Tyrosine kinase B protein expression is reduced in the cerebellum of patients with bipolar disorder

Background

The role of the cerebellum in coordinating mental activity is supported by its connections with cerebral regions involved in cognitive/affective functioning, with decreased activities on functional neuroimaging observed in the cerebellum of schizophrenia patients performing mental tasks. Brain-derived neurotrophic factor (BDNF)-induced activation of tyrosine kinase B (TrkB) is essential to synaptic plasticity. We hypothesized that alterations in BDNF and TrkB expression in the cerebellum were associated with schizophrenia and affective disorders.

Methods

We employed immunohistochemistry and immunoblotting to quantify protein expression of BDNF and TrkB in the cerebellum of patients with schizophrenia, bipolar disorder, and major depression compared to controls (n = 15 each).

Results

While TrkB immunoreactivity in each of the molecular and granule-cell layers was reduced in all 3 disease groups (12-34%) compared to the control (P = 0.018 and 0.038, respectively, ANOVA), only the reduction in bipolar disorder remained statistically significant upon Tukey-Kramer post hoc analyses (P = 0.019 and 0.021, respectively). Apparent decreases in BDNF immunoreactivity in all 3 disease groups (12-30%) compared to the control were not statistically significant. TrkB immunoreactivity was not significantly associated with any of the demographic, clinical, and postmortem variables. Immunoblotting displayed an 85-kDa TrkB-immunoreactive band, consistent with a truncated isoform, in all 60 cases.

Limitations

On immunoblotting, apparent decreases in 85-kDa-TrkB levels in all 3 disease groups compared to the control were not statistically significant.

Conclusions

Our finding of reduced TrkB expression in bipolar disorder suggests that dysregulation of TrkB-mediated neurotrophin signaling in the cerebellum may play a role in the pathophysiology of this disease.     

Protocadherin PCDH10, involved in tumor progression,is a frequent and early target of promoter hypermethylation in cervical cancer

Cervical cancer (CC) is the second most common cancer in women. Currently, no tractable molecular‐based therapeutic targets exist for patients with invasive CC and no predictive markers of risk assessment for progression of precancerous lesions are identified. New molecular insights into CC pathogenesis are urgently needed. Towards this goal, we first determined the copy number alterations of chromosome 4 and then examined the role of PCDH10 mapped to 4q28 as a candidate tumor suppressor gene. We identified monosomy 4 in 47% of 81 invasive CC studied by SNP array and found that 91% of 130 invasive CC harboring methylation in the promoter region of the PCDH10 gene. We then showed that aberrant promoter hypermethylation of PCDH10 is associated with downregulation of gene expression and cell lines exposed to demethylating agent resulted in profound reactivated gene expression. We also showed that the promoter methylation in the PCDH10 gene occurs at an earliest identifiable stage of low‐grade squamous intraepithelial lesion. Our studies demonstrate that inactivation of PCDH10 may be a critical event in CC progression and form a potentially useful therapeutic target for CC. © 2009 Wiley‐Liss, Inc.     

Auditory development in progressive motor neuronopathy mouse mutants

The present study was performed to elucidate the hearing development in the progressive motor neuronopathy (pmn) mouse mutant. This mouse has been used as a model for human motoneuron disease. A missense mutation in the tubulin-specific chaperon E (Tbce) gene on mouse chromosome 13 was localized as the underlying genetic defect. The protein encoded by the Tbce gene is essential for the formation of primary tubulin complexes. Studies on motoneurons show disorganization in microtubules and disturbed axonal transport, followed by retrograde degeneration of the motoneurons. A similar pathomechanism is also possible for hearing disorders where disrupted microtubules could cause functional deficits in spiral ganglion neurons or in cochlear hair cells. Click auditory brainstem response (ABR) audiometry in homozygous pmn mutants showed a normal onset of hearing, but an increasing hearing threshold from postnatal day 26 (P26) on to death, compared to heterozygous mutants and wild-type mice. Histological sections of the cochlea at different ages showed a regular morphology. Additionally, spiral ganglion explants from mutant and wild-type mice were cultured. The neurite length from pmn mutants was shorter than in wild-type mice, and the neurite number/explant was significantly decreased in pmn mutants. We show that the pmn mouse mutant is a model for a progressive rapid hearing loss from P26 on, after initially normal hearing development. Heterozygous mice are not affected by this defect. With the knowledge of the well-known pathomechanism of this defect in motoneurons, a dysfunction of cellular mechanisms regulating tubulin assembling suggests that tubulin assembling plays an essential role in hearing function and maintenance.     

