Extended stereotactic brain biopsy in suspected primary central nervous system angiitis: good diagnostic accuracy and high safety

Journal of Neurology - To evaluate the diagnostic accuracy and safety of extended stereotactic brain biopsy (ESBB) in a single center cohort with suspected primary angiitis of the central nervous...     

Cervical artery dissection goes frequently undiagnosed

Cervical artery dissection (CeAD) is a frequent cause of stroke among young patients. It is unclear how many CeADs occur asymptomatically or cause subtle and unspecific clinical symptoms. We hypothesize that CeAD remains often unrecognized. Accordingly, the incidence of CeAD might be higher and the stroke risk lower than generally assumed. Lack of CeAD-indicating clinical symptoms is regarded as the main cause of missed diagnoses. We further hypothesize that underrepresentation of asymptomatic and oligosymptomatic patients in CeAD studies may have biased the association between ischemia and local symptoms in CeAD patients as well as the associations of CeAD with risk factors or co-morbidities. We finally hypothesize that symptomatic CeAD may be preceded by an initial asymptomatic phase. According to this final hypothesis, the time of onset of CeAD should be considered uncertain. The issue of unrecognized CeAD is relevant, as it may affect the associations between CeAD and putative risk factors. Furthermore, the existence of clinically silent CeADs may explain why recurrent and familial CeAD have been rarely observed.     

Tumor–microenvironment interactions studied by zonal transcriptional profiling of squamous cell lung carcinoma

Invasion is a critical step in lung tumor progression. The interaction between tumor cells and their surroundings may play an important role in tumor invasion and metastasis. To better understand the mechanisms of tumor invasion and tumor–microenvironment interactions in lung tumors, total RNA was isolated from the inner tumor, tumor invasion front, adjacent lung, and distant normal lung tissue from 17 patients with primary squamous cell lung carcinoma using punch‐aided laser capture microdissection. Messenger RNA expression profiles were obtained by microarray analysis, and microRNA profiles were generated from eight of these samples using TaqMan Low Density Arrays. Statistical analysis of the expression data showed extensive changes in gene expression in the inner tumor and tumor front compared with the normal lung and adjacent lung tissue. Only a few genes were differentially expressed between tumor front and the inner tumor. Several genes were validated by immunohistochemistry. Evaluation of the microRNA data revealed zonal expression differences in nearly a fourth of the microRNAs analyzed. Validation of selected microRNAs by in situ hybridization demonstrated strong expression of hsa‐miR‐196a in the inner tumor; moderate expression of hsa‐miR‐224 in the inner tumor and tumor front, and strong expression of hsa‐miR‐650 in the adjacent lung tissue. Pathway analysis placed the majority of genes differentially expressed between tumor and nontumor cells in intrinsic processes associated with inflammation and extrinsic processes related to lymphocyte physiology. Genes differentially expressed between the inner tumor and the adjacent lung/normal lung tissue affected pathways of arachidonic acid metabolism and eicosanoid signaling. © 2012 Wiley Periodicals, Inc.     

Inhibition of apoptosis by the intrinsic but not the extrinsic apoptotic pathway in myocardial ischemia-reperfusion

SummaryThe detailed molecular mechanisms following activation of apoptosis in ischemia-reperfusion injury are unknown. This study using different transgenic mouse models provided first evidence that apoptosis in myocardial ischemia-reperfusion injury is rather linked to the mitochondrial pathway than to death receptor pathway.IntroductionThere is a wealth of evidence for activation of apoptosis in ischemia-reperfusion injury. However, the understanding of detailed molecular mechanism is lacking.MethodsThe extent of myocardial infarction after ligation of the left anterior descending artery in mice carrying different transgenes for inhibition of either the intrinsic or the extrinsic or a combination of both apoptotic cascades was evaluated. The extent of myocardial damage was assessed by echocardiographic determination of left ventricular (LV) ejection fraction, LV hemodynamics, troponin T, and histology. The rate of apoptosis was analyzed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase-3 staining.ResultsHighest perioperative rate of death was observed in the dominant-negative form of a truncated Fas-associated death domain (FADD-DN) group. Infarction size by 2,3,5-triphenyltetrazolium chloride (TTC) staining was smaller in the Bcl-2, but not in the other groups as compared to wild-type mice. This was accompanied by lower troponin T values in Bcl-2 transgenic mice as compared to the all other groups. Troponin T correlated well with macroscopic extent of myocardial infarction by TTC staining. A lower decline of LV ejection fraction was seen in the Bcl-2 as compared to wild-type or FADD-DN mice. A smaller number of TUNEL- and caspase-3-positive myocyte nuclei were observed in the Bcl-2 and FADD-DN group as compared to wild-type mice.ConclusionsWe provide first evidence for protective effects on the myocardium in a transgenic mouse model of myocardial ischemia-reperfusion due to inhibition of the Bcl-2, but not the FADD pathway despite that reduced apoptotic cells were observed in both groups as compared to wild-type mice.     

Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele‐Specific Expression

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication‐based mechanisms such fork stalling and template switching or microhomology‐mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele‐specific LMNB1 expression levels.     

