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The optimal high-dose methotrexate (HDMTX)-based combination therapy for primary central nervous system lymphoma is unknown. We report our experience with rituximab, HDMTX, procarbazine and lomustine (R-MPL) given as first-line treatment in our center. Fifty-two patients between 2006 and 2019 were included. Eighteen patients proceeded to autologous transplant or two cycles of intermediate-dose cytarabine. The median age was 62 y (range 28-94) and the Eastern Cooperative Oncology Group performance status (ECOG-PS) was ≥2 in 62% (32/52). The overall/complete response rates were 79% (41/52) and 52% (27/52), respectively. The median progression-free/overall survival was 19 m/84m, respectively. Grade 3-4 adverse events included infections (17%) and kidney injury (13%). Ten patients (19%) discontinued therapy for toxicity. There were no treatment-related deaths. In summary, in a cohort enriched in frail patients, R-MPL achieved good responses and OS and was safe for all ages. The PFS was sub-optimal, possibly explained by a low proportion of consolidation. This regimen should be evaluated prospectively.

Radiotherapy has an important role in the treatment of brain metastases (BrM) but carries risk of short and/or long-term toxicity, termed radiation-induced neurotoxicity (RIN). As the diagnosis of RIN is crucial for correct pa-tient management, there is an unmet need for reliable biomarkers for RIN. The aim of this proof-of concept study was to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as RIN biomarkers. Twenty-four patients with BrM were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. During follow-up nine RIN events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RIN correlated with de-crease in BncfDNA. Changes in BncfDNA were independent of tumor response. Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy, further research is needed to establish BncfDNA as a novel plasma-based biomarker for RIN.

Purpose: To examine the applicability and efficacy of Cognitive Retraining and Functional Treatment (CRAFT) combining remote computerized cognitive training (CCT) and occupation-based treatment in adults with cancer-related cognitive impairment (CRCI). Methods: Three-armed randomized controlled trial including 74 individuals with CRCI, randomized into 12 weeks of either CRAFT, CCT alone, or treatment-as-usual. Assessments evaluating participation in daily life, perceived cognition, cognitive performance, quality-of-life, and treatment satisfaction were administered at baseline, post-intervention and 3-month follow up. Results: Significant time X group interactions in favor of the CRAFT and CCT groups were found for participation in daily life (F2,34=5.31, p=.01, eta=.238), perceived cognition (F2,34=4.897, p=.014, eta=.224) and cognitive performance on speed of processing test (F=5.678, p=.009, eta=.289). CRAFT group demonstrated significantly larger clinically meaningful gains on participation in daily life (Chi-square= 6.91, p=.032) and significantly higher treatment satisfaction. All treatment gains were maintained at a 3-month follow-up (n=32). Conclusions: CCT and CRAFT were found to have a positive impact on participation and cognitive outcomes among individuals with CRCI. The CRAFT showed an additional advantage in improving self-chosen occupation-based goals suggesting that a combination of cognitive training with occupation-based intervention has a positive synergistic effect resulting in ‘real world’ health benefits. Implications for Cancer Survivors: A combination of cognitive training with occupation-based intervention has a positive effect resulting in clinically meaningful improvements in participation in daily life, objective cognitive performance, and subjective cognitive impairment. Clinical Trial Registration: ClinicalTrials.gov NCT04210778, December 26, 2019, retrospectively registered.

Background: Venous thromboembolism (VTE) is a frequent, potentially lethal complication in individuals with cancer. Patients with brain tumors are at particularly high risk for VTE. Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B cell lymphoma, involving the craniospinal axis. The incidence of VTE in patients with PCNSL was reported as very high, occurring mostly in the early period of therapy. Objectives: We aimed to evaluate the efficacy and safety of prophylactic low-molecular-weight heparin (LMWH) throughout the treatment of PCNSL. Patients: All patients >18 years of age diagnosed and treated for PCNSL at our institution in 2005–2017 were included. Results: There were 44 patients; mean age at diagnosis was 61.5 years. Three patients (6.8%) had a personal history of thrombosis, 11 (25%) had a history of diabetes or smoking, and 32 (72%) had an Eastern Cooperative Oncology Group performance status of 0–1 at diagnosis. During treatment with LMWH, no VTE events were recorded; 2 (4.5%) patients experienced a minor bleeding event and 1 (2.3%) a major bleeding event. Conclusions: Among our 44 patients with PCNSL treated with prophylactic LMWH, no VTE events were recorded, and only 1 (asymptomatic) intracranial bleed was recorded. Within the limitations of a retrospective nonrandomized study, our findings suggest that VTE prophylaxis may be beneficial for individuals with PCNSL.

