Gene therapy of malignant brain tumors: a rat glioma line bearing the herpes simplex virus type 1-thymidine kinase gene and wild type retrovirus kills other tumor cells.

Tumor cells infected with a retrovirus vector (VIK) containing the herpes simplex virus thymidine kinase (HSV-TK) gene can be selectively killed by treatment with nucleoside analogues, such as ganciclovir. To mediate delivery of the HSV-TK gene to "recipient" tumor cells, "donor" C6 rat glioma cells infected with the VIK vector (C6VIK) were superinfected with wild type Moloney murine leukemia virus (WT Mo-MLV). These modified donor cells (C6VIKWT) produced both wild type retrovirus and the VIK vector. In culture, C6VIKWT cells were 300-fold more sensitive to the toxicity of ganciclovir than were C6VIK cells, suggesting that the presence of wild type retrovirus contributed to the toxicity. Co-culture of C6VIKWT cells with the C6 subline, C6BAG, sensitized the latter to ganciclovir treatment. Nude mice inoculated subcutaneously with a mixture of C6VIKWT and C6BAG cells showed regression of subsequent tumors when treated with ganciclovir. The observations show that tumor cells modified in culture by infection with a retrovirus bearing the HSV-TK gene and wild type retrovirus are not only sensitive to ganciclovir, but can transfer this sensitivity to neighboring "naive" tumor cells in culture and in vivo.     

Chronic neuroprotective effects of low concentration lithium on SH-SY5Y cells:possible involvement of stress proteins and gene expression

To investigate the molecular mechanism underlying the neuroprotective effect of lithium on cells, in this study, we exposed SH-SY5Y cells to 0.5 mmol/L lithium carbonate(Li2CO2) for 25–50 weeks and then detected the expression levels of some neurobiology related genes and post-translational modifications of stress proteins in SH-SY5Y cells. cDNA arrays showed that pyruvate kinase 2(PKM2) and calmodulin 3(CaM 3) expression levels were significantly down-regulated, phosphatase protein PP2A expression was lightly down-regulated, and casein kinase II(CK2), threonine/tyrosine phosphatase 7(PYST2), and dopamine beta-hydroxylase(DBH) expression levels were significantly up-regulated. Besides, western blot analysis of stress proteins(HSP27, HSP70, GRP78 and GRP94) showed an over-expression of two proteins: a 105 kDa protein which is a hyper-phosphorylated isoform of GRP94, and a 108 kDa protein which is a phosphorylated tetramer of HSP27. These results suggest that the neuroprotective effects of lithium are likely related to gene expressions and post-translational modifications of proteins cited above.     

Human herpesvirus 6 is associated with status epilepticus and hyponatremia after umbilical cord blood transplantation

Status epilepticus after allogeneic hematopoietic cell transplantation (alloHCT) is rare. The authors report a case involving a 65-year-old man with nonconvulsive status epilepticus 34 days after umbilical cord blood transplantion for chronic lymphocytic leukemia. Cerebrospinal fluid and serum were positive for human herpesvirus 6 (HHV6). Magnetic resonance imaging of the brain showed symmetric T2 hyper-intensity bilaterally in the mesial temporal lobes, and T2 hyperintensi-ties and restricted diffusion of bilateral putamina. Despite aggressive anticonvulsive therapy, his seizures only abated with initiation of ganciclovir therapy. The patient completed six weeks of combination antiviral therapy (ganciclovir and foscarnet). His cognitive function gradually improved and, after prolonged rehabilitation, the patient was discharged home with residual intermittent memory loss but otherwise functional. HHV6 should be considered in the differential diagnosis of nonconvulsive status epilepticus after alloHCT, especially in patients with hyponatremia. Empirical antiviral therapy targeting HHV6 should be administered to these patients.     

EDEN-dependent translational repression of maternal mRNAs is conserved between Xenopus and Drosophila.

Translational control is a key level in regulating gene expression in oocytes and eggs because many mRNAs are synthesized and stored during oogenesis for latter use at various stages of oocyte maturation and embryonic development. Understanding the molecular mechanisms that underlie this translational control is therefore crucial. Another important issue is the evolutionary conservation of these mechanisms--in other words the determination of their universal and specific aspects. We report here a comparative analysis of a translational repression mechanism that depends on the EDEN (embryo deadenylation element) element. This small cis-acting element, localized in the 3' untranslated region of c-mos and Eg mRNAs, was shown to be involved in a deadenylation process. We demonstrate here that in Xenopus embryos, mRNAs that contain an EDEN are translationally repressed. Next, transgenic flies were used to study the effect of the EDEN motif on translation in Drosophila oocytes. We show that this element also causes the translational repression of a reporter gene in Drosophila demonstrating that the EDEN-dependent translational repression is functionally conserved between Xenopus and Drosophila.     

Bilateral frontal polymicrogyria and Ehlers-Danlos syndrome.]

The authors describe the case of a six-year-old girl with Ehlers-Danlos syndrome associated to bilateral symmetrical frontal polymicrogyria. Several extracellular matrix components, including collagen, are directly implicated in the neuronal migration. We think that a defect in collagen or in another extracellular matrix protein during fetal development could result in this association.     

