Long-term outcomes of transmesenteric portal vein recanalization for the treatment of chronic portal vein thrombosis after pediatric liver transplantation.

Portal vein thrombosis (PVT) may occur at any time following liver transplantation. We describe our experience with portal vein recanalization in cases of thrombosis after liver transplantation. Twenty-eight children (5%) out of 566 liver transplant recipients underwent portal vein recanalization using a transmesenteric approach. All children received left hepatic segments, developed PVT, and had symptoms or signs of portal hypertension. Portal vein recanalization was performed via the transmesenteric route in all cases. Twenty-two (78.6%) patients underwent successful recanalization and stent placement. They received oral anticoagulants after the procedure, and clinical symptoms subsided. Symptoms recurred due to portal vein restenosis/thrombosis in seven patients. On an intention-to-treat basis, the success rate of the proposed treatment was 60.7%. Only 17 out of 28 children with posttransplant chronic PVT retained stent patency (primary + assisted) at the end of the study period. In cases of portal vein obstruction, the transmesenteric approach via minilaparotomy is technically feasible with good clinical and hemodynamic results. It is an alternative procedure to reestablish the portal flow to the liver graft that can be performed in selected cases and a therapeutic addition to other treatment strategies currently used to treat chronic PVT.

Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3+IL-17+ cells.

T-regulatory cells (Tregs) are essential for immune tolerance, and animal studies implicate their dysfunction in type 1 diabetes (T1D) pathogenesis. Tregs require interleukin-2 (IL-2) for their suppressive function, and variants in IL-2/IL-2R pathway genes have been associated with T1D. We previously reported that recent-onset T1D subjects have an increased population of FOXP3lo Tregs that secrete the pro-inflammatory cytokine, interleukin-17 (IL-17). We hypothesize that IL-2 signaling defects may drive T1D development by skewing protective Tregs towards an inflammatory Th17 phenotype. Overall, we found that the proportion of FOXP3+IL-17+ cells in T1D subjects pre-diagnosis was unchanged compared with healthy controls. However, stratification by IL2RA single-nucleotide polymorphisms revealed that T1D subjects with the rs3118470 CC risk variant have Tregs with IL-2 signaling defects and an increased proportion of FOXP3+IL-17+ cells before diagnosis. These data suggest a potential mechanism for genetically controlled loss of Treg function via dysfunctional IL-2 signaling in T1D.

The Crohn's disease-associated polymorphism in ATG16L1 (rs2241880) reduces SHIP gene expression and activity in human subjects.

Crohn's disease (CD) is a polygenic immune-mediated disease characterized by gastrointestinal inflammation. Mice deficient in the hematopoietic-restricted SH2 domain-containing inositolpolyphosphate 5'-phosphatase (SHIP) develop spontaneous CD-like ileal inflammation. Intriguingly, SHIP mRNA is not upregulated in biopsies from patients with ileal CD despite immune cell infiltration, but SHIP's role in human CD remains unknown. We analyzed SHIP mRNA expression and activity in biopsies and peripheral blood mononuclear cells (PBMCs) from control and treatment-naive subjects with ileal CD, and demonstrated that SHIP mRNA and activity were lower in hematopoietic cells in ileal biopsies and PBMCs from subjects with CD. In all tissues from our patient cohort and in PBMCs from a second healthy control cohort, subjects homozygous for the autophagy-related 16-like protein (ATG16L1) CD-associated gene variant (rs2241880), had low SHIP mRNA expression and activity. SHIP protein expression increased during autophagy and SHIP upregulation was dependent on ATG16L1 and/or autophagy, as well as the ATG16L1 CD-associated gene variant. Finally, homozygosity for the ATG16L1 risk variant and low SHIP mRNA expression is inversely related to increased (LPS+ATP)-induced IL-1ß production by PBMCs in our cohorts and was regulated by increased transcription of ILIB. These data suggest a novel mechanism by which the ATG16L1 CD-associated gene variant may predispose people to develop intestinal inflammation.

Toll-like receptor 4 polymorphisms and idiopathic chromosomally normal miscarriage.

BACKGROUND: Lipopolysaccharide (LPS or endotoxin) exposure resulting from microbial invasion of the endometrium disturbs the Th1/Th2 balance at the feto-maternal interface and has been linked to the risk of idiopathic miscarriage in a range of human and animal studies. Toll-like receptor 4 (TLR4) mediates LPS signalling, and the human TLR4 gene harbours two single-nucleotide polymorphisms (SNPs) known to reduce LPS responsiveness. We hypothesized that genetic variation altering TLR4 function may influence the risk of idiopathic pregnancy loss. METHODS AND RESULTS: We examined fetal TLR4 genotypes in a case-control cohort of chromosomally normal miscarriages (n=96) and healthy term newborns (n=113). The allele frequencies of the Asp299Gly and Thr399Ile TLR4 SNPs were determined by quantitative PCR using DNA extracted from extraembryonic tissues and umbilical cord blood, respectively. TLR4 genotype frequencies were not significantly different between cases and controls. CONCLUSIONS: There was no association between fetal TLR4 polymorphisms, Asp299Gly and Thr399Ile, known to blunt LPS responsiveness, and the risk of idiopathic, chromosomally normal miscarriage. Nevertheless, TLR4 or perhaps other LPS-binding chaperone molecules are biologically plausible candidate genes that may alter the risk of idiopathic miscarriage.

