Major intensification of Atlantic overturning circulation at the onset of Paleogene greenhouse warmth.

During the Late Cretaceous and early Cenozoic the Earth experienced prolonged climatic cooling most likely caused by decreasing volcanic activity and atmospheric CO2 levels. However, the causes and mechanisms of subsequent major global warming culminating in the late Paleocene to Eocene greenhouse climate remain enigmatic. We present deep and intermediate water Nd-isotope records from the North and South Atlantic to decipher the control of the opening Atlantic Ocean on ocean circulation and its linkages to the evolution of global climate. The marked convergence of Nd-isotope signatures 59 million years ago indicates a major intensification of deep-water exchange between the North and South Atlantic, which coincided with the turning point of deep-water temperatures towards early Paleogene warming. We propose that this intensification of Atlantic overturning circulation in concert with increased atmospheric CO2 from continental rifting marked a climatic tipping point contributing to a more efficient distribution of heat over the planet.

A case of late-onset, thymoma-associated myasthenia gravis with ryanodine receptor and titin antibodies and concomitant granulomatous myositis.

BACKGROUND: Myasthenia gravis is an autoimmune neuromuscular disorder, which has only rarely been reported to co-manifest with myositis. The diagnosis of concomitant myositis in patients with myasthenia gravis is clinically challenging, and requires targeted investigations for the differential diagnosis, including EMG, autoantibody assays, muscle biopsy and, importantly, imaging of the mediastinum for thymoma screening. CASE PRESENTATION: This report presents a case-vignette of a 72-year-old woman with progressive proximal muscle weakness and myalgias, diagnosed with thymoma-associated myasthenia and bioptically verified granulomatous myositis, with positive autoantibody status for ryanodine receptor and titin antibodies. CONCLUSIONS: The diagnosis of concurrent myositis and myasthenia gravis, especially in the presence of ryanodine receptor and titin antibodies, should lead neurologists to adopt different treatment strategies compared to those applied in myasthenia or myositis alone. Moreover, further evidence is warranted that titin and, particularly, ryanodine receptor antibodies may co-occur or be pathophysiologically involved in myasthenia-myositis cases.

[Lysosomal storage diseases: A brief summary]. / Lysosomale Speicherkrankheiten : Ein kurzer Abriss.

BACKGROUND: A considerable number of lysosomal storage diseases (LSD), which can occur at any age in life, should be included in the differential diagnosis of histiocytic diseases. OBJECTIVE: To what extent can pathologists contribute to the diagnostics of LSD? MATERIAL AND METHODS: In material collected from LSD, morphological storage phenomena in some disease forms, particularly in histiocytic cells from bone marrow smears and some tissues are highlighted, presented and described. Due to the multitude and heterogeneity of LSDs this list is by no means exhaustive. RESULTS: In Gaucher disease, the forms of Niemann-Pick disease, cholesteryl ester storage disease (CESD), GM1 gangliosidosis and other LSDs, the histiocytic storage cells seen, for example, in bone marrow smears can be finely and ultrastructurally differentiated. Thereby, not only the presence of an LSD in general but also some individual types of LSD can be identified, even though preliminarily. To confirm the diagnosis the genetic and sometimes biochemical analysis of blood samples or fibroblast cultures from patients is usually required. CONCLUSION: The pathologist may be the first to suspect LSD and this applies to LSDs that show storage histiocytes or one of a number of other LSDs in which only minor or absent storage is seen in histiocytes but marked storage phenomena are found in other cell systems. Some of the numerous, extremely heterogeneous LSDs may, however, be overlooked as detailed knowledge of the generally rare LSDs is the domain of LSD specialists. Clinicians, pathologists, geneticists and biochemists should cooperate in solving the diagnostic problems.

Spinocerebellar ataxia type 1 (SCA1): new pathoanatomical and clinico-pathological insights.

