Erratum to "Cellular mechanisms underlying acquired epilepsy: the calcium hypothesis of the induction and maintenance of epilepsy." [Pharmacol. Ther. 105(3) (2005) 229-266

Epilepsy is one of the most common neurological disorders. Although epilepsy can be idiopathic, it is estimated that up to 50% of all epilepsy cases are initiated by neurological insults and are called acquired epilepsy (AE). AE develops in 3 phases: (1) the injury [central nervous system (CNS) insult]. (2) epileptogenesis (latency), and (3) the chronic epileptic (spontaneous recurrent seizure) phases. Status epilepticus (SE), stroke, and traumatic brain injury (TBI) are 3 major examples of common brain injuries that can lead to the development of AE. It is especially important to understand the molecular mechanisms that cause AE because it may lead to innovative strategies to prevent or cure this common condition. Recent studies have offered new insights into the cause of AE and indicate that injury-induced alterations in intracellular calcium concentration levels ([Ca(2+)](i)) and calcium homeostatic mechanisms play a role in the development and maintenance of AE. The injuries that cause AE are different, but the share a common molecular mechanism for producing brain damage--an increase in extracellular glutamate and are exposed to increased [Ca(2+)](i) are the cellular substrates to develop epilepsy because dead cells do not seize. The neurons that survive injury sustain permanent long-term plasticity changes in [Ca(2+)](i) and calcium homeostatic mechanisms that are permanent and are a prominent feature of the epileptic phenotype. In the last several years, evidence has accumulated indicating that the prolonged alteration in neuronal calcium dynamics plays an important role in the induction and maintenance of the prolonged neuroplasticity changes underlying the epileptic phenotype. Understanding the role of calcium as a second messenger in the induction and maintenance of epilepsy may provide novel insights into therapeutic advances that will prevent and even cure AE.     

Altered calcium/calmodulin kinase II activity changes calcium homeostasis that underlies epileptiform activity in hippocampal neurons in culture

Epilepsy is characterized by the occurrence of spontaneous recurrent epileptiform discharges (SREDs) in neurons. A decrease in calcium/calmodulin-dependent protein kinase II (CaMK-II) activity has been shown to occur with the development of SREDs in a hippocampal neuronal culture model of acquired epilepsy, and altered calcium (Ca(2+)) homeostasis has been implicated in the development of SREDs. Using antisense oligonucleotides, this study was conducted to determine whether selective suppression of CaMK-II activity, with subsequent induction of SREDs, was associated with altered Ca(2+) homeostasis in hippocampal neurons in culture. Antisense knockdown resulted in the development of SREDs and a decrease in both immunocytochemical staining and enzyme activity of CaMK-II. Evaluation of [Ca(2+)](i) using Fura indicators revealed that antisense-treated neurons manifested increased basal [Ca(2+)](i), whereas missense-treated neurons showed no change in basal [Ca(2+)](i). Antisense suppression of CaMK-II was also associated with an inability of neurons to restore a Ca(2+) load. Upon removal of oligonucleotide treatment, CaMK-II suppression and Ca(2+) homeostasis recovered to control levels and SREDs were abolished. To our knowledge, the results demonstrate the first evidence that selective suppression of CaMK-II activity results in alterations in Ca(2+) homeostasis and the development of SREDs in hippocampal neurons and suggest that CaMK-II suppression may be causing epileptogenesis by altering Ca(2+) homeostatic mechanisms.     

IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis

Transverse myelitis (TM) is an immune-mediated spinal cord disorder associated with inflammation, demyelination, and axonal damage. We investigated the soluble immune derangements present in TM patients and found that IL-6 levels were selectively and dramatically elevated in the cerebrospinal fluid and directly correlated with markers of tissue injury and sustained clinical disability. IL-6 was necessary and sufficient to mediate cellular injury in spinal cord organotypic tissue culture sections through activation of the JAK/STAT pathway, resulting in increased activity of iNOS and poly(ADP-ribose) polymerase (PARP). Rats intrathecally infused with IL-6 developed progressive weakness and spinal cord inflammation, demyelination, and axonal damage, which were blocked by PARP inhibition. Addition of IL-6 to brain organotypic cultures or into the cerebral ventricles of adult rats did not activate the JAK/STAT pathway, which is potentially due to increased expression of soluble IL-6 receptor in the brain relative to the spinal cord that may antagonize IL-6 signaling in this context. The spatially distinct responses to IL-6 may underlie regional vulnerability of different parts of the CNS to inflammatory injury. The elucidation of this pathway identifies specific therapeutic targets in the management of CNS autoimmune conditions.     

Reevaluation of the cefepime minimal inhibitory concentrations and disk diffusion test zone diameter relationship for a worldwide collection of Enterobacteriaceae enriched for extended-spectrum beta-lactamase-producing organisms

