Dyspnea resulting from fibromyalgia

Two patients with chronic, severe, episodic dyspnea underwent prolonged, extensive, and invasive evaluations without a diagnosis being made. Both were subsequently diagnosed with fibromyalgia, and therapy directed at this condition resulted in resolution of their symptoms. Fibromyalgia is rarely included in the differential diagnosis of dyspnea, and timely diagnosis and treatment may be delayed. However, this condition must be considered because it can only be established by seeking the appropriate history and physical findings.     

Comparison of single- and two-layer Percoll separation for selection of motile spermatozoa

OBJECTIVE: Sperm recovery using a single-layer Percoll procedure is significantly better than using the swim-up technique for infertile men and patients with normal sperm characteristics; however, in normal men results have been contradictory. Some studies have shown further improvement in semen quality with multiple layers. Therefore, this study compared the effect of single-layer and two-layer Percoll procedures on sperm characteristics of normozoospermic men. METHODS: Semen specimens from 10 normal donors were processed by layering 1 mL of the liquefied ejaculate on a single layer of 80% Percoll or on a two-layer (47% and 90%) Percoll gradient. Computer-assisted semen analysis was done to examine total motile sperm, percentage of recovery of motile cells, percent motility, curvilinear velocity, linearity, and amplitude of lateral head displacement. Each specimen was evaluated by the hypo-osmotic swelling (HOS) test, bovine cervical mucus penetration test, viability (eosin-nigrosin stain), and sperm morphology (World Health Organization and Kruger's strict criteria). RESULTS: Specimens processed with the two-layer Percoll procedure had significantly better recovery of spermatozoa, and significantly better percentage motility, linearity, amplitude of lateral head displacement, percentage tail swelling, and percentage viability than those separated on single-layer Percoll. Results for sperm morphology using WHO and Kruger's criteria were similar between the two methods (P = 0.92 for both sets of criteria). CONCLUSIONS: In normozoospermic men, the two-layer Percoll separation procedure significantly improves semen characteristics compared with separation on a single layer.     

Potent cyano and carboxamido side-chain analogues of 1', 1'-dimethyl-delta8-tetrahydrocannabinol

The synthesis and pharmacological profile of several cyano (1a-e) and carboxamido (2a-h) side-chain-substituted analogues of 1', 1'-dimethyl-Delta8-THC are described. Commercially available cyano compound 3 was transformed to the resorcinol 6 in a three-step sequence. Condensation of 6 with p-menth-2-ene-1,8-diol formed the THC 7a which, with sodium cyanide/DMSO, gave 1b. Protection of the phenol in 7a as the MOM derivative provided the common intermediate 8 for the synthesis of 1a,c,e. Compound 1d was also synthesized from 7a via the aldehyde 9a. Base hydrolysis of 1b gave the acid 10 which, via its acid chloride and subsequent treatment with the appropriate amine, formed the target compounds 2a-h. The pharmacological profile indicated that the cyano analogues 1a-e had very high CB1 binding affinity (0.36-13 nM) and high in vivo potency as agonists. Two analogues (1a,b) had extremely high potency in the mouse tetrad tests. The dimethylcarboxamido analogue 2a showed a similar profile to 1a,b. The high potency was also retained in analogue 2c. In contrast the sulfonamide analogue 2d was unique as it had greater affinity than Delta9-THC, yet it was practically devoid of agonist effects. This study suggests that the incorporation of a cyano or an amide substituent in the side chain of Delta8-THC-DMH can enhance potency and can also lead to compounds with a unique profile which have high binding affinity and are practically devoid of agonist effects.     