The purpose of the current study was to examine the unique contribution of personal and medical factors, objective and subjective cognition, and self-efficacy to the explained variance of quality of life (QoL) among survivors with self-reported cancer related cognitive impairment (CRCI).Seventy-three cancer survivors (non-central nervous system) with CRCI (mean age: 50.85 ± 10.82 years old, mean years post-treatment: 3 ± 2.7) participated in this cross-sectional study. QoL was assessed using the Functional Assessment of Cancer Therapy (FACT)-GP, while the cognitive function was assessed both objectively using tests of attentional control, speed of processing and sustained attention, and subjectively using the FACT-Cognition perceived cognitive impairments (FACTcog-PCI) subscale. Self-efficacy was assessed using the New General Self-Efficacy Scale (NGSE).A hierarchical multiple linear regression analysis revealed that sustained attention, perceived cognitive impairment and self-efficacy, accounted for 54% of the variance of QoL (Considering that these variables may be amenable to change, this model can serve as a conceptual framework for designing effective cognitive treatment options for CRCI.

Lymphoma of the nervous system is rare and usually involves the brain, spinal cord, or peripheral nerves. Hence, it has varied clinical presentations, and correct diagnosis is often challenging. Incorrect diagnosis delays the appropriate treatment and affects prognosis. We report 5 patients with delayed diagnosis of lymphoma involving the central and/or peripheral nervous system, initially evaluated for other neurological diagnoses. We also discuss the challenge of diagnosis and appropriate testing. Retrospective review of 2011–2019 records of patients with confirmed nervous system lymphoma diagnosed in a tertiary care medical center. We present 5 adult patients initially evaluated for inflammatory myelopathy, inflammatory lumbosacral plexopathy, atypical parkinsonism, and demyelinating disease of the CNS. Final diagnosis of the nervous system lymphoma was delayed by 4 to 18 months and was based on tissue biopsy in 4, and on CSF and bone marrow examination in 1 patient. Lymphoma may imitate various central and peripheral nervous system disorders. We suggest several red flags that indicate the need to consider lymphoma, including subacute but progressive symptomatic evolution, painful neurological deficit, unclear clinical diagnosis, and transient steroid responsiveness. Correct diagnosis often requires a combination of diagnostic tests, while pathology testing is crucial for early diagnosis and is strongly recommended in the appropriate clinical setting.

BACKGROUND Brain radiotherapy is the main therapeutic modality for brain metastases (BM), but carries short and long term toxicities, termed radiation-induced neurotoxicity (RIN), and classified to acute, early-delayed and late-delayed RIN according to its time onset. Although diagnosis of RIN is crucial for patient management, there is an unmet need for sensitive biomarkers for RIN. Here we report on a novel non-invasive biomarker for detection and monitoring RIN. As radiotherapy is known to induce brain cells apoptosis as well as BBB disruption, we hypothesized that circulating cell free DNA fragments derived from dying brain cells will be elevated in the blood of patients with RIN. Using comparative methylome analysis we identified 13 genomic loci showing brain-specific DNA methylation patterns, including markers for neurons, oligodendrocytes, and astrocytes. We searched for these brain-derived cfDNA (bncfDNA) in plasma samples of patients following brain irradiation. METHODS We followed 24 patients treated by brain radiotherapy for BM by clinical and radiological examinations before, during and after treatment. In addition, we serially collected blood samples for DNA analysis, and correlated bncfDNA levels with clinical and radiological assessment. RESULTS Patient`s median age was 60 years. Most common primary tumor sites were breast (25%), lung (20.8%) and melanoma (12.5%). RIN was detected in 10 patients (62%). BncfDNA levels increased up to 292.4 fold in acute RIN, up to 138533.1 in early-delayed RIN, and up to 58.4 fold in late-delayed RIN. Resolution of RIN correlated with decrease in bncfDNA. Changes in bncfDNA levels were independent of tumor response and suggested to reflect both symptomatic and asymptomatic RIN. CONCLUSION Increase in bncfDNA levels characterizes RIN independent of tumor response. Thus, BncfDNA may serve as a novel biomarker for brain cells death incurred by radiotherapy. Further studies are required to explore the clinical utility of bncfDNA as a RIN biomarker.

