FTY720-induced human pulmonary endothelial barrier enhancement is mediated by c-Abl.

Strategies to improve pulmonary endothelial barrier function are needed to reverse the devastating effects of vascular leak in acute respiratory distress syndrome. FTY720 is a pharmaceutical analogue of the potent barrier-enhancing phospholipid sphingosine 1-phosphate (S1P). FTY720 decreases vascular permeability by an incompletely characterised mechanism that differs from S1P. Here, we describe its barrier-promoting effects on intracellular signalling and junctional assembly formation in human pulmonary endothelium. Permeability of cultured human pulmonary endothelial cells was assessed using transendothelial electrical resistance and dextran transwell assays. Junctional complex formation was assessed using membrane fractionation and immunofluorescence. Pharmacological inhibitors and small interfering (si)RNA were utilised to determine the effects of individual components on permeability. Unlike S1P, FTY720 failed to induce membrane translocation of adherens junction or tight junction proteins. ß-catenin, occludin, claudin-5 or zona occludens protein (ZO)-1/ZO-2 siRNAs did not alter FTY720-induced barrier enhancement. FTY720 induced focal adhesion kinase (FAK) phosphorylation and focal adhesion formation, with FAK siRNA partially attenuating the prolonged phase of barrier enhancement. Inhibition of Src, protein kinase (PK)A, PKG, PKC or protein phosphatase 2A failed to alter FTY720-induced barrier enhancement. FTY720 increased c-Abl tyrosine kinase activity and c-Abl siRNA attenuated peak barrier enhancement after FTY720. FTY720 enhances endothelial barrier function by a novel pathway involving c-Abl signalling.

Frequency of myocarditis, left ventricular dysfunction and ventricular tachycardia in the acquired immune deficiency syndrome.

To evaluate possible relations between clinical and histopathologic cardiac findings in patients with the acquired immune deficiency syndrome (AIDS), 58 consecutively autopsied AIDS patients were reviewed retrospectively. Twenty-six (45%) had histopathologic myocarditis. Fifteen of these 26 (58%) had greater than or equal to 1 clinical cardiac abnormalities: 6 had congestive heart failure or left ventricular (LV) dysfunction, or both, 4 had ventricular tachycardia (VT), 10 had electrocardiographic abnormalities and 4 had pericardial abnormalities. Of the 32 patients without myocarditis, 6 (19%) had pericardial or electrocardiographic abnormalities, or both, but none had congestive heart failure, LV dysfunction or VT. Overall, clinical cardiac abnormalities were found in 21 patients (36%). Patients with myocarditis had a significantly higher incidence of clinical cardiac abnormalities than patients without myocarditis (58 vs 19%, p less than 0.01). All patients with congestive heart failure, LV dysfunction or VT had myocarditis. Thus, serious clinical cardiac abnormalities were common in patients with AIDS and were associated with myocarditis.

Prospective evaluation of hepatic imaging studies in the detection of colorectal metastases: correlation with surgical findings.

Nineteen patients with isolated colorectal liver metastases were preoperatively evaluated with five hepatic imaging studies. The results of these studies were correlated with operative findings. One study involved the use of EOE-13, an intravenously administered lipid contrast agent that enhances liver parenchyma on computed tomography (CT) scans (EOE-CT). Another study, arterial portography (AP-CT), was performed with injection of a water-soluble contrast agent into the superior mesenteric artery during CT scanning. Delayed CT scanning (DS-CT) was completed 4 hours after AP-CT. In addition, T1- and T2-weighted magnetic resonance imaging (MRI) (T1-MRI, T2-MRI) scans were done. All patients subsequently underwent laparotomy with identification of 78 lesions. A lesion-by-lesion analysis revealed that the sensitivity of EOE-CT (83%), AP-CT (78%), DS-CT (82%), and T1-MRI (84%) was comparable. T2-MRI had a significantly lower sensitivity (64%) compared with EOE-CT, DS-CT, and T1-MRI. The false-positive rate for AP-CT was 31%, which was significantly higher than that of all other studies. The T1-MRI examination had the lowest false-positive rate and proved to be the best hepatic imaging study in the detection of colorectal metastases. EOE-CT and DS-CT were comparable, whereas AP-CT and T2-MRI proved to be inferior tests.

Magnetic resonance imaging in Huntington disease.

Four patients with Huntington disease were imaged using CT and inversion-recovery magnetic resonance (MR) imaging. In all four patients the caudate nucleus and corpus striatum were well demonstrated and noted to be atrophic. MR is believed to be superior to CT for imaging morphologic changes of Huntington disease.