Fever in subarachnoid hemorrhage: relationship to vasospasm and outcome

OBJECTIVE: To investigate the causes of fever in subarachnoid hemorrhage (SAH) and examine its relationship to outcome. BACKGROUND: Fever adversely affects outcome in stroke. Patients with SAH are at risk for cerebral ischemia due to vasospasm (VSP). In these patients, fever may be both caused by, and potentiate, VSP-mediated brain injury. METHODS: The authors prospectively studied patients admitted to a neurologic intensive care unit with nontraumatic SAH, documenting Hunt-Hess grade, Fisher group, Glasgow Coma Score, bacterial culture data, daily transcranial Doppler mean velocities, and maximum daily temperatures. Patients were classified as febrile (temperature above 38.3 degrees C for at least 2 consecutive days) or afebrile (no fever or isolated episodes of temperature above 38.3 degrees C). VSP was verified by either transcranial Doppler or angiographic criteria. Rankin scale scores on discharge were dichotomized into good (0 to 2) or poor (3 to 6) outcomes. RESULTS: Ninety-two consecutive patients were studied. Thirty-eight patients were classified as febrile. No source for infection was found in 10 of 38 (26%) patients. In a multivariate analysis, three variables independently predicted fever occurrence: ventriculostomy (OR, 8.5 [CI, 2.4 to 29.7]), symptomatic VSP (OR, 5.0 [CI, 1.03 to 24.5]), and older age (OR, 1.75 per 10 years [CI, 1.02 to 3.0]). Poor outcome was related to fever (OR, 1.4 per each day febrile [CI, 1.1 to 1.88]), older age (OR, 1.64 per 10 years [CI, 1.04 to 2.58]), and intubation (OR, 21.8 [CI, 5.6 to 84.5]). CONCLUSION: Fever in SAH is associated with vasospasm and poor outcome independently of hemorrhage severity or presence of infection.     

Comparison of MRI and CT for detection of acute intracerebral hemorrhage

Context  Noncontrast computed tomography (CT) is the standard brain imaging study for the initial evaluation of patients with acute stroke symptoms. Multimodal magnetic resonance imaging (MRI) has been proposed as an alternative to CT in the emergency stroke setting. However, the accuracy of MRI relative to CT for the detection of hyperacute intracerebral hemorrhage has not been demonstrated. Objective  To compare the accuracy of MRI and CT for detection of acute intracerebral hemorrhage in patients presenting with acute focal stroke symptoms. Design, Setting, and Patients  A prospective, multicenter study was performed at 2 stroke centers (UCLA Medical Center and Suburban Hospital, Bethesda, Md), between October 2000 and February 2003. Patients presenting with focal stroke symptoms within 6 hours of onset underwent brain MRI followed by noncontrast CT. Main Outcome Measures  Acute intracerebral hemorrhage and any intracerebral hemorrhage diagnosed on gradient recalled echo (GRE) MRI and CT scans by a consensus of 4 blinded readers. Results  The study was stopped early, after 200 patients were enrolled, when it became apparent at the time of an unplanned interim analysis that MRI was detecting cases of hemorrhagic transformation not detected by CT. For the diagnosis of any hemorrhage, MRI was positive in 71 patients with CT positive in 29 (P<.001). For the diagnosis of acute hemorrhage, MRI and CT were equivalent (96% concordance). Acute hemorrhage was diagnosed in 25 patients on both MRI and CT. In 4 other patients, acute hemorrhage was present on MRI but not on the corresponding CT—each of these 4 cases was interpreted as hemorrhagic transformation of an ischemic infarct. In 3 patients, regions interpreted as acute hemorrhage on CT were interpreted as chronic hemorrhage on MRI. In 1 patient, subarachnoid hemorrhage was diagnosed on CT but not on MRI. In 49 patients, chronic hemorrhage, most often microbleeds, was visualized on MRI but not on CT. Conclusion  MRI may be as accurate as CT for the detection of acute hemorrhage in patients presenting with acute focal stroke symptoms and is more accurate than CT for the detection of chronic intracerebral hemorrhage.      

Functional imaging of a large demyelinating lesion.

PURPOSE: To determine the metabolic characterization of a large solitary demyelinating lesion. METHODS: Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) studies with 2-deoxy-2-[F-18]fluoro-d-glucose (FDG), carbon-11-methionine (methionine) and carbon-11-choline (choline) were done on the demyelinating lesion. RESULTS: The demyelinating lesion exhibited a low glucose uptake, prominent methionine uptake and a minimal choline uptake on the PET studies. MRS data revealed an increased choline to creatine (cho/cr) ratio and a decreased N-acetyl-aspartate to creatine (NAA/cr) ratio, which demonstrated a return to near normal ratios on follow-up study. CONCLUSION: The report summarizes the metabolic characteristics of a demyelinating plaque.     

Treatment of AL Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement 2020 Update

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder leading to progressive and life-threatening organ failure. The heart and the kidneys are the most commonly involved organs, but almost any organ can be involved. Because of the nonspecific presentation, diagnosis delay is common, and many patients are diagnosed with advanced organ failure. In the era of effective therapies and improved outcomes for patients with AL amyloidosis, the importance of early recognition is further enhanced as the ability to reverse organ dysfunction is limited in those with a profound organ failure. As AL amyloidosis is an uncommon disorder and given patients’ frailty and high early death rate, management of this complex condition is challenging. The treatment of AL amyloidosis is based on various anti–plasma cell therapies. These therapies are borrowed and customized from the treatment of multiple myeloma, a more common disorder. However, a growing number of phase 2/3 studies dedicated to the AL amyloidosis population are being performed, making treatment decisions more evidence-based. Supportive care is an integral part of management of AL amyloidosis because of the inherent organ dysfunction, limiting the delivery of effective therapy. This extensive review brings an updated summary on the management of AL amyloidosis, sectioned into the 3 pillars for survival improvement: early disease recognition, anti–plasma cell therapy, and supportive care.