Two cases of unexpected long-term improvement of Parkinson's disease after subthalamic nucleus deep brain stimulation removal.

Two patients with Parkinson's disease (PD) treated successfully with subthalamic nucleus deep brain stimulation (STN-DBS) for 3-4 years are reported, who demonstrated a persistent improvement following removal of STN-DBS for late infection. Possible hypotheses are discussed--whether a microlesioning effect or a disease-modifying effect of STN-DBS, though neither adequately explain this phenomenon.

Genotype-restricted growth and aging patterns in hematopoietic stem cell populations of allophenic mice.

We have studied contributions to hematopoiesis of genetically distinct stem cell populations in allophenic mice. Chimeras were made by aggregating embryos of inbred strains known to differ with respect to stem cell population kinetics. One partner strain (DBA/2) has previously been shown to normally have a stem cell (CFU-S) population of which 24% are in S-phase of the cell cycle, whereas the homologous population of the other partner strain (C57BL/6) was characterized by having only 2.6% in cycle (7). Contributions of the chimeric stem cell population to mature blood cell pools were studied throughout the life of the mice and intrinsic differences in stem cell function and aging were reflected in dynamic patterns of blood cell composition. The DBA/2 stem cell population was eclipsed by stem cells of the C57BL/6 genotype and, after 1.5-3 yr, the hemato-lymphoid composition of 22 of 27 mice studied for this long had shifted by at least 25 percentage points toward the C57BL/6 genotype. 8 of the 27 had hematolymphoid populations solely of C57BL/6 origin. To test whether or not a population of stem cells with an inherently higher cycling rate (DBA/2) might have a competitive advantage during repopulation, we engrafted allophenic marrow into lethally irradiated (C57BL/6 x DBA/2)F1 recipients. DBA/2 hematopoiesis was predominant early, far outstripping its representation in the marrow graft. Perhaps as a consequence of inherently greater DBA/2 stem cell proliferation, the populations of developmentally more restricted precursor populations (CFU-E, BFU-E, CFU-GM, CFU-GEMM) showed an overwhelming DBA/2 bias in the first 2-3 mo after engraftment. However, as in the allophenic mice themselves during the aging process, the C57BL/6 genotypic representation was ascendant over the subsequent months. The shift toward C57BL/6 genotype was first documented in the marrow and spleen precursor cell populations and was subsequently reflected in the circulating, mature blood cells. Bone marrow-derived stromal cell cultures from engrafted mice were studied and genotypic analyses showed donor representation in stromal cell populations that reflected donor hematopoietic contributions in the same recipient. Results from these studies involving two in vivo settings (allophenic mice and engraftment by allophenic marrow) are consistent with the notion that a cell autonomous difference in stem cell proliferation confers on one population a competitive repopulating advantage, but at the expense of longevity.

A population of murine hematopoietic progenitors expresses an endogenous retroviral gp70 linked to the Rmcf gene and associated with resistance to erythroleukemia.