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.

Date Presented 04/7/21 This study describes the feasibility of a combined telehealth intervention of computerized cognitive training together with occupation-based treatment for patients with cancer-related cognitive impairment (CRCI). The intervention was found feasible, and positive outcomes on occupational performance, cognitive functions, quality of life, and mood were revealed. This treatment can possibly add to the therapeutic landscape of CRCI, which currently impairs the life of millions worldwide. Primary Author and Speaker: Yafit Gilboa Contributing Authors: Anita Tollen, Marie Holmefur

Purpose: Heat intolerance (HI) is determined in the Israel Defense Force according to a heat tolerance test (HTT) before returning to duty after an exertional heat stroke (EHS) event. Recently, inc...

Date Presented 03/27/20 This pilot study describes the impact of a combined remote intervention of computerized cognitive training together with occupational-based treatment on patients with cancer-related cognitive impairment. Positive outcomes were found in occupational performance, cognitive functions, quality of life, and mood. This treatment can possibly add to the therapeutic landscape of cancer-related cognitive impairment, which currently impairs the lives of millions worldwide. Primary Author and Speaker: Talia Maeir Additional Authors and Speakers: Yafit Gilboa Contributing Authors: Afik Hoba, Mor Nahum, Chen Makranz, Tamar Peretz-Yablonsky

INTRODUCTION: Radiotherapy is a common treatment for brain metastases. However, it is commonly associated with central nervous system (CNS) toxicity. There are no biomarkers for early detection of radiotoxicity. Here we explore the utility of cell-free circulating DNA (cfDNA) for detection of brain cells death in the context of brain metastases. Using comparative methylome analysis we have previously identified 12 genomic loci showing brain-specific DNA methylation patterns, including markers for neurons, oligodendrocytes and astrocytes. These brain-specific methylation markers were identified in plasma of patients suffering from multiple sclerosis, as well as traumatic and ischemic brain damage. We hypothesize that brain-derived cell-free DNA (bncfDNA) can be identified in patients suffering from brain metastases receiving radiotherapy, and can potentially be used as a biomarker to help guide treatment. MATERIALS AND METHODS: We recruit oncological patients treated by brain radiotherapy for brain metastases. We serially assess each patient before, during and after treatment by neurological examination and MRI studies. In each study visit a blood sample is collected for bncfDNA measurement. RESULTS: Preliminary results on samples from 22 patients show elevation of bncfDNA in patients suffering from brain metastases (average 8501 copies/ml; range 0-112336 copies/ml) compared with an extremely low background in healthy individuals (average 6 copies/ml; range 0–33 copies/ml); p < 0.0001). We observed elevation of cfDNA derived from neurons, oligodendrocytes and astrocytes. Next, we studied bncDNA levels following brain radiotherapy. Preliminary results from a patient suffering from an acute central facial paralysis during radiotherapy show clinical correlation of bncfDNA levels with neurological impairment related to acute radiotoxicity. Other patients are still followed-up with bncfDNA measurement during and after radiotherapy. CONCLUSION: BncfDNA reflects brain cells death incurred by metastases, as well as damage associated with radiotherapy, and may serve as circulating biomarker for neurotoxicity in patients suffering from brain metastases.

BACKGROUND: Radiotherapy is a common treatment for brain metastases. However, it is commonly associated with central nervous system (CNS) toxicity, leading to functional disability. There are no biomarkers capable of detecting preclinical neurotoxicity for the purpose of early detection of radiation-induced CNS damage. Here we explore the utility of cell-free circulating DNA (cfDNA), shed from dying cells, for detection of brain cell death in the context of brain metastases. Using comparative methylome analysis we have previously identified 12 genomic loci showing brain-specific DNA methylation patterns, including markers for neurons, oligodendrocytes and astrocytes. These brain-specific methylation markers were identified in the plasma of patients suffering from multiple sclerosis, as well as traumatic and ischemic brain damage. We hypothesize that brain-derived cell-free DNA (bncfDNA) can be identified in patients suffering from brain metastases receiving radiotherapy, and can potentially be used as a biomarker to help guide treatment. MATERIAL AND METHODS: We recruit oncological patients treated by brain radiotherapy for brain metastases. We serially assess each patient before, during and after treatment by neurological examination. MRI studies are performed before and after radiotherapy in 2–3 months intervals. In each study visit a blood sample is collected for bncfDNA. We measure bncfDNA from serial blood samples of each patient, and correlate bncfDNA levels with clinical assessment. RESULTS: Preliminary results on samples from 22 patients show elevation of bncfDNA in patients suffering from brain metastases (average 8501 copies/ml; range 0-112336 copies/ml) compared with an extremely low background in healthy individuals (average 6 copies/ml; range 0–33 copies/ml); p

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.

