Clinical Features, Imaging Characteristics, and Long-term Outcome of Dogs with Cranial Meningocele or Meningoencephalocele.

BACKGROUND: The term meningoencephalocele (MEC) describes a herniation of cerebral tissue and meninges through a defect in the cranium, whereas a meningocele (MC) is a herniation of the meninges alone. HYPOTHESIS/OBJECTIVES: To describe the clinical features, magnetic resonance imaging (MRI) characteristics, and outcomes of dogs with cranial MC and MEC. ANIMALS: Twenty-two client-owned dogs diagnosed with cranial MC or MEC. METHODS: Multicentric retrospective descriptive study. Clinical records of 13 institutions were reviewed. Signalment, clinical history, neurologic findings and MRI characteristics as well as treatment and outcome were recorded and evaluated. RESULTS: Most affected dogs were presented at a young age (median, 6.5 months; range, 1 month - 8 years). The most common presenting complaints were seizures and behavioral abnormalities. Intranasal MEC was more common than parietal MC. Magnetic resonance imaging identified meningeal enhancement of the protruded tissue in 77% of the cases. Porencephaly was seen in all cases with parietal MC. Cerebrospinal fluid (CSF) analysis identified mild abnormalities in 4 of 11 cases. Surgery was not performed in any affected dog. Seventeen patients were treated medically, and seizures were adequately controlled with anti-epileptic drugs in 10 dogs. Dogs with intranasal MEC and mild neurologic signs had a fair prognosis with medical treatment. CONCLUSION AND CLINICAL IMPORTANCE: Although uncommon, MC and MEC should be considered as a differential diagnosis in young dogs presenting with seizures or alterations in behavior. Medical treatment is a valid option with a fair prognosis when the neurologic signs are mild.

Patient doses in abdominal aortogram and aorta femoral runoff examinations.

Radiation doses to adult male patients from abdominal aortogram and aorta femoral runoff examinations in a medical center were determined with the help of a dose-area product meter. The abdominal aortogram and aorta femoral runoff examination consisted of scout radiographs, fluoroscopy (to position a catheter near the area of interest), and serial films (to record the flow of contrast media). Measurements were converted to effective doses with the help of published results from Monte Carlo simulation calculations. Data from 19 male adult patients weighing 53 to 86 kg were analyzed. The resulting total effective dose had a value of 14.0 +/- 4A mSv (mean and standard deviation). The percent contribution by fluoroscopy was 18.5 +/- 9.9%. The fluoroscopy effective dose had a stronger correlation with the dose-area product (correlation coefficient of 0.97) than with duration of exposure (correlation coefficient of 0.84). Most of the radiation exposure in the observed abdominal aortogram and aorta femoral runoff examination was attributed to radiography.

Fistula between a posterior communicating artery aneurysm and the cavernous sinus.

We report the angiographic appearance of a posterior communicating artery aneurysm with a fistula to the cavernous sinus, which had been misinterpreted as a direct carotid-cavernous fistula, on which endovascular repair was unsuccessfully attempted.

Epidural blood patch improves postdural puncture headache in a patient with benign intracranial hypertension.

Benign intracranial hypertension (BIH) is a disorder of elevated resting intracranial pressure without associated intracranial abnormality. When medical therapy fails to halt visual impairments or recalcitrant headaches progress, lumbar dural puncture and cerebral spinal fluid (CSF) drainage procedures are instituted. The authors report on a patient with BIH in whom a severe postdural puncture headache (low CSF pressure syndrome) paradoxically developed after therapeutic CSF drainage. This postdural puncture headache was successfully treated with an epidural blood patch without complicating the patient's underlying BIH condition.

Transjugular intrahepatic portosystemic shunt (TIPS): a promising nonsurgical treatment for bleeding gastroesophageal varices.

Transjugular intrahepatic portosystemic shunts (TIPS) is a relatively new procedure for variceal decompression and alleviation of variceal bleeding. A central connection is made transjugularly between the right hepatic vein and portal vein confluence. The shunt is then buttressed with metallic stents. Between March and August 1992, nine patients with cirrhosis and recurrent variceal hemorrhage have undergone the TIPS procedure at Oklahoma Memorial Hospital. The procedure was successfully performed in all patients. The mean initial direct portosystemic gradient of 22.4 mm Hg was reduced to 9.7 mm Hg. All patients have survived to date with no evidence of recurrent variceal hemorrhage following discharge or transfer. Initial results from our institution and internationally suggest that the TIPS procedure will become an attractive alternative to operative portosystemic shunts.

Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice.

