Collapsibility of the internal jugular veins in the lateral decubitus body position: A potential protective role of the cerebral venous outflow against neurodegeneration.

Recent research has revealed that patients with neurodegenerative disease sleep longer in the supine position, while healthy controls prefer sleeping in the lateral decubitus position. Thus, sleeping in the lateral position seems to be protective against neurodegeneration. It has also been suggested that a protective role of this body position could be associated with better cerebral venous drainage in this body position, which results in more active glymphatic system of the brain (the system responsible for clearance of the cerebral tissue from waste products, e.g. amyloid-ß). Since no published evidence exists regarding venous outflow from the cranial cavity in the lateral decubitus position, we performed a pilot sonographic study of the internal jugular veins in 3 young healthy volunteers and 2 patients presenting with abnormal jugular valves. In all healthy volunteers both internal jugular veins were opened in the supine position and collapsed in the sitting one. In the right lateral decubitus position the right internal jugular vein was opened, while the left one was partially collapsed; and-vice versa-in the left lateral decubitus position the right internal jugular vein was partially collapsed and the left one opened. In patients with abnormal jugular valves both internal jugular veins were opened in both lateral decubitus body positions. We hypothesize that in the lateral decubitus body position, because of decreased flow resistance in the extracranial veins, cerebral venous outflow is optimal, which in turn optimizes the activity of the glymphatic system. Therefore, people intuitively prefer this body position during sleep, while other positions are associated with a higher risk of neurodegenerative disorders. Yet, it should be emphasized that our results need to be interpreted with caution, since only a few individuals have been assessed and this discovery should be confirmed in more patients and healthy controls, and by precise quantitative measurements.

Adiponectin--its potential to predict and prevent coronary artery disease.

BACKGROUND: Recent evidence suggests that epicardial adipose tissue may contribute locally to the pathogenesis of coronary artery disease (CAD). We investigated how local and systemic adiponectin, an adipokine with anti-inflammatory and insulin sensitizing properties, is related to the presence of CAD and cardiovascular risk factors. METHODS: Serum and adipose tissue samples from subcutaneous and pericoronary depots were collected from sixty consecutive patients with CAD who required coronary artery bypass grafting or patients without CAD who underwent cardiac surgery for aortic valve replacement. Western blot, ELISA and PCR were used to detect and determine the adiponectin concentrations and expression in the samples. RESULTS: Adiponectin concentrations in the serum and pericoronary fat of patients without CAD were significantly higher than in patients with CAD ( P < 0.01). However, the expression of adiponectin mRNA did not differ in any instances. Male gender, BMI > 30 and type 2 diabetes were significantly correlated to decreased serum adiponectin ( P < 0.03). CONCLUSION: Pericoronary fat specifically secretes metabolically active adiponectin. Its local and systemic concentrations are inversely correlated to the presence of coronary artery disease, indicating its anti-atherogenic effects. As for patients with CAD, adiponectin might be a promising marker for intra-individual monitoring of cardiovascular risk factors and thus a course of secondary prevention. Further evaluation is necessary to elucidate whether a novel therapeutic option could be derived against the onset and progression of CAD.

Structural and serological studies of the related O-specific polysaccharides of Proteus vulgaris O21 and Proteus mirabilis O48 having oligosaccharide-phosphate repeating units.

The O-specific polysaccharide chains (O-antigens) of the lipopolysaccharides (LPSs) of Proteus mirabilis O48 and Proteus vulgaris O21 were found to have tetrasaccharide and pentasaccharide repeating units, respectively, interlinked by a glycosidic phosphate. Polysaccharides and an oligosaccharide were derived from the LPSs by various degradation procedures and studied by 1H and 13C NMR spectroscopy, including 2D COSY, TOCSY, NOESY, H-detected 1H,13C and 1H,31P HMQC experiments. The following related structures of the repeating units of the O-antigens were established (top: Proteus mirabilis O48; bottom: Proteus vulgaris O21) The O-specific polysaccharide of P. vulgaris O21 has the same structure as that of Hafnia allvei 744 and PCM 1194 [Petersson C., Jachymek, W., Klonowska, A., Lugowski, C., Niedziela, T. & Kenne, L. (1997) Eur. J. Biochem., 245, 668-675], except that the GlcN residue carries the N-acetyl rather than the N-[(R)-3-hydroxybutyryl] group. Serological investigations confirmed the close relatedness of the Proteus and Hafnia O-antigens studied.

Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo.

The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.

Structural studies of the O-specific polysaccharide from Plesiomonas shigelloides strain CNCTC 113/92.

