however, in the animals receiving botulinum toxin A injections into the gastrocnemius, the antagonist tibialis anterior suffered up to 9% less fibrosis than distraction alone (p = 0.024). Use of botulinum A toxin did not appear to promote or improve neogenesis of muscle fibers, nor did it decrease fibrosis in the injected muscles. It appears from this study, and a previously published study on the effects of this toxin on muscle function, that botulinum A toxin maybe of some benefit in decreasing morbidity in the antagonist muscle but not the muscle injected with the toxin. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:310–317, 2009     

Good outcome after liver transplantation for ALD without a 6 months abstinence rule prior to transplantation including post‐transplant CDT monitoring for alcohol relapse assessment – a retrospective study

Alcoholic liver disease (ALD) is the second most common indication for liver transplantation (LT). The utility of fixed intervals of abstinence prior to listing is still a matter of discussion. Furthermore, post‐LT long‐term observation is challenging, and biomarkers as carbohydrate‐deficient transferrin (CDT) may help to identify alcohol relapse. We retrospectively analyzed data from patients receiving LT for ALD from 1996 to 2012. A defined period of alcohol abstinence prior to listing was not a precondition, and abstinence was evaluated using structured psychological interviews. A total of 382 patients received LT for ALD as main (n = 290) or secondary (n = 92) indication; median follow‐up was 73 months (0–213). One‐ and five‐year patient survival and graft survival rates were 82% and 69%, and 80% and 67%, respectively. A total of 62 patients (16%) experienced alcohol relapse. Alcohol relapse did not have a statistically significant effect on patient survival (P = 0.10). Post‐transplant CDT measurements showed a sensitivity and specificity of 84% and 85%, respectively. In conclusion, this large single‐center analysis showed good post‐transplant long‐term results in patients with ALD when applying structured psychological interviews before listing. Relapse rates were lower than those reported in the literature despite using a strict definition of alcohol relapse. Furthermore, post‐LT CDT measurement proved to be a useful supplementary tool for detecting alcohol relapse.     

Vascular damage as a risk factor for benign prostatic hyperplasia and erectile dysfunction

OBJECTIVE: To assess benign prostatic hyperplasia (BPH) and erectile dysfunction (ED), both considered to be associated with urogenital ageing, in ageing men in a cross-sectional population study, comparing them with healthy controls by using symptom scores and contrast-enhanced colour Doppler ultrasonography (CDUS). PATIENTS, SUBJECTS AND METHODS: Transrectal CDUS and quantitative measurement of colour pixel intensity (CPI) are excellent minimally invasive techniques for assessing normal and pathological blood flow. CDUS was performed using the microbubble-based ultrasound enhancer for evaluating prostate, bladder neck and corpus cavernosum vascularity in young healthy men, men with BPH, and men with severe vascular damage (diabetes mellitus type 2). Resistive index measurements and computer-assisted quantification of CPI were used to objectively evaluate perfusion. The International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF) were applied to quantify the symptoms. RESULTS: In patients with BPH, perfusion of the transition zone (TZ) of the prostate was significantly lower and the resistive index of the TZ significantly higher (both P < 0.001) than in healthy controls. The perfusion patterns of men with BPH and those who also had severe vascular damage (diabetes mellitus type 2) showed that vascularity in the latter group was lower in the prostatic TZ and the corpora cavernosa. In patients with BPH the IPSS, quality-of-life and IIEF scores were significantly worse than in the control group. Men with concomitant atherosclerosis had even worse symptom scores. CONCLUSION: These results strongly support the hypothesis that age-related impairment of blood supply to the lower urinary tract is important in the development of BPH and ED. Vascular damage may cause chronic ischaemia and thus be a contributing factor in the pathogenesis of BPH and ED.     

MRT bei Myokarditis

Cardiovascular magnetic resonance imaging (CMRI) has become the primary tool for the non-invasive assessment in patients with suspected myocarditis, especially after exclusion of acute coronary syndrome (ACS) for the differential diagnosis. Various MRI parameters are available which have different accuracies. Volumetric and functional ventricular assessment and the occurrence of pericardial effusion alone demonstrate only a poor sensitivity and specificity. The calculation of the T2-ratio (edema assessment), the early or global relative myocardial enhancement (gRE) and the late gadolinium enhancement (LGE), which represents irreversibly injured myocardium, are more specific parameters. All MRI parameters demonstrate the best accuracy in infarct-like acute myocarditis, whereas in chronic myocarditis sensitivity and specificity are less accurate. Therefore, a multisequential (at least two out of three parameters are positive) approach is recommended. The assessment of the value of newer, more quantitative MRI sequences, such as T1 and T2-mapping is still under investigation.     

