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The scrambled actin I gene in Uroleptus pisces.

The micronuclear gene encoding actin I in Uroleptus pisces occurs in two segments. Segment I contains 638 bp divided into six macronuclear destined subsegments, or MDSs, by five internal eliminated segments, or IESs. The MDSs in segment 1 are in the scrambled disorder, 1-2-4-8-6-15, with MDSs 8 and 6 inverted. Segment II contains 2452 bp divided into ten MDSs by nine IESs in the scrambled disorder, 3-5-7-10-13-12-9-14-16-11, with MDSs 12, 9, and 11 inverted. Extensive attempts by polymerase chain reaction to connect the two segments failed. We conclude that the two segments are separated by a very long IES or are in different loci. The pattern of the 16 scrambled MDSs is entirely different from the scrambled pattern observed for the actin I gene in six other stichotrichs. We conclude that the actin I gene became scrambled on two separate occasions during stichotrich evolution: once in the lineage leading to the group of six stichotrichs, which includes, among others, Sterkiella species and Stylonychia lemnae, and once in the lineage leading to Uroleptus pisces. Repeated sequence pairs (pointers) of three to 14 bases at the ends of MDSs appear to be essential for correct splicing of MDSs during macronuclear development. However, the micronuclear actin gene also contains 40 matches of eight or more bases between IESs and MDSs that do not function as pointers. To prevent these ectopic repeats from causing improper processing of the micronuclear gene appears to demand a template of DNA or RNA from the old macronucleus to guide splicing of MDSs in the orthodox order.

Actins↗

Enteryx Implant for Gastroesophageal Reflux Disease.

Although pharmacologic therapy is safe and effective for gastroesophageal reflux disease (GERD), patients requiring chronic drug treatment often seek alternatives. Surgical alternatives to chronic drug treatment are associated with increased morbidity and long-term failure rates in more than 50% of surgically treated patients. Newer endoluminal therapies using modifications of standard endoscopy techniques are under evaluation as alternatives to chronic drug treatment or surgical intervention for GERD. Appropriate patient selection is KEY. Patients considered for any endoluminal therapy should have well documented GERD and demonstrated appropriate and successful response to medical therapy with a proton pump inhibitor (PPI). The Enteryx implant is an injectable biocompatible polymer approved by the US Food and Drug Administration for the management of GERD symptoms. Clinical trial data indicate that the Enteryx procedure is a safe and effective GERD treatment that manages symptoms of GERD and addresses the underlying anatomic and functional aspects of the disorder. Multicenter clinical trials have shown that the Enteryx procedure safely and effectively eliminates or significantly reduces PPI use in approximately 84% of patients at 1 year and 72% of patients at two years. The risk-benefit profile of this procedure and alternative treatment options should be carefully evaluated for each patient considered a candidate for Enteryx and all endoluminal therapies. Randomized-controlled studies comparing the Enteryx procedure to placebo and cost-effective analyses comparing treatment options will further define the use of the Enteryx implant in patients with GERD.

Journal Article↗

A methodological critique of the current status of eye movement desensitization (EMD).

Eye Movement Desensitization (EMD) has been recently advocated as a rapid treatment for the elimination of traumatic memories responsible for the maintenance of a number of anxiety disorders and their clinical correlates. Despite a limited conceptual framework, EMD has attracted considerable interest among clinicians and researchers. The popularity and interest generated by EMD will likely result in wide usage. We present a methodological critique of it with reference to assessment, treatment outcome, and treatment process. We also provide guidelines for judging the methodological adequacy of research on EMD and suggest intensive research to assess effectiveness, treatment components, and comparisons with other procedures.

Anxiety Disorders↗

Orthotopic liver transplantation for familial amyloidotic polyneuropathy: a pathological study.

