Functional dyspepsia and nonerosive reflux disease: clinical interactions and their implications

Functional dyspepsia or nonulcer dyspepsia, and nonerosive reflux disease (NERD) or endoscopy-negative reflux disease, are common reasons for referral to a gastroenterologist. Although there is much confusion with regard to definition, recent research would suggest that these 2 conditions are linked and may represent components in the spectrum of the same disease entity, in terms of both symptoms and pathophysiology. Several theories have been proposed regarding the etiology of these disorders, including acid exposure, visceral hypersensitivity, impaired fundal accommodation, delayed gastric emptying, and Helicobacter pylori infection.     

Carotid Doppler evaluation in cerebrovascular disease.

The Doppler technique has proven to be a useful noninvasive technique for evaluating the patency of the carotid artery in patients at risk of stroke. The data obtained from 246 carotid Doppler examinations were compared with the angiographic findings in the same patients. The sensitivity, specificity and accuracy were high when the degree of stenosis was greater than 50%, but occlusions were less reliably detected, with 8 (33%) of the 24 being misdiagnosed as high-grade stenoses. Carotid Doppler evaluation guides and accelerates decisions regarding further investigations, such as cerebral angiography. It helps one decide whether a neck bruit is of arterial origin and aids assessment following cerebrovascular surgery. It is not a substitute for cerebral angiography because it poorly visualizes both the posterior and the intracranial circulations and cannot accurately detect low-grade (less than 50%) stenoses or ulcerated arterial plaques. Detection of stenosis in a carotid artery in an otherwise uncertain case is an indication for cerebral angiography, so the Doppler technique will probably increase the number of angiograms performed. However, this technique is also useful in follow-up, being without hazard, and should, therefore, reduce the likelihood of unnecessary angiographic examinations.     

Multidrug efflux pumps in Staphylococcus aureus and their clinical implications

Antibiotic resistance is rapidly spreading among bacteria such as Staphylococcus aureus, an opportunistic bacterial pathogen that causes a variety of diseases in humans. For the last two decades, bacterial multidrug efflux pumps have drawn attention due to their potential association with clinical multidrug resistance. Numerous researchers have demonstrated efflux-mediated resistance in vitro and in vivo and found novel multidrug transporters using advanced genomic information about bacteria. This article aims to provide a concise summary of multidrug efflux pumps and their important clinical implications, focusing on recent findings concerning S. aureus efflux pumps.     

Epidemiologic features of cerebrovascular disease in Manitoba: incidence by age,sex and residence,with etiologic implications.

To determine the incidence of and risk factors in cerebrovascular disease in Manitoba, all 1367 new cases in defined areas (population, 660 391) in an 18-month period were studied. Pertinent data were collected from hospital records, death certificates and autopsy reports. The annual incidence of cerebrovascular disease in these areas was 138/100 000 and the incidence was generally higher in men than in women. The incidence of cerebral infarction (INF) and that of hemorrhage (HGE) were similar in men and women less than 50 years old; thereafter the incidence of INF increased faster with age than did that of HGE, the disparity being greater in men than in women, whereas the incidence of HGE increased at similar rates in the two sexes. The incidence of INF was significantly greater in men than in women in urban areas, and in men it was greater in urban than in rural areas. Elevated concentrations of serum lipids and smoking are implicated as risk factors in INF, and hypertension as a risk factor in HGE.     

Mechanisms of adenosine-induced cytotoxicity and their clinical and physiological implications

Extracellular ATP (ATPo) and adenosine are cytotoxic to several cancer cell lines, suggesting their potential use for anticancer therapy. Adenosine causes cytotoxicity, either when added exogenously or when generated from ATPo hydrolysis, via mechanisms which are not mutually exclusive and which involve, adenosine receptor activation, pyrimidine starvation and/or increases in intracellular S-adenosylhomocysteine: S-adenosylmethionine ratio. Given that adenosine also appears to protect against cytotoxicity via mechanisms including immunity against damage by oxygen free radicals, an understanding of the contribution of adenosine to ATPo-induced cytotoxicity is thus crucial, when considering any potential therapeutic use for these compounds. However, such an understanding has been largely hindered by the fact that many studies have not focused enough on the possibility that both ATPo and adenosine may mediate cytotoxicity in the same system. Such studies can benefit from use a range of ATPo concentrations when assessing the contribution of adenosine to ATPo-induced cytotoxicity. Whilst future molecular and pharmacological studies are needed to establish the nature of the cytotoxic adenosine receptor, it is possible that more than just one adenosine receptor type is involved and that the cytotoxic receptor(s) type is more likely to have a low affinity for adenosine. Activation of the adenosine receptor(s) would thus lead to cytotoxicity only at relatively high adenosine concentrations, while lower adenosine concentrations mediate non-cytotoxic physiological effects.     

Phenotype/genotype correlations in Gaucher disease type I: clinical and therapeutic implications.