Long-term management of bilateral metastases of renal cell carcinoma to the choroid plexus.

BACKGROUND: Metastatic tumors to the brain presenting exclusively in the choroid plexus are exceedingly rare. These events are frequently associated with renal cell carcinoma (RCC), of which all reported cases have been solitary lesions. METHODS: The authors present the unusual case of a patient with metastatic RCC who developed bilateral tumors of the choroid plexus. These tumors, one of which was confirmed to be metastatic RCC by histologic analysis, were treated over a 5-year period with a combination of interventions, including surgical resection, stereotactic radiosurgery, and chemotherapy, in conjunction with continual radiological monitoring. FINDINGS: Follow-up over a 5-year period demonstrated good control of the patient's intracranial disease and very little neurologic sequelae. INTERPRETATION: This strategy was successful in keeping the patient in good health with minimal neurological symptoms, despite the bilateral nature of the disease and its generally poor prognosis.

Hemorrhage within brain tumors in association with long air travel.

Two cases of hemorrhage within brain tumors after air travel are described. The hemorrhages occurred in a meningotheliomatous meningioma and in a melanoma metastasis after the patients had taken transatlantic flights lasting more than seven hours. The literature concerning bleeding associated with brain tumors is reviewed, and possible mechanisms by which air travel may have precipitated these hemorrhages, based on known physiological changes that occur in-flight, are discussed.

Hypertrophied cauda equina presenting as intradural mass: case report and review of literature.

BACKGROUND: Hereditary motor and sensory neuropathy types I and III usually lead to enlargement of peripheral nerves. Rarely, spinal nerve roots may also be involved, leading to radiculopathy and/or myelopathy. METHODS: This 44-year-old man with back and lower extremity radicular pain and distal lower extremity weakness and numbness was found to have a nonenhancing intradural mass that caused a nearly complete myelographic block from L1-L4. He underwent a decompressive laminectomy with intradural exploration. RESULTS: Hypertrophic but otherwise normal-looking nerve roots were observed. Subsequent electrodiagnostic testing and sural nerve biopsy confirmed that this patient had a previously unsuspected hereditary motor and sensory neuropathy (HMSN). His pain resolved, but at latest follow-up his weakness and numbness persisted. CONCLUSIONS: Nonenhancing spinal intradural mass lesions may represent enlarged nerve roots, which have a number of potential etiologies. Electrodiagnostic studies and peripheral nerve biopsy are instrumental in establishing the diagnosis of HMSN.

Comparison between 201Tl-chloride and 99Tc(m)-sestamibi SPET brain imaging for differentiating intracranial lymphoma from non-malignant lesions in AIDS patients.

The aim of this study was to compare 201Tl-chloride and 99Tc(m)-sestamibi (MIBI) SPET brain imaging for differentiating brain lymphoma from other intracranial lesions in AIDS patients. Both studies were performed on the same day in 17 AIDS patients with intracranial enhancing lesions on either CT or MRI. Eleven patients underwent brain biopsy and six patients were followed clinically. We calculated the radiopharmaceutical uptake ratio of the lesion to that on the contralateral side with the guidance of CT or MRI findings. Ratios of 1.5 or more were considered to represent malignant lesions and ratios < 1.5 were considered to represent benign lesions. Biopsy revealed four cases of lymphoma, four cases of toxoplasmosis and two cases of progressive multi-focal leukoencephalopathy; one biopsy yielded necrosis. Both the MIBI and 201Tl studies yielded no false-negative cases of lymphoma (sensitivity 100%). Of the 13 non-lymphoma cases, the 201Tl studies showed seven true-negative cases (specificity 54%) and the MIBI studies showed nine true-negative cases (specificity 69%). The biopsies of the false-positive cases (toxoplasmosis) showed a pattern of healing after medical treatment. We conclude that MIBI is more helpful than 201Tl because of higher specificity and equal sensitivity. The medical treatment of toxoplasmosis is a cause of false-positive 201Tl and MIBI studies.

Stereotactic brain biopsies in AIDS patients: superior diagnostic yield with side-cutting needle than with cup forceps.