Familial amyloidotic polyneuropathy (FAP), a hereditary form of systemic amyloidosis with clinically significant neuropathy and cardiomyopathy, is caused by a genetic defect of the transthyretin gene, which is mostly synthesized in the liver. Orthotopic liver transplantation (OLT) is thought to eliminate the amyloidogenic protein and currently is the only definitive treatment for this disorder. The aim of this study was to define the distribution and extent of amyloid deposition in tissues from these patients and evaluate the suitability of the resected FAP livers for transplantation into non-FAP patients. Surgical specimens from 14 patients removed at the time of OLT and autopsy tissues from 3 of the 14 were examined histologically using hematoxylin and eosin and Congo red-stained sections. The extent of amyloid deposits was evaluated, semiquantitatively graded from negative to marked, and correlated with clinical course and patient outcome. Amyloid deposits were consistently seen in hilar and vagus nerves. Liver lobular involvement was minimal in 1 and absent in the other 13 cases, with portal arterial amyloid deposits seen in 7 cases. At autopsy, extensive amyloid deposition in the heart was seen in all 3 cases with involvement of the conduction system. The extent of amyloid deposition at OLT did not correlate with the duration of symptoms before OLT or patient outcome after OLT. In conclusion, liver parenchymal involvement in FAP is minimal, and these explants are suitable for grafting in non-FAP patients. The recipients of such grafts must be carefully observed for the development of any amyloid-related disease, particularly cardiomyopathy. Of the tissues removed at OLT, the histopathologic confirmation of FAP is most consistently made by the examination of hilar and vagus nerves.

Adult↗

Epidemiologic and etiologic factors of pancreatic cancer.

Ranking fourth as a cause of death from cancer for men and women in the United States, pancreatic cancer represents a significant challenge for physicians and surgeons. In addition to the elderly, high-risk groups include blacks, men, smokers, and patients with certain preexisting diseases such as pancreatitis and long-standing diabetes. Various inherited genetic disorders cause approximately 5% to 10% of the total cases of pancreatic cancer. Smoking doubles the risk of pancreatic cancer. Control of smoking offers the best available strategy for reducing the incidence of this disease. Dietary measures to reduce the risk of pancreatic cancer include maintenance of normal body weight and consumption of a well balanced diet with adequate amounts of fruits and vegetables. Chronic pancreatitis caused by heavy alcohol consumption or, rarely, by an underlying inherited disorder is another strong risk factor, but because this benign disease is uncommon, elimination of this underlying cause would have minimal impact on the frequency of pancreatic cancer.

Adenocarcinoma↗

Functional asymmetry of nucleotide-binding domains in ABCG5 and ABCG8.

The ATP-binding cassette half-transporters ABCG5 (G5) and ABCG8 (G8) promote secretion of neutral sterols into bile, a major pathway for elimination of sterols. Mutations in either ABCG5 or ABCG8 cause sitosterolemia, a recessive disorder characterized by impaired biliary and intestinal sterol secretion, sterol accumulation, and premature atherosclerosis. The mechanism by which the G5G8 heterodimer couples ATP hydrolysis to sterol transport is not known. Here we examined the roles of the Walker A, Walker B, and signature motifs in the nucleotide-binding domains (NBD) of G5 and G8 using recombinant adenoviruses to reconstitute biliary sterol transport in G5G8-deficient mice. Mutant forms of each half-transporter were co-expressed with their wild-type partners. Mutations at crucial residues in the Walker A and Walker B domains of G5 prevented biliary sterol secretion, whereas mutations of the corresponding residues in G8 did not. The opposite result was obtained when mutations were introduced into the signature motif; mutations in the signature domain of G8 prevented sterol transport, but substitution of the corresponding residues in G5 did not. Taken together, these findings indicate that the NBDs of G5 and G8 are not functionally equivalent. The integrity of the canonical NBD formed by the Walker A and Walker B motifs of G5 and the signature motif of G8 is essential for G5G8-mediated sterol transport. In contrast, mutations in key residues of the NBD formed by the Walker A and B motifs of G8 and the signature sequence of G5 did not affect sterol secretion.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

Transient global amnesia: perplexing to patient and physician alike.