The structure of the O-specific side chain of the lipopolysaccharide (LPS) of Plesiomonas shigelloides, strain CNCTC 113/92 has been investigated by NMR spectroscopy, matrix-assisted laser desorption/ionization time of flight mass spectrometry and sugar and methylation analysis. It was concluded that the polysaccharide is composed of a hexasaccharide repeating unit with the following structure: in which D-beta-D-Hepp is Dglycero-beta-Dmanno-heptopyranose and 6d-beta-D-Hep is 6-deoxy-beta-Dmanno-heptopyranose. This structure represents a novel hexasaccharide repeating unit of bacterial O-antigen that is characteristic and unique to the Plesiomonas shigelloides strain. Using the high-resolution magic angle spinning technique, 1H-NMR spectra were also obtained for the O-polysaccharide components of isolated LPS and in their original form directly on the surface of bacterial cells.

Structures of the O-specific polysaccharides from Yokenella regensburgei (Koserella trabulsii) strains PCM 2476, 2477, 2478, and 2494: high-resolution magic-angle spinning NMR investigation of the O-specific polysaccharides in native lipopolysaccharides and directly on the surface of living bacteria.

The structures of the carbohydrate O-specific side-chain moiety of the lipopolysaccharides (LPS) of Yokenella regensburgei, strains PCM 2476, 2477, 2478, and 2494, have been investigated by (1)H and (13)C NMR, fast atom bombardment tandem mass spectrometry (FAB-MSMS), matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry, methylation analysis, partial acid hydrolysis, and immunological methods. It was concluded that the O-specific polysaccharides of strains 2476, 2477, 2478, and 2494 are composed of the same basic trisaccharide repeating unit having the structure -->3)-alpha-D-FucpNAc-(1-->2)-L-alpha-D-Hepp-(1-->3)-6-deoxy -alpha-L- Talp-(1-->, in which L-alpha-D-Hepp is L-glycero-alpha-D-manno-heptopyranose. The detailed analysis revealed, however, differences in O-acetylation patterns of the 6-deoxy-L-talose residue, with 2- and 4-O-acetyl disubstituted -->3)-6-deoxy-alpha-L-Talp-(1--> in strain PCM 2476 and a 2-O-acetylated residue in strains 2477, 2478, and 2494. These structures represent novel, trisaccharide repeating units of bacterial O-antigens that are characteristic and unique to the Y. regensburgeispecies. By use of the high-resolution magic-angle spinning (HR-MAS) technique, (1)H NMR spectra of the O-polysaccharides directly in isolated LPS were obtained. This allowed for almost full assignment and structural determination of the polysaccharide. By this technique the O-polysaccharide components were also observed in their original form directly on the surface of living bacterial cells.

Structural studies of the O-specific polysaccharide of Hafnia alvei strain PCM 1207 lipopolysaccharide.

The structure of the O-specific side-chain of the Hafnia alvei strain PCM 1207 lipopolysaccharide (LPS) has been investigated. Methylation analysis, partial acid hydrolysis, matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) MS, fast atom bombardment (FAB)-MS/MS and 1H- and 13C-NMR spectroscopy were the principal methods used. Glycerol phosphate was identified as a constituent in the polysaccharide and the following structure of a pentasaccharide repeating unit was established: The polysaccharide is partially (approximately 10%) substituted with O-acetyl groups. The lipopolysaccharide was also subjected to high resolution magic angle spinning (HR-MAS) NMR analysis, which showed both the signals of the O-specific polysaccharide as well as several signals from unsubstituted core oligosaccharides. This confirmed the presence of the described structure in the native LPS.

The correlation between ciliary ultrastructure and ciliary beat frequency in experimental chronic sinusitis.

Ciliary ultrastructural abnormalities secondary to chronic sinusitis may cause abnormal mucociliary transport clearance. We examined the relationship between anatomic abnormalities of ciliary ultrastructure secondary to chronic sinusitis and ciliary beat frequency (CBF) before and after middle meatal antrostomy (MMA) in rabbits. Ultrastructural abnormalities of cilia included absence of axoneme membrane, blebs of the axoneme membrane, compound cilia, and ciliary orientation. Two groups of rabbits were studied: Uninfected (group A control, n = 3) and infected (group B, n = 10); 10(8) CFU S. pneumoniae were used to infect the animals in group B after sinus ostial occlusion and chronic sinusitis developed. After 6 weeks with infection, 6 of 10 group B animals underwent MMA and were restudied 6 weeks later. Uninfected animals had mean CBF = 11.75 Hz. Animals with chronic sinusitis had mean CBF = 8.5 Hz (p < 0.05). Six weeks after MMA, mean CBF = 11.82 Hz. This was not different from control. There were significant changes in ciliary ultrastructure when uninfected and infected rabbits were compared. These changes were reversed with MMA. Changes in ciliary ultrastructure correlated significantly with changes in CBF for all animals. Abnormalities in ciliary ultrastructure may account for the abnormal mucociliary transport clearance seen in chronic sinusitis in rabbits.