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.

Introduction: Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome characterized with headaches, seizures, confusional state and visual disturbances associated with transient predominantly bilateral posterior white mater MRI lesions. It is reported in the setting of hypertension, acute renal failure, peripartum eclampsia, autoimmune diseases, immunosuppression and chemotherapy. Thrombotic microangiopathy (TMA), hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are also reported as potential PRES inducers. We present 2 patients with PRES associated with TMA caused by chemotherapy. METHODS: We retrospectively summarize clinical and imaging data of 2 patients diagnosed and treated at our institution. Results: The first patient was a 36 year-old woman diagnosed with HUS-induced PRES that developed 11 weeks after treatment with mitomycin-C for metastatic colon adenocarcinoma. She presented with acute confusional state, cortical visual deficit and generalized tonic-clonic seizures that responded to IV Phenytoin. Brain MRI demonstrated extensive hypertintense posterior white matter lesions on T2-weighted images, typical of PRES. Laboratory examination showed acute renal failure, hemolytic anemia, and thrombocytopenia compatible with the diagnosis of hemolytic uremic syndrome (HUS) induced by maximal doses of mitomycin-C. She was treated with steroids, plasmapheresis, Intravenous immunoglobulins, aspirin, antihypertensive drugs and diuretics. 6 weeks later she was neurologically intact. Follow-up MRI 7 month later revealed resolution of most of the signal changes appeared during the acute phase. The second patient was 47 year- old woman treated with carboplatin and gemcitabine for metastatic breast carcinoma, along with herbal medication. She presented with subacute progressive dysphasia and right hemiparesis. MRI demonstrated left frontal, right insular and bilateral parieto-occipital hyperintense lesion on T2 and T2/FLAIR with restricted diffusion and hemorrhagic components compatible mainly with vasculitis or PRES. She also had hemolytic anemia, thrombocytopenia and large number of schiziocytes on blood smear. After ruling out vasculitis she was diagnosed with TMA-induced PRES following re-administration of gemcitabine 2 months after it had been stopped. Although she was treated with plasmapheresis her laboratory parameters, signal changes on follow-up MRI and neurological status were all deteriorated. Unfortunately she had died 3 weeks after admission. CONCLUSION: This report is an example of the extreme variability in the clinical course of chemotherapy induced PRES associated with TMA. Different chemotherapy related pathogenesis and various additional factors (such as the use of herbal medication) can attribute to an extreme different course and prognosis of PRES.

Exertional heat stroke (EHS) is a life-threatening condition, which deteriorates rapidly. Immediate cooling treatment can, therefore, be life saving. Over the past two winters, we witnessed three cases of hypothermia resulting from treatment of suspected EHS. Since no such cases were described in the literature before, we, therefore, in this study present one of those cases. In addition, recommended approaches for proper management of similar situations are discussed. We suggest that in order to avoid hypothermia following aggressive cooling, core temperature (T core) should be continuously monitored. Upon reaching 38°C, cooling must be discontinued, and the patient should be dried and covered.