Transient global amnesia is a benign condition in which an isolated episode of amnesia occurs and then clears completely. No loss of motor or sensory function occurs and patients are not aphasic during the episodes. Neurologic workup is not likely to reveal any specific cause. It is necessary to eliminate treatable causes of transient ischemic attacks and also to rule out seizure disorders and brain tumors as a cause of this often unrecognized phenomenon. Cerebrovascular disease is often postulated as the underlying mechanism.

Aged↗

Heatstroke. Underlying processes and lifesaving management.

Heatstroke occurs during intense physical exertion or environmental exposure to heat without exertion. The ability to eliminate heat is limited by volume depletion, cardiac and vascular insufficiency, and skin disorders or protective coverings that prevent sweating and evaporative heat loss. Also, many drugs predispose patients to heatstroke by impairing normal thermoregulatory function. Critical management strategies include (1) recognition of hyperthermia, (2) rapid cooling, and (3) supportive care and observation for heat-related complications of tissue injury (eg, hepatic failure, renal failure, disseminated intravascular coagulation).

Acclimatization↗

Acquired hemophilia A.

Acquired hemophilia A is a rare but severe autoimmune bleeding disorder, resulting from the presence of autoantibodies directed against clotting factor VIII. The etiology of the disorder remains obscure, although approximately half of all cases are associated with other underlying conditions. A prompt diagnosis and appropriate management enable effective control of this acquired hemorrhagic disorder: the aims of therapy are to terminate the acute bleeding episode and eliminate or reduce the inhibitor. The recent availability of bypassing agents, first activated prothrombin complex concentrates and then recombinant activated factor VII, has significantly reduced mortality during the acute phase of the disease in patients with high titer inhibitors. On another front, immunosuppressive therapy (corticosteroids and cytotoxic agents, alone or in various combinations) has resulted in long-term inhibitor suppression in up to 70% of the cases. Moreover, new therapeutic strategies (anti-CD20 monoclonal antibody and immune tolerance protocols) are very promising and may further improve the prognosis of acquired hemophilia A.

Autoimmune Diseases↗

Mechanisms of hypoxemia in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension is characterized by widespread central obstruction of the pulmonary arteries with organized thrombus and thereby differs substantially from other forms of pulmonary hypertension. We studied 25 patients using the multiple inert gas elimination technique to identify and quantitate the physiologic mechanisms of hypoxemia in this disorder. All patients had chronic obstruction of the central pulmonary arteries, which was demonstrated angiographically and later surgically confirmed. All patients but one were hypoxemic (PaO2 = 65 +/- 11 mm Hg, PaCO2 = 32 +/- 4 mm Hg, AaPO2 = 45 +/- 14 mm Hg), and all patients had pulmonary hypertension (mean Ppa = 45 +/- 11 mm Hg) with an elevated pulmonary vascular resistance (mean PVR = 1,000 +/- 791 dyne/s/cm5, normal less than 300). The cardiac index was reduced (1.7 +/- 0.6 L/min/m2), as was the P-vO2 (31 +/- 5 mm Hg). Inert gas studies revealed widened unimodal Va/Q distributions in 20 of 25 subjects, with a log standard deviation of 1.01 +/- 0.32 (upper limit of normal, 0.6; ages 20 to 40), shunt = 0.03 +/- 0.05 of cardiac output, and dead space of 3.4 +/- 1.1 ml/kg (upper limit of normal, 2.9). The VD/VT ratio was 0.51 +/- 0.10. No low (VA/Q less than 0.1) or high (VA/Q greater than 10.0) regions were present, and no evidence for diffusion limitation of O2 transfer at rest was found. The low cardiac output and resulting low P-VO2 were responsible for approximately 33% of the increased AaPO2. The magnitude of the VA/Q abnormality correlated poorly with the PVR, the mean Ppa, or the magnitude of vascular obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Gas Analysis↗

Catheter ablation for atrial fibrillation: mechanism-based curative treatment.

