Chen Makranz

cAMP cascade (PKA, Epac, adenylyl cyclase, Gi, and phosphodiesterases) regulates myelin phagocytosis mediated by complement receptor-3 and scavenger receptor-AI/II in microglia and macrophages.

The removal by phagocytosis of degenerated myelin is central for repair in Wallerian degeneration that follows traumatic injury to axons and in autoimmune demyelinating diseases (e.g., multiple sclerosis). We tested for roles played by the cAMP cascade in the regulation of myelin phagocytosis mediated by complement receptor‐3 (CR3/MAC‐1) and scavenger receptor‐AI/II (SRAI/II) separately and combined in mouse microglia and macrophages. Components of the cAMP cascade tested are cAMP, adenylyl cyclase (AC), Gi, protein kinase A (PKA), exchange protein directly activated by cAMP (Epac), and phosphodiesterases (PDE). PKA inhibitors H‐89 and PKI14‐22 amide inhibited phagocytosis at normal operating cAMP levels (i.e., those occurring in the absence of reagents that alter cAMP levels), suggesting activation of phagocytosis through PKA at normal cAMP levels. Phagocytosis was inhibited by reagents that elevate endogenous cAMP levels to above normal: Gi‐inhibitor Pertussis toxin (PTX), AC activator Forskolin, and PDE inhibitors IBMX and Rolipram. Phagocytosis was inhibited also by cAMP analogues whose addition mimics abnormal elevations in endogenous cAMP levels: nonselective 8‐bromo‐cAMP, PKA‐specific 6‐Benz‐cAMP, and Epac‐specific 8‐CPT‐2′‐O‐Me‐cAMP, suggesting that abnormal high cAMP levels inhibit phagocytosis through PKA and Epac. Altogether, observations suggest a dual role for cAMP and PKA in phagocytosis: activation at normal cAMP levels and inhibition at higher. Furthermore, a balance between Gi‐controlled cAMP production by AC and cAMP degradation by PDE maintains normal operating cAMP levels that enable efficient phagocytosis. ©2005 Wiley‐Liss, Inc.

Non-PKC DAG/Phorbol-Ester receptor(s) inhibit complement receptor-3 and nPKC inhibit scavenger receptor-AI/II-mediated myelin phagocytosis but cPKC, PI3k, and PLCγ activate myelin phagocytosis by both

Complement‐receptor‐3 (CR3/MAC‐1), scavenger‐receptor‐AI/II (SRAI/II), and Fcγ‐receptor (FcγR) can mediate myelin phagocytosis in macrophages and microglia. Paradoxically, after injury to CNS axons these receptors are expressed but myelin is not phagocytosed, suggesting that phagocytosis is subject to regulation between efficient and inefficient states. In the present work, we focus on CR3/MAC‐1 and SRAI/II‐mediated myelin phagocytosis. Phagocytosis by CR3/MAC‐1 and SRAI/II was inhibited by cPKC inhibitor Go‐6976, general‐PKC inhibitors Ro‐318220 and calphostin‐C, and BAPTA/AM, which chelates intracellular Ca2+ required for cPKC activation. Signaling/activation by cPKC are thus suggested. PMA, which mimics diacylglycerol (DAG) as an activator of cPKC, novel‐PKC (nPKC), and non‐PKC DAG‐driven molecule(s), produced a dose‐dependent dual effect on phagocytosis by CR3/MAC‐1 and SRAI/II, i.e., augmentation at low concentrations and inhibition at high concentrations. Inhibition of phagocytosis by CR3/MAC‐1 was enhanced by combining inhibiting concentrations of PMA with PKC inhibitors Go‐6976 or Ro‐318220, suggesting inhibition by PMA/DAG‐driven non‐PKC molecule(s). In contrast, inhibition of phagocytosis by SRAI/II was enhanced by combining inhibiting concentrations of PMA with cPKC inhibitor Go‐6976 but not with general‐PKC inhibitor Ro‐318220, suggesting inhibition by nPKC. Phagocytosis by CR3/MAC‐1 and SRAI/II was further inhibited by PI3K inhibitors wortmannin and LY‐294002 and PLCγ inhibitor U‐73122. Altogether, our observations suggest that CR3/MAC‐1 and SRAI/II‐mediated myelin phagocytosis share activation by PI3K, PLCγ and cPKC. The two differ, however, in that non‐PKC DAG‐driven molecule(s) inhibit CR3/MAC‐1‐mediated phagocytosis, whereas nPKC inhibit SRAI/II‐mediated phagocytosis. Each of these signaling steps may be targeted for regulating CR3/MAC‐1 and/or SRAI/II‐mediated phagocytosis between efficient and inefficient states.