Multiple copies of retroviral sequences are stably integrated in the genomes of many higher organisms, and are thus transmitted vertically to offspring via the germline (1). Most of these heritable viral genes are not expressed, and expression, when observed, is commonly limited to envelope (env) genes as demonstrated by the presence of cell surface and serum envelope glycoprotein (gp70) in mice. Studies of the mouse have shown that certain tissues such as the reproductive tract and lymphoid organs are common sites for the expression of endogenous env genes, suggesting that the transcription of at least some endogenous sequences is tissue specific. The transcription of endogenous viral genes is regulated by both cis and trans mechanisms (2-5) and their expression can be temporally linked to differentiation and development (6-8). The consequences to the host of endogenous retroviral genes are varied. At one extreme, expression of endogenous virus can result in the development of leukemia and death. Another potentially detrimental effect is that of insertional mutagenesis, seen when the integration of retroviral sequences interrupts the functioning of a cellular gene (9, 10). However, it is now clear that expression of endogenous retroviral genes may also have a beneficial effect for the host: namely, mediating resistance to retroviral leukemias as has been demonstrated for the Fv-4 gene in mice (11) and some ea loci in chickens (12). This form of resistance is due to the blockage of cellular viral receptors by the expression of envelope glycoprotein on the cell surface. The Rmcf locus of the mouse is another resistance gene that may exert its effect by the expression of an endogenous env gene. A summary of our current state of knowledge concerning the Rmcf gene is shown in Table I. The Rmcf gene was originally described when it was observed that fibroblast cell cultures derived from certain strains of mice restricted the replication of recombinant mink cell focus-forming(MCF)1 viruses (13). As detailed in Table I, DBA/2 mice are the prototypic strain exhibiting the Rmcf resistance (Rmcf(r)) phenotype. Cell cultures from other strains, such as C57BL/6 and IRW, are permissive for MCF viral replication and are termed Rmcf sensitive (Rmcf(s)). Previously, we described two allelic forms of an endogenous env gene, whose expression is linked to the Rmcf gene (14). Cell cultures from Rmcf(r) mice express gp70 related to that of MCF viruses, whereas cultures derived from Rmcf(s) mice either express no gp70 (IRW) or express an endogenous xenotropic gp70 (C57BL/6). These two gp70 alleles are detectable by type-specific mAbs.

Deep brain stimulation in dystonia: State of art and future directions.

When considering Deep Brain Stimulation (DBS) surgical treatment of dystonia syndromes, it is important to consider multiple aspects of the disease and its presentation. It is crucial to know if the dystonia is idiopathic, inherited or acquired as well as focal, segmental or generalised. Careful phenotyping of idiopathic as well as inherited dystonias and accurate diagnosis of acquired dystonias informs the decision-making process for patients and clinicians by providing them with useful predictors of outcomes of the proposed surgery. Here, we provided a review of the current literature, highlighted the areas where evidence is scarce and suggested future directions for research.

Risk factors for early post-operative psychiatric symptoms in patients undergoing epilepsy surgery for temporal lobe epilepsy.

OBJECTIVE: De-novo psychiatric symptoms may develop within 3 months after a temporal lobectomy for epilepsy. The objective of this study was to identify presurgical risk factors for psychiatric symptoms. METHODS: Twenty-seven patients who had a temporal lobectomy for epilepsy were included. Twenty-four had hippocampal sclerosis or gliosis, and three had cavernous haemagiomata. Twelve had operations on the left, and 15 on the right side. Twenty-four patients were rendered free of seizures (SZ) with loss of awareness, three had early post-operative convulsions, one continued to have habitual SZ. RESULTS: Nine patients (33%) developed low mood, anxiety and emotional lability within 3 months after surgery. Patients with early post-operative psychiatric symptoms were younger (27.9/34.8 years, P = 0.01), and more anxious on the presurgical Hospital Anxiety and Depression Scale (12/8.44, P = 0.02) than patients without post-operative psychiatric symptoms. There was also an association between right temporal lobectomies and early post-surgical symptoms (P = 0.02 Fisher's exact test). CONCLUSION: Potential risk factors were age, anxiety and operation on the right side. Larger studies are required to determine if these risk factors are independent.

Predictors of outcome after temporal lobectomy for refractory temporal lobe epilepsy.

OBJECTIVE: To identify predictors of outcome after epilepsy surgery in patients with temporal lobe epilepsy (TLE). METHODS: Seventy-six patients with normal magnetic resonance imaging (MRI) or hippocampal sclerosis on MRI who underwent anterior temporal lobe resections were included. Outcome 2 years after surgery was classified as good (Engel I and II) or poor (Engel III and IV). Gender, age at onset and duration of epilepsy, history of febrile convulsions, auras, right- or left-sided TLE, memory ipsilateral to seizure onset (Wada test), hippocampal asymmetry (HA) and T2 relaxation time, amygdala, temporal lobe and hemispheral volume were tested for associations with outcome. RESULTS: Sixty-seven percent had a good outcome. Of all parameters tested, only a history of febrile convulsions and HA on quantitative MRI were significantly associated with a good seizure outcome. The absence of these parameters did not exclude a good outcome, but only five of 18 patients (28%) without HA and without a history of febrile convulsions had a good outcome. CONCLUSION: Febrile convulsions and HA were predictors of outcome after epilepsy surgery in TLE. Subtle volume loss in amygdala, temporal lobe or hemispheres and the memory ipsilateral to the side of resection were not associated with outcome.