The considerable cumulative morbidity and mortality burden resulting from atrial fibrillation has prompted renewed efforts to seek curative and widely applicable therapies. Currently used drugs are not only frequently ineffective at eliminating fibrillation, but may actually be life threatening. Extensive surgery involving both atria has shown that atrial fibrillation can be eliminated in most, if not all, patients, but at a significant cost. The recent discovery of the pivotal role that myocardial extensions into the pulmonary veins play in the initiation, and probably also the maintenance, of atrial fibrillation, has provided a relatively limited target conducive to catheter-based interventions. In experienced hands, paroxysmal atrial fibrillation can be eliminated in more than 85% of patients by a percutaneous intervention lasting less than 3 h with an attendant nonlethal complication risk of 1 to 2%. Thromboembolic complications and pulmonary vein stenosis are the principal complications that may result from this treatment, but their incidence is decreasing. Success rates in patients with persistent or permanent atrial fibrillation are lower, and it is anticipated that increased understanding of the underlying mechanisms will allow doctors to identify those subsets with the greatest potential for benefit from percutaneous catheter-based interventions. Such progress may allow doctors to extend the benefits of eliminating atrial fibrillation to the widest possible range of patients with this recalcitrant disorder.

Atrial Fibrillation↗

The blood serum concentration of cystatin C (gamma-trace) as a measure of the glomerular filtration rate.

The blood serum concentrations of creatinine and the low molecular weight proteins cystatin C, beta 2-microglobulin and retinol-binding protein were measured in 106 patients whose glomerular filtration rates were assessed by Cr-ethylenediaminetetraacetate (EDTA)-clearance determinations. The reciprocals of the serum concentrations of creatinine, cystatin C and beta 2-microglobulin were closely correlated to the Cr-EDTA-clearance (r = 0.73, 0.75 and 0.70, respectively) in contrast to the corresponding values for retinol-binding protein (r = 0.39). The calculated values of the glomerular elimination rate for creatinine and cystatin C were normally distributed in contrast to those for beta 2-microglobulin. The calculated glomerular elimination rate of cystatin C was not correlated to age, sex, type of disorder or disease activity. The results demonstrate that the serum level of cystatin C is a better measure of the glomerular filtration rate than the serum level of beta 2-microglobulin.

Adolescent↗

[Direct detection of mutations in the LDL receptor gene in patients with familial hypercholesterolemia].

BACKGROUND: Familial hypercholesterolemia is one of the most frequent hereditary metabolic diseases. As a result of the functional disorder of the molecule of the LDL receptor LDL cholesterol is not sufficiently eliminated from the blood stream and exerts an atherogenic effect. The objective of the study was to introduce direct detection of mutations in the gene for the LDL receptor and characterize the spectrum of mutations in the Czech population. METHODS AND RESULTS: The authors analyzed a group of 84 unrelated patients where on the basis of clinical and biochemical criteria the diagnosis of FH was established. From the group 12 patients were eliminated (14.3%) where a mutation 3500 in the gene for apolipoprotein (apo) B-100 was detected. This mutation is most frequently the cause of a familial defect of apo B-100 (FDB), which cannot be differentiated clinically or biochemically from FH. In the LDL receptor gene a total of 11 mutations were found in 14 unrelated patients (16.7%), incl. 7 mutations not described hitherto. CONCLUSIONS: This is the first systematic characteristic of the spectrum of mutations in the LDL receptor gene in the Czech population. Molecular genetic analysis of the gene for the LDL receptor in affected families can contribute towards early assessment of the diagnosis of FH and thus to prevention of life threatening cardiovascular episodes in asymptomatic subjects.

Apolipoprotein B-100↗

Protein content of human seminal plasma and spermatozoa in relation to sperm counts.