Impaired immune responses occur frequently in cancer patients or in tumor-bearing mice, but the mechanisms of the tumor-induced immune defects remain poorly understood. In an in vivo murine colon carcinoma model (MCA-38), animals bearing a tumor longer than 26 days develop CD8+ T cells with impaired cytotoxic function, decreased expression of the tumor necrosis factor-alpha and granzyme B genes, and decreased ability to mediate an antitumor response in vivo. T lymphocytes from tumor-bearing mice expressed T cell antigen receptors that contained low amounts of CD3 gamma and completely lacked CD3 zeta, which was replaced by the Fc epsilon gamma-chain. Expression of the tyrosine kinases p56lck and p59fyn was also reduced. These changes could be the basis of immune defects in tumor-bearing hosts.

Immunoregulation in cancer-bearing hosts. Down-regulation of gene expression and cytotoxic function in CD8+ T cells.

The causes of the decreased immune responsiveness in tumor-bearing hosts are incompletely understood. The impact of a decreased immune response in cancer patients on the clinical response in immunotherapy trials has not been evaluated. The present report demonstrates a marked decrease in the therapeutic efficacy of adoptively transferred T lymphocytes obtained from murine hosts bearing tumor for greater than 30 days [late tumor-bearing mice (TBM)] as compared with normal mice and mice bearing tumor for less than 21 days (early TBM). In vitro analysis of the functions of the T lymphocytes from late TBM showed an apparently normal proliferative response to anti-CD3 and IL-2 with adequate lymphokine production from CD4+ cells, but a significant decrease in the cytotoxic function of CD8+ cells. The decreased cytotoxicity was not because of cell-mediated suppression. The expression of granzyme B mRNA was significantly delayed and decreased in magnitude in CD8+ cells from late TBM. Culture supernatants from two unrelated tumor cell lines were able to inhibit the cytotoxic activity of normal CD8+ cells in vitro. The tumor-derived suppressive factor is not transforming growth factor-beta (TGF-beta), but it has not been further characterized. The data suggest that one potential mechanism responsible for immunologic defects in patients with large tumor burdens is a tumor-induced defect that compromises the function of CD8+ effector T cells.

Proliferation and cytolytic function of anti-CD3 + interleukin-2 stimulated peripheral blood mononuclear cells following bone marrow transplantation.

We evaluated the proliferation, cytolytic function, and phenotypic characteristics of anti-CD3 plus interleukin-2 (IL-2) stimulated peripheral blood mononuclear cells (PBMCs) from 44 patients with leukemia or non-Hodgkin's lymphoma (NHL) treated with multiagent chemotherapy or following bone marrow transplantation (BMT). BMT patients had decreased cell growth with only a 1.35 +/- 0.25 (autologous BMT for acute lymphoblastic leukemia [ALL]), 1.24 +/- 0.25 (autologous BMT for NHL), and 0.8 +/- 0.1 (allogeneic BMT for leukemia) mean fold increase by day 5 of culture compared with controls (4.0 +/- 0.4), P less than .001. Anti-CD3 + IL-2 activated cells from patients with ALL and NHL who had received autologous BMT and cells from patients with leukemia who underwent allogeneic BMT were more effective in lysing the natural killer (NK) sensitive target, K562, and the NK-resistant target, Daudi, compared with controls. In contrast, cytolysis of K562 and Daudi by cultured PBMCs from patients with ALL and NHL receiving multi-agent chemotherapy was similar to that of controls. Cultures from BMT recipients had a significant increase in CD16+ (autologous ALL 5.7 +/- 1.5%, P less than .01; autologous NHL 12.4 +/- 3.5%, P less than .001; allogeneic 14.3 +/- 2.9%, P less than .001) and CD56+ cells (autologous ALL 27.6 +/- 12.0%, P less than .01; autologous NHL 39.3 +/- 9.5%, P less than .001; allogeneic 42.7 +/- 7.4%, P less than .001) compared with controls (CD16+ 2.5 +/- 0.4%; CD56+ 6.9 +/- 0.9%). Stimulation of PBMCs with anti-CD3 + IL-2 is effective in generating cells with high cytolytic function post-BMT.

Antitumor effects of interleukin 2 liposomes and anti-CD3-stimulated T-cells against murine MCA-38 hepatic metastasis.