Controversy still exists over the indicators for, and usefulness of, performing brain biopsies in AIDS patients with focal cerebral lesions. One of the sources of doubt is the relatively poor diagnostic yield in biopsying lesions in AIDS patients compared with patients who do not have AIDS. In our institution, we performed 25 CT-guided stereotactic biopsies using the Brown-Roberts-Wells system within a 1-year period. Of these, 11 were performed with a 2-mm-diameter cup forceps, and 14 with a 10-mm-long x 2-mm-diameter side-cutting needle. Abnormal tissue was obtained from all patients, but, in the first group, 5 (45%) biopsies were nondiagnostic, and, in the second group, none (0%) were nondiagnostic. Of the diagnostic biopsies, there was roughly an equal proportion of lymphoma, progressive multifocal leukoencephalopathy, and toxoplasmosis between the two techniques. It is surmised that the deciding factor leading to an enhanced diagnostic yield with the side-cutting needle was the larger amount of tissue obtained with this instrument.

Radiation Therapy Oncology Group: radiosurgery quality assurance guidelines.

A multidisciplinary Radiation Therapy Oncology Group (RTOG) task force has developed quality assurance guidelines for radiosurgery. The purpose of the guidelines are fourfold: (1) To ensure that participating institutions have the proper equipment and appropriate technique(s) to administer radiosurgery; (2) to outline a standard data set for each treated patient to assess protocol compliance; (3) to define minor and major deviations in protocol treatment; and (4) to set forth clinical data necessary to determine treatment efficacy, including failure patterns, and treatment toxicity. These guidelines are being implemented into active and developing radiosurgery protocols.

The evaluation of patients with human immunodeficiency virus-related disorders and brain mass lesions.

In patients at risk for acquired immunodeficiency syndrome who present with a mass lesion, a dilemma arises as to whether to treat empirically for toxoplasmosis or perform a brain biopsy. We present data that further define the indications for performing brain biopsy vs empiric treatment. We reviewed charts on 59 patients with acquired immunodeficiency syndrome--related disorders and cerebral mass lesions. Thirty-two patients met diagnostic criteria for toxoplasmosis. Bayesian analysis demonstrated that the prior probability of toxoplasmosis was increased by the presence of contrast enhancement on computed tomographic scans (0.68) and toxoplasmosis titers greater than 1:64 (0.81). Features associated with decreasing probabilities of toxoplasmosis included the absence of contrast enhancement on computed tomographic scans (0.29) and toxoplasmosis titers less than or equal to 1:64 (0.14). Ten percent of patients had complications of brain biopsy. Treatment with pyrimethamine and sulfadiazine produced complications in 29% and serious complications in 8% of treated patients. These data favor empiric therapy for patients with typical features of toxoplasmosis and brain biopsy for defined subsets of patients with atypical features.

Primary central nervous system lymphoma in acquired immune deficiency syndrome. A clinical and pathologic study with results of treatment with radiation.

Primary central nervous system (CNS) lymphoma occurs frequently in patients with the acquired immune deficiency syndrome (AIDS). Seventeen patients with AIDS and biopsy-proven CNS lymphoma were treated with whole-brain radiation. At presentation, most patients were severely debilitated from previous AIDS-related illnesses. Patients generally had focal neurologic symptoms such as seizures and paralysis. Headaches and mental status changes, often noticed after hospital admission, seldom brought our patients to seek medical attention. Computed tomography (CT) scan showed low-density, contrast-enhancing, mass lesions with variable amounts of peritumor edema. Size, location, and pattern of contrast enhancement of the lesions varied. No specific pattern was seen that could be used to distinguish between CNS lymphoma, toxoplasmosis, or other CNS diseases that occur in patients with AIDS. Biopsy results showed angiocentric, high-grade, large cell tumors with frequent necrosis. Immunohistochemical analysis showed B-cell phenotype with small amounts of T-cells, presumably reactive. All patients received irradiation to the whole brain with parallel opposed fields. A variety of doses and treatment regimens were used. Mean survival was only 72 days. Survival was longer in patients with higher pretreatment Karnofsky scores. The correlation between dose and survival was not significant. At completion of therapy, most patients showed improvement in Karnofsky score and had partial improvement in neurologic symptoms. CNS lymphomas in patients with AIDS are responsive to radiation. Posttreatment CT scans showed regression of tumors. Autopsy examinations showed regression of tumors, but also showed concurrent CNS infections, AIDS encephalopathy, and radiation-induced changes within the normal CNS tissue. Opportunistic infections rather than cerebral herniation or uncontrolled lymphoma was the most common cause of death.

CT appearance of primary CNS lymphoma in patients with acquired immunodeficiency syndrome.