Neurologic complications of immune checkpoint inhibitors

Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days–19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.

Sandfly virus seroconversion associated with neurologic presentation

Objective: To describe the clinical presentation and unique neurologic manifestations of sandfly viruses (SFVs) in the Jerusalem area. Methods: We identified all patients with acute seroconversion to SFV at the Hadassah-Hebrew University Medical Centers during the years 2008–2013 and retrospectively collected and analyzed the clinical and imaging data. Results: Nine patients (ranging from 1.5 to 85 years old) were identified. Presentation included acute neurologic disease, mostly with fever, change in consciousness and behavior, seizures, headache, meningitis, limb paresis, or myelitis. Eight patients had clinical signs of meningitis, meningoencephalitis, or encephalitis alone. Four patients had myelitis. MRI identified pathologic symmetrical changes in the basal ganglia, thalami, and other deep structures in 5 patients, and additional myelitis of the spine was noted on imaging in 3 patients. Seven patients had long-term follow-up: 4 completely recovered and 3 had remaining neurologic sequelae, among them 1 with permanent severe brain damage. Conclusion: Neurologic involvement associated with acute SFV infections is considered to be benign. However, in this series, all 9 patients presented with significant neurologic pathology associated with a unique finding of myelitis and symmetrical basal ganglia, thalami, or white matter involvement. Thus, acute SFV infection should be included in the differential diagnosis in febrile onset of neurologic manifestations and neuroradiologic changes.

Early hydrocephalus in Listeria meningitis: Case report and review of the literature

Highlights • Early hydrocephalus is common in L. monocytogenes meningitis.• Suspect hydrocephalus when neurological deterioration occurs few days after initial presentation, especially when treatment was not directed against L. monocytogenes.• Appropriate antimicrobial treatment and surgical ventriculostomy usually result in a favorable outcome.• Meningitis complicated by hydrocephalus should raise to possibility of L. monocytogenes.

Lenalidomide-Related Spinal Cord Infarction in Primary Amyloidosis

Spinal cord infarction is a rare but often devastating disorder caused by disruption in the vascular spinal supply. We report a patient with spinal cord infarction associated with lenalidomide therapy for primary amyloidosis, in the background of other predisposing factors. We describe the clinical case and discuss the possible explanation for this rare complication. As spinal cord infarction is not a known complication of lenalidomide therapy or amyloidosis, this description raises the potential of such a side effect in some certain conditions and discusses the role of the old and new anticoagulant agents in prevention of thromboembolic complications in high-risk patients.

Neurological variability in chemotherapy‑induced posterior reversible encephalopathy syndrome associated with thrombotic microangiopathy: Case reports and literature review

Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized by headaches, seizures, a confusional state and visual disturbances associated with transient predominantly bilateral posterior white mater magnetic resonance imaging lesions. It is primarily reported in the setting of hypertension, acute renal failure, peripartum eclampsia, autoimmune disease, immunosuppression and chemotherapy. Thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) has also been reported as potential PRES inducer. The present study reviews two cases of patients with PRES, associated with TMA caused by chemotherapy. Their clinical and imaging data, and the relevant literature were reviewed. Patient 1 presented with TMA-induced PRES following mitomycin-C for metastatic colon adenocarcinoma. Treatment with steroids, plasma exchange, intravenous immunoglobulins, aspirin, antihypertensive drugs, and diuretics resulted in resolution of the neurological and imaging deficits. Patient 2 presented with TMA-induced PRES following gemcitabine for metastatic breast carcinoma. Treatment was ineffective and the patient deteriorated despite verapamil, dexamethasone, and plasma exchange. In this report, the relevant literature regarding pathogenesis, treatment and prognosis of chemotherapy-induced PRES associated with TMA was reviewed. We conclude that several chemotherapy agents may cause PRES through various pathogenic mechanisms, leading to clinical variability and divergent response to therapy.

Spinal ischemic stroke following dialysis: clinical and radiologic findings

Spinal cord ischemia (SCI) is a relatively common cause of noncompressive myelopathy.1 SCI frequently involves the thoracic or lumbar cord manifesting as acute painful paraparesis but may also involve the posterior columns and autonomic fibers.2 Most infarcts affect the central parts of the anterior spinal artery supply.2–4 Outcome depends on the initial severity of the neurologic deficits and may be surprisingly benign especially if proprioception remains intact.1,2 Because hypoperfusion may cause SCI,5,6 our goal was to describe SCI as a potential complication of hemodialysis-associated hypoperfusion.