Primary Nocardia farcinica brain abscess with secondary meningitis and ventriculitis in an immunocompetent patient, successfully treated with moxifloxacin.

We report a rare case of Nocardia farcinica occipital brain abscess in an immunocompetent patient with no underlying risk factors successfully treated with the antibiotic moxifloxacin. The patient underwent craniotomy and abscess drainage. Initial post-operative treatment with co-trimoxazole produced a limited response. Despite the development of skull base meningitis and ventriculitis subsequent addition of moxifloxacin produced an excellent outcome.

The seizure outcome after amygdalohippocampectomy and temporal lobectomy.

The aim of this study was to compare the seizure outcome of two different types of epilepsy surgery, selective amygdalohippocampectomy (AHE) and anterior temporal lobectomy (ATLE) in patients with temporal lobe epilepsy. We included 114 patients who had mesio-temporal lobe epilepsy and hippocampal sclerosis or gliosis on histology. Patients had ATLE if the non-dominant hemisphere was affected or if the whole temporal lobe was atrophic. Patients had AHE if the dominant hemisphere was affected. Standardized seizure outcome at 1 year following surgery was used. Overall 40% of the 114 patients who had temporal lobe epilepsy surgery were seizure-free at 1-year (Engel's class Ia). A good outcome (Engel's classes I and II) was significantly more frequent in ATLE than in AHE. (66% and 44%, respectively, P = 0.03). ATLE had a better seizure outcome than AHE.

Genotype-limited changes in platelet and erythroid kinetics in Friend-virus-infected allophenic mice.

We report here results suggesting that cells of the megakaryocytic lineage or uncommitted precursor cells may be targets for Friend-virus-induced proliferation, and that genetic differences (other than Fv-2) between strains C57BL/6 and DBA/2 affect the susceptibility of these cells to Friend virus. The evidence suggesting this was derived from experiments with C57BL/6 in equilibrium DBA/2 allophenic mice. Within the first few weeks following infection of these mice with the polycythemic NB-tropic strain of Friend virus (FV-P), we observed a rapid shift in the genotypic composition of both red cells and platelets in favor of those of the DBA/2 genotype. Infection with the anemia-inducing strain of Friend virus (FV-A) also resulted in preferential production of DBA/2 strain erythrocytes, but its effect on platelet kinetics was nil. The FV-P- and FV-A-induced change in red cell composition is consistent with the view that erythroid precursors are target cells for Friend virus and that viral infection preferentially stimulates proliferation of susceptible strain (DBA/2) erythroid precursors. As for the platelet shifts induced by FV-P (and not FV-A), we believe the changes in platelet mosaicism also could be caused by viral-induced proliferation of DBA/2 platelet precursors, or more primitive progenitors, over the C57BL/6 ones. Thus, these results implicate the existence of nonerythroid target cells for FV-P-induced proliferation, as well as the existence of genetic differences between strains C57BL/6 and DBA/2 that modulate the responsiveness of such cells to infection.

Friend viral pathogenesis in C57BL/6 reversible DBA/2 allophenic mice.