Surgical management of early-stage hypopharyngeal carcinoma.

There is little consensus regarding the extent of surgical ablation that is needed to attain cure in early-stage hypopharyngeal carcinoma (HPC). To determine effective surgical management of early-stage HPC, we retrospectively reviewed all cases of stage I or stage II HPC treated at our institution between 1970 and 1992. Of 305 patients identified with HPC, 50 (16%) had stage I (N = 13) or stage II (N = 37) cancer at diagnosis. Thirty-seven of the 50 (74%) underwent surgery alone or combined with preoperative or postoperative radiotherapy (RT). Patients were divided into three surgical groups. Group 1 underwent partial pharyngectomy (N = 9), group 2 underwent total laryngectomy and partial pharyngectomy (N = 17), and group 3 underwent total laryngopharyngectomy with cervical esophagectomy and reconstruction (N = 11). Overall and disease-specific survivals were determined from Kaplan-Meier survival analysis. Disease-free 5-year survival in stage I and II HPCs was 40.1%. Univariate analysis showed a statistically significant decrease in survival for patients undergoing partial pharyngectomy when compared with those undergoing more extensive procedures (p < .03). This was confirmed with multivariate loglogistic regression analysis (p < .03) correcting for confounding variables of site and RT. These data suggest that wide resection improves disease-free survival in patients with early-stage HPC.

Differential expression of thyrotropin receptor mRNA in the porcine heart.

Thyrotropin receptor (TSHR) mRNA expression has previously been detected in human heart, suggesting a possible role for the receptor in cardiac function and pathophysiology. In the present study we examined the regional distribution of TSHR mRNA in pig heart to map potential cardiac sites of TSH action. Polyadenylated mRNA extracted from thyroid, atria, ventricles, aorta, coronary arteries, epicardial fat, and purified preparations of atrial and ventricular cardiomyocytes was subjected to reverse-transcriptase polymerase chain reaction (RT-PCR) using primers designed to amplify a 311 base pair (bp) DNA segment of the human TSHR. After reverse transcription of 100 ng mRNA, cDNA was amplified by PCR using TSHR primers and compared by electrophoresis on 2% agarose gels. Relative levels of TSHR cDNA (normalized to glyceraldehyde 3-phosphate dehydrogenase [GAPDH]) were as follows: Coronary arteries, epicardial fat > right atrium > left atrium > right ventricle, aorta > left ventricle, ventricular cardiocytes. In contrast to ventricular cardiocytes, purified atrial cardiocytes expressed levels of TSHR mRNA readily detectable with RT-PCR. These findings demonstrate that TSHR mRNA expression in porcine heart varies regionally, and furthermore suggest that areas of highest expression (coronary arteries, adipose tissue, right atrium) are potential sites for a functional or pathologic role of the TSHR.

The surgical management of laryngotracheal invasion by well-differentiated papillary thyroid carcinoma.

OBJECTIVES: To determine prognostic factors for survival in patients with invasive well-differentiated thyroid carcinoma, specifically examining laryngotracheal invasion as an independent prognostic factor, and to compare types of surgical resection to determine treatment efficacy. DESIGN: Retrospective review of patients with papillary invasive well-differentiated thyroid carcinoma surgically treated over 45 years. SETTING: Academic tertiary care medical center. PATIENTS: A total of 292 patients with invasive well-differentiated thyroid carcinoma were surgically treated between 1940 and 1995. Informed consent was obtained from all patients. Extent and location of tumor invasion were determined. Invasion of larynx and/or trachea occurred in 124 patients (41%). Patterns of invasion and techniques of surgical resection were evaluated. INTERVENTION: Types of surgical resection performed: complete tumor removal (n = 34), "shave" excision (n = 75), and incomplete tumor excision (n = 15). MAIN OUTCOME MEASURES: Cox regression analysis was used to determine significance of prognostic factors for survival; Kaplan-Meier curves were used to evaluate survival. A P value of less than .05 was statistically significant. RESULTS: Patterns of invasion by thyroid carcinoma included direct spread through laryngeal framework into paraglottic space or spread from involved lymph nodes. Laryngotracheal invasion was a significant, independent, prognostic factor for survival (P < .05). Significance was reached when types of resection were compared for all patients (P < .05) as well as for those with laryngotracheal invasion alone (P < .001). CONCLUSIONS: Laryngotracheal invasion was a significant independent prognostic factor for survival (P < .05). When types of surgical resection were compared, the survival rates of patients who underwent shave excision were not different from those of patients who underwent radical tumor resection if gross tumor did not remain (P > .05). Tumors with minimal invasion may be treated by shaving tumor from the aerodigestive tract. Gross intraluminal involvement should be resected completely to prevent complications.