Protein concentrations of seminal plasma and spermatozoa were estimated in human normospermic, oligospermic and azoospermic semens. The protein content of seminal plasma ranged from 20 to 60 mg per ml semen and was found to be unrelated to sperm counts. Suspended sediments of azoospermic specimens were found to contain on the average 570+/-86 microng protein per ml semen. This value is about four times higher than in severe oligospermic specimens (0.2 X 10(6) -6.5 X 10(6) cells per ml semen). It is suggested that in azoospermic disorders seminiferous tubules secrete abnormally high amounts of proteinacous material which cannot be eliminated by washings. In addition, destruction of immature cells may contribute to increased protein conten in these specimens. Protein determinations in washed spermatozoa showed a negative relationship between the amount of protein calculated per 10(6) cells and original sperm counts. This trend demonstrates an altered protein metabolism in the spermatozoa of oligospermic specimens which might be responsible for fertility incompetence.

Adult↗

Dopamine agonist therapy in hyperprolactinemia.

Introduction of the dopamine agonist bromocriptine heralded a major advance in the management of hyperprolactinemic disorders. Although its side effects of nausea, dizziness and headache and its short elimination half-life are limiting factors, its efficacy established it as a reference compound against the activity of which several dopamine agonists, like pergolide, lysuride, metergoline, terguride and dihydroergocristine, fell by the wayside. More recently, two new agents, cabergoline and quinagolide, have been introduced and appear to offer considerable advantages over bromocriptine. Cabergoline, an ergoline D2 agonist, has a long plasma half-life that enables once- or twice-weekly administration. Quinagolide, in contrast, is a nonergot D2 agonist with an elimination half-life intermediate between those of bromocriptine and cabergoline, allowing the drug to be administered once daily. Comparative studies indicate that cabergoline is clearly superior to bromocriptine in efficacy (prolactin suppression, restoration of gonadal function) and in tolerability. In similar studies, quinagolide appeared to have similar efficacy and superior tolerability to that of bromocriptine. Results of a small crossover study indicate that cabergoline is better tolerated, with a trend toward activity superior to that of quinagolide. In hyperprolactinemic men and in women not seeking to become pregnant, cabergoline may be regarded as the treatment of choice.

Aminoquinolines↗

[Antitoxic properties of hepazan--a novel inducer of microsomal enzyme system].

The antitoxic properties of hepazan (dihydrothiazolexanthine), a new inductor of the microsomal enzyme system (MES) of liver were studied in white mice with the MES disorder induced by P. Aeruginosa toxin. It was found that hepazan not only eliminates the toxin-induced depression, but also decreases the toxic effects of ketoconazole, digoxin, and propranolol under the toxinemia conditions.

Animals↗

Skin manifestations of food allergy.

The pediatrician is faced with evaluating a panoply of skin rashes, a subset of which may be induced by food allergy. Acute urticaria is a common manifestation of an allergic skin response to food, but food is rarely a cause of chronic urticaria. Approximately one third of infants/children with moderate to severe atopic dermatitis have food allergy. Although diagnosis of acute urticaria provoked by a food may be evident from a straightforward history and confirmed by diagnostic tests to detect food-specific IgE antibody, determination of the role of food allergy in patients with atopic dermatitis is more difficult and may require additional diagnostic maneuvers, including elimination diets and oral food challenges. The immunopathologic basis of food-allergic disorders that affect the skin and a rational approach to diagnosis and treatment are discussed. Additional disorders that are caused by or mimic ones caused by food allergy are reviewed.

Animals↗

[Myelodysplastic syndromes--pathogenesis and treatment].

The essence of myelodysplastic syndromes is damage of CFU. We can also observe different chromosomes' defects which in consequence cause disorder of differentiation and maturation of hematopoietic cells. The aim of therapy is elimination of damaged CFU, possible only by bone marrow transplant. Patients who can not qualify for a transplant are treated by pharmacologic means. Pharmacological treatment aims to induce differentiation of hematopoietic cells and also to inhibit apoptosis. Since in this disease multiple genetics anomalies are affirmed, in the future gene therapy will play a big role in the treatment.

Apoptosis↗