Pregnant teens: differential pregnancy resolution and treatment implications.

Profiles on three groups of pregnant teens in a comprehensive social service agency were identified: those who followed through with a parenting plan, those who followed through with an adoption plan, and those who switched from an adoption plan to a parenting plan. Pregnant teens who switched plans were identified as high risk in terms of health histories and psychosocial profiles. Since they represent as much as one-third of the total population, service plans must be made for them that focus on these risk areas. This article addresses the identification of new subgroups in the universe of pregnant teenagers, and treatment implications.

Inferior thyroid artery arising from common carotid artery with aberrant right subclavian artery.

We describe an unusual variant in the blood supply to the inferior portion of the right thyroid gland encountered during parathyroid localization studies. A brief review of other possible variants is given.

Multiple system atrophy (Shy-Drager syndrome): MR imaging.

The Shy-Drager syndrome (SDS) is a form of progressive autonomic nervous system failure (PAF) with orthostatic hypotension and associated extrapyramidal involvement that is often mistaken for Parkinson disease. SDS includes olivopontocerebellar atrophy and striatonigral degeneration which is attended by PAF. Eight patients with SDS were studied on a 0.5-T superconducting system utilizing T1-weighted inversion recovery (IR) and T2-weighted spin-echo pulse sequences and also on a 1.5-T system using spin-echo sequences. With IR sequences, atrophy of the putamina was demonstrated in patients with SDS that is consistent with findings of neuronal loss in these nuclei reported on postmortem examinations. An abnormal decrease in signal intensity of the putamina, particularly along their lateral and posterior portions, was also detected, predominantly on T2-weighted sequences, and in three cases on T1-weighted spin-echo sequences. Abnormalities were detected on both imagers but were shown with greater clarity on the 1.5-T device. SDS is the first disease in which convincing basal ganglia changes have been shown in vivo exclusively by MR imaging.

An epidemiologic study of risk factors in two teenage suicide clusters.

Two clusters of teenage suicides occurred in Texas between February 1983 and October 1984. The eight suicides from the first cluster and the six from the second were investigated together in a case-control study using a closed-response questionnaire administered to parents. Three control teenagers were matched with each case subject on the basis of school district, grade, race, and sex. Questions concerned the direct and indirect exposures of subjects to previous suicides as well as their life circumstances and behaviors. Case subjects were not more likely than control subjects to have had direct exposure to suicide as measured by their acquaintance with a person who committed suicide. Similarly, indirect exposure to suicide through the media was not associated significantly with suicide. Case subjects were more likely to have attempted or threatened suicide previously, to have damaged themselves physically, and to have known someone closely who died violently. Case subjects were more likely to have broken up with their girlfriends or boyfriends recently. They also had moved more often than control subjects, attended more schools, and lived with more parent figures. Identification of high-risk youths through knowledge of relevant risk factors can help to direct preventive services to those young people most susceptible to suicide.

Effects of intravenous vasopressin on canine mesenteric arterial blood flow, bowel oxygen consumption, and cardiac output.

The effects of various doses of intravenous vasopressin on mesenteric arterial blood flow, intestinal oxygen consumption, and cardiac output in anesthetized dogs were investigated. Optimal dose rate of intravenous vasopressin was found to be 3.0 mU/kg/min. At this dose rate, mesenteric arterial blood flow, intestinal oxygen consumption, and cardiac output decreased by 57%, 57% and 26%, respectively. Increasing the dose rate to 8.0 mU/kg/min did not offer significant gains. Maximum effect was observed 20 min after the beginning of the infusion. The effects disappeared 10-20 min after the infusion was discontinued, with the exception of superior mesenteric blood flow which showed a rebound increase. We conclude that in the anesthetized dog, intravenous infusions of vasopressin at low dose rates (3.0 mU/kg/min) substantially reduce mesenteric blood flow and intestinal oxygen extraction with moderate reduction of cardiac output. Possible clinical applications of low dose intravenous infusions of vasopressin would include reduction of portal hypertension and bowel protection during radiation therapy.

MRI in autonomic failure.

A significant rank correlation between rigidity and putaminal signal dropout on magnetic resonance imaging (MRI) in patients with multiple system atrophy suggests that putaminal degeneration may cause this clinical finding. Absence of putaminal abnormalities on MRI in patients with pure autonomic failure may prove useful in differentiating these two autonomic disorders.

