Immune activation in amyloid-ß-related angiitis correlates with decreased parenchymal amyloid-ß plaque load.

BACKGROUND: Primary angiitis of the central nervous system (PACNS) is a rare but serious condition. A fraction of patients suffering from PACNS concurrently exhibit pronounced cerebral amyloid angiopathy (CAA) which is characterized by deposits of amyloid-ß (Aß) in and around the walls of small and medium-sized arteries of the brain. PACNS with CAA has been identified as a distinct disease entity, termed Aß-related angiitis (ABRA). Evidence points to an immune reaction to vessel wall Aß as the trigger of vasculitis. OBJECTIVE: To investigate whether the inflammatory response to Aß has (1) any effect on the status of immune activation in the brain parenchyma and (2) leads to clearance of Aß from brain parenchyma. METHODS: We studied immune activation and Aß load by quantitative immunohistochemical analysis in brain parenchyma adjacent to affected vessels in 11 ABRA patients and 10 matched CAA controls. RESULTS: ABRA patients showed significantly increased immune activation and decreased Aß loads in the brain parenchyma adjacent to affected vessels. CONCLUSION: Our results are in line with the hypothesis of ABRA being the result of an excessive immune response to Aß and show that this can lead to enhanced clearance of Aß from the brain parenchyma by immune-mediated mechanisms.

Association of exercise-induced hyperinsulinaemic hypoglycaemia with MCT1-expressing insulinoma.

AIMS/HYPOTHESIS: Exercise-induced hyperinsulinism (EIHI) is a hypoglycaemic disorder characterised by inappropriate insulin secretion following anaerobic exercise or pyruvate load. Activating promoter mutations in the MCT1 gene (also known as SCLA16A1), coding for monocarboxylate transporter 1 (MCT1), were shown to associate with EIHI. Recently, transgenic Mct1 expression in pancreatic beta cells was shown to introduce EIHI symptoms in mice. To date, MCT1 has not been demonstrated in insulin-producing cells from an EIHI patient. METHODS: In vivo insulin secretion was studied during an exercise test before and after the resection of an insulinoma. The presence of MCT1 was analysed using immunohistochemistry followed by laser scanning microscopy, western blot analysis and real-time RT-PCR of MCT1. The presence of MCT1 protein was analysed in four additional insulinoma patients. RESULTS: Clinical testing revealed massive insulin secretion induced by anaerobic exercise preoperatively, but not postoperatively. MCT1 protein was not detected in the patient's normal islets. In contrast, immunoreactivity was clearly observed in the insulinoma tissue. Western blot analysis and real-time RT-PCR showed a four- to fivefold increase in MCT1 in the insulinoma tissue of the EIHI patient compared with human pancreatic islets. MCT1 protein was detected in three of four additional insulinomas. CONCLUSIONS/INTERPRETATION: We show for the first time that an MCT1-expressing insulinoma was associated with EIHI and that MCT1 might be present in most insulinomas. Our data suggest that MCT1 expression in human insulin-producing cells can lead to EIHI and warrant further studies on the role of MCT1 in human insulinoma patients.

Long-term follow-up of high-dose chemotherapy with autologous stem-cell transplantation and response-adapted whole-brain radiotherapy for newly diagnosed primary CNS lymphoma: results of the multicenter Ostdeutsche Studiengruppe Hamatologie und Onkologie OSHO-53 phase II study.

BACKGROUND: We previously reported the results of a phase II study for patients with newly diagnosed primary central nervous system lymphoma treated with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiotherapy (WBRT). Now, we update the initial results. PATIENTS AND METHODS: From 1999 to 2004, 23 patients received high-dose methotrexate. In case of at least partial remission, high-dose busulfan/thiotepa (HD-BuTT) followed by aPBSCT was carried out. Patients refractory to induction or without complete remission after HD-BuTT received WBRT. Eight patients still alive in 2011 were contacted and Mini-Mental State Examination (MMSE) and the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 were carried out. RESULTS: Of eight patients still alive, median follow-up is 116.9 months. Only one of nine irradiated patients is still alive with a severe neurologic deficit. In seven of eight patients treated with HD-BuTT, health condition and quality of life are excellent. MMSE and QLQ-C30 showed remarkably good results in patients who did not receive WBRT. All of them have a Karnofsky score of 90%-100%. CONCLUSIONS: Follow-up shows an overall survival of 35%. In six of seven patients where WBRT could be avoided, no long-term neurotoxicity has been observed and all patients have an excellent quality of life.