AIMS: Spinocerebellar ataxia type 1 (SCA1) represents the first molecular genetically characterized autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG-repeat or polyglutamine diseases. Owing to limited knowledge about SCA1 neuropathology, appropriate pathoanatomical correlates of a large variety of SCA1 disease symptoms are missing and the neuropathological basis for further morphological and experimental SCA1 studies is still fragmentary. METHODS: In the present study, we investigated for the first time serial tissue sections through the complete brains of clinically diagnosed and genetically confirmed SCA1 patients. RESULTS: Brain damage in the three SCA1 patients studied went beyond the well-known brain predilection sites of the underlying pathological process. Along with neuronal loss in the primary motor cortex, it included widespread degeneration of gray components of the basal forebrain, thalamus, brainstem and cerebellum, as well as of white matter components in the cerebellum and brainstem. It involved the motor cerebellothalamocortical and basal ganglia-thalamocortical circuits, the visual, auditory, somatosensory, oculomotor, vestibular, ingestion-related, precerebellar, basal forebrain cholinergic and midbrain dopaminergic systems. CONCLUSIONS: These findings show for the first time that the extent and severity of brain damage in SCA1 is very similar to that of clinically closely related spinocerebellar ataxias (that is, SCA2, SCA3 and SCA7). They offer suitable explanations for poorly understood SCA1 disease symptoms and will facilitate the interpretation of further morphological and experimental SCA1 studies.

Hypericin for visualization of high grade gliomas: first clinical experience.

AIMS: We aimed to demonstrate that Hypericin, a component of St. Johns Wort, selectively visualizes malignant gliomas. Hypericin is known as one of the most powerful photosensitizers in nature with excellent fluorescent properties. METHODS: In five patients with a recurrence of a malignant glioma a newly developed water soluble formulation of hypericin was given intravenously (0.1 mg/kg body weight) 6 h before the surgical procedure. Tumor resection was performed under white light and fluorescence mode. The intensity grade of the tissue fluorescence was categorisized by the surgeon in three grades, highly fluorescent, weakly fluorescent and not fluorescent. In these areas tissue samples were taken and investigated by two blinded independent neuropathologists. Tissue samples were histologically classified differentiating between tumor tissue, tumor necrosis, tissue with scattered tumor cells and normal brain tissue. RESULTS: In all patients tumor tissue was clearly distinguishable by its typically red fluorescence color from normal brain tissue which was colored blue under a special fluorescent filter. Histological evaluation of the 110 tissue samples showed a specificity of 100% and sensitivity of 91% for one of the two neuropathologists, whereas specificity for second pathologist was 90% and sensitivity 94%. The i.v. application of Hypericin proofed to be safe in all cases and there were no side effects observed. CONCLUSION: Hypericin in its water soluble form is a well tolerated drug. In addition to its high photosensitizing properties hypericin will open up interesting new therapeutic possibilities especially when used in combination with fluorescence detection and simultaneously photodynamic therapy.

Cerebral low-grade lymphoma and light chain deposition disease: exceedingly high IgG levels in the cerebrospinal fluid as a diagnostic clue.

Herein, we report the case of a 72-year-old male with an exceedingly rare manifestation of a low-grade lymphoma in the brain associated with light chain deposition disease (LCDD). The patient presented with epileptic seizures. Magnetic resonance imaging (MRI) of the brain revealed multiple hyperintense lesions in the right parietal lobe that were suspicious of vasculitis, low-grade glioma, or neurosarcoidosis. In the cerebrospinal fluid (CSF), but not in the serum, highly elevated IgG was found. A stereotactic biopsy of one cerebral lesion was performed. Histopathology revealed a low grade lymphoplasmacytic B-cell lymphoma with light chain deposition disease (LCDD). Bone marrow biopsy and laboratory workup did not show any systemic involvement. LCDD exclusively affecting the brain is an exceedingly rare finding. It can be associated with low-grade B-cell lymphoma. This is the first report of LCDD exclusively affecting the brain in an elderly patient. Compared with the two younger patients previously reported, the course of the disease was of a slow-evolving nature. In constellations of highly elevated IgG in CSF and multiple white matter lesions, LCDD should be considered as underlying pathology.

Andermann syndrome can be a phenocopy of hereditary motor and sensory neuropathy--report of a discordant sibship with a compound heterozygous mutation of the KCC3 gene.

Andermann syndrome is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum (ACC), progressive motor-sensory neuropathy, mental retardation and facial features. We report on two siblings with the clinical picture of a demyelinating hereditary motor and sensory neuropathy (HMSN), where only the presence of ACC in the younger brother pointed to the diagnosis of Andermann syndrome. Mutation analysis of the KCC3 (SLC12A6) gene showed a compound heterozygous mutation; a maternal missense mutation c.1616G>A (p.G539D) and a paternal splice mutation c.1118+1G>A in both siblings. We hypothesize that mutations of the KCC3 gene may result in non-syndromic childhood onset HMSN.

[Myositides]. / Myositiden.