Prednisone metabolism in recipients of kidney or liver transplants and in lung recipients receiving ketoconazole

BACKGROUND: Actual prednisone exposure in low-dose prednisone regimens, in part determined by cytochrome P450 metabolism, has been shown to be important for allograft survival. METHODS: Prednisolone (the principal active metabolite of prednisone) metabolism was determined in eight nontransplant patients and in transplant recipients receiving oral prednisone maintenance therapy (20 kidney and 6 liver recipients receiving cyclosporine [CsA] and eight lung recipients receiving ketoconazole and CsA or tacrolimus [FK506]). RESULTS: Prednisolone area under the curve (AUC)-dose-normalized (PNAUCn) to 1 mg/kg was 8,288+/-1,513 ng.hr/mL in kidney recipients, versus 4,826+/-999 ng/mL per hr in healthy subjects (P<0.001); it was also increased in liver recipients versus healthy subjects (11,456+/-1,214 ng.hr/mL, P<0.001). Liver recipients also metabolized prednisolone more slowly than kidney recipients (P<0.001). PNAUCn in lung recipients was similar in kidney recipients despite the effect of ketoconazole to slow CsA metabolism. In kidney transplant recipients, the rate of CsA metabolism was correlated with the rate of prednisolone metabolism (r=0.54, P=.026). Basal cortisol levels in all transplant recipients were lower than in healthy subjects, suggesting more prednisolone exposure in transplant patients. CONCLUSIONS: Prednisolone metabolism is slower in solid-organ transplant recipients than in healthy subjects. The slower metabolism of prednisolone, particularly in liver recipients, may help explain the immunologic effectiveness of low-dose prednisone regimens in these patients.     

Early results of bladder-cancer screening in a high-risk population of heavy smokers

OBJECTIVE

To report first results of an early bladder‐cancer detection programme, and to evaluate the detection rate and the diagnostic value of the tests used.

SUBJECTS AND METHODS

Urine samples of 183 screened subjects with a history of smoking of ≥40 pack‐years were collected for analysis with a urinary dipstick test for haematuria, the nuclear matrix protein‐22 test (BladderChek®, Matritech, Inc., Newton, MA, USA), voided urine cytology and a molecular cytology test (UroVysion, Abbott Molecular Inc., Des Plaines, IL, USA). Participants with at least one positive test result had a further evaluation including cystoscopy and radiological imaging. The subjects’ risk factors, test results and histological findings were analysed.

RESULTS

In all, 75 subjects had at least one positive test result and were evaluated further; abnormal histological findings were detected in 18 (24% of those who had cystoscopy, 9.8% of the original 183), 15 of those in the urinary bladder, with pTaG1 (one), carcinoma in situ (two), dysplastic lesions (11) and one an inverted papilloma. In the upper urinary tract, two urothelial tumours (pTaG1 and pTxN2G3) and one renal cell carcinoma (pT1G2) were detected by computed tomography. In summary, six of 183 subjects (3.3%) had a histologically confirmed malignant tumour and another 12 (6.6%) were identified with a possible pre‐cancerous lesion of the urinary tract. The urinary dipstick, BladderChek, cytology and UroVysion detected (i.e. were true‐positive in) nine (50%), one (6%), seven (39%) and 11 (61%) of the 18 tumours found, while they failed to detect nine (50%), 17 (94%), 11 (61%) and seven (39%) of these lesions, respectively. Omitting the urine dipstick test, the BladderChek, cytology or UroVysion from the test setting could have spared 40, five, two or one subjects(s) from unnecessary invasive interventions; however, three, none, two or six lesions, would have been missed. More positive screening tests per subject was associated with a higher probability of a (pre)‐malignant lesion.

CONCLUSION

Screening a high‐risk group with a history of smoking of ≥40 pack‐years showed a significant proportion (3.3%) with malignancy. These first results are encouraging and warrant continuation of the screening programme. In this series the most efficient screening tool was the combination of UroVysion, cytology and urinary dipstick testing. Of special scientific interest will be the follow‐up of those patients with a possible pre‐cancerous lesion.     

Pathological features of Gleason score 6 prostate cancers in the low and intermediate range of prostate‐specific antigen level: is there a difference?

OBJECTIVE

To assess the pathological features of Gleason score 6 prostate cancers after radical prostatectomy in the low (<4 ng/mL) and intermediate range of prostate‐specific antigen level (4–10 ng/mL), as such prostate cancers are considered to be well differentiated tumours with a low risk for recurrence after therapy.

