Focal intestinal lipogranulomatous lymphangitis in 6 dogs (2008-2011).

BACKGROUND: Lipogranulomatous lymphangitis is inflammation of the intestinal lymphatic vessels and surrounding tissues caused by chronic leakage of lipid-laden chyle. Grossly, lipogranulomas are typically disseminated small masses on the serosa and surrounding lymphatic vessels and consist of epithelioid macrophages, multinucleated giant cells, and cholesterol. Lipogranulomatous lymphangitis is occasionally seen in patients with lymphangiectasia and protein-losing enteropathy (PLE). OBJECTIVES: To characterize the historical features, clinical signs, treatment, histopathology, and outcome of dogs with focal lipogranulomatous lymphangitis. ANIMALS: Six dogs with ultrasonographic evidence of focal, regional small intestinal masses, often with involvement of the adjacent mesentery, and a diagnosis of focal lipogranulomatous lymphangitis based on histopathology of biopsied masses. RESULTS: The median age of dogs was 6.9 years (range 3-10 years). All dogs had total protein, globulin, and albumin concentrations within the reference range at initial presentation and had intestinal masses identified on abdominal ultrasound examination. Histopathologic evaluation of lesions identified severe mural and mesenteric lipogranulomatous lymphangitis. Lymphangiectasia was noted in 5 cases and only in sections within the mass-like lesion; tissue without lipogranulomas had minimal lymphangiectasia, suggesting a localized phenomenon. Postoperative outcomes ranged from remission of clinical signs with no subsequent treatment for 10-12 months in 2 dogs, postoperative management with medical and nutritional management in 3 dogs, and no outcome for 1 case. CONCLUSIONS AND CLINICAL IMPORTANCE: This case series describes a unique mass-like manifestation of intestinal lipogranulomatous lymphangitis and should be considered as a possible differential diagnosis in dogs with an intestinal mass.

Cytokine mRNA expression and serum cortisol evaluation during murine lung inflammation induced by Mycobacterium tuberculosis.

A model system was characterized for investigating the potential role of cortisol in MTB induced immunopathology. Serum cortisol levels were evaluated in two mouse strains; C57BL/6 mice develop lung granulomas following acute Mycobacterium tuberculosis infection while A/J mice are deficient in this process. Serum cortisol levels were examined post infection, as well as immunoregulatory mRNA expression in the lung, measured using bioluminescent RT-PCR techniques. Prior to infection, the A/J mice constitutively maintain nearly 75&percent; higher serum cortisol than C57BL/6 mice. Both A/J and C57BL/6 mice exhibited approximately 30&percent; reduction in relative serum cortisol following infection. At no time did serum cortisol levels in the A/J fall below constitutive levels in the non-infected C57BL/6. The overall elevated cortisol in the A/J may affect pulmonary immunoresponsiveness; A/J mice exhibited earlier induction of IL-10 and TNF-alpha than C57BL/6 mice, with a relative lack of IL-2 during late infection. Conversely, the C57BL/6 mice demonstrated higher IL-12(p40) and IL-2 messages at the latter stages of disease than the A/J mice. Both mice demonstrated high IFN-&gama; mRNA. The high constitutive serum cortisol in the A/J mice may therefore contribute to establishment of an environment counter-productive to initiation of protective Th1 cell and granulomatous responses.

Apoptosis in mycobacterium tuberculosis infection in mice exhibiting varied immunopathology.

This study examined mechanisms contributing to pulmonary immunopathology following acute Mycobacterium tuberculosis (MTB) infection in vivo in a murine model. A/J and C57BL/6 mice were intravenously infected with MTB (Erdman). Pathological differences were found between strains, unrelated to pulmonary load of bacilli. A/J mice developed progressive interstitial pneumonitis, while C57BL/6 mice maintained granuloma formation. The contribution of FAS and FAS ligand-mediated apoptosis was assessed via bioluminescent reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemical staining, and TUNEL assessment of DNA fragmentation. Cytokine messages for pulmonary tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), as well as for the lytic molecules perforin and granzyme B, were quantified. Immunohistochemical staining for CD3 receptor was performed to monitor lymphocytic lung infiltration. Soon after infection, A/J mice exhibited increased pulmonary IFN-gamma message, concurrent with the appearance of CD3+ lymphocytes distributed throughout the lung. C57BL/6 mice exhibited perivascular cuffing, with no accompanying increase in IFN-gamma message. A/J mice also had elevated levels of FAS and FAS ligand message and protein early after infection, while the C57BL/6 mice had no increased expression of these molecules. Both strains exhibited qualitatively similar numbers of TUNEL-positive cells throughout infection, with a marked increase on day 7. Apoptotic cells appeared to co-localize with acid fast bacilli. It is therefore proposed that apoptosis during initial granuloma formation following MTB infection may occur through a FAS/FAS ligand-independent pathway. Moreover, a failure of completion of the FAS/FAS ligand-mediated apoptosis pathway in the A/J mice may contribute to inefficient elimination of lymphocytes, thus further aggravating pulmonary pathology.