Infection of mice with Friend erythroleukemia virus initially causes massive proliferation of erythroid precursors accompanied by splenomegaly and reticulocytosis. Strains of mice differ among themselves in susceptibility to Friend virus and one of the major genes affecting the early response to viral infection is Fv-2. Allophenic mice compounded from a resistant strain C57BL/6 (Fv-2rr) and a susceptible one DBA/2 (Fv-2ss) were infected with the polycythemic strain of Friend virus to determine whether susceptibility/resistance was limited to cells of the respective genotypes or if there was an influence across the genotypic barriers. The manifestations of viral pathogenesis monitored were splenomegaly, reticulocytosis and leukocytosis. In addition, the proportion of red cells of the two genotypes in each animal was monitored before and after viral infection by analyses for strain specific electrophoretic variants of hemoglobin and glucose phosphate isomerase. The group of allophenic mice with 25% or more susceptible-strain red blood cells all developed symptoms of virus-induced disease and also revealed dramatic increases in the number of red cells of the susceptible-strain genotype. Thus, no evidence for protection of susceptible-strain cells by ones of the resistant strain could be observed and the disease developed primarily in susceptible strain cells. On the other hand infected animals with 15% or less DBA/2 red cells were severely retarded in the development of Friend disease. Under these circumstances susceptible strain target cells might fail to undergo viral induced replication as a result of direct protection by resistant strain cells. Alternatively, other more complex mechanisms might be involved such as protective anti-viral immune reactions.

Chimeric antigen receptor-redirected CD45RA-negative T cells have potent antileukemia and pathogen memory response without graft-versus-host activity.

Chimeric antigen receptor (CAR)-redirected cellular therapy is an attractive modality for cancer treatment. We hypothesized that allogeneic CAR-engineered CD45RA-negative T cells can control cancer and infection without the risk of graft-versus-host disease (GVHD). We used CD19(+) MLL-rearranged leukemia as prototype because it is an aggressive and generally drug-resistant malignancy. CD45RA(-) cells that were transduced with anti-CD19 CAR containing 4-1BB and CD3ζ signaling domains effectively lysed MLL-rearranged leukemia cell lines and primary blasts in vitro. In a disseminated leukemia mouse model, CAR(+)CD45RA(-) cells significantly reduced leukemia burdens and prolonged overall survival without GVHD. CAR(+) cells were sustainable in blood, and all the treated mice remained leukemia-free even after they were re-challenged with leukemia cells. Despite the transduction process, CD45RA(-) cells retained recall activity both in vitro and in vivo against human pathogens commonly found in cancer patients. In comparison with CD45RA(+) cells, CD45RA(-) cells showed less allogeneic activity in mixed leukocyte reactions and in mouse models. Thus, the use of CAR(+)CD45RA(-) cells can separate GVHD from graft-versus-malignancy effect and infection control. These cells should also be useful in nontransplant settings and may be administered as off-the-shelf third-party cells.

Rapid memory T-cell reconstitution recapitulating CD45RA-depleted haploidentical transplant graft content in patients with hematologic malignancies.

T-cell depletion of an HLA-haploidentical graft is often used to prevent GVHD, but the procedure may lead to increased graft failure, relapse and infections due to delayed immune recovery. We hypothesized that selective depletion of the CD45RA+ subset can effectively reduce GVHD through removal of naive T cells, while providing improved donor immune reconstitution through adoptive transfer of CD45RA- memory T cells. Herein, we present results from the first 17 patients with poor-prognosis hematologic malignancy, who received haploidentical donor transplantation with CD45RA-depleted progenitor cell grafts following a novel reduced intensity conditioning regimen without TBI or serotherapy. Extensive depletion of CD45RA+ T cells and B cells, with preservation of abundant memory T cells, was consistently achieved in all 17 products. Neutrophil engraftment (median day +10) and full donor chimerism (median day +11) was rapidly achieved post transplantation. Early T-cell reconstitution directly correlated with the CD45RA-depleted graft content. T-cell function recovered rapidly with broad TCR Vß spectra. There was no infection-related mortality in this heavily pretreated population, and no patient developed acute GVHD despite infusion of a median of >100 million per kilogram haploidentical T cells.

Recovery of nerve conduction following microvascular decompression for trigeminal neuralgia.