Hepatic metastasis detection: comparison of three CT contrast enhancement methods.

A prospective, blinded comparison of three methods of hepatic contrast enhancement in computed tomography (CT) was conducted in 15 patients with colorectal carcinoma metastatic to the liver. Arterial portography (AP-CT) was performed with injection of contrast material into the superior mesenteric artery during CT. Delayed scanning (DS-CT) was performed 4 hours after intravascular administration of contrast material (mean dose, 280 mL). CT with an ethiodized oil emulsion (EOE-CT) was performed 1 hour after slow intravenous infusion of the emulsion. All patients underwent laparotomy following imaging studies. A lesion-by-lesion analysis of 56 metastases showed no significant differences in sensitivity (AP-CT, 77%; DS-CT, 83%; EOE-CT, 82%), but the false-positive rate for AP-CT was significantly higher than that for DS-CT (P less than .001) or EOE-CT (P less than .01). False-positive rates for EOE-CT and DS-CT were not significantly different. The predictive value of a positive test was 63% for AP-CT, 90% for DS-CT, and 81% for EOE-CT. AP-CT does not appear to be clinically useful for detection of hepatic metastases because of the high false-positive rate. No difference could be demonstrated between DS-CT and EOE-CT. DS-CT is a valuable method for hepatic contrast enhancement.

Nonspecific interstitial pneumonitis in patients with AIDS: radiologic features.

Chest radiographic abnormalities in patients with AIDS usually are associated with opportunistic infection or neoplasm. One hundred five patients with AIDS and clinical evidence of pneumonitis had chest radiographs and underwent bronchoscopy with bronchoalveolar lavage, transbronchial biopsy, or open-lung biopsy. Chest radiographs were abnormal in 73 (70%). Pneumocystis carinii pneumonia was identified at bronchoscopy or open-lung biopsy in 52 (50%). Nonspecific interstitial pneumonitis occurring in the absence of an identifiable infection was documented histologically in 36 (34%). Twenty (56%) of these 36 patients had abnormal chest radiographs. No currently recognized infectious agents were recovered from lavage fluid or were seen histopathologically in patients with nonspecific interstitial pneumonitis. The results show that nonspecific interstitial pneumonitis is clinically and radiologically indistinguishable from Pneumocystis carinii pneumonitis and should be considered in the differential diagnosis of AIDS patients with interstitial infiltrates.

Acquired immunodeficiency syndrome: Ga-67 citrate imaging.

All gallium-67 citrate scans obtained in patients with acquired immunodeficiency syndrome (AIDS) at the Clinical Center, National Institutes of Health (Bethesda, Md.) were retrospectively analyzed and correlated with the results of bronchoscopy, chest radiography, and endoscopy. There were 164 scans of 95 patients. Twenty scans were from patients with Pneumocystis carinii pneumonia; 19 were abnormal, for a sensitivity of 95%. Ga-67 uptake tended to be less in patients receiving therapy for P. carinii pneumonia. Chest radiographs were normal at least initially in three patients with abnormal scans and P. carinii pneumonia. Unusually prominent colonic activity was associated with infection in some patients. No lesions of Kaposi sarcoma showed tracer uptake. Gallium scanning is useful for detecting P. carinii pneumonia and other opportunistic infections in patients with AIDS, but it is not useful for localizing Kaposi sarcoma.

The effect of vasopressin on hepatic arterial blood flow.

Vasopressin was successively infused into the hepatic and superior mesenteric arteries and a systemic vein, and its levels monitored by blood samples drawn from the portal and hepatic veins and a systemic vein. Blood flow was monitored in the hepatic and superior mesenteric arteries and in the ascending aorta. Hepatic blood flow was inversely correlated with mesenteric blood flow, rising about 50% above baseline levels during hepatic and systemic artery infusions and 96% during superior mesenteric artery infusion. Hepatic artery and systemic vein infusions caused a reduction in mesenteric flow about 20% less than that caused by direct superior mesenteric artery infusion.

Angiographic ablation of parathyroid adenomas: lessons from a 10-year experience.

Angiographic ablation of parathyroid adenomas with ionic contrast material was performed in 24 patients with persistent hyperparathyroidism who had undergone at least one prior unsuccessful surgical resection; 23 had mediastinal adenomas. The success rate was 83% at 1 month after ablation and 71% at both 5 and 9 years. Ablation was successful in 85% of the patients in whom the catheter could be wedged into the artery feeding the adenoma. Long-term success was achieved in 89% of the patients in whom contrast enhancement persisted in the adenoma on computed tomographic scans obtained 24 hours later. Acute complications were seen only in patients with glands supplied by the inferior or superior thyroid arteries. Long-term complications were limited to permanent hypocalcemia, present in 8% of patients. Even if unsuccessful for ablation, the procedure may provide localization and does not preclude surgical resection. It is recommended for most patients with persistent hyperparathyroidism and mediastinal adenomas, especially adenomas supplied by the internal thoracic artery.