Prevalence of lymph nodes in the parametrium of radical vaginal trachelectomy (RVT) specimen

Objective

In order to evaluate radicality in fertility preserving surgery in women with early invasive cervical cancer we analyzed the parametrium of specimens of patients treated by radical vaginal trachelectomy for the presence of lymph nodes. We tried to identify morphologic factors associated with the presence of parametrial lymph nodes.

Methods

We analyzed surgical specimens of 112 patients who underwent radical trachelectomy between June 2004 and April 2009 at the Department of Gynecologic Oncology at Charité Campus Benjamin Franklin and Campus Mitte. All parametrial tissue was step sectioned and a total of 1878H&;E stained histological sections were analyzed.

Results

In 8 patients (7.1%) a total of 13 lymph nodes were detected. Five lymph nodes in four patients had been primarily detected by routine histological examination. In one of these patients (0.9%) a 2 mm lymph node metastasis was found. Serial sectioning revealed additional seven lymph nodes in four patients. The thickness of parametrium correlated significantly with the presence of lymph nodes in the parametrium.

Conclusion

The presence of small lymph nodes in the parametrium of specimens of radical trachelectomy is low. In patients with early-stage cervical cancer, the incidence of metastasis is less than 1%. Preoperative assessment of the volume of the parametrium may indicate which patients need parametrial resection.     

Visual imagery and functional connectivity in blindness: a single-case study

We present a case report on visual brain plasticity after total blindness acquired in adulthood. SH lost her sight when she was 27. Despite having been totally blind for 43 years, she reported to strongly rely on her vivid visual imagery. Three-Tesla magnetic resonance imaging (MRI) of SH and age-matched controls was performed. The MRI sequence included anatomical MRI, resting-state functional MRI, and task-related functional MRI where SH was instructed to imagine colours, faces, and motion. Compared to controls, voxel-based analysis revealed white matter loss along SH’s visual pathway as well as grey matter atrophy in the calcarine sulci. Yet we demonstrated activation in visual areas, including V1, using functional MRI. Of the four identified visual resting-state networks, none showed alterations in spatial extent; hence, SH’s preserved visual imagery seems to be mediated by intrinsic brain networks of normal extent. Time courses of two of these networks showed increased correlation with that of the inferior posterior default mode network, which may reflect adaptive changes supporting SH’s strong internal visual representations. Overall, our findings demonstrate that conscious visual experience is possible even after years of absence of extrinsic input.     

视网膜母细胞瘤眼球的病理取材方法

目的：探讨视网膜母细胞瘤病理标本的不同取材方法对脉络膜浸润检出率的影响，寻求理想的常规取材方法。方法：复查297只原发摘除的视网膜母细胞瘤眼球的病理切片，比较五平面取材法（151只眼）和单平面取材法（146只眼）对脉络膜浸润的检出率。结果：五平面取材法对脉络膜浸润的检出率（31％）明显高于单平面取材法（17％），且主要是对玻璃膜在肿瘤细胞影响下发生变化的检出率高。脉络浸润的各期都主要分布在五平面取材法的各平面上。结论：五平面取材法能提供判断视网膜母细胞瘤患者预后的较大量病理信息，在日常医疗工作中从人力、物力、财力上能够承受，可作为常规取材方法应用于临床。连续切片取材只作为在特殊情况下对五平面取材法的补充。单平面取材法有可能丢失一些重要的病理信息而应由五平面取材法代替。     

Efficacy of 5-week doxycycline treatment on adult Onchocerca volvulus

The effects of 5-week doxycycline treatment on the depletion of Wolbachia endobacteria from Onchocerca volvulus, on the interruption of embryogenesis and on microfilariae production, and with regard to macrofilaricidal activity were studied. In 2003, in an endemic area in Ghana, 22 onchocerciasis patients received 100 mg/day doxycycline for 5 weeks. Two years after the start of the study, 20 treated and ten untreated patients were nodulectomized and skin microfilariae were counted. The onchocercomas were examined by immunohistology for the presence of Wolbachia, embryogenesis, and vitality of adult filariae. The latter two parameters were further assessed by alternating logistic regression analysis, taking into account the dependency of worms and nodules in patients. Doxycycline resulted in depletion of Wolbachia and in complete interruption of embryogenesis in all worms that were assumed to have been present during treatment. In the treated patients, only 51% of the female worms were alive, compared to 84% in the untreated patients, indicating a moderate but distinct macrofilaricidal activity of doxycycline at this dose. It is concluded that, in areas with ongoing transmission, doxycycline cannot replace regular ivermectin mass treatment because new infections would require repeated rounds of doxycycline. However, doxycycline can be used for the treatment of individuals outside transmission areas, in foci where ivermectin resistance may occur, and in countries where onchocerciasis and loiasis are co-endemic.     