PATIENTS AND METHODS

In all, 1354 patients with T1c prostate cancer and PSA levels of <10.0 ng/mL had a radical retropubic prostatectomy. Patients with Gleason score 6 tumours were divided into two groups, those with PSA levels of <4 and 4.0–10.0 ng/mL. Extracapsular extension, positive surgical margins, biochemical recurrence (BCR) and mean time to BCR were evaluated.

RESULTS

Of the 1354 patients, there were 437 (32.3%) with Gleason score 6 prostate cancers. Patients in the low PSA group had less extraprostatic disease than those with a higher level (5.9% vs 14.5%) and both groups had an almost equal proportion of positive surgical margins (9.4% vs 11.0%). In the low PSA group there was statistically significantly shorter BCR than in the high PSA group, with a mean time to BCR of 1.7 vs 3.1 years.

CONCLUSIONS

These results show a statistically significantly higher rate of extraprostatic disease and earlier BCR in men with a high than a low PSA level even in Gleason score 6 prostate cancer. As the rate of BCR and extracapsular extension are significantly related to prostate cancer mortality, these findings further support the concept of screening using low PSA levels.     

S-Classification of Sentinel Lymph Node Predicts Axillary Nonsentinel Lymph Node Status in Patients with Breast Cancer

Background One-half of breast cancer patients with positive sentinel lymph node (SN) have no further metastases in the axillary lymph node basin. The aim of the present study was to identify patients with positive SN who are unlikely to have further metastases in the axillary lymph node basin, using a new classification of SN, namely the S-classification. Methods Specimens of positive SN were subjected to a pathological review according to the previously published S-classification. S-stages of positive SN were correlated with the status of further metastases in the axillary lymph node basin after axillary lymph node dissection (ALND). Results Of 117 patients who underwent sentinel lymph node biopsy, 36 (30.8%) had a positive SN and were subjected to level I and II ALND. The occurrence of positive nonsentinel nodes was significantly related to the S-stage of SN. No patient with stage SI had additional metastases in the nonsentinel lymph nodes, while 14.3% of patients with SII stage disease and 60.9 % of patients with SIII disease had other non-SN that were metastatic. Conclusion S-stages of positive SN are highly predictive for axillary nonsentinel node status. Especially patients with SI sentinel node metastases appear to be at low risk for further nonsentinel node metastases.     

Gamma Knife surgery for adrenocorticotropic hormone-producing pituitary adenomas after bilateral adrenalectomy

OBJECT: Patients with adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas may require a bilateral adrenalectomy to treat their Cushing's disease. Approximately one third of these patients, however, will experience progressive enlargement of the residual pituitary adenoma, develop hyperpigmentation, and have an elevated level of serum ACTH. These patients with Nelson's syndrome can be treated with Gamma Knife surgery (GKS). METHODS: The prospectively collected University of Virginia Gamma Knife database of patients with pituitary adenomas was reviewed to identify all individuals with Nelson's syndrome who were treated with GKS. Twenty-three patients with a minimum of 6 months of follow up were identified in the database. These patients were assessed for tumor control (that is, lack of tumor growth over time) with neuroimaging studies (median follow-up duration 22 months) and for biochemical normalization of their ACTH levels (median follow-up duration 50 months). Neuroimaging follow-up studies were available for 22 patients, and endocrine follow up was available for 15 patients in whom elevation of ACTH levels was documented prior to GKS. In the 22 patients in whom neuroimaging follow-up studies were available, 12 had a decrease in tumor size, eight had no tumor growth, and two had an increase in tumor volume. Ten of 15 patients with elevated ACTH levels prior to GKS showed a decrease in their ACTH levels at last follow up; three of these 10 patients achieved normal ACTH levels (< 50 pg/ml) and the other five patients with initially elevated values had an increase in ACTH levels. Ten patients were thoroughly evaluated for post-GKS pituitary function; four were found to have new pituitary hormone deficiency and six did not have hypopituitarism after GKS. One patient suffered a permanent third cranial nerve palsy and four patients are now deceased. CONCLUSIONS: Gamma Knife surgery may control the residual pituitary adenoma and decrease ACTH levels in patients with Nelson's syndrome. Delayed hypopituitarism or cranial nerve palsies can occur after GKS. Patients with Nelson's syndrome require continued multidisciplinary follow-up care. Given the difficulties associated with management of Nelson's syndrome, even the modest results of GKS may be helpful for a number of patients.