Introduction: Venous thromboembolism (VTE) is a frequent, potentially lethal, complication in patients with cancer. Patients with brain tumors are at a particularly high risk for VTE. Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma, involving the cranio-spinal axis. The incidence of VTE in patients with PCNSL is as high as 30-60% in various series, occurring mostly in the early period of therapy. Due to this high incidence, the policy in our medical center since the year 2005, is to treat with prophylactic low molecular weight heparin (LMWH) from the time of PCNSL diagnosis until the end of treatment. We aimed to evaluate the incidence of VTE in patients with PCNSL treated with prophylactic LMWH. Material and methods: All patients ≥18 years who were diagnosed and treated for PCNSL in Hadassah-Hebrew University Medical Center between the years 2005-2017 were included in the study. We retrospectively reviewed their medical records for demographic details and initial disease characteristics (age at diagnosis, sex, performance status, laboratory results such as LDH, cerebrospinal fluid content and location of the growth), for details of risk factors for VTE such as diabetes, smoking or heart failure, and for personal or familial history of thrombosis. Therapeutic details including chemotherapy protocol, response to treatment and supportive care were compiled. Specifically we noted if prophylactic LMWH was given, if any complications developed due to the LMWH treatment and whether a VTE event occurred. Results: Forty four patients were included in the study. Mean age at diagnosis was 60.2 years and there were 27 (61%) females. Three (6.8%) patients had a personal history of thrombosis and 13 (29%) had a history of diabetes or smoking. Thirty two (72%) had an ECOG performance study of 0-1 at diagnosis and seven (16%) had leptomeningeal involvement. Forty one (93%) of patients were treated with a systemic high dose methotrexate (HDMTX) based protocol (mean of 7.6 courses of HDMTX per patient) and thirty two (73%) patients were treated with systemic rituximab. All 44 patients were treated with prophylactic LMWH, mostly at a dose of 40 mg per day (41 patients, 93%). Of the 44 patients, five (11%) discontinued treatment; 2 due to side effects (abnormal liver function tests and subdural hematoma (SDH)) and 3 for an unknown reason. Three (7%) patients had a minor bleeding event (gum, conjunctival, Ommaya reservoir catheter tract). One patient (2.3%) had a major bleeding event (SDH) while on LMWH treatment which was found on routine MRI imaging of the brain as he was asymptomatic. No VTE events (0%) were recorded in patients treated with LMWH. Two patients had a VTE, however both patients were off LMWH treatment at the time of VTE (one stopped LMWH, the other was diagnosed with VTE concurrently with the diagnosis of PCNSL). Conclusions: In our group of 44 PCNSL patients, prophylactic use of LMWH was highly effective, with no VTE events. Two cases of VTE occurred in our patient group, both occurred while the patients were off LMWH treatment. Only one, asymptomatic, intracranial bleed was recorded, indicating the relative safety of this treatment in PCNSL patients. Further prospective studies should be done to support the routine use of this prophylactic strategy. Disclosures No relevant conflicts of interest to declare.

Complement-receptor-3 (CR3/MAC-1), scavenger-receptor-AI/II (SRAI/II), and Fcgamma-receptor (FcgammaR) 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 PLCgamma inhibitor U-73122. Altogether, our observations suggest that CR3/MAC-1 and SRAI/II-mediated myelin phagocytosis share activation by PI3K, PLCgamma 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.

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 PKI(14-22) 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.

Listeria monocytogenes is a gram-positive bacterium with a predilection to infect the central nervous system, often affecting immunocompromised or elderly patients. The most common manifestations are meningitis and rhomboencephalitis. We report two cases of Listeria meningitis complicated by acute hydrocephalus several days after presentation and we further review the literature of similar cases. We conclude that acute hydrocephalus is a significant, not often recognized, complication of Listeria meningitis, usually occurring several days from onset when coverage did not include anti-Listeria antimicrobials. In high risk patients, meningitis combined with acute hydrocephalus is suggestive of LM infection. Keywords: Listeria monocytogenes meningitis, Hydrocephalus

INTRODUCTION: Exertional heat stroke (EHS) is the most dangerous heat-related injury. EHS may be followed by a state of heat intolerance. The Israeli Defense Forces (IDF) performs heat tolerance tests (HTT) to all heat injury victims 6-8 wk following injury as part of the "return to duty" process. The HTT protocol and normal values are based on vast experience with young healthy men. Over the last several years an increasing number of female soldiers have been joining combat units. Heat injuries and, thus, HTT among women have become more frequent. Due to potential gender-related physiological and thermoregulatory differences, we examined the necessity for validating the HTT protocol for women. METHODS: Retrospective physiological data from our database on heat injuries and HTT between the years 2008-2010 was compared between 9 female subjects and 170 male subjects who had similar background characteristics. RESULTS: Defining heat intolerance as peak rectal temperature > 38.5 degrees C, peak heart rate > 150 bpm, or the inability to reach equilibrium in these values, we diagnosed 67% of the female subjects as heat intolerant. In the male subjects, only 26% were diagnosed as heat intolerant using the same criteria. CONCLUSIONS: Using the standard HTT criteria, women are more frequently diagnosed as heat intolerant than men. Further studies should be performed in order to re-evaluate the normal values for a "female HTT" in order to optimize the process of safe return to duty of female heat injury victims and to minimize false positive results among female soldiers. Language: en

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.