[Serotonin receptor 1A-modulated dephosphorylation of glycine receptor α3: a new molecular mechanism of breathing control for compensation of opioid-induced respiratory depression without loss of analgesia]. / Die von Serotoninrezeptor 1A modulierte Dephosphorylierung des Glyzinrezeptors α3: Ein neuer molekularer Mechanismus der Atmungskontrolle zur Kompensation opioidinduzierter Atemdepression ohne Verlust der Analgesie.

To control the breathing rhythm the medullary respiratory network generates periodic salvo activities for inspiration, post-inspiration and expiration. These are under permanent modulatory control by serotonergic neurons of the raphe which governs the degree of phosphorylation of the inhibitory glycine receptor α3. The specific activation of serotonin receptor type 1A (5-HTR(1A)), which is strongly expressed in the respiratory neurons, functions via inhibition of adenylate cyclase and the resulting reduction of the intracellular cAMP level and a gradual dephosphorylation of the glycine receptor type α3 (GlyRα3). This 5-HTR(1A)-GlyRα3 signal pathway is independent of the µ-opioidergic transduction pathway and via a synaptic inhibition caused by an increase in GlyRα3 stimulates a disinhibition of some target neurons not only from excitatory but also from inhibitory neurons. Our physiological investigations show that this 5-HTR(1A)-GlyRα3 modulation allows treatment of respiratory depression due to opioids without affecting the desired analgesic effects of opioids. The molecular mechanism presented here opens new pharmacological possibilities to treat opioid-induced respiratory depression and respiratory disorders due to disturbed inhibitory synaptic transmission, such as hyperekplexia.

Structural dynamics of incommensurate charge-density waves tracked by ultrafast low-energy electron diffraction.

We study the non-equilibrium structural dynamics of the incommensurate and nearly commensurate charge-density wave (CDW) phases in 1T- TaS 2 . Employing ultrafast low-energy electron diffraction with 1 ps temporal resolution, we investigate the ultrafast quench and recovery of the CDW-coupled periodic lattice distortion (PLD). Sequential structural relaxation processes are observed by tracking the intensities of main lattice as well as satellite diffraction peaks and the diffuse scattering background. Comparing distinct groups of diffraction peaks, we disentangle the ultrafast quench of the PLD amplitude from phonon-related reductions of the diffraction intensity. Fluence-dependent relaxation cycles reveal a long-lived partial suppression of the order parameter for up to 60 ps, far outlasting the initial amplitude recovery and electron-phonon scattering times. This delayed return to a quasi-thermal level is controlled by lattice thermalization and coincides with the population of zone-center acoustic modes, as evidenced by a structured diffuse background. The long-lived non-equilibrium order parameter suppression suggests hot populations of CDW-coupled lattice modes. Finally, a broadening of the superlattice peaks is observed at high fluences, pointing to a non-linear generation of phase fluctuations.

[Rare cause of hypercalcemia]. / Seltene Differenzialdiagnose einer schweren Hyperkalzämie.

We report a 47-year-old women who presented to her general practitioner and our hospital with weight loss of unknown etiology. Eight years previously she had undergone a hemithyroidectomy for nodular goiter with one cold nodule. Laboratory results revealed hypercalcemia, evidence of primary hyperparathyroidism and computer tomography of the thorax showed bilateral pulmonary metastasis. After undergoing CT-guided biopsy of a metastasis, histology revealed an endocrine primary tumor with low parathyroid hormone expression. In view of the history, clinical and biochemical findings we diagnosed a recently metastasized functioning parathyroid carcinoma, which eight years previously has been labeled as a benign atypical thyroid adenoma. The patient underwent surgical resection of all detected metastases. Afterwards the serum calcium and parathyroid hormone levels normalized. Parathyroid carcinoma is an uncommon tumor. In the absence of pathognomonic diagnostic criteria a definitive pathological diagnosis of parathyroid carcinoma often is not possible. The treatment of parathyroid carcinoma is essentially surgical. Patients with parathyroid carcinoma mostly die from uncontrollable hypercalcemia rather than from other tumor-related complications.

Neurofilament expression in the rat brain after cerebral infarction: effect of age.