Nasofrontal duct reconstruction with silicone rubber sheeting for inflammatory frontal sinus disease: analysis of 164 cases.

The authors reviewed their experience in reconstructing the nasofrontal duct with thin silicone rubber sheeting in patients who had chronic inflammatory frontal sinus disease. The 164 patients were divided into four groups. The patients in group 1 had the traditional modified Lynch procedure, while those in group 2 had certain technical variations of the modified Lynch operation. The patients in the other two groups had major technical variations: those in group 3 had a primary osteoplastic flap approach and those in group 4 had revisions of failed osteoplastic flap with fat obliteration operations. Surgical indications included mucopyocele (87 patients), chronic frontal sinusitis (71 patients), osteomyelitis (2 patients), acute sinusitis (2 patients), and subacute sinusitis (2 patients). Follow-up averaged 47 months. At their last clinic visit, 157 patients (96%) were asymptomatic. Forty-six revision procedures were performed in 30 patients (18% of initial cases). There were no major complications. Nasofrontal duct reconstruction using thin silicone rubber sheeting is technically straightforward, safe, and effective.

Acoustic measurement of subglottic stenosis.

A device that determines cross-sectional area (CSA) of the airway by acoustic reflections (Hood, Inc) was used to measure subglottic area. Airway models were made from Plexiglas rings with known internal dimensions similar to clinically encountered stenoses of various lengths and diameters. Acoustic measurements of airway area were made and compared to actual CSA. There is a strong correlation between CSA measured acoustically and the actual area of simulated stenoses. However, when the CSA of the stenosis was < 0.64 cm2, the signal was impaired, resulting in overestimation of the stenotic CSA. In simulated stenoses with a CSA of < 0.38 cm2, acoustic measurement of the CSA beyond the stenotic segment was unreliable. Determination of the origin of stenosis was accurate with this method. The CSA of cadaver airways was also measured acoustically. The CSA 2.0 cm below the glottis of normal airways in males ranged from 1.28 to 2.74 cm2 and in females 0.87 to 1.43 cm2, with means of 2.16 and 1.09 cm2. It appears that acoustic measurement of CSA of subglottic stenosis is a feasible clinical technique that yields dimensions of the airway in situations in which direct measurements are impossible. It was suggested that this technique be used for assessment of subglottic stenosis and evaluation of the efficacy of treatment of subglottic stenosis.

Signal transduction mechanisms in substance P-mediated ciliostimulation.

Substance P is a neuropeptide released by afferent neurons in the respiratory tract during inflammatory reactions. It produces effects on blood vessels, bronchial smooth muscle, nasal glands, and respiratory cilia. We studied the in vitro effect of substance P on the ciliary beat frequency of human adenoid explants and its mechanism of action. Substance P was added to cultured adenoid at concentrations of 10(-10), 10(-8), 10(-6), and 10(-4) mol/L. Ciliary beat frequency was determined with phase-contrast microscopy and microphotometry. Substance P increased ciliary beat frequency a maximum of 11.9% +/- 3.8% (p < 0.01). Diclofenac (10(-6) mol/L) significantly blocked the ciliostimulatory effects of SP (p < 0.022), indicating that prostaglandin synthesis is an intermediate step in the action of substance P on ciliary beat frequency. The L-arginine analogs, NG-nitro-L-arginine methyl ester and NG-monomethyl-L-arginine, inhibit nitric oxide synthesis from L-arginine. L-Arginine analogs (10(-4) to 10(-2) mol/L) inhibited the effect of substance P (p < 0.02 at the higher concentration). This inhibition was reversed by adding L-arginine, demonstrating that nitric oxide production is a required step in substance P-induced ciliostimulation. Substance P stimulates ciliary activity in human nasal mucosa as a result of secondary production and release of endogenous prostaglandins and nitric oxide. It is likely that inflammatory disease processes that stimulate release of substance P and subsequent prostaglandin and nitric oxide production modify mucociliary transport. Pharmacologic modification of substance P and its second messengers may eventually permit regulation of this important defense mechanism and control of neurogenic inflammation.

In situ choriocarcinoma arising in partial hydatidiform mole: implications for the risk of persistent trophoblastic disease.