The stimulation of murine splenocytes with the monoclonal antibody anti-CD3 and interleukin 2 (IL-2) results in the propagation of large numbers of cells (T-activated killer; T-AK) which demonstrate high therapeutic efficacy when infused with IL-2 into mice bearing pulmonary metastases. Interleukin 2 infusions are required to maintain the function of the adoptively transferred cells. Recent data demonstrate that the therapeutic efficacy can be enhanced by encapsulating IL-2 in liposomes. The present work tested the combination of T-AK cells with IL-2 liposomes in an immunotherapy model utilizing the MCA-38 murine colon adenocarcinoma. Expansion of murine splenocytes was achieved with anti-CD3 monoclonal antibody plus IL-2 and was consistently greater than 50-fold during a 9-day culture period. Cytolytic activity of the murine T-AK cells was mediated primarily by Lyt-2+ cells. In vivo results demonstrate synergistic therapeutic efficacy of the combination of IL-2 liposomes and T-AK cells. Evaluation of the in vivo distribution of these T-AK cells utilizing congenic mice demonstrates that Lyt-2+ cells from these in vitro cultures infiltrate hepatic metastases in vivo. The activation of lymphocytes with anti-CD3 monoclonal antibody and IL-2 appears to be a reproducible and convenient method of producing cells capable of producing antitumor effects in models of adoptive immunotherapy.

Diagnosis and treatment of cytomegalovirus disease in transplant patients based on gastrointestinal tract manifestations.

Infection due to cytomegalovirus is a substantial cause of morbidity and mortality in immunocompromised patients. In particular, cytomegalovirus infection has been associated with a significant detrimental effect on patient and allograft survival after solid-organ transplantation. We are evaluating a new antiviral agent, ganciclovir 9-[1,3-dihydroxy-2-2 propoxymethyl] guanine (DHPG), used in solid-organ transplant recipients who developed life-threatening cytomegalovirus infections. Between March 1, 1987, and June 30, 1989, we treated 93 solid-organ transplant patients who developed tissue-invasive cytomegalovirus disease. From this group of patients we have identified 14 patients with primary gastrointestinal cytomegalovirus disease who received treatment with DHPG. Tissue diagnosis was made by endoscopy of the upper gastrointestinal tract (11 patients) or colonoscopy (three patients). Invasive cytomegalovirus disease was identified prior to severe complications of the gastrointestinal tract in all but one patient, who suffered colonic perforation prior to treatment with DHPG and subsequently died of bacterial sepsis. While 13 of the 14 patients improved after treatment with DHPG, four patients required additional treatments for recurrent cytomegalovirus disease and recovered. No DHPG toxicity was observed. We believe treatment with DHPG is indicated in this patient population, but that further studies are indicated to fully define the impact of this recommendation on both patient and allograft survival after solid-organ transplantation.

Importance in timing of cyclophosphamide on the enhancement of interleukin-2-induced cytolysis.

We investigated the in vivo effects of cyclophosphamide (CY) on interleukin-2(IL-2)-induced cytolytic function and spleen cell immunophenotype. Pretreatment of A/J mice with CY (25 mg/kg or 75 mg/kg) i.p. on days -10 and -15 followed by IL-2 (50,000 U i.p. on days 0 to +3) resulted in increased lysis of YAC-1 target cells compared to the group receiving IL-2 without previous CY therapy. In contrast, when CY was given on day -5, the cytotoxicity against YAC-1 was not enhanced. Phenotypic analysis of splenocytes obtained from mice treated with CY on day -10 or -15 revealed a relative decrease in L3T4- and Lyt2-positive T cells. In vivo depletion of natural killer (NK) cells by anti-asialoGM1, prior to IL-2 therapy, abrogated the enhancing effect of CY on cytolysis while in vivo elimination of T cells by anti-L3T4 and anti-Lyt2 monoclonal antibodies did not, indicating that in the absence of T cell antigenic challenge, the increased cytolytic function after CY administration is probably mediated through NK cells. These findings provide evidence that CY may be used more effectively in IL-2-based immunotherapy protocols, if consideration is given to timing of CY and IL-2 administration.

Treatment of invasive cytomegalovirus disease in solid organ transplant patients with ganciclovir.

