Pinealectomy interferes with the circadian clock genes expression in white adipose tissue

Melatonin, the main hormone produced by the pineal gland, is secreted in a circadian manner (24‐hr period), and its oscillation influences several circadian biological rhythms, such as the regulation of clock genes expression (chronobiotic effect) and the modulation of several endocrine functions in peripheral tissues. Assuming that the circadian synchronization of clock genes can play a role in the regulation of energy metabolism and it is influenced by melatonin, our study was designed to assess possible alterations as a consequence of melatonin absence on the circadian expression of clock genes in the epididymal adipose tissue of male Wistar rats and the possible metabolic repercussions to this tissue. Our data show that pinealectomy indeed has impacts on molecular events: it abolishes the daily pattern of the expression of Clock, Per2, and Cry1 clock genes and Pparγ expression, significantly increases the amplitude of daily expression of Rev‐erbα, and affects the pattern of and impairs adipokine production, leading to a decrease in leptin levels. However, regarding some metabolic aspects of adipocyte functions, such as its ability to synthesize triacylglycerols from glucose along 24 hr, was not compromised by pinealectomy, although the daily profile of the lipogenic enzymes expression (ATP‐citrate lyase, malic enzyme, fatty acid synthase, and glucose‐6‐phosphate dehydrogenase) was abolished in pinealectomized animals.     

Characterization of Aerosols of Human Recombinant Deoxyribonuclease I (rhDNase) Generated by Jet Nebulizers

Recombinant human deoxyribonuclease I (rhDNase) is a new therapeutic agent developed to improve clearance of purulent sputum from the human airways. It is delivered by inhalation. Four jet nebulizers, T Up-Draft II (Hudson), Customized Respirgard II (Marquest), Acorn II (Marquest), and Airlife Misty (Baxter), were evaluated in vitro for their ability to deliver aerosols of rhDNase. The aerosols were generated from 2.5-mL aqueous solutions of rhDNase, at concentrations of either 1 or 4 mg/mL. In all experiments, the Pulmo-Aide Compressor (De Vilbiss) was used to supply the air to the nebulizers. Between 20 and 28% of the rhDNase dose initially placed in the nebulizers was delivered to the mouthpiece in the respirable range (1-6 µm). Evaluation of the rhDNase following nebulization in all four devices indicated that there was no loss in enzymatic activity and no increase in aggregation. Circular dichroism spectrophotometry indicated there was no change in either the secondary or the tertiary structure in rhDNase following nebulization. These results show that all four nebulizers are essentially equivalent in their ability to deliver respirable doses of rhDNase in an intact, fully active form. Changing the concentration of the solution in the nebulizer from 4 to 1 mg/mL rhDNase leads to a proportional reduction in the respirable dose delivered to the mouthpiece.     

Pulmonary complications after tricyclic antidepressant overdose

We studied 82 consecutive patients admitted to the ICU with predominant tricyclic antidepressant overdose (mean plasma tricyclic level, 1,025 ng/ml) to determine the nature and incidence of respiratory complications. The majority of patients (80.4 percent) had a decreased arterial to alveolar oxygen tension ratio (PaO2/PAO2) on initial emergency room arterial blood gas analysis (mean, 0.56). Mechanical ventilation was required in 76.8 percent of the patients for a mean duration of 46.2 h. Chest radiograph abnormalities developed during the first 48 h in 32/82 patients (39 percent). The group with radiographic abnormalities had higher mean drug levels than the group without (p less than 0.05). Of 82 patients, nine (11 percent) developed radiographic evidence of bilateral alveolar infiltrates suggestive of acute lung injury. This group had significantly higher mean drug levels than the groups with other types of radiographic abnormalities (p less than 0.001). Charcoal was recovered from the airway of 18/72 patients who received activated charcoal slurry by nasogastric tube in the emergency room after endotracheal intubation. The group who aspirated did not show statistically significant difference in the incidence of chest radiograph abnormalities, gas exchange, or survival compared with the group that did not aspirate.     