Idiopathic inflammatory myopathies (IIM) are diseases that are potentially amenable to immunomodulatory therapy. The challenge for the neuropathologist consists in distinguishing these myopathies from secondary inflammatory myopathies, especially in the context of some muscular dystrophies and metabolic diseases that may also show inflammatory infiltrates. There are generalized IIMs (dermatomyositis, polymyositis, sporadic inclusion body myositis) and focal ones (e.g., proliferative myositis, macrophagic myofasciitis). This review provides diagnostic criteria for each of these and includes pathogenetic mechanisms where available.

Basement membrane remodelling and segmental fibrosis in sporadic inclusion body myositis.

Sporadic inclusion body myositis (sIBM) is a debilitating idiopathic inflammatory myopathy. Little is known about the pathogenetic mechanisms that lead to myofiber degeneration. In the present study, we evaluated the integrity of the myofiber basement membrane in non-necrotic myofibers invaded by inflammatory infiltrates. We used 100 ten mum thick serial sections obtained from biopsies of 5 patients suffering from sIBM. Biopsies from 5 patients suffering from polymyositis served as controls. We performed sequential HE staining and immunolabeling using anti-CD68, -CD8, -merosin, -laminin alpha4 chain, and -collagen IV antibodies. In sIBM, we detected a total of 89 non-necrotic myofibers that were invaded by inflammatory cells. The invasive process and its sequelae were segmental in nature and included destruction of the myofiber basement membrane, and eventually, partial replacement by fibrosis of the invaded myofiber. In polymyositis, we found only two myofibers that were affected in this way. In sIBM, basement membrane remodelling and irreversible replacement by fibrosis of myofibers appear to represent the end result of a process in which the balance between injury and repair are disrupted.

[Sporadic adult form of nemaline myopathy--a difficult differential diagnosis]. / Sporadische adulte Form der Nemalinmyopathie--eine schwierige Differenzialdiagnose.

We report on a 79 years old female patient with slowly progressive painful weakness of the proximal upper and lower limbs. CK was slightly elevated (242 U 7 l). MRI guided biopsy of the proximal lower limbs revealed the rare findings of nemaline myopathy.

The microglial/macrophagic response at the tumour-brain border of invasive meningiomas.

AIMS: Little is known about the immune response of the brain to invasive meningiomas. The present study was based upon the hypothesis that the microglial/macrophagic response towards brain-invasive meningiomas is dependent on the intactness of the pial-glial basement membrane. METHODS: We immunostained sections from 40 brain-invasive meningiomas that were graded according to World Health Organization (WHO) 2007 criteria. Thirty-three tumours were histologically WHO grade II (18, 'otherwise benign', and 15, 'otherwise atypical'), and seven, grade III. Microglial/macrophagic cells were labelled with antibodies directed against major histocompatibility complex class II, CD68, CD14 and CD163. Anti-collagen IV was used to visualize basement membranes. RESULTS: Twenty-five per cent (10/40) meningiomas (1/18 WHO grade II 'otherwise benign', 3/15 grade II 'otherwise atypical' and 6/7 WHO grade III) contained microglial/macrophagic cells at the tumour-brain border. The presence of these cells correlated with the absence of the pial-glial basement membrane (BM) and with WHO grade III. The monocytic response was of two kinds: one consisted of a dense layer of mononuclear cells at the tumour-brain border in nine cases, the other of an elevated number of microglial cells expressing CD14 or CD163 (two cases). CONCLUSIONS: The immune response at the tumour-brain interface correlates with the absence of the pial-glial BM and with malignancy grade. It remains to be established whether the mononuclear cells at the tumour-brain border are native microglia or blood-derived macrophages.

Spinal cord compression through extraosseous extension of a vertebral low-grade hemangioendothelioma with histiocytoid differentiation.

Herein, we report the case of a 47-year-old man clinically presenting a slow progressive loss of lower extremity functions within 8 weeks followed by an acute neurogenic bladder dysfunction. The patient exhibited high-grade paralysis of both legs with reduced sensation from dermatome Th11 downwards as well as marked spasticity of the lower extremity. Neuroradiological examinations revealed a protruding spinal tumor with extraosseous-intraspinal extension. The resected tumor mass exhibited a highly vascularized tumor with architectural complexity and high cellularity finally leading to the diagnosis of a hemangioendothelioma. Interesting was the fact that the tumor vasculature exhibited many CD68-positive cells protruding into the lumen and, therefore, being part of a partially histiocytoid differentiation which is all the more uncommon in hemangioendothelioma. The time frame of 3 hours between embolization and tumor resection is too short to explain a monocytic intravascular reaction. Usually, hemangioendotheliomas arise from the soft tissue, lungs or liver, but intraspinal manifestations are only rarely observed. Furthermore, the clinical course with a progressive development of a paraparesis due to a hemangioendothelioma is very uncommon.