The occurrence of cytomegalovirus infection after solid organ transplantation has been correlated with decrease patient and allograft survival. The disease has not been conquered for two majors reasons: the length of time to establish the diagnosis of CMV has been excessive, and suitable, nontoxic antiviral agents have not been available for use. The purpose of this study was to examine the current incidence and impact of tissue-invasive cytomegalovirus (TI-CMV) disease that developed in 93 patients who underwent solid organ transplantation at University of Minnesota Hospitals (3/1/87 and 6/30/89) and who were treated with antiviral agent ganciclovir ( [9-(1,3-dihydroxy-2-2-propoxymethyl)-guanine [DHPG]). During this same period of time 323 patients received kidney transplants and 71 received kidney-pancreas transplants. Three patient groups were defined: (1) no CMV; (2) CMV infection (cultural or serologic evidence of noninvasive CMV infection); and (3) evidence of TI-CMV disease based upon initial complaints of fever, malaise, dyspnea, or abdominal pain, leukopenia (WBC less than 3000/ml), and evidence of a positive CMV rapid antigen test, CMV culture, or the presence of characteristic CMV inclusion bodies upon examination of material obtained by means of bronchoscopy, upper-gastrointestinal endoscopy, colonoscopy, or liver or renal biopsy. Patients with solely fever, leukopenia, but without a rising CMV serum titer, or positive CMV urine or blood cultures were excluded from the study. A multivariate analysis revealed that rejection therapy, age greater than 50 years, and receiving an organ from a seropositive donor were all significant variables that predisposed to TI-CMV. Analysis of patient and kidney allograft survival indicated that asymptomatic CMV infection had little current impact upon patient or allograft survival, while patients who developed TI-CMV exhibited higher rates of allograft loss and mortality, despite DHPG therapy. Comparison with historical group of patients indicated that TI-CMV DHPG-treated patients exhibited a trend toward improved allograft survival that may be relevant because the historical group of patients included patients with mild CMV infection. DHPG therapy was well tolerated and produced minimal toxicity, and excellent 30-day cure rates (89.2%), although 21.2% of patients required retreatment subsequently. We are currently conducting a trial to compare the ability of DHPG administered plus an anti-CMV immune globulin preparation with acyclovir to prevent posttransplant TI-CMV disease.

Sensory integrative processing in delinquent-prone and non-delinquent-prone adolescents.

The purposes of this study were to obtain a preliminary description of the sensory integrative and practic abilities of 114 non-delinquent-prone adolescents aged 12 through 18 years and to compare their performances with those of 12 delinquent-prone adolescents with learning problems. Ten of the 17 subtests of the Sensory Integration and Praxis Tests (SIPT) (Ayres, 1989) as well as the Finger Posture Imitation Test (Druker, 1980) and the MacQuarrie Test for Mechanical Ability (MacQuarrie, 1925/1953) were administered to both groups. It was hypothesized that performance on some tests would correlate with age in the non-delinquent-prone adolescents. It was also hypothesized that some delinquent-prone adolescents with learning problems would perform significantly worse on the tests of sensory integrative and practic abilities than would the non-delinquent-prone adolescents. A data analysis indicated that performance on the praxis tests, Manual Form Perception, Graphesthesia, and Bilateral Motor Coordination showed a significant age correlation. The results of this study indicated a difference between the two groups, and it was concluded that the delinquent-prone group performed more poorly on all of the praxis-related tests and on the absolute values of the tests of Postrotary Nystagmus, Standing and Walking Balance, and Bilateral Motor Coordination. Some of the vestibular- and praxis-related tests, therefore, may still provide useful information on children older than 8 years of age.

Increased local antitumor effects of interleukin 2 liposomes in mice with MCA-106 sarcoma pulmonary metastases.

The effects of liposome formulations of interleukin 2 (IL-2) and local route were studied in C57BL/6 mice with MCA-106 sarcoma pulmonary metastases. IL-2 liposomes made by hydration of powdered dimyristoyl-phosphatidylcholine with aqueous recombinant IL-2 had 95% of the IL-2 associated with the lipid fraction. When mice with pulmonary micrometastases were treated once daily with free cytokine on days 5, 6, and 7 after tumor inoculation, the intrathoracic route was superior to the i.p. or s.c. routes. When IL-2 liposomes were administered by the local intrathoracic route, significantly better antitumor effects (P less than 0.01) were seen compared to empty liposomes or free IL-2 as determined by (a) increased survival and (b) reduced numbers of pulmonary metastases. Minimal toxicity was observed. Results indicate that local route and incorporation of IL-2 in liposomes may enhance therapeutic efficacy and facilitate more practical daily dosing regimens.

Synchronous and asynchronous systems of threshold elements.

The role of synchronism in systems of threshold elements (such as neural networks) is examined. Some important differences between synchronous and asynchronous systems are outlined. In particular, important restrictions on limit cycles are found in asynchronous systems along with multi-frequency oscillations which do not appear in synchronous systems. The possible role of deterministic chaos in these systems is discussed.

Isolation and partial characterization of a low molecular weight trypsin inhibitor from human urine.

A low molecular weight glycoprotein which completely inhibited trypsin at a 1 : 1 molar ratio was isolated from human urine. It was generated from a precursor molecule which in turn derived from plasma inter-alpha-trypsin inhibitor. It had one polypeptide chain with a molecular weight of about 20 000 and a high content of half-cystine residues. Its amino-terminal amino-acid sequence was Val-Thr-Glu-Val-Thr-X-Leu-Glu-Asp-.