In this study the role of neurofilaments (NFs) in brain plasticity after cerebral infarction in young and middle aged rats was evaluated. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. After 1 week, brains were removed and in situ hybridization and immunostaining was performed for NF-68 kDa, 160 kDa and 200 kDa in different phosphorylation states. After focal cerebral ischemia the levels of gene and protein expression of neurofilament proteins were increased in the border zone of the infarcted area compared with the unaffected contralateral site. Furthermore, the level of gene expression was significant lower in aged as in young animals. Focal cerebral ischemia resulted in a clearly increased number of immunostained axons in the penumbral region in both young and aged rats. On the other hand the immunostained apical dendrites became thicker and vacuolization appeared. Our results suggest that that neurofilament proteins are involved in response of brain to focal ischemia.

Persistent expression of a soluble form of Fas/APO1 in continuously activated T cells from a patient with SLE.

OBJECTIVE: To report a patient with SLE whose T cells expressed disproportionally increased amounts of an alternatively spliced form of Fas/APO1 transcript and secreted a soluble form of Fas. METHODS: We established continuously activated, short-term T cell lines from 16 patients with SLE and from 6 normal controls. The structure, expression and function of Fas was examined using RT-PCR and sequencing, flow cytometry (surface expression of Fas), ELISA (measurement of soluble Fas) and a PI-based cytotoxicity assay (functional analysis). RESULTS: A soluble form of Fas which originates from an alternatively spliced transcript and lacks the transmembrane domain of the original molecule was the dominant product of the Fas-gene in one line (S18B) derived from a patient with very active SLE. Compared to a control line, the S18B cells displayed decreased surface Fas expression but increased accumulation of Fas inside the cell. The amount of soluble Fas in the culture supernatant of S18B was found to be 1.8 times higher than that of a control line. Culture supernatants from S18B cells inhibited anti-Fas mAb-medicated T cell death. CONCLUSION: Continuously activated T cells from one patient with SLE displayed increased amounts of soluble Fas that inhibits anti-Fas mediated cell death. Although the frequency of this abnormality among patients with SLE and other diseases is unknown, increased production of soluble Fas may have contributed to the pathogenesis of SLE in the patient presented here.

Activated microglia do not mediate the early deposition of Abeta in carriers of the apolipoprotein Eepsilon4 allele.

Activated microglia are a prominent component of the senile plaques in end-stage Alzheimer's disease, but whether microglia contribute to the initiation of the lesions remains unknown. In a previous postmortem study of non-demented elderly cases, we found that amyloidogenesis is advanced by at least 10 years in carriers of the apoEepsilon4 allele. To determine whether microglia are involved in the initial stages of beta-amyloid pathogenesis and whether apoE genotype influences microglial activation, we quantified HLA-DR-immunoreactive microglia in the medial temporal lobe of 229 non-demented humans of various APOE genotypes who had died between 50 and 91 years of age. Our results show that the number of HLA-DR-immunoreactive microglia increases with advancing age in both the gray matter and the white matter. In contrast to amyloid plaques and neurofibrillary tangles, there is no significant correlation between apoE genotype and density of microglia, although apoEepsilon4 homozygotes tended to have more microglia than did other apoE groups. In sections double-immunostained for Abeta and activated microglia, activated microglia were associated with dense-cored plaques but not with diffuse plaques, suggesting that microglial activation is a relatively late event in the genesis of beta-amyloid. Activation of microglia thus appears not to be the initial impetus for Abeta-deposition in the elderly.

Expression of multidrug transporters in dysembryoplastic neuroepithelial tumors causing intractable epilepsy.

OBJECTIVE: Dysembryoplastic neuroepithelial tumors (DNT) are relatively benign brain lesions that often cause medically intractable epilepsy. There is mounting evidence that multidrug transporters such as P-glycoprotein (P-gp) or multidrug resistance-associated proteins (MRP) play an important role in the development of resistance to antiepileptic drugs (AED). MATERIAL AND METHODS: In the present study, we examined the expression of several multidrug transporters in 14 cases of DNT. The peritumoral brain tissue as well as 9 cases of arteriovenous malformations (AVM) served as controls. P-gp, MRP2, MRP5 and breast cancer resistance protein (BCRP) expression was evaluated qualitatively and quantitatively using immunohistochemistry. RESULTS: All transporters were overexpressed quantitatively in DNT, but each revealed a different labeling pattern. P-gp and BCRP were predominantly located in the endothelium of brain vessels. MRP5 was detected primarily in endothelial cells, but notably also in neurons. The expression of P-gp, MRP2 and MRP5 was low in AVM, whereas BCRP demonstrated strong staining. Examination of MDR1 gene polymorphisms revealed no correlation with P-gp expression whereas the MRP2 exon 10 G1249A polymorphism was associated with different MRP2 labelling. CONCLUSIONS: Our results show that multidrug transporters are overexpressed in DNT. This finding supports the view that several of these transport proteins may play an important role in the mechanisms of drug resistance in epileptic brain tissue.