Open compared with laparoscopic approach to Burch colposuspension: a cost analysis

OBJECTIVE: To compare postoperative course and hospital charges of an open versus laparoscopic approach to Burch colposuspension for the treatment of genuine stress urinary incontinence. METHODS: A retrospective chart review was performed to identify all patients undergoing open or laparoscopic Burch colposuspension by the same surgeon over a 2-year period. Patients undergoing additional surgical procedures at the time of colposuspension were excluded from the study. Twenty-one patients underwent open Burch colposuspension and 17 patients underwent laparoscopic colposuspension. Demographic data including age, parity, height, and weight were collected for each group. Both groups also were compared with regard to operative time, operating room charges, estimated blood loss, intraoperative complications, change in postoperative hematocrit, time required to resume normal voiding, length of hospital stay, and total hospital charges. RESULTS: The laparoscopic colposuspension group had significantly longer operative times (110 versus 66 minutes, P < .01) and increased operating room charges ($3479 versus $2138, P < .001). There was no statistical difference in estimated blood loss or change in postoperative hematocrit between the two groups. No major intraoperative complications occurred in either group. Mean length of hospital stay was 1.3 days for the laparoscopic group and 2.1 days for the open group (P < .005). However, total hospital charges for the laparoscopic group were significantly higher ($4960 versus $4079, P < .01). CONCLUSION: Laparoscopic colposuspension has been described as a minimally invasive, cost-effective technique for the surgical correction of stress urinary incontinence. Although the laparoscopic approach was found to be associated with a reduction in length of hospital stay, it had significantly higher total hospital charges than the traditional open approach because of expenses associated with increased operative time and use of laparoscopic equipment.     

Effect of different albuterol dosing regimens in the treatment of acute exacerbation of chronic obstructive pulmonary disease

There is substantial evidence for an activation of the sympathetic nervous system in man as well as in genetic models of hypertension, such as the spontaneously hypertensive rat (SHR), but we are only beginning to understand the central mechanisms that generate changes in sympathetic activity and elevate blood pressure (BP). Significant recent advances have been made in defining the neural pathways involved in BP regulation and in identifying the neurotransmitters these neurones utilise. In this overview, we describe the neural pathways within the medulla oblongata and spinal cord that participate in BP control and examine the role of amino acid neurotransmitters within these pathways. We demonstrate how alterations in these pathways explain the sympathetic activation observed in the SHR and contribute to hypertension in this model. Lastly, we examine the application of modern molecular biological approaches to further our understanding of the neural regulation of the circulation. In these studies, we used the administration of antisense oligonucleotides to interrupt gene expression.     

Chronic electrical stimulation of the auditory nerve at high stimulus rates: a physiological and histopathological study

The ubiquitous distribution of peroxisomes and the identification of a number of inherited diseases associated with peroxisomal dysfunction indicate that peroxisomes play an essential part in cellular metabolism. Some of the most important metabolic functions of peroxisomes include the synthesis of plasmalogens, bile acids, cholesterol and dolichol, and the oxidation of fatty acids (very long chain fatty acids > C22, branched chain fatty acids (e.g. phytanic acid), dicarboxylic acids, unsaturated fatty acids, prostaglandins, pipecolic acid and glutaric acid). Peroxisomes are also responsible for the metabolism of purines, polyamines, amino acids, glyoxylate and reactive oxygen species (e.g. O-2 and H2O2). Peroxisomal diseases result from the dysfunction of one or more peroxisomal metabolic functions, the majority of which manifest as neurological abnormalities. The quantitation of peroxisomal metabolic functions (e.g. levels of specific metabolites and/or enzyme activity) has become the basis of clinical diagnosis of diseases associated with the organelle. The study of peroxisomal diseases has also contributed towards the further elucidation of a number of metabolic functions of peroxisomes.     

Cell interactions with collagen matrices in vivo and in vitro depend on phosphatidylinositol 3-kinase and free cytoplasmic calcium

