Yigal Shoshan

Accelerated Fas-Mediated Apoptosis of Monocytes and Maturing Macrophages from Patients with Systemic Lupus Erythematosus: Relevance to In Vitro Impairment of Interaction with iC3b-Opsonized Apoptotic Cells

Impaired handling of apoptotic cells has been suggested as an important factor in the development of systemic lupus erythematosus (SLE), and a role for complement in the removal of apoptotic cells was shown recently. We studied the in vitro function of macrophages from 40 patients with SLE and their matched controls in the removal of heterologous apoptotic cells opsonized by iC3b. Interaction index of apoptotic cells opsonized by iC3b was significantly lower in patients with SLE and averaged 71% ± 37 of that of healthy individuals (p < 0.002) and 69% ± 35 of patients with rheumatoid arthritis (p < 0.007). SLE patients had increased apoptosis of both freshly isolated monocytes (p < 0.001) and maturing macrophages (p < 0.04) that led to decreased density of monocyte-derived macrophages. Apoptosis was inhibited by adding soluble Fas receptor indicating Fas-mediated apoptosis. As demonstrated in both healthy controls and patients with SLE, decreased macrophage density by itself caused significant decreased uptake of apoptotic cells by the remaining macrophages. Maintaining normal density in SLE patients either by an increased initial density or by using soluble Fas restored the interaction capacity of the individual macrophages in the majority of patients. We concluded that impaired in vitro interaction of iC3b-opsonized apoptotic cells with macrophages from patients with SLE was mainly associated with Fas-dependent accelerated apoptosis of the monocytes/macrophages. Accelerated apoptosis of phagocytes may represent a novel in vitro mechanism of impairment of interaction with apoptotic cells that, apart from reducing the number of professional phagocytes, alters the function of the remaining macrophages.

Diagnosis and management of Rosai-Dorfman disease involving the central nervous system

Abstract Introduction: Rosai–Dorfman disease is a benign non-neoplastic proliferative disorder of histiocytes originally described in the cervical lymph nodes. Extranodal sites were later recognized, and by 1990, they were shown to represent over 40% of cases; however, central nervous system involvement is still considered rare. We review the literature, which shows a steady increase in reports of Rosai–Dorfman disease involving the brain and/or spine. Methods: A literature search was performed for the period 1969–2008, using multiple search engines, with keywords Rosai–Dorfman disease, central nervous system Rosai–Dorfman disease and sinus histiocytosis with massive lymphadenopathy. Results: By December 2008, 111 cases of Rosai–Dorfman disease involving the central nervous system had been reported in the literature, including our cases. In the central nervous system, Rosai–Dorfman disease is ubiquitous. Although it is characterized by unique, indeed pathognomonic, histopathological cytoarchitecture, it may be mistaken for many other neoplastic and inflammatory histioproliferative diseases. Surgical resection with post-operative corticosteroids remains the treatment of choice. Conclusions: Rosai–Dorfman disease involving the central nervous system appears to be more common than previously thought and may well assume a more prominent place in the differential diagnoses of dural-based lesions. Expert awareness of the characteristic histopathology and immunohistochemistry of the disease is required for accurate diagnosis.

D-Cycloserine improves functional outcome after traumatic brain injury with wide therapeutic window

It has been long thought that hyperactivation of N-methyl-D-aspartate (NMDA) receptors underlies neurological decline after traumatic brain injury. However, all clinical trials with NMDA receptor antagonists failed. Since NMDA receptors are down-regulated from 4h to 2weeks after brain injury, activation at 24h, rather than inhibition, of these receptors, was previously shown to be beneficial in mice. Here, we tested the therapeutic window, dose regimen and mechanism of action of the NMDA receptor partial agonist D-cycloserine (DCS) in traumatic brain injury. Male mice were subjected to trauma using a weight-drop model, and administered 10mg/kg (i.p.) DCS or vehicle once (8, 16, 24, or 72h) twice (24 and 48h) or three times (24, 48 and 72h). Functional recovery was assessed for up to 60days, using a Neurological Severity Score that measures neurobehavioral parameters. In all groups in which treatment was begun at 24 or 72h neurobehavioral function was significantly better than in the vehicle-treated groups. Additional doses, on days 2 and 3 did not further improve recovery. Mice treated at 8h or 16h post injury did not differ from the vehicle-treated controls. Co-administration of the NMDA receptor antagonist MK-801 completely blocked the protective effect of DCS given at 24h. Infarct volume measured by 2,3,5-triphenyltetrazolium chloride staining at 48h or by cresyl violet at 28days was not affected by DCS treatment. Since DCS is used clinically for other indications, the present study offers a novel approach for treating human traumatic brain injury with a therapeutic window of at least 24h.