OBJECTIVE: To assess the function of trigeminal nerve before and after microvascular decompression for trigeminal neuralgia. BACKGROUND: To date there is no direct evidence that microvascular decompression of the trigeminal root restores normal conduction in the nerve. METHODS: The authors examined 10 patients with trigeminal neuralgia in whom preoperative MRI and MR angiography demonstrated neurovascular contact. During microvascular decompression, the trigeminal nerve was monitored by recording early scalp trigeminal evoked potentials immediately before, during, and after decompression. Direct recordings from the root entry zone were also performed. RESULTS: In all patients preoperative scalp evoked potentials showed impaired conduction of the trigeminal root. Microvascular decompression was associated with immediate recovery of conduction in seven patients, demonstrated by both scalp evoked potentials and direct root recordings. All 10 patients were pain free postoperatively. CONCLUSIONS: Improvement in trigeminal neuralgia following microvascular decompression is often associated with normalization of neurophysiologic data, suggesting recovery of nerve function. Rapid electrophysiologic recovery and pain relief following microvascular decompression argue that neither phenomenon is linked to remyelination. It is possible that the trigeminal evoked potentials might predict an effective microvascular decompression.

In vitro assessment of bacterial adhesion to Hydromer-coated cerebrospinal fluid shunts.

The adherence of five strains of Staphylococcus epidermidis and one strain of S. aureus to both untreated and Hydromer-coated silicone rubber cerebrospinal fluid shunts was studied in vitro using epifluorescent image analysis. All five strains of S. epidermidis showed similar levels of adherence to untreated shunts, whilst S. aureus adhered slightly better. The Hydromer coating, a hydrogel material which creates a hydrophilic layer on the shunt surface, was found to reduce bacterial adhesion levels by approximately 90% in the six strains of bacteria tested. Unfortunately, uniform coverage of the shunt surfaces (particularly internally) with Hydromer coating was not achieved during sample preparation. Bacterial adhesion levels in such areas were identical to untreated controls. This may pose problems in the in vivo use of Hydromer-coated shunts.

Artifactually low glycated haemoglobin in a patient with severe hypertriglyceridaemia.

This report describes a case of artifactually low glycated haemoglobin (Hb) in a patient with type II diabetes and severe hypertriglyceridaemia. The effect of hypertriglyceridaemia on glycated Hb determination using the Abbott Vision method was investigated in a series of patients with diabetes. The interference of triglycerides in glycated Hb assays was also investigated by two other methods, the Beckman Synchron CX4 delta immunoturbidimetric method, and the Primus affinity chromatography high performance liquid chromatography assay.

Primary intradural classic chondrosarcoma: case report and literature review.

OBJECTIVE AND IMPORTANCE: The exact origin of rare intradural chondrosarcomas remains obscure. We present a case report of an intradural classic chondrosarcoma (a very rare subtype of chondrosarcoma in this location), with a review of the literature, in an attempt to clarify the histogenesis of these tumors. CLINICAL PRESENTATION: A 48-year-old man presented with a 12-month history of progressive right hemiparesis. Computed tomography and magnetic resonance imaging demonstrated a left parietal space-occupying lesion. INTERVENTION: The patient underwent an image-guided, left parietal parasagittal craniotomy. An extrinsic tumor, which seemed to arise from the dura, was macroscopically removed. There was no bone involvement. The histological examination revealed a Grade II classic chondrosarcoma with tumor infiltration into the dura. Adjuvant radiotherapy was administered. CONCLUSION: Intradural chondrosarcomas are rare tumors, the majority of which are mesenchymal. Classic chondrosarcomas in this location are much rarer. Their histogenesis is uncertain. In this case, the origin seems to be from the dura. Because of the malignant potential of these tumors, radical extirpation whenever possible, followed by radiotherapy, is indicated.

Trigeminal neuralgia: a quantitative sensory perception threshold study in patients who had not undergone previous invasive procedures.

The authors investigated 28 patients with "idiopathic" trigeminal neuralgia who had undergone no previous invasive procedures; together these patients had a total of 50 affected trigeminal divisions. Quantitative sensory perception thresholds were measured before operation. Preoperative measurements in the affected divisions indicated raised thresholds for touch (von Frey filaments) and temperature, but not for pinprick or heat pain, in agreement with the findings of Nurmikko. Only the tactile threshold was also significantly affected in the unaffected divisions on the affected side. The authors discuss their findings in relation to the pathophysiology of trigeminal neuralgia, concluding that the origin of the condition is almost certainly central to the gasserian ganglion.