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PubMed1989

Mortality in Crohn's disease--a clinical analysis.

We have examined the causes of death and the changing pattern of mortality over time among 769 patients with Crohn's disease under long-term review between 1944 and 1984. One hundred and fifty-six patients have died. The cause of death could not be classified in five. The deaths were divided into those related directly to Crohn's disease and unrelated deaths from incidental causes. The cause and age at death among 59 unrelated deaths was similar to that expected in the general population. The common causes of related deaths were sepsis, digestive tract cancer, pulmonary embolus and metabolic disorders. There were 30 deaths after surgery, usually from sepsis after emergency surgical treatment. There have been fewer deaths in recent years and the cause of death has altered. Sepsis and electrolyte imbalance have declined in importance and cancer of the digestive tract is now the most common cause of related death. Occasional death from sepsis occurs in elderly patients. Elective rather than emergency surgical treatment and the routine use of antimicrobial prophylaxis before surgery has probably reduced mortality. With the exception of cancer of the digestive tract the appropriate medical and surgical treatment of patients with Crohn's disease can eliminate excess mortality previously associated with the disorder.

Adolescent↗
PubMed2006

Adult pulmonary Langerhans' cell histiocytosis.

Adult pulmonary Langerhans' cell histiocytosis is a rare disorder of unknown aetiology that occurs predominantly in young smokers, with an incidence peak at 20-40 yrs of age. In adults, pulmonary involvement with Langerhans' cell histiocytosis usually occurs as a single-system disease and is characterised by focal Langerhans' cell granulomas infiltrating and destroying distal bronchioles. High-resolution computed tomography (HRCT) of the chest is essential to the diagnosis, typically showing a combination of nodules, cavitated nodules, and thick- and thin-walled cysts. A high macrophage count in bronchoalveolar lavage (BAL) fluid is a common but nonspecific finding that merely reflects exposure to tobacco smoke. BAL is useful for eliminating infections and the other infiltrating lung disorders that can be seen in young adults. Langerhans' cells can be identified in BAL fluid, but, in contrast to what was initially hoped, this test shows a very low sensitivity and is rarely useful in the diagnosis of the disease. The definite diagnosis of pulmonary Langerhans' cell histiocytosis requires identification of Langerhans' cell granulomas, which is usually achieved by surgical lung biopsy at a site selected by chest HRCT. In practice, however, lung biopsy is performed on a case-by-case basis. No effective treatment is available to date, and improved understanding of the mechanisms involved in the pathogenesis of pulmonary Langerhans' cell histiocytosis is urgently needed, and should help in the development of specific therapeutic strategies for patients with this orphan disease.

Adult↗
PubMed2006

[Immunological disorders and correction of them in surgical patients with atherosclerosis obliterance].

Atherosclerosis obliterance and critical lower limb ischemia lead to immunodeficiency and disbalance of T- and B- components of immune system. Surgical treatment doesn't eliminate but in a number of cases aggravates immune disorders. Immunocorrection stimulates anti-infectious protection. Indications to different variants of immunocorrection are formulated.

Antibodies, Anti-Idiotypic↗
PubMed2001

Pharmacokinetics of valproic acid in patients with bipolar disorder.

The pharmacokinetics of valproic acid (VPA) were studied in nine patients with bipolar disorder who were receiving VPA as prophylactic therapy, following the full daily dose (400-1500 mg), on which the patients had been maintained for at least the past 3 months. The data from our study showed that the pharmacokinetics of valproate followed a two compartment open model. A time lag of 1-2 h was observed in each patient, followed by rapid absorption, with the peak concentrations being recorded approximately 4 h after drug administration. The average 12 h trough concentration was found to be 54.73+/-11.96 microg/ml. The plasma level decline was biphasic with a terminal half-life of 14.2+/-6.39 h. Total plasma clearance was 0.095+/-0.035 ml/min/kg. The steady-state apparent volume of distribution was found to be 0.11+/-0.05 l/kg. A positive correlation (r = 0.69) was found between the dose (mg/kg) and steady-state serum concentration (Css) of VPA and all patients, except one, had their Css above 50 microg/ml. Most of the pharmacokinetic parameters in this study involving euthymic bipolar patients on long-term VPA monotherapy were found to be in agreement with those reported in literature on seizure disorder patients on similar regime; however, the plasma elimination half-life appears to be prolonged in bipolar patients.

Adult↗
PubMed2003

Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1.

Endogenous thyroid receptor hormones 3,5,3',5'-tetraiodo-l-thyronine (T(4), 1) and 3,5,3'-triiodo-l-thyronine (T(3), 2) exert a significant effects on growth, development, and homeostasis in mammals. They regulate important genes in intestinal, skeletal, and cardiac muscles, the liver, and the central nervous system, influence overall metabolic rate, cholesterol and triglyceride levels, and heart rate, and affect mood and overall sense of well being. The literature suggests many or most effects of thyroid hormones on the heart, in particular on the heart rate and rhythm, are mediated through the TRalpha(1) isoform, while most actions of the hormones on the liver and other tissues are mediated more through the TRbeta(1) isoform of the receptor. Some effects of thyroid hormones may be therapeutically useful in nonthyroid disorders if adverse effects can be minimized or eliminated. These potentially useful features include weight reduction for the treatment of obesity, cholesterol lowering for treating hyperlipidemia, amelioration of depression, and stimulation of bone formation in osteoporosis. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism