POEMS syndrome with vascular transformation of the lymph node sinuses: A case report.

POEMS syndrome is a rare multisystem disorder associated with the clinical signs of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes. However, there is often a delay in the diagnosis due to a lack of overall consideration of the symptoms collectively. For this reason, POEMS syndrome is frequently mistaken for other diseases, such as chronic inflammatory demyelinating polyneuropathy. The present study reports the case of a 40-year-old female patient, who presented with a progressive lack of strength in the lower limbs and a unilateral cervical lump. The patient's enlarged cervical lymph nodes were mistaken for local hemangioma. However, subsequently POEMS syndrome with vascular transformation of the lymph node sinuses (VTS) was diagnosed. The patient received glucocorticoid treatment (20 mg prednisone acetate, daily), which is ongoing. The most recent follow-up examination revealed that the patient's strength had improved and at the time of writing the patient remained alive. The study discusses the clinical manifestations, auxiliary examinations and reason for the misdiagnosis. Hematoxylin and eosin staining and cluster of differentiation 31 immunostaining were adopted to identify the VTS. To the best of our knowledge, this is the first report of POEMS syndrome with VTS.

Swedish mutant APP-based BACE1 binding site peptide reduces APP ß-cleavage and cerebral Aß levels in Alzheimer's mice.

BACE1 initiates amyloid-ß (Aß) generation and the resultant cerebral amyloidosis, as a characteristic of Alzheimer's disease (AD). Thus, inhibition of BACE1 has been the focus of a large body of research. The most recent clinical trials highlight the difficulty involved in this type of anti-AD therapy as evidenced by side effects likely due to the ubiquitous nature of BACE1, which cleaves multiple substrates. The human Swedish mutant form of amyloid protein precursor (APPswe) has been shown to possess a higher affinity for BACE1 compared to wild-type APP (APPwt). We pursued a new approach wherein harnessing this greater affinity to modulate BACE1 APP processing activity. We found that one peptide derived from APPswe, containing the ß-cleavage site, strongly inhibits BACE1 activity and thereby reduces Aß production. This peptide, termed APPswe BACE1 binding site peptide (APPsweBBP), was further conjugated to the fusion domain of the HIV-1 Tat protein (TAT) at the C-terminus to facilitate its biomembrane-penetrating activity. APPwt and APPswe over-expressing CHO cells treated with this TAT-conjugated peptide resulted in a marked reduction of Aß and a significant increase of soluble APPα. Intraperitoneal administration of this peptide to 5XFAD mice markedly reduced ß-amyloid deposits as well as improved hippocampal-dependent learning and memory.

Anticoagulation therapy is harmful to large-sized cerebellar infarction.

AIM: Anticoagulants are commonly used to treat ischemic stroke. Its impact on cerebellar infarction has not been fully understood. METHODS: In the clinical study, we reviewed a consecutive series of patients with large-sized cerebellar infarction (diameter > 3 cm, n = 30) treated with or without anticoagulation. In animal study, cerebellar infarction operation was performed in 12 Cynomolgus monkeys. Then the animals were administrated with low molecular weight heparin (LMWH) or vehicle for 14 days. RESULTS: Six patients died during the following treatment. All the subjects that died received anticoagulation therapy, while nobody in the survival group received such a therapy. Compared with sham-operated animals, all monkeys with cerebellar infarction have obvious neurological deficits. The number and size of the Purkinje cells in the cerebellar area were also reduced. Two animals in the LMWH group (33%) died, while all animals in the vehicle control group survived. Compared with the vehicle group, the neurological score in the LMWH group was significantly increased (P < 0.05). The water content in the cerebella was also significantly higher (P < 0.05). Edema, hemorrhage, and subarachnoid hemorrhage occurred in the cerebella as well as brainstem of all the LMWH treated animals. CONCLUSIONS: These results indicated the harmful effects of anticoagulation therapy on large-sized cerebellar infarction.

Octyl gallate markedly promotes anti-amyloidogenic processing of APP through estrogen receptor-mediated ADAM10 activation.

Our previous studies showed that the green tea-derived polyphenolic compound (-)-epigallocatechin-3 gallate (EGCG) reduces amyloid-ß (Aß) production in both neuronal and mouse Alzheimer's disease (AD) models in concert with activation of estrogen receptor-α/phosphatidylinositide 3-kinase/protein kinase B (ERα/PI3K/Akt) signaling and anti-amyloidogenic amyloid precursor protein (APP) α-secretase (a disintegrin and metallopeptidase domain-10, ADAM10) processing. Since the gallate moiety in EGCG may correspond to the 7α position of estrogen, thereby facilitating ER binding, we extensively screened the effect of other gallate containing phenolic compounds on APP anti-amyloidogenic processing. Octyl gallate (OG; 10 µM), drastically decreased Aß generation, in concert with increased APP α-proteolysis, in murine neuron-like cells transfected with human wild-type APP or "Swedish" mutant APP. OG markedly increased production of the neuroprotective amino-terminal APP cleavage product, soluble APP-α (sAPPα). In accord with our previous study, these cleavage events were associated with increased ADAM10 maturation and reduced by blockade of ERα/PI3k/Akt signaling. To validate these findings in vivo, we treated Aß-overproducing Tg2576 mice with OG daily for one week by intracerebroventricular injection and found decreased Aß levels associated with increased sAPPα. These data indicate that OG increases anti-amyloidogenic APP α-secretase processing by activation of ERα/PI3k/Akt signaling and ADAM10, suggesting that this compound may be an effective treatment for AD.

Baicalein reduces ß-amyloid and promotes nonamyloidogenic amyloid precursor protein processing in an Alzheimer's disease transgenic mouse model.