Accelerated Autoimmune Disease in MRL/MpJ-Faslpr but not in MRL/MpJ Following Immunization with High Load of Syngeneic Late Apoptotic Cells

Numerous studies have shown that autoantigens may be clustered in the blebs of apoptotic cells. However, it is not yet clear in what circumstances apoptotic cells could be immunogenic rather than tolerogenic when interacting with macrophages, dendritic cells, and B cells. In order to further study this question we compared immunization of high load of syngeneic late apoptotic cells in two genetically close pro-autoimmune mice strains: MRL/MpJ and MRL/MpJ-Faslpr. We show that high apoptotic load could accelerate the generation of anti-dsDNA and anticardiolipin, and the extent of kidney disease, in MRL/MpJ-Faslpr but could not generate autoimmunity in MRL/MpJ. Thus, in this model, a high load of apoptotic cells could augment the autoimmune response in established autoimmunity, but did not generate de novo autoimmune response in pro-autoimmune mice. Taken together with previous observations, apoptotic cell load may modify autoimmune disease generating either immune inhibition and down regulation of autoimmunity or immune stimulation and acceleration of an autoimmune disease.

Spontaneous spinal epidural hematoma: The importance of preoperative neurological status and rapid intervention

We describe the presentation, management, and outcome of spontaneous spinal epidural hematoma (SSEH) in two tertiary academic centers. We retrospectively reviewed clinical and imaging files in patients diagnosed with SSEH from 2002-2011. Neurologic status was assessed using the American Spinal Injury Association (ASIA) Impairment Scale (AIS). A total of 17 patients (10 females; mean age 54 years, range 10-89) were included. Among patients presenting with AIS A, 5/8 showed no improvement and 3/8 reached AIS C. Among those presenting with AIS C, 5/6 reached AIS E and 1/6 reached AIS D. Of those presenting with AIS D, 3/3 reached AIS E. Mean time-to-surgery (TTS) was 28 hours (range 3-96). TTS surgery in two patients remaining at AIS A was ⩽ 12 hours; in 4/8 patients recovering to AIS E it was > 12 hours, including three patients operated on after > 24 hours. In patients remaining at AIS A, a mean of 4.4 levels were treated compared with means of 3.7 and 3.5 in those with AIS C and E, respectively, at late follow-up. In this series, preoperative neurological status had greater impact on late outcome than time from symptom onset to surgery in patients with SSEH.

Do cranial subdural hematomas migrate to the lumbar spine

We report a patient with minor head trauma-related bilateral hemispheric subdural hematoma (SDH) and subsequent delayed spinal SDH or presumed migration to the lumbar spine. An acutely confused 88-year-old man presented to the Emergency Department after minor head trauma. Head CT scan revealed a small hemispheric SDH. The patient was admitted for observation. CT scan 6 hours later showed bilateral SDH with extension to the tentorium. Three days later SDH had resolved leaving bilateral subdural hygromas. Local leg weakness localized to the lumbar spine developed on day 6; spinal CT scan and MRI revealed a posterior L5-S1 collection. A pure subacute subdural hematoma compressing the cauda equina was drained after an L5 laminectomy. His lower leg weakness improved. The patient was discharged to rehabilitation two weeks after surgery. Patients with traumatic SDH who develop late-onset neurological deterioration attributable to any region of the spine should be evaluated for spinal SDH.