Cardiac effects of contrast media in MR angiography: evaluation in an experimental model of myocardial ischemia

RATIONALE AND OBJECTIVES: The authors evaluated the cardiac tolerability of paramagnetic contrast agents for magnetic resonance (MR) angiography in an in vitro model of ischemic rat heart. MATERIALS AND METHODS: The left anterior descending coronary artery was temporarily occluded in a perfused rat heart model to induce cardiac ischemia and reperfusion. A dose of 0.4 mL of gadobenate dimeglumine, of gadopentetate dimeglumine, or of D-mannitol was injected directly into the aorta both during the ischemia and during the reperfusion period. The left ventricular pressure and heart rate were recorded. RESULTS: Myocardial ischemia resulted in decreased cardiac activity, with a reduction in left ventricular pressure and heart rate. A further decrease in cardiac activity was temporarily induced by injection of contrast medium during both the ischemic and early reperfusion phases. Less marked responses were induced by a hyperosmolal solution of mannitol. CONCLUSION: These results suggest that the transient cardiac effects induced by bolus injection of paramagnetic contrast medium may be regarded as the combined effects of the osmotoxicity of the contrast medium solution and the chemotoxicity of the contrast medium molecule.     

Atrial fibrillation after operation for lung cancer: clinical and prognostic significance

BACKGROUND: Atrial fibrillation is a common complication of early postoperative period in lung cancer thoracotomy. Its clinical incidence and short- and long-term impact on overall mortality has never been definitely assessed; moreover, it is unclear whether the arrhythmia represents an independent cardiac risk factor. METHODS: We prospectively studied 233 consecutive patients undergoing operation for lung cancer (170 with non-small-cell lung cancer). Postoperative atrial fibrillation incidence was related to different clinical factors possibly involved in its occurrence and to both short- and long-term survival. RESULTS: Atrial fibrillation occurred in 28 patients (12%) (same percentage in non-small-cell lung cancer); a strong relationship was observed between arrhythmia and age, history of hypertension and associated lymph node resection. The mean hospitalization time was 14 +/- 4 days in patients developing atrial fibrillation and 13 +/- 4 days in those who did not (p = not significant). No difference was observed between the two groups with regard to short- or long-term mortality or to long-term atrial fibrillation recurrences, also when considering the entire population and only non-small-cell lung cancer, separately. CONCLUSIONS: At our institution, early atrial fibrillation occurrence after operation for lung cancer does not show any negative impact on short- and long-term mortality or on recurrence rate.     

Primary lymphoma of the small intestine. Radiographic image of enteroclysis with double-contrast media

The authors retrospectively reviewed the radiographic (double-contrast small-bowel enema) examinations of 20 patients with primitive small intestinal lymphomas. The diagnosis was histologically confirmed in all cases. The technique was very sensitive (100%) in detecting small-bowel abnormalities. On the contrary, a definite differential diagnosis was difficult to make (65%), except for 4 cases of lymphoma complicating celiac disease in which the presence of a nodular pattern and of thickened and irregular mucosal folds seemed to be highly specific. The most difficult differential diagnosis was with Crohn's disease. In all the cases with surgical confirmation (17), disease extent exactly corresponded to that suggested by small-bowel enema. Primitive small intestinal lymphoma is not radiologically distinguishable from secondary involvement during systemic lymphoma. From the analysis of radiological abnormalities, the authors observed that, different from previous reports, severe luminal narrowing was frequent, whereas "aneurysmal" dilatations of intestinal loops were never observed. CT was confirmed as the best technique for staging. Clinical implications of double-contrast enema in the diagnosis of primitive small intestinal lymphomas are discussed; radiographic patterns are reviewed.     

The influence of pregnancy and gender on perivascular innervation of rat posterior cerebral arteries

The authors investigated the influence of pregnancy and gender on the density of trigeminal and sympathetic perivascular nerves in posterior cerebral arteries (PCA) and the reactivity to norepinephrine and calcitonin gene-related peptide (CGRP). PCAs were isolated from nonpregnant, late-pregnant, postpartum, and male rats, mounted and pressurized on an arteriograph chamber to obtain concentration-response curves to norepinephrine and CGRP. Arteries were immunostained for CGRP-, tyrosine hydroxylase-, and protein gene product 9.5 (PGP 9.5)-containing perivascular nerves, and nerve density was determined morphologically. Pregnancy had a trophic effect on trigeminal perivascular innervation (P < .01 vs male); however, this was not accompanied by a change in reactivity to CGRP. Sympathetic and PGP 9.5 nerve densities were not altered by pregnancy or gender, and there were no differences in reactivity to norepinephrine. Together, these results suggest that the increase in trigeminal innervation during pregnancy is more related to nociception than in controlling resting cerebral blood flow.     

Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease

Tick-borne encephalitis virus (TBEV) is an emerging human pathogen that causes potentially fatal disease with no specific treatment. Mouse monoclonal antibodies are protective against TBEV, but little is known about the human antibody response to infection. Here, we report on the human neutralizing antibody response to TBEV in a cohort of infected and vaccinated individuals. Expanded clones of memory B cells expressed closely related anti-envelope domain III (EDIII) antibodies in both groups of volunteers. However, the most potent neutralizing antibodies, with IC₅₀s below 1 ng/ml, were found only in individuals who recovered from natural infection. These antibodies also neutralized other tick-borne flaviviruses, including Langat, louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. Structural analysis revealed a conserved epitope near the lateral ridge of EDIII adjoining the EDI–EDIII hinge region. Prophylactic or early therapeutic antibody administration was effective at low doses in mice that were lethally infected with TBEV.     

Tumor M2-Pyruvate Kinase, a New Metabolic Marker for Pancreatic Cancer

An isoenzyme of pyruvate kinase (Tu M2-PK) is overexpressed by tumor cells and can be measured in blood by a specific immunoenzymatic assay. Our objective was to investigate the diagnostic value of Tu M2-PK in comparison with that of CA 19-9 in pancreatic cancer. We studied 265 subjects: 60 with histologically confirmed pancreatic cancer, 43 with benign pancreatic diseases (acute and chronic pancreatitis), 5 with benign cystic neoplasms of the pancreas, 9 with neuroendocrine tumors, 77 with other abdominal malignancies, 47 with benign digestive diseases, and 24 healthy controls. Levels of plasma Tu M2-PK and serum CA 19-9 were determined by commercially available specific immunoassays. The diagnostic sensitivity and specificity of Tu M2-PK for pancreatic cancer were 85 and 41%, respectively, while those of CA 19-9 were 75 and 81%. The combination of the two tests significantly increased sensitivity (97%) but lowered specificity (38%). In discriminating between pancreatic cancer and acute or chronic pancreatitis, Tu M2-PK turned out to be less accurate than CA 19-9. In patients without pancreatic tumor, cholestasis appeared not to affect the values of Tu M2-PK, while CA 19-9 was found to be significantly higher. Tu M2-PK was also abnormally high in the majority of patients with other digestive malignancies or neuroendocrine tumors. The results demonstrate that Tu M2-PK has a satisfactory sensitivity but a poor specificity in the diagnosis of pancreatic cancer. Used together with CA 19-9, the sensitivity increases considerably.     

Effect of pregnancy on autoregulation of cerebral blood flow in anterior versus posterior cerebrum

Endothelin receptor antagonists and phosphodiesterase type 5 inhibitors are used to treat pulmonary arterial hypertension. We tested the hypothesis that a selective endothelin type A receptor antagonist (ambrisentan) and a phosphodiesterase type 5 inhibitor (tadalafil) may act synergistically to relax endothelin-constricted pulmonary arteries. Rat isolated intrapulmonary arterial rings contracted with 8 nmol/L endothelin-1 were relaxed by 10 nmol/L ambrisentan and 30 nmol/L tadalafil alone by 26±3% and 21±1%, respectively, whereas both drugs in combination acted synergistically to relax arterial rings by 83±6%. The nonselective endothelin type A and B receptor antagonists bosentan (100 nmol/L) and macitentan (30 nmol/L) alone relaxed endothelin-contracted rings by 30±5% and 24±3%, respectively. Combinations of 30 nmol/L tadalafil with 100 nmol/L bosentan or 30 nmol/L macitentan relaxed endothelin-contracted rings by 53±5% or 46±7%, respectively; these values are similar to the calculated sums of the individual effects of these compounds. Denudation of endothelium from pulmonary arterial rings abolished the vasodilator response to 30 nmol/L tadalafil and the synergistic vasorelaxant effect of tadalafil with ambrisentan. In the presence of 1 μmol/L BQ-788, a selective endothelin type B receptor antagonist, the vasorelaxant effects of 10 nmol/L ambrisentan and 30 nmol/L tadalafil were additive but not synergistic. These data can be interpreted to suggest that ambrisentan and tadalafil synergistically inhibit endothelin-1-induced constriction of rat intrapulmonary arteries and that endothelin type B receptors in endothelium are necessary to enable a synergistic vasorelaxant effect of the drug combination.