During exercise certain metabolic and physiological processes influence fluid and electrolyte balance. Fluid loss, mostly through sweating, that is not properly compensated for by drinking, may result in dehydration. Clinical manifestations of dehydration depend on the amount of fluid lost. The more severe the level of dehydration is, the greater the reduction in physical and cognitive performance. It is recommended to drink water frequently and in small amounts. In order to encourage drinking, the fluid should be cool, palatable, readily available, and not carbonated. During exercise the ability of the kidney to excrete water is restricted, and therefore, there is a risk of hyperhydration and hyponatremia, mainly under conditions of overdrinking. Sodium loss through sweating and the development of hyponatremia will primarily occur during strenuous exercise lasting more than 4 hours. Symptoms of hyponatremia will generally appear at sodium concentrations below 130 mmol/l. In order to avoid hyponatremia one must avoid overdrinking, and during prolonged physical activity (4 hours) sodium intake must match the amount lost by sweating. Proper electrolyte and carbohydrate consumption through a normal diet is preferable to sport beverages or exogenous sodium supplements. In order to avoid dehydration, on one hand, and hyponatremia due to hyperhydration, on the other hand, the amount of fluid consumed should complement the amount of fluid lost during exercise. Given that there is intra- (depending on the type of activity and environmental conditions) and interindividual variability in the rate of fluid and salt loss, fluid and salt intake should be determined on an individual basis, as outlined in this standpoint.

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.

Complement-receptor-3 (CR3/MAC-1), scavenger-receptor-AI/II (SRAI/II) and Fcgamma-receptor (FcgammaR) can mediate phagocytosis of degenerated myelin in macrophages and microglia. However, CR3/MAC-1 and SRAI/II, but not FcgammaR, mediate phagocytosis after axonal injury. We tested for phosphatidylinositol 3-kinase (PI3K), phosphoinositide-specific phospholipase-Cgamma (PLCgamma) and protein kinase-C (PKC) signaling in myelin phagocytosis mediated by CR3/MAC-1 alone and by CR3/MAC-1 combined with SRAI/II. Phagocytosis was inhibited by PI3K inhibitors wortmannin and LY-294002, PLCgamma inhibitor U-73122, classical PKC (cPKC) inhibitor Go-6976, general PKC inhibitors Ro-318220 and calphostin-C, and BAPTA/AM which chelates intracellular Ca(2+) required for cPKC activation. PKC activator PMA augmented phagocytosis and further alleviated inhibitions induced by PI3K and PLCgamma inhibitors. Overall, altering PKC activity modulated phagocytosis 4- to 6-fold between inhibition and augmentation. PLCgamma activation did not require tyrosine phosphorylation. Thus, signaling of myelin phagocytosis mediated by CR3/MAC-1 alone and by CR3/MAC-1 combined with SRAI/II involves PI3K, PLCgamma and cPKC, the cascade PI3K--PLCgamma--cPKC, and wide-range modulation by PKC. This pathway may thus be targeted for in vivo modulation, which may explain differences in the efficiency of CR3/MAC-1-mediated myelin phagocytosis in different pathological conditions.

The removal of damaged myelin is central to repair after injury to axons and in autoimmune demyelinating diseases. Complement receptor 3 (CR3/MAC-1) plays a major role in mediating the phagocytosis of damaged myelin by macrophages and microglia. We studied the modulation (inhibition and augmentation) of CR3/MAC-1 mediated myelin phagocytosis by mAbs that bind to distinct epitopes of subunits alphaM and beta2 of CR3/MAC-1. mAb M1/70 anti-alpha(M) and mAb 5C6 anti-alpha(M) inhibited, whereas mAb M18/2 anti-beta2 augmented myelin phagocytosis. This mAb-induced modulation of myelin phagocytosis occurred in the presence and absence of active complement. Inhibition induced by M1/70 or 5C6 did not add when the two were combined. Combining M1/70 or 5C6 with M18/2 reduced the augmentation induced by M18/2 alone. CR3/MAC-1-mediated myelin phagocytosis may thus be subjected to modulation between efficient and inefficient functional/activation states. These observations and conclusions may offer an explanation for the observed discrepancy between efficient myelin phagocytosis in experimental allergic encephalomyelitis and inefficient myelin phagocytosis after injury to CNS axons, although in both instances macrophages/microglia express CR3/MAC-1.