Serum S100B levels after meningioma surgery: A comparison of two laboratory assays

BackgroundS100B protein is a potential biomarker of central nervous system insult. This study quantitatively compared two methods for assessing serum concentration of S100B.MethodsA prospective, observational study performed in a single tertiary medical center. Included were fifty two consecutive adult patients undergoing surgery for meningioma that provided blood samples for determination of S100B concentrations. Eighty samples (40 pre-operative and 40 postoperative) were randomly selected for batch testing. Each sample was divided into two aliquots. These were analyzed by ELISA (Sangtec) and a commercial kit (Roche Elecsys®) for S100B concentrations. Statistical analysis included regression modelling and Bland-Altman analysis.ResultsA parsimonious linear model best described the prediction of commercial kit values by those determined by ELISA (y = 0.045 + 0.277*x, x = ELISA value, R2 = 0.732). ELISA measurements tended to be higher than commercial kit measurements. This discrepancy increased linearly with increasing S100B concentrations. At concentrations above 0.7 μg/L the paired measurements were consistently outside the limits of agreement in the Bland-Altman display. Similar to other studies that used alternative measurement methods, sex and age related differences in serum S100B levels were not detected using the Elecsys® (p = 0.643 and 0.728 respectively).ConclusionAlthough a generally linear relationship exists between serum S100B concentrations measured by ELISA and a commercially available kit, ELISA values tended to be higher than commercial kit measurements particularly at concentrations over 0.7 μg/L, which are suggestive of brain injury. International standardization of commercial kits is required before the predictive validity of S100B for brain damage can be effectively assessed in clinical practice.

Control of vasogenic edema in a brain tumor model: comparison between dexamethasone and superoxide dismutase.

OBJECTIVEnThe production of prostaglandin (PG) within brain tumors probably generates excessive amounts of oxygen free radicals that may disrupt microvessel permeability within the tumor and in the adjacent brain. We evaluated the effect of systemic therapy with recombinant human manganese-superoxide dismutase (r-hMnSOD) and with dexamethasone on the vascular permeability (VP) of a brain tumor and the adjacent brain. Treatment effect was also evaluated in control animals subjected to mild penetration injury.nnnMETHODSnFischer rats were injected stereotactically with either 10(5) cells of malignant sarcoma or with vehicle into the right parietal hemisphere. Nine days later, the animals were treated with r-hMnSOD (50 mg/kg of body weight every 12 h [one intravenous, then two intraperitoneal injections]; serum levels, 1100-1800 micrograms/ml), dexamethasone (2 mg/kg every 12 h [one intravenous, then two intraperitoneal injections]), or vehicle and were killed after 30 hours for evaluation of VP and PG production.nnnRESULTSnThe VP was markedly increased within the tumor (P < 0.001), in the brain adjacent to it, and in the vehicle injection site. The VP of the normal brain was unaffected by r-hMnSOD or dexamethasone treatment, unlike the VP in the tumor, the adjacent brain, and the injection sites of control animals, where it was reduced by 50, 54, and 23%, respectively (P < 0.04), for r-hMnSOD and 50, 41, and 71%, respectively (P < 0.05), for dexamethasone. A one- to threefold increase in synthesis of thromboxane and PGE2 was measured within the tumor, the adjacent brain, and the injection sites of control animals (P < 0.0001). Treatment with r-hMnSOD had no effect on tumor PG production, but it reduced the synthesis in the brain tissue adjacent to the tumor and in traumatized control animals (P < 0.04). Immunohistochemical evaluation revealed vascular proliferation with abnormal basal membrane, atypical astrocytes, and large numbers of reactive macrophages present in the adjacent brain and at the injection sites of control animals but not within the tumor mass.nnnCONCLUSIONnOxygen free radicals probably enhance vasogenic brain edema resulting from tumor and penetration injury. The edema can be attenuated by systemic r-hMnSOD therapy, which has been proven to be as effective as steroid treatment. An inflammatory response may account for oxygen free radical production in brain tissue adjacent to the tumor and at the injection site of vehicle solution, but other mechanisms probably generate oxygen free radicals within the tumor mass.