MR findings in patients with disabling musculocutaneous chronic graft-versus-host disease.

OBJECTIVE: To describe musculocutaneous MR-findings responsible for disability in chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT). MATERIAL AND METHODS: Between June 2005 and February 2008, we performed whole-body musculoskeletal magnetic resonance imaging (MRI; n = 12) or regional MRI (n = 4) in 16 consecutive patients presenting with disabling sclerodermatous cGVHD (e.g., skin edema, fixed deep dermal sclerosis, joint contractures, painful muscular contractures, or myalgia). RESULTS: In all patients, MRI showed musculocutaneous abnormalities reflecting different degrees of inflammation and collagen tissue involvement of the skin (n = 10), subcutaneous fat tissue (n = 13), muscle fasciae (n = 16), subfascial muscular septae (n = 6), or findings compatible with myositis (n = 3). The most frequently involved muscle fasciae comprised those of the vastus lateralis muscle (n = 12), biceps femoris muscle (n = 11), gastrocnemius medialis muscle (n = 8), serratus anterior muscle, and latissimus dorsi muscle (each, n = 5). Increased signal of involved tissues on STIR-images and fat-saturated postgadolinium T1-weighted images represented the most frequent MR-signal abnormalities. CONCLUSION: MR imaging of musculocutaneous cGVHD allows accurate evaluation including assessment of deep tissue infiltration and assists in the differential diagnosis.

Hypericin uptake: a prognostic marker for survival in high-grade glioma.

Currently adjuvant chemotherapy for glioblastoma patients can prolong survival time relative to patients who receive only surgery and radiotherapy. Despite these improvements and experimental and clinical efforts the prognosis for glioblastoma patients remains poor. At present, interest is focused on individual prognostic factors influencing patient responses to therapy. Photodynamic therapy may be a promising therapeutic option in the treatment of glioblastoma. In this investigation we examined whether uptake of hypericin (HY), a fluorescent photosensitization agent, by ex vivo glioblastoma cell lines correlates with prognosis of the individual from which the cell lines were derived. Twelve primary human glioma cell cultures were incubated with 20 micromol HY. Fluorescence intensity was measured using fluorescence microscopy. Three patients suffered from an anaplastic astrocytoma, WHO grade III, nine had a glioblastoma, WHO grade IV. In 6/12 patients complete tumour resection was possible. The mean survival time of the six patients in whom complete tumour resection was performed was 26 months, compared with 5 months for those who underwent incomplete resection. Eleven patients received radiation therapy. The five patients who received chemotherapy survived for a mean duration of 26 months, compared with the seven patients who survived for a mean duration of 5 months without chemotherapy. Statistical analysis using a parametric survival model based on the Weibull distribution showed that fluorescence intensity was the variable with the lowest p-value associated with survival (p=0.0225). An increase of 553 arbitrary units of fluorescence intensity is predicted to double survival time. Uptake of HY, a lipophilic molecule, is assumed to be related to low-density lipoprotein (LDL) uptake and metabolism. Cell proliferation is associated with a high turnover of cholesterol and membrane growth, which is related to cholesterol uptake by LDL. In summary, HY uptake by ex vivo glioblastoma cell cultures seems to be positively associated with survival of patients with malignant glioma.

Tuberculum sellae meningioma symptomatic during pregnancy: pathophysiological considerations.

A 31 year old woman in her second pregnancy presented in the 31st (+4) week of gestation with progressive visual impairment of the right eye. Magnetic resonance imaging (MRI) demonstrated a tuberculum sellae meningioma that was displaced upward by a markedly enlarged pituitary gland. Neuro-ophthalmological follow-up examinations showed a progressive decrease of visual acuity and right temporal field loss. Therefore, a caesarean section was performed in the 34th (+8) week. The meningioma was removed three days after childbirth via a right-sided pterional approach. Post-operatively, visual function was completely restored. Immunohistochemical examination showed positive staining for progesterone receptors (PR) in approximately 50% of tumour cells. Enlargement of the pituitary gland during late pregnancy in conjunction with a preexisting tuberculum sellae meningioma is the most likely pathophysiological factor responsible for visual loss. Enlargement of the PR-positive meningioma in the hormonal milieu of pregnancy might have contributed additionally to visual loss.