Nonspecific interstitial pneumonitis: a common cause of pulmonary disease in the acquired immunodeficiency syndrome.

During a 4.4-year period, nonspecific interstitial pneumonitis was seen in 41 of 110 (38%) patients with the acquired immunodeficiency syndrome and accounted for 32% (48/152) of all episodes of clinical pneumonitis. Diffuse alveolar damage was typically a feature of nonspecific interstitial pneumonitis, but neither lung biopsy nor bronchoalveolar lavage detected a pathogen. Of these 41 patients, 13 had no associated pulmonary tumor and had not been exposed to pulmonary toxins, whereas 28 patients had either concurrent pulmonary Kaposi sarcoma, previous experimental therapies, or a history of pneumocystis pneumonia or drug abuse. Of these 41, 23 had normal chest radiographs. The clinical features of patients with nonspecific interstitial pneumonitis were similar to those of patients with pneumocystis pneumonia, although histologic findings showed less severe alveolar damage in patients with nonspecific interstitial pneumonitis (p less than 0.001). Pathologic evaluation and clinical follow-up suggest that many clinical episodes of pneumonitis in patients with the acquired immunodeficiency syndrome are due to nonspecific interstitial pneumonitis of unknown cause.

Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia.

To assess determinants of prognosis for 43 patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia, objective clinical and histopathologic characteristics were analyzed for acute and long-term prognostic significance. Severe abnormalities on initial chest radiographs and alveolar-arterial oxygen differences (AaPO2) greater than 30 mm Hg were associated with higher mortality during the period of treatment for the acute episode (p less than 0.05). Decreased long-term survival after the diagnosis of Pneumocystis pneumonia correlated with the severity of interstitial edema (a component of diffuse alveolar damage) on initial transbronchial biopsy and elevation of AaPO2 at the time of diagnosis (Cox proportional hazards analysis, p less than 0.05). The persistence of Pneumocystis cysts after 3 wk of therapy was associated with significantly decreased long-term survival (p less than 0.05) when follow-up biopsy was performed in 27 of the patients. Patients with a diagnosis of Pneumocystis pneumonia before July 1985 had more advanced disease at the time of diagnosis and a worse prognosis than did those in whom the diagnosis was made after July 1985 (p less than 0.05). This study demonstrates that important prognostic information can be derived from information obtained at initial presentation and follow-up bronchoscopic evaluation in patients with AIDS and Pneumocystis carinii pneumonia, and suggests that early detection and initiation of therapy may improve chances for survival.

Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome.

Preclinical studies have demonstrated that trimetrexate is a potent inhibitor of dihydrofolate reductase from Pneumocystis carinii. On the basis of this evidence, this lipid-soluble antifolate was used as an antipneumocystis agent in 49 patients with the acquired immunodeficiency syndrome (AIDS) and pneumocystis pneumonia. Simultaneous treatment with the reduced folate leucovorin was used as a specific antidote to protect host tissues from the toxic effects of the antifolate without affecting the antipneumocystis action of trimetrexate. Patients were assigned to three groups and treated for 21 days: in Group I, trimetrexate with leucovorin was used as salvage therapy in patients in whom standard treatments (both pentamidine isethionate and trimethoprim-sulfamethoxazole) could not be tolerated or had failed (16 patients); in Group II, trimetrexate with leucovorin was used as initial therapy in patients with a history of sulfonamide inefficacy or intolerance (16 patients); and in Group III, trimetrexate with leucovorin plus sulfadiazine was used as initial therapy (17 patients). The response and survival rates were, respectively, 69 percent and 69 percent in Group I; 63 percent and 88 percent in Group II; and 71 percent and 77 percent in Group III. Trimetrexate therapy had minimal toxicity; transient neutropenia or thrombocytopenia occurred in 12 patients and mild elevation of serum aminotransferases in 4. We conclude that the combination of trimetrexate and leucovorin is safe and effective for the initial treatment of pneumocystis pneumonia in patients with AIDS and for the treatment of patients with intolerance or lack of response to standard therapies.