Early postoperative serum S100β levels predict ongoing brain damage after meningioma surgery: a prospective observational study

IntroductionElevated serum levels of S100β, an astrocyte-derived protein, correlate with unfavourable neurological outcomes following cardiac surgery, neurotrauma, and resuscitation. This study evaluated whether pre-/postoperative serum S100β levels correlate with unfavourable clinical and radiological findings in patients undergoing elective meningioma resection.MethodsIn 52 consecutive patients admitted for meningioma surgery, serum S100β levels were determined upon admission and immediately, 24 hours, and 48 hours after surgery. All patients underwent complete pre- and postoperative neurological examination and mini-mental state examination. Radiological evaluation included preoperative magnetic resonance imaging (MRI) and postoperative computed tomography. Tumour volume, brain edema, and bleeding volume were calculated using BrainSCAN™ software.ResultsPreoperative S100β levels did not correlate with the tumour characteristics demonstrated by preoperative MRI (for example, tumour volume, edema volume, ventricular asymmetry, and/or midline shift). Preoperative serum S100β levels (0.065 ± 0.040 μg/l) were significantly lower than the levels measured immediately (0.138 ± 0.081 μg/l), 24 hours (0.142 ± 0.084 μg/l), and 48 hours (0.155 ± 0.119 μg/l) postoperatively (p < 0.0001). Significantly greater postcraniotomy S100β levels were observed with prolonged surgery (p = 0.039), deterioration in the mini-mental state examination (p = 0.005, 0.011, and 0.036 for pre versus immediate, 24 hours, and 48 hours postsurgery, respectively), and with postoperative brain computed tomography evidence of brain injury; bleeding was associated with higher serum S100β levels at 24 and 48 hours after surgery (p = 0.046, 95% confidence interval [CI] -0.095 to -0.001 and p = 0.034, 95% CI -0.142 to -0.006, respectively) as was the presence of midline shift (p = 0.005, 95% CI -0.136 to -0.025 and p = 0.006, 95% CI -0.186 to -0.032, respectively). Edema was associated with higher serum S100β levels immediately (p = 0.022, 95% CI -0.092 to -0.007) and at 48 hours after surgery (p = 0.017, 95% CI -0.142 to -0.026). The degree of elevation in S100β levels at 24 and 48 hours after surgery also correlated with the severity of midline shift and edema.ConclusionIn patients with meningioma, serum S100β levels perform poorly as an indicator of tumour characteristics but may suggest ongoing postcraniotomy injury. Serum S100β levels may serve as a potentially useful early marker of postcraniotomy brain damage in patients undergoing elective meningioma resection.

Intracranial pressure monitoring following decompressive hemicraniectomy for malignant cerebral infarction

Randomized controlled trials have demonstrated the efficacy of decompressive craniectomy in substantially decreasing mortality and improving functional outcome in middle cerebral artery infarction. The role of intracranial pressure (ICP) monitoring following decompressive craniectomy for stroke has not been well studied. We present a retrospective review of our experience with postoperative ICP monitoring in 12 stroke patients who underwent decompressive craniectomy. All elevations of ICP above a 20 mm Hg threshold were noted. ICP was recorded for 1417 hours during which 68 ICP elevations were seen. Nine out of 12 patients had events of raised ICP, including eight with more than three elevations. A total of 81 interventions were employed to treat elevated ICP; 71 were effective in reducing ICP below the 20 mm Hg threshold. The most frequent intervention was cerebrospinal fluid drainage via an external ventricular drain, which was effective in 85.4% of cases. Eleven out of 12 patients survived (92%) and attained a median modified Rankin Scale score of 4 (interquartile range 4-5) at a mean 15 month follow-up. In our experience, elevated ICP may commonly occur following decompressive craniectomy for stroke. Monitoring ICP influenced postoperative management and standard measures for reducing ICP were usually effective in the current series.