Biometrical analysis of the shoulder joint regarding glenoid implant dimensions for arthroplasty

Purpose

Reduced bone stock and difficult intraoperative orientation are challenges in glenoid replacement surgery. New implant designs and methods for fixation, such as locking screws, extra-long central pegs and/or central compression screws are targeting these issues. The objective of this study is the analysis of the glenoid dimension regarding maximum central peg diameter and peg length (PL), and maximum screw length (SL) for glenoid fixation.

Methods

Retrospective analysis of magnetic resonance imaging (n = 50) scans. Measurement of the maximum inferior glenoid diameter (GD), SL, maximum length of a 9.9, 10 and 11.4 mm central peg (PL) in the transverse plane; glenoid version (GV), humeral head diameter (HHD). Two independent measurements.

Results

Mean age: 49.0 ± 15.7 years (17–80) (n = 20 female, 49.6 ± 16.0; n = 30 male, 48.6 ± 15.7). Mean values of measurement were GD: 28.9 ± 3.7 mm (21–39); SL: 34.1 ± 4.9 mm (26–44); PL 9.9 mm: 19.4 ± 4.3 mm (9–30); PL 10 mm: 19.0 ± 4.4 mm (8–30); PL 11.4 mm: 16.5 ± 4.1 mm (7–26) with significant gender differences (p = 0.001; p = 0.022; p = 0.001); GV: ?0.6° ± 4.9° (?10 to 11); HHD: 50.0 mm ± 4.9 (41–61). There was good correlation between PL and SL (r = 0.32, p = 0.024) and for GD and PL (r = 0.61, p = 0.001; r = 0.57, p = 0.001; r = 0.96, p = 0.001). The ratio of HHD and GD was very constant with 0.6 ± 0.07.

Conclusions

These data indicate the high interindividual variability of glenoid morphology including significant gender-related differences. The good correlation between humeral head size and GD and maximum central PL can be helpful for cases with reduced bone stock in decision-making about implant size and bone grafting.     

PLAG1 immunohistochemistry is a sensitive marker for pleomorphic adenoma: a comparative study with PLAG1 genetic abnormalities

Aims

Pleomorphic adenoma gene 1 (PLAG1) gene rearrangement is the most common genetic abnormality in pleomorphic adenoma (PA), resulting in overexpression of PLAG1 protein. PA and carcinoma ex pleomorphic adenoma (CA ex‐PA) can mimic various benign and malignant salivary gland tumours. The aims of this study are to evaluate the sensitivity and specificity of PLAG1 immunohistochemistry (IHC) in the differential diagnosis of PA and CA ex‐PA and to compare the PLAG1 immunohistochemical results to PLAG1 gene abnormalities as detected by fluorescence in‐situ hybridisation (FISH).

Methods and results

PLAG1 immunostaining was performed on 83 salivary gland tumours, including 23 PA, 15 CA ex‐PA and 45 other salivary gland tumours. In addition, PLAG1 FISH was performed in 44 cases for the presence of gene rearrangements/amplifications. The results showed high sensitivity of PLAG1 IHC in 96% of PA; however, discordant results between PLAG1 FISH abnormalities and IHC were noted in 15 of 44 cases (34%). Seven PA, four de‐novo myoepithelial carcinomas and one basal cell adenocarcinoma had negative FISH results, but were positive for IHC; while three salivary duct carcinomas (SDC) ex‐PA were positive for FISH but negative for IHC. PLAG1 IHC can differentiate CA ex‐PA from de‐novo SDC (P = 0.02), but not from de‐novo myoepithelial carcinoma. PLAG1 IHC is a sensitive marker for PA. This could be due to PLAG1 gene abnormalities beyond FISH resolution.

Conclusions

A negative PLAG1 IHC might be helpful in excluding a PA diagnosis. Interestingly, in the context of CA ex‐PA, FISH is more sensitive than IHC in detecting PLAG1 abnormalities.