Itraconazole is a new triazole compound with a broad spectrum of activity against a number of fungal pathogens, including Aspergillus species. The drug is being used increasingly as prophylaxis in patients with immunodepression. Itraconazole is highly lipophilic and only ionised at low pH. The absolute availability of capsules in healthy volunteers under fasting conditions is about 55% and is increased after a meal. Itraconazole is 99.8% bound to human plasma proteins and its apparent volume of distribution is about 11 L/kg. The drug is extensively metabolised by the liver. Among the metabolites, hydroxy-itraconazole is of particular interest because its antifungal activity measured in vitro is similar to that of the parent drug and its plasma concentration is 2 to 3 times higher than that of itraconazole. Mean total itraconazole blood clearance determined in healthy volunteers following a single intravenous infusion was 39.6 L/h. After a single oral dose, the terminal elimination half-life of itraconazole is about 24 hours. The drug exhibits a dose-dependent pharmacokinetic behaviour. Renal failure does not affect the pharmacokinetic properties of itraconazole; however, little is known about the effects of hepatic insufficiency. In immunocompromised patients the absorption of itraconazole is affected by gastrointestinal disorders caused by diseases and cytotoxic chemotherapy. The pharmacokinetics of itraconazole may be significantly altered when the drug is coadministered with certain other agents. Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A4 and, thus, can also considerably change the pharmacokinetics of other drugs. Such changes may have clinically relevant consequences. Itraconazole appears to be well tolerated. Gastrointestinal disturbances and dizziness are the most frequently reported adverse effects. Clinical studies in patients with haemotological malignancies suggest that plasma concentrations [measured by high performance liquid chromatography (HPLC)] > or = 250 micrograms/L itraconazole, or 750 to 1000 micrograms/L for itraconazole plus hydroxy-itraconazole, are required for effective prophylactic antifungal activity. It seems that a curative effect may be enhanced by ensuring that itraconazole plasma concentrations exceed 500 micrograms/L. The marked intra- and inter-patient variability in the pharmacokinetics of the drug, and the fact that it is impossible to predict steady-state plasma concentrations from the initial dosage are major factors obscuring any clear relationship between dose and plasma concentrations and clinical efficacy. Thus, in patients with life-threatening fungal infections treated with itraconazole drug, plasma concentrations should be regularly monitored to ensure sufficient drug exposure for antifungal activity.     

Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study

BACKGROUND: Whether Parkinson disease (PD) and dementia with Lewy bodies (DLB) represent 2 distinct nosologic entities or are diverse phenotypes of Lewy body disease is subject to debate. OBJECTIVES: To determine the accuracy of the diagnoses of Lewy body disease, PD, and DLB by validating the clinical diagnoses of 6 neurologists with the neuropathologic findings and to identify early predictors of the diagnoses. METHODS: Six raters who were unaware of the neuropathologic diagnoses analyzed 105 clinical vignettes corresponding to 29 cases of Lewy body disease (post hoc analysis of 15 patients with PD and 14 with DLB) and 76 patients without PD or DLB whose cases were confirmed through autopsy findings. MAIN OUTCOME MEASURES: Sensitivity and positive predictive value (PPV) were chosen as validity measures and the K statistic as a reliability measure. RESULTS: Interrater reliability for the diagnoses of Lewy body disease and PD was moderate for the first visit and substantial for the last, whereas agreement for diagnosis of DLB was fair for the first visit and slight for the last. Median sensitivity for diagnosis of Lewy body disease was 56.9% for the first visit and 67.2% for the last; median PPV was 60.0% and 77.4%, respectively. Median sensitivity for the diagnosis of PD was 73.3% for the first visit and 80.0% for the last; median PPV was 45.9% and 64.1%, respectively. Median sensitivity for the diagnosis of DLB was 17.8% for the first visit and 28.6% for the last; median PPV was 75.0% for the first visit and 55.8% for the last. The raters' results were similar to those of the primary neurologists. Several features differentiated PD from DLB, predicted each disorder, and could be used as clinical pointers. CONCLUSIONS: The low PPV with relatively high sensitivity for the diagnosis of PD suggests overdiagnosis. Conversely, the extremely low sensitivity for the diagnosis of DLB suggests underdiagnosis. Although the case mix included in the study may not reflect the frequency of these disorders in practice, limiting the clinical applicability of the validity measures, the raters' results were similar to those of the primary neurologists who were not exposed to such limitations. Overall, our study confirms features suggested to predict these disorders, except for the early presence of postural imbalance, which is not indicative of either disorder.     