To reassess the validity of existing susceptibility breakpoint criteria and to propose alternative breakpoint criteria for disk diffusion testing at lower susceptible MIC breakpoints, we analyzed a contemporary global collection of Enterobacteriaceae isolates (350) strains enriched for extended-spectrum beta-lactamase (ESBL) producers (68 strains, 19.4%). The majority of the isolates (88.3% of the entire collection and 83.8% of the ESBL subset) were from bloodstream infections. Cefepime minimal inhibitory concentrations (MICs) were determined by broth microdilution methods and compared with the results obtained from disk diffusion testing for the entire collection of Enterobacteriaceae and for the ESBL subset alone. The regression coefficient was excellent for both scattergrams (r = 0.92-0.94). The intermethod categorical agreement remained excellent for the current breakpoints (susceptible at < or = 8 microg/mL or > or = 18 mm and resistant at > or = 32 microg/mL or < or = 14 mm) published by the National Committee for Clinical Laboratory Standards at 94.0%. The 2 alternative interpretive criteria considered at lower MIC breakpoints (i.e., susceptible as < or = 4 microg/mL and > or = 21 mm and susceptible as < or = 2 microg/mL and > or = 24 mm) did not compromise the intermethod test categorical accuracy, which remained excellent at 96.9% and 94.0%, respectively. Adopting the existing breakpoint criteria that remain accurate for ESBL-producing strains or any one of the above two alternative sets of breakpoint criteria analyzed would be acceptable, with excellent intermethod concordance between the MIC and disk diffusion results.     

Evolution and dissemination of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae: epidemiology and molecular report from the SENTRY Antimicrobial Surveillance Program (1997-2003)

During 2001, occurrences of extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae isolates were detected in a single medical center (Hospital A) from the SENTRY Antimicrobial Surveillance Program that became endemic in long-term acute care areas and in the intensive care unit in 2002-2003. Between 2001 and 2003, 123 patients were infected or colonized with ESBL-positive K. pneumoniae. Resistance profiles were determined by reference broth microdilution methods, and automated ribotyping and pulsed-field gel electrophoresis (PFGE) were performed. The ESBL-positive K. pneumoniae isolates were resistant to aztreonam, ceftazidime, aminoglycosides, and trimethoprim/sulfamethoxazole and susceptible to ciprofloxacin and tetracycline. In 1997, 1998, and 2000, 9 ESBL-producing K. pneumoniae strains from 2 New York City hospitals shared the same antibiograms and ribotype (204.2) as the strains from Hospital A. PFGE patterns divided Hospital A isolates into 2 subtypes (A and A1) and 3 New York City strains were similar to the Hospital A isolates (A2, A3, and A4). Isoelectric focusing studies of 1 New York City isolate (A4) revealed pIs at 5.4, 7.7, and 8.2. PCR and sequencing results from 1 strain of each Hospital A and 1 New York PFGE pattern determined that TEM-1 and SHV-5 (ESBL) were present in all strains. In addition, 2 New York isolates from 1998 (A3 and A4) also had an OXA-2 enzyme. ESBL-producing K. pneumoniae isolates with ribotype 204.2 from SENTRY Program sites have been recognized in New York only since 1997 and in Hospital A beginning in 2001. The similarities of the antibiogram and epidemiological patterns suggest that these isolates have persisted over time and may have evolved into different but genetically related endemic ESBL-positive K. pneumoniae clones that have the ability to cause sustained epidemic outbreaks in US medical centers.     

Kasabach-Merritt syndrome: a case report

Kasabach-Meritt syndrome is a combination of thromobocytopenia, hemolytic anemia, and acute or chronic consumptive coagulopathy in association with rapidly enlarging hemangioma. A male infant of 5 days was admitted in paediatric ward with this syndrome. The baby had ecchymotic patches over face and extremities and bleeding through umbilical stump. The child expired due to severe thrombocytopenia with consumptive coagulopathy leading to precipituous hemorrhage superimposed by septicemia. An autopsy was performed which confirmed retroperitoneal lesion as kaposiform hemangioendothelioma.     

Gonadoblastoma with unusual mixed germ cell overgrowth--a case report

Gonadoblastoma is an uncommon tumour of ovary occurring exclusively in patients with inter sex disorders. We are presenting an unusual case of gonadoblastoma with distinctly rare pattern of germ cell overgrowth on the other side in an eighteen year old girl.     

Pulmonary thrombosis in steroid-sensitive nephrotic syndrome

Thrombo-embolic episodes are an uncommon but known complication of nephrotic syndrome. However, pulmonary thrombosis/thromboembolism is rare, especially in children. We describe the cases of two girls, aged 12 years, who presented with severe oedema in relapse. They had intermittent tachypnoea, and CT pulmonary angiography (CTPA) provided a less invasive and more definitive way of confirming pulmonary thrombosis/thromboembolism. They received heparin with resolution of the tachypnoea. Anticoagulation was continued for 6 months after the episode in one patient. They have been in remission for more than 1 year, and a thrombophilia screen does not indicate a predisposing tendency to the formation of clots. Pulmonary thrombosis/thromboembolism could present with subtle symptoms and needs prompt diagnosis and treatment to prevent a fatal outcome.     

An experimental study of pressure-volume dynamics of casting materials

Casting materials are commonly used in a trauma and post-operative setting in orthopaedic practice. Swelling after trauma or surgery is universal, hence, the importance of understanding the pressure-volume dynamics of various materials commonly used for casting. This study attempts to define the pressure response of casts made from three commonly used materials to increasing volume, using a cylindrical model cast. Plaster of Paris (PoP), rigid fibreglass and semi-rigid non-fibreglass (Softcast) were chosen for comparison. Softcast had the best compliance and rate dependency characteristics, accommodating significantly more volume of fluid compared to plaster of Paris or Rigid fibreglass material. The latter two had similar compliance. All three materials demonstrated stress-relaxation which is of advantage in reducing peak pressures for a given volume change. This study shows that the casting materials behave in a viscoelastic manner, which allows them to accommodate more volume change than would otherwise be possible. The use of semi-rigid material may be safer than other materials as far as response to swelling (volume expansion) is concerned.