Cranial CT studies of 32 patients with biopsy-proven AIDS-related primary CNS lymphoma were reviewed retrospectively. A wide variety of different CT appearances were identified. Mass lesions varied in location, size, and number. Most lesions were either iso- or hyperdense and all enhanced with contrast medium. Several different patterns of enhancement were observed. Mass effect and edema were seen in almost all patients. After radiotherapy, most tumors decreased in diameter, became hypodense, and no longer enhanced with contrast medium. Edema and mass effect decreased or resolved in all but one patient. Postradiotherapy CT scans also revealed interval enlargement of the ventricles and cortical sulci. This study demonstrates the wide diversity of CT appearances of AIDS-related primary CNS lymphoma. The CT findings cannot be used in lieu of biopsy for diagnosis of this disorder. The appearance of postradiotherapy CT scans was consistent with regressing lymphoma.

Spinal epidural lipomatosis: a serious complication of iatrogenic Cushing's syndrome.

Our experience and review of the literature demonstrate that spinal epidural lipomatosis is a rare but serious neurologic complication of iatrogenic Cushing's syndrome. Most patients develop slowly progressive paraparesis over months, but a subgroup exists which presents with acute, irreversible paraplegia. We consider therapeutic options.

Stereotactic techniques in the management of cerebral neoplasms.

Stereotactic devices are being used by neurosurgeons for the diagnosis and treatment of both primary and metastatic brain tumors. Although stereotactic surgery has been performed for over forty years, a resurgence in its use, especially for the management of such anatomically definable lesions as brain tumors, has come about due to the wide availability of computerized imaging of the brain and the almost natural adaptability of stereotaxy to these diagnostic modalities. Stereotactic surgery is now being performed in over 100 centers throughout the United States. The author explains the basic principles of stereotaxy and discusses the broad range of its uses in the management of brain tumors.

Spinal epidural compression secondary to osteoblastic metastatic vertebral expansion.

We present two cases in which spinal epidural compression was caused by the expansion of bony elements into the spinal canal as a result of osteoblastic metastases. The precise nature of the compression was appreciated only on computed tomography. One patient had immediate and sustained neurological improvement after laminectomy. The other benefited temporarily, but widespread involvement of his spine ultimately led to paraplegia despite two more decompressive procedures. We think that bony expansion of the spine secondary to osteoblastic metastasis is not reversible with radiation therapy alone and is, therefore, an absolute indication for surgical decompression.

Brain death determination by angiography in the setting of a skull defect.

The absence of cerebral blood flow is presently considered the most reliable ancillary test in diagnosing brain death. A patient with an open skull fracture who met all criteria for brain death, including confirmatory postmortem studies, had a cerebral angiogram that showed unilateral preservation of cerebral circulation with diffuse extravasation of contrast material. We conclude that a skull defect may result in pressure reduction within the cranial cavity and persistent ipsilateral cerebral circulation, even after brain death. In this setting, diffuse extravasation of contrast material on angiography may reflect diffuse autolysis and suggest the diagnosis of brain death.

Cytomembranous inclusions in the brain of a patient with the acquired immunodeficiency syndrome.

Ultrastructural studies of cells and tissues in the acquired immunodeficiency syndrome (AIDS) have revealed two distinct cytomembranous inclusions referred to as "tubuloreticular inclusions" (TRI) and "confronting cylindrical cisterns" (CCC). TRI are found most often in leukocytes and endothelial cells in conditions with elevated levels of alpha-interferon, such as viral infections, autoimmune diseases and certain neoplasms. On the other hand, CCC are detected almost exclusively in mononuclear inflammatory cells and are limited to a few conditions, of which AIDS is the most common. CCC have been proposed as an ultrastructural marker for human immunodeficiency virus (HIV) infection. We describe CCC in mononuclear inflammatory cells in the brain tissue with no other specific feature such as multinucleated giant cells, nevertheless, should alert the neuropathologist to the possibility that the patient might have AIDS.

Effect of sodium butyrate on S-100 protein levels and the cAMP response.

Sodium butyrate (NaB), when added to cell cultures, produces a variety of morphological and biochemical changes. We examined its effects, in nM concentrations, on the expression of two glioma cell-associated proteins, glial fibrillary acidic protein (GFAP) and S-100 protein in human glioma-derived cell line (RF), and of S-100 protein in the C6 rat glioma cell line. GFAP levels decreased by about 50% in the RF cell line, and S-100 protein levels decreased protein levels decreased by about 40% after treatment with 1 mM NaB for 48 h. In the C6 rat glioma cell line, isoproterenol with theophylline was found to increase S-100 levels by two-fold over basal levels. NaB was found to inhibit the induction of S-100 protein but exhibited no effect on the basal levels of the protein. Other short chain fatty acids, including sodium propionate and sodium isobutyrate, exhibited partial inhibitory activity. NaB, at an EC50 of 1 mM, was also found to inhibit both the beta-adrenergic and the forskolin-mediated increase in cAMP levels in these cells. This suggests that NaB may inhibit cells from expressing S-100 protein by attenuating cAMP levels.