Gastroesophageal reflux disease versus Helicobacter pylori infection as the cause of gastric carditis

To explore the potential contributions of gastroesophageal reflux disease, as opposed to Helicobacter pylori infection, to the development of gastric carditis, we evaluated gastric carditis (using the criteria of the updated Sydney system for the classification of gastritis), clinical and morphologic features of esophagitis, and H. pylori infection (evaluation of Steiner stains) in biopsy specimens from the gastroesophageal squamocolumnar junction. We correlated clinical, endoscopic, and histologic features in an unselected group of 116 patients. Some degree of carditis was found in 107 (92%) of the patients. The mean age of the patients increased with increasing severity of carditis (P < .05). The various groups of patients with different degrees of carditis did not differ significantly in sex ratio, ethnic background, presence of obesity, percentage having symptoms of gastroesophageal reflux disease (such as heartburn, regurgitation, dysphagia, or odynophagia), endoscopic evidence of esophagitis and columnar epithelium in the distal esophagus, or histologic evidence of active esophagitis. The presence, however, of active gastritis and H. pylori infection in the distal stomach and/or in the cardia was significantly associated with carditis. In patients without carditis, H. pylori was not detected in any cardiac or distal gastric biopsy specimen. In contrast, H. pylori was demonstrated in gastric tissue samples (either from the cardia or distally) of patients with carditis, with the prevalence rate increasing with greater degrees of cardiac inflammation. The H. pylori prevalence rate was 12% in the group with mild carditis, 40% in those with moderate carditis, and 57% in patients with marked carditis (P = .0001). In summary, carditis is commonly found in patients with symptoms related to upper gastrointestinal diseases. From analysis of our study cohort, we concluded that carditis was significantly associated with H. pylori infection and active gastritis but not with symptoms or signs of gastroesophageal reflux disease. These findings suggest that carditis with histologic features similar to those of gastritis in the distal stomach was a sequel of H. pylori infection and represented a part of an H. pylori--associated gastric inflammation.     

Regulation of ganglioside metabolism by phosphorylation and dephosphorylation

Cell differentiation is frequently accompanied by alterations in the composition of gangliosides in the plasma membrane resulting from a regulation of the enzyme activities involved. The regulation of CMP-NeuAc:GM1 alpha2-3-sialyltransferase (ST-IV) and UDP-GalNAc:GM3 N-acetylgalactosaminyltransferase (Gal-NAc-T) by the degree of enzyme phosphorylation was analyzed by determination of the enzyme activity on incubation of NG108-15 cells with various protein phosphatase inhibitors (okadaic acid and orthovanadate) or protein kinase activators (phorbol ester and forskolin). Incubation with okadaic acid, but not with orthovanadate, inhibited the ST-IV activity to 45% of that of control cells with t(1/2) = 60 min for the inactivation reaction. This indicates a rapid hyperphosphorylation of ST-IV due to the inhibition of a serine/threonine-specific phosphatase. A similar rate of inactivation was found on stimulation of protein kinase C with phorbol ester. In contrast to ST-IV, the activity of GalNAc-T was increased on stimulation of intracellular phosphorylation systems. The fastest activation of GalNAc-T was achieved with forskolin, yielding up to 160% of the initial activity within 30 min of effector incubation. Up-regulation of GalNAc-T in conjunction with down-regulation of ST-IV by stimulation of phosphorylation is suggested to serve as a physiological mechanism to increase the concentration of GM1, which was found to be elevated in correlation with the cell density. This assumption was corroborated by metabolic labeling studies with radioactive ganglioside precursors indicating an enhancement of the relative amount of a-series gangliosides subsequent to GM3 on phosphorylation stimulation. In particular, the biosynthesis of GM1 was specifically elevated within 2 h of incubation with forskolin. We conclude from the overall data that the ganglioside composition during the cell differentiation of NG108-15 cells can be specifically regulated by both protein kinase A- and protein kinase C-related phosphorylation systems.