Gaucher disease is the most frequent lysosomal storage disease and the most prevalent genetic disease among Ashkenazi Jews. Gaucher disease type 1 is characterized by marked variability of the phenotype and by the absence of neuronopathic involvement. To test the hypothesis that this phenotypic variability was due to genetic compounds of several different mutant alleles, 161 symptomatic patients with Gaucher disease type 1 (> 90% Ashkenazi Jewish) were analyzed for clinical involvement, and their genotypes were determined. Qualitative and quantitative measures of disease involvement included age at onset of the disease manifestations, hepatic and splenic volumes, age at splenectomy, and severity of bony disease. Highly statistically significant differences (P < .005) were found in each clinical parameter in patients with the N370S/N370S genotype compared with those patients with the N370S/84GG, N370S/L444P, and N370S/? genotypes. The symptomatic N370S homozygotes had onset of their disease two to three decades later than patients with the other genotypes. In addition, patients with the latter genotypes have much more severely involved livers, spleens, and bones and had a higher incidence of splenectomy at an earlier age. These predictive genotype analyses provide the basis for genetic care delivery and therapeutic recommendations in patients affected with Gaucher disease type 1.     

Unraveling monogenic channelopathies and their implications for complex polygenic disease

Ion channels are a large family of >400 related proteins representing >1% of our genetic endowment; however, ion-channel diseases reflect a relatively new category of inborn error. They were first recognized in 1989, with the discovery of cystic fibrosis transmembrane conductance regulator, and rapidly advanced as positional and functional studies converged in the dissection of components of the action potential of excitable tissues. Although it remains true that diseases of excitable tissue still most clearly illustrate this family of disease, ion-channel disorders now cover the gamut of medical disciplines, causing significant pathology in virtually every organ system, producing a surprising range of often unanticipated symptoms, and providing valuable targets for pharmacological intervention. Many of the features shared among the monogenic ion-channel diseases provide a general framework for formulating a foundation for considering their intrinsically promising role in polygenic disease. Since an increasingly important approach to the identification of genes underlying polygenic disease is to identify "functional candidates" within a critical region and to test their disease association, it becomes increasingly important to appreciate how these ion-channel mechanisms can be implicated in pathophysiology.     

UDPglucose dehydrogenase. Kinetics and their mechanistic implications.

Initial velocity and product inhibition studies were carried out on UDP-glucose dehydrogenase (UDPglucose: NAD+ 6-oxidoreductase, EC 1.1.1.22) from beef liver to determine if the kinetics of the reaction are compatible with the established mechanism. An intersecting initial velocity pattern was observed with NAD+ as the variable substrate and UDPG as the changing fixed substrate. UDPglucuronic acid gave competitive inhibition of UDPG and non-competitive inhibition of NAD+. Inhibition by NADH gave complex patterns.Lineweaver-Burk plots of 1/upsilon versus 1/NAD+ at varied levels of NADH gave highly non-linear curves. At levels of NAD+ below 0.05 mM, non-competitive inhibition patterns were observed giving parabolic curves. Extrapolation to saturation with NAD+ showed NADH gave linear uncompetitive inhibition of UDPG if NAD+ was saturating. However, at levels of NAD+ above 0.10 mM, NADH became a competitive inhibitor of NAD+ (parabolic curves) and when NAD+ was saturating NADH gave no inhibition of UDPG. NADH was non-competitive versus UDPG when NAD+ was not saturating. These results are compatible with a mechanism in which UDPG binds first, followed by NAD+, which is reduced and released. A second mol of NAD+ is then bound, reduced, and released. The irreversible step in the reaction must occur after the release of the second mol of NADH but before the release of UDPglucuronic acid. This is apparently caused by the hydrolysis of a thiol ester between UDPglucoronic acid and the essential thiol group of the enzyme. Examination of rate equations indicated that this hydrolysis is the rate-limiting step in the overall reaction. The discontinuity in the velocities observed at high NAD+ concentrations is apparently caused by the binding of NAD+ in the active site after the release of the second mol of NADH, eliminating the NADH inhibition when NAD+ becomes saturating.     

Progressive lymphangiomatosis and Gorham's disease: case report and clinical implications

Lymphangiomatosis is a rare proliferative disorder of the lymphatic system. The etiology is unknown, rendering it difficult to manage. This case report of lymphangiomatosis with features of Gorham's disease reveals the progressive and unexpected nature of the condition. It highlights the need for further research into the pathophysiology and management of lymphangiomatosis as current treatment options are limited.     

Some new pitch paradoxes and their implications.

This paper explores two new paradoxical sound patterns. The tones used to produce these patterns consist of six octave-related harmonics, whose amplitudes are scaled by a bell-shaped spectral envelope; these tones are clearly defined in terms of pitch class (C, C#, D, and so on) but are poorly defined in terms of height. One pattern consists of two tones that are separated by a half-octave. It is heard as ascending when played in one key, yet as descending when played in a different key. Further, when the pattern is played in any one key it is heard as ascending by some listeners but as descending by others (the tritone paradox). Another pattern that consists of simultaneous pairs of tones displays related properties (the semitone paradox). It is shown that the way the tritone paradox is perceived correlates with the speech characteristics of the listener, including his or her linguistic dialect. The findings suggest that the same, culturally acquired representation of pitch classes influences both speech production and also perception of this musical pattern.