The risk of persistent trophoblastic disease following partial hydatidiform mole is controversial. In spite of claims that 4 to 11% of cases require chemotherapy, there is a paucity of affected patients in the literature. A critical review of those patients suggests an alternative or unproven diagnosis in the majority. An instance of placental in situ choriocarcinoma arising in a partial mole is reported. Because in situ choriocarcinoma may represent the incipient lesion in the majority of the one-third of cases of gestational choriocarcinoma that follow a normal pregnancy, we postulate that the presence of the in situ lesion in a partial mole supports the view that the risk of persistent trophoblastic disease may be no greater after partial mole than after a normal gestation.

Changes in the tonotopic map of the dorsal cochlear nucleus following induction of cochlear lesions by exposure to intense sound.

Hamsters were exposed to intense tones (10 kHz) at levels and durations sufficient to cause stereocilia lesions. The purpose was to determine how the tonotopic map of the dorsal cochlear nucleus (DCN) readjusts to loss of receptor sensitivity. Neural population thresholds and tonotopic organization was mapped over the surface of the DCN in normal unexposed animals and those showing tone-induced lesions. The results indicate that cochlear lesions characterized mainly by loss of stereocilia in a restricted portion of the organ of Corti cause changes in a corresponding region of the tonotopic map which reflect primarily changes in the shape and thresholds of neural tuning curves. In many cases the center of the lesion was represented in the DCN as a distinct characteristic frequency (CF) gap in the tonotopic map in which responses were either extremely weak or absent. In almost all cases the map area representing the center of the lesion was bordered by an expanded region of near-constant CF, a feature superficially suggestive of map reorganization. These expanded map areas had abnormal tip thresholds and showed other features suggesting that their CFs had been shifted downward by distortion and deterioration of their original tips. Such changes in neural tuning are similar to those observed by others in the auditory nerve following acoustic trauma, and thus would seem to have a peripheral origin. Thus, it is not necessary to invoke plastic changes in the cochlear nucleus to explain the changes observed in the tonotopic map.

Pharmaceutical and biopharmaceutical quality of a sustained release carbamazepine preparation: a contribution to quality assurance.

Side effects observed during treatment with non-sustained release carbamazepine preparations are often due to the steep rise in plasma carbamazepine concentrations. To maintain plasma levels with only minor fluctuations between narrow limits, sustained release formulations have been developed which release the active constituent at a constant rate which is not too high. Bioavailability tests (single dosage, crossover design) and several investigations into the dissolution profile were carried out on three test batches of a sustained release carbamazepine preparation (Timonil 300 retard). The aim was a release model which, in the context of quality assurance, would not only facilitate reliable statements with regard to batch conformity, but would also be validated in respect of pharmacokinetic parameters such as rate of absorption and bioavailability. Correlations between mean dissolution times (MDT) and mean absorption times (MAT) at level B were found [Skelly et al. 1990]. A dissolution test differing from the pharmacopoeial tests was selected, which permitted the assessment of both batch conformity and biopharmaceutical batch quality.

Investigations into the relative bioavailability of carbamazepine after single oral administration of three test batches of a carbamazepine-containing sustained release formulation in healthy subjects.

A bioavailability study with three test batches of a sustained release formulation of carbamazepine, which differed only in their in vitro dissolution profiles, was performed in 18 healthy subjects to compare the respective plasma concentration profiles and to determine the relative bioavailability of carbamazepine (CBZ). This investigation was designed to examine the extent to which these differences in dissolution properties can be determined from the results of in vivo tests. The randomized, single-dose, crossover study comprised three experimental periods, separated by washout intervals of three weeks' duration. A sensitive, validated HPLC method was used for the analysis of serum carbamazepine concentrations. Bioequivalence was only accepted if the 90% confidence interval (parametric or nonparametric) for the quotients of the mean values of the variables for each test and reference preparation was completely within the bioequivalence range. For this calculation, all three test preparations were compared with one another. The following relative bioavailability values were obtained: A/B: AUC = 87% (83%, 92%), MRT = 106% (103%, 109%), HVD = 109% (105%, 113%). C/B: AUC = 106% (101%, 110%), MRT = 98% (96%, 99%), HVD = 87% (82%, 91%). C/A: AUC = 124% (117%, 130%), MRT = 92% (89%, 94%), HVD = 79% (74%, 84%). There was a positive correlation between the in vitro dissolution rates of the different test batches and the respective degree of carbamazepine absorption as determined in vivo, while an inverse correlation existed between the in vitro dissolution rates on one side and the mean residence time (MRT) as well as the half value duration (HVD) on the other.(ABSTRACT TRUNCATED AT 250 WORDS)