Saphenous vein interposition graft for recurrent carotid stenosis after prior endarterectomy and stent placement. Case report.

Although the use of carotid artery stents is increasing, the management of recurrent stenosis after their placement is undefined. The authors report on a patient who underwent two left carotid endarterectomies followed by left carotid angioplasty and stent placement for recurrent stenosis. A third symptomatic recurrence was subsequently managed by placement of a saphenous vein interposition graft from the common carotid artery to the distal cervical internal carotid artery. The patient remained without hemispheric or retinal ischemia at his 5-month follow-up visit. Interposition grafting should be considered as a treatment option for carotid restenosis after initial endarterectomy and stent placement.

Intra-arterial administration of carboplatin and the blood brain barrier permeabilizing agent, RMP-7: a toxicologic evaluation in swine.

RMP-7 is a bradykinin B2 receptor agonist shown to permeabilize the blood-brain barrier, especially that associated with brain tumors, when administered via both intracarotid and intravenous routes. Both routes of administration are currently being tested in human trials in combination with the chemotherapeutic agent carboplatin as therapy for gliomas. As an essential prerequisite to the initial intracarotid clinical trials, the potential neurotoxicity of intra-arterial administration of RMP-7 (at a high or low dose), alone and in combination with carboplatin, was assessed in anesthetized Red Duroc swine. Five treatment groups were evaluated with each pig receiving a series of alternating, intra-arterial infusions of RMP-7 (or saline) followed by carboplatin (or saline), as follows: (1) vehicle control: saline/saline; (2) carboplatin only control: saline/carboplatin (50 mg total); (3) RMP-7 only control: RMP-7 (750 ng/kg)/saline; (4) low dose combination: RMP-7 (75 ng/kg)/carboplatin (50 mg total); and (5) high dose combination: RMP-7 (750 ng/kg)/carboplatin (50 mg total). For each subject, one of the alternating dosing sequences (above) was repeated four times during a single dosing session which lasted approximately 40 minutes. Assessments during the in-life phase of the study in the pre- and post-treatment periods consisted of heart rate, arterial blood pressure (systolic, diastolic, and mean), blood gases, body weight, general clinical observations (including evaluation for neurological deficit) and clinical pathology (including a comprehensive battery of standard blood coagulation, hematological and serum chemistry tests). In addition, during the time of treatment, heart rate and arterial blood pressure were monitored. The animals were terminated two weeks after dosing and the brain and rete mirabile (distal to site of infusion) were evaluated for gross and histopathological abnormalities. The histopathology analysis included a reader-blinded analysis using low and high power light microscopic examination of both H&E and Kluver-Berrera stained sections through several key cortical and subcortical brain regions. Transient decreases in arterial blood pressure (mean of 10-25 mmHg) were observed in both groups receiving the high dose of RMP-7 (i.e., 750 ng/kg). No other side effects attributable to RMP-7 and/or carboplatin were observed, and clinical observations revealed no evidence of neurologic deficits. Post-mortem examination revealed no evidence of CNS or cerebral vascular pathology attributable to carboplatin and RMP-7. This study demonstrates that intracarotid administration of the maximum tolerated dose of RMP-7 (750 ng/kg) alone, or in combination with carboplatin (50 mg) is not accompanied by any serious adverse effect, apparent cerebrovascular abnormality or neuropathologic consequence and offers further evidence for the safety of this novel therapeutic approach for enhancing delivery of chemotherapeutics to brain tumors.