PSA bounce after <Superscript>125</Superscript>I-brachytherapy for prostate cancer as a favorable prognosticator

Background

Permanent low-dose-rate brachytherapy (BT) with iodine 125 is an established curative treatment for localized prostate cancer. After treatment, prostate-specific antigen (PSA) kinetics may show a transient rise (PSA bounce). Our aim was to investigate the association of PSA bounce with biochemical control.

Patients and methods

Patients treated with BT in Switzerland were registered in a prospective database. Only patients with a follow-up of at least 2 years were included in our analysis. Clinical follow-up and PSA measurements were assessed after 1.5, 3, 6, and 12 months, and annually thereafter. If PSA increased, additional follow-up visits were scheduled. Cases of PSA bounce were defined as a rise of at least 0.2 ng/ml above the initial PSA nadir with a subsequent decline to or below the initial nadir without treatment. Biochemical failure was defined as a rise to nadir +?2 ng/ml.

Results

Between March 2001 and November 2010, 713 patients with prostate cancer undergoing BT with at least 2 years of follow-up were registered. Median follow-up time was 41 months. Biochemical failure occurred in 28 patients (3.9?%). PSA bounce occurred in 173 (24.3?%) patients; only three (1.7?%) patients with PSA bounce developed biochemical failure, in contrast to 25 (4.6?%) patients without previous bounce (p?<?0.05). The median time to bounce was 12 months, the median time to biochemical failure was 30 months. The median bounce increase was 0.78 ng/ml. Twenty-eight patients with bounce (16.5?%) had a transient PSA rise of +?2 ng/ml above the nadir.

Conclusion

In most cases, an early increase in PSA after BT indicates PSA bounce and is associated with a lower risk of biochemical failure.

     

In vitro and in vivo evaluation of heparin mediated growth factor release from tissue‐engineered constructs for anterior cruciate ligament reconstruction

Anterior cruciate ligament (ACL) rupture is a common injury often necessitating surgical treatment with graft reconstruction. Due to limitations associated with current graft options, there is interest in a tissue‐engineered substitute for use in ACL regeneration. While they represent an important step in translation to clinical practice, relatively few in vivo studies have been performed to evaluate tissue‐engineered ACL grafts. In the present study, we immobilized heparin onto electrospun polycaprolactone scaffolds as a means of incorporating basic fibroblast growth factor (bFGF) onto the scaffold. In vitro, we demonstrated that human foreskin fibroblasts (HFFs) cultured on bFGF‐coated scaffolds had significantly greater cell proliferation. In vivo, we implanted electrospun polycaprolactone grafts with and without bFGF into athymic rat knees. We analyzed the regenerated ACL using histological methods up to 16 weeks post‐implantation. Hematoxylin and eosin staining demonstrated infiltration of the grafts with cells, and picrosirius red staining demonstrated aligned collagen fibers. At 16 weeks postop, mechanical testing of the grafts demonstrated that the grafts had approximately 30% the maximum load to failure of the native ACL. However, there were no significant differences observed between the graft groups with or without heparin‐immobilized bFGF. While this study demonstrates the potential of a regenerative medicine approach to treatment of ACL rupture, it also demonstrates that in vitro results do not always predict what will occur in vivo. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:229–236, 2015.     

Relationship Between Minor Myocardial Damage and Inflammatory Acute-Phase Reaction in Acute Coronary Syndromes

Background: In severe acute coronary syndromes (ACS) elevation of markers of inflammation and acute phase reaction (APR) like C-reactive protein (CRP) as well as a release of troponin have been reported.Using a high sensitivity troponin T (TnT) test we investigated whether an APR occurs in ACS only in the presence of ischemic myocardial damage. Methods: In 85 patients with ACS C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, thrombin antithrombin III complexes (TAT) and kallikrein were determined vs. high sensitive TnT (0.02 ng/ml) initially and 2 d later vs. 45 patients with stable angina pectoris and 42 controls. Results: In stable angina pectoris, markers of inflammation and coagulation were slightly elevated (p < 0.05). Initially in ACS elevations of CRP to 1.2 ± 0.3 mg/dl, SAA to 4.8 ± 2.6 mg/dl and fibrinogen to 448 ± 21 mg/dl (all p < 0.01 vs. controls) were found followed by a significant APR (p < 0.01).In the subgroup of TnT positive ACS patients, an APR with increased CRP (4.1 ± 1.3 mg/dl), SAA (20.4 ± 8.3 mg/dl), and fibrinogen (641 ± 45 mg/dl) was detectable (all p < 0.05 vs. TnT negative patients). In contrast, patients without TnT release showed APR markers comparable to patients with stable angina pectoris. Conclusion: Our findings demonstrate an association between myocardial injury in ACS and acute phase reaction as evidenced by several molecular markers. A highly sensitive TnT-test identified myocardial inury in about all patients with APR while a standard TnT cut-off (0.1 ng/ml) missed 32% of these patients. Thus, the APR in patients with ACS is strongly associated with at least minor ischemic myocardial damage and prior findings of an APR independent from myocardial injury are probably based on less sensitive troponin tests.