Baicalein, a flavonoid isolated from the roots of Scutellaria baicalensis, is known to modulate γ-aminobutyric acid (GABA) type A receptors. Given prior reports demonstrating benefits of GABAA modulation for Alzheimer's disease (AD) treatment, we wished to determine whether this agent might be beneficial for AD. CHO cells engineered to overexpress wild-type amyloid precursor protein (APP), primary culture neuronal cells from AD mice (Tg2576) and AD mice were treated with baicalein. In the cell cultures, baicalein significantly reduced the production of ß-amyloid (Aß) by increasing APP α-processing. These effects were blocked by the GABAA antagonist bicuculline. Likewise, AD mice treated daily with i.p. baicalein for 8 weeks showed enhanced APP α-secretase processing, reduced Aß production, and reduced AD-like pathology together with improved cognitive performance. Our findings suggest that baicalein promotes nonamyloidogenic processing of APP, thereby reducing Aß production and improving cognitive performance, by activating GABAA receptors.

ALDH2 protects against stroke by clearing 4-HNE.

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that metabolizes ethanol and toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE). Using an unbiased proteomic search, we identified ALDH2 deficiency in stroke-prone spontaneously hypertensive rats (SHR-SP) as compared with spontaneously hypertensive rats (SHR). We concluded the causative role of ALDH2 deficiency in neuronal injury as overexpression or activation of ALDH2 conferred neuroprotection by clearing 4-HNE in in vitro studies. Further, ALDH2-knockdown rats revealed the absence of neuroprotective effects of PKCε. Moderate ethanol administration that is known to exert protection against stroke was shown to enhance the detoxification of 4-HNE, and to protect against ischemic cerebral injury through the PKCε-ALDH2 pathway. In SHR-SP, serum 4-HNE level was persistently elevated and correlated inversely with the lifespan. The role of 4-HNE in stroke in humans was also suggested by persistent elevation of its plasma levels for at least 6 months after stroke. Lastly, we observed that 21 of 1 242 subjects followed for 8 years who developed stroke had higher initial plasma 4-HNE levels than those who did not develop stroke. These findings suggest that activation of the ALDH2 pathway may serve as a useful index in the identification of stroke-prone subjects, and the ALDH2 pathway may be a potential target of therapeutic intervention in stroke.

Rapamycin promotes beta-amyloid production via ADAM-10 inhibition.

Rapamycin is a well known immunosuppressant drug for rejection prevention in organ transplantation. Numerous clinical trials using rapamycin analogs, involving both children and adults with various disorders are currently ongoing worldwide. Most recently, rapamycin gained much attention for what appears to be life-span extending properties when administered to mice. The risk for Alzheimer disease (AD) is strongly and positively correlated with advancing age and is characterized by deposition of beta-amyloid peptides (Abeta) as senile plaques in the brain. We report that rapamycin (2.5muM), significantly increases Abeta generation in murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP). In concert with these observations, we found rapamycin significantly decreases the neuroprotective amino-terminal APP (amyloid precursor protein) cleavage product, soluble APP-alpha (sAPP-alpha) while increasing production of the beta-carboxyl-terminal fragment of APP (beta-CTF). These cleavage events are associated with decreased activation of a disintegrin and metallopeptidase domain-10 (ADAM-10), an important candidate alpha-secretase which opposes Abeta generation. To validate these findings in vivo, we intraperitoneal (i.p.) injected Tg2576 Abeta-overproducing transgenic mice with rapamycin (3mg/kg/day) for 2weeks. We found increased Abeta levels associated with decreased sAPP-alpha at an average rapamycin plasma concentration of 169.7+/-23.5ng/mL by high performance liquid chromatography (HPLC). These data suggest that although rapamycin may increase the lifespan in some mouse models, it may not decrease the risk for age-associated neurodegenerative disorders such as AD.

Worsened MRI findings during the early period of treatment with penicillin in a patient with general paresis.

A 52-year-old man was diagnosed with general paresis, whose HIV antibodies were negative. After initiation of treatment with penicillin on the first day, no obvious clinical Jarisch-Herxheimer reaction was found. However, 6 days after treatment, the patient was found more irritable and was unable to fall asleep at night. On the seventh day, worsened magnetic resonance imaging (MRI) abnormalities in the bilateral medial and anterior temporal lobes were unexpectedly discovered. These worsened MRI abnormalities improved quickly after the addition of dexamethasone treatment. We consider that these transient and slight mental symptoms may be associated with the transiently worsening phenomenon in cerebral MRI findings during the early period of treatment with penicillin. This indicates that some nonspecific inflammatory process has happened in the early stage of treatment, which necessitates the use of corticosteroids after the occurrence of systemic or mental symptoms.

DNA analysis in a suspected individual with myotonic dystrophy family history and her abortus.

OBJECTIVE: To observe trinucleotide repeat number, (CTG)n in the 3'-untranslated region of the myotonic protein kinase (MTPK) gene in a clinically suspected woman with myotonic dystrophy (DM) family history and her abortus, in order to confirm the necessity of exerting antenatal examination in patients or suspected individuals with DM family history. METHODS: Long Expand Template polymerase chain reaction (PCR) system was used to analyze CTG trinucleotide repeat numbers located in the 3' untranslated region of MTPK on chromosome 19q13.2-3 in both peripheral white cells and muscles of the suspected mother and the other two DM patients in the family. The tissues of her abortus and blood of a health woman were detected, too. RESULTS: CTG repeats in both peripheral white cells and muscles of the suspected mother and the tissue of abortus were higher than normal range of CTG repeat number. There is no significant difference between blood and muscle samples. High CTG repeats were detected in blood and muscles of the typical DM members in the family, but in the blood sample of control, CTG repeats is normal. CONCLUSION: CTG trinucleotide analyses and antenatal examination should be done in pregnant with a DM family history, in order to reduce the birth rate of DM offspring.