The many guises of amyloidosis. Clinical presentations and disease associations.

Amyloidosis occurs in association with many diseases and can also be idiopathic. It is usually a systemic disease with variable presentations. The diagnosis should be suspected in patients with unexplained proteinuria, cardiomyopathy, congestive heart failure, peripheral neuropathy, carpal tunnel syndrome, macroglossia, or hepatosplenomegaly. Amyloidosis generally has a poor prognosis and responds poorly to therapy. Much needs to be learned about its pathogenesis and treatment possibilities.

Postoperative joint infections in rheumatoid arthritis patients on methotrexate therapy.

The effect of low dose methotrexate (MTX) on postoperative complications in rheumatoid arthritis patients undergoing elective total joint arthroplasty was observed prospectively in 32 patients. Patients were assigned to discontinue MTX the week prior to and during the week of surgery (Group 1, n = 19) or to continue MTX throughout the perioperative period (Group 2, n = 13). Nineteen patients in Group 1 had 26 procedures, with no postoperative infections. Thirteen patients in Group 2 had 16 procedures, with 4 postoperative infections: 2 infected prostheses, 1 infected joint fusion, and 1 deep wound infection (P = .03). No patient had a postoperative flare of rheumatoid arthritis. Temporary discontinuation of MTX prior to joint arthroplasty appears to decrease the risk of postoperative infection.

MDR1-P-glycoprotein (ABCB1)-mediated disposition of amyloid-ß peptides: implications for the pathogenesis and therapy of Alzheimer's disease.

The accumulation of neurotoxic amyloid-ß (Aß) peptides within the brain represents a hallmark of Alzheimer's disease (AD). It is proposed to be partly due to reduced elimination of Aß from the brain into the blood. Diverse mechanisms of Aß clearance out of the brain have been suggested. As discussed here, several lines of evidence suggest a significant role of the MDR1-P-glycoprotein (ABCB1), which is a major component of the blood-brain barrier (BBB).

Malignant brain oedema after radiosurgery of a medium-sized vestibular schwannoma.

CASE REPORT: We present a patient with an unusual malignant brain oedema occurring after gamma knife radiosurgery of a medium-sized vestibular schwannoma. CLINICAL PRESENTATION: A 62-year-old female with a large vestibular schwannoma underwent partial microsurgical resection; 6 months later she underwent a second intervention with gamma knife radiosurgery for a medium-sized tumour remnant. With a latency period of 6 months after radiosurgery, she presented with progressive neurological deterioration. Serial magnetic resonance imaging revealed progression of the tumour and of the perifocal oedema which finally extended up to the ipsilateral internal capsule. The patient became comatose. INTERVENTION: The tumour was nearly completely removed via a standard retrosigmoid craniotomy. Histopathological examination demonstrated increased mitotic activity compared to the initial histology. The patient became conscious 10 days after surgery and recovered slowly. Surprisingly, the brain oedema resolved rapidly. The CT scan obtained 11 days after surgery showed almost complete disappearance of the oedema. CONCLUSION: Although rare, radiosurgery of medium-sized vestibular schwannomas causing brainstem compression may lead to life-threatening tumour progression and malignant brain oedema. Therefore, microsurgical gross total resection should be the preferred treatment option in vestibular schwannomas causing significant brainstem compression.

Hypocalcemia associated with estrogen therapy for metastatic adenocarcinoma of the prostate.

We report 2 cases of true hypocalcemia (not caused by decreased binding proteins) associated with metastatic prostate cancer and review previously reported cases. Hypocalcemia is a common but frequently unrecognized complication of prostatic cancer. Estrogen therapy often is associated with the hypocalcemia, which may be asymptomatic. The hypocalcemia is always associated with osteoblastic metastases and usually it is associated with increased serum alkaline phosphatase activity, acid phosphatase activity and serum parathyroid hormone concentration. Serum concentrations of magnesium, phosphorus and vitamin D frequently are decreased. Patients are in a positive calcium balance. The osteoblastic metastases seem to act as a calcium sink, creating a "hungry tumor phenomenon". The role of estrogens may be to stop the resorption of normal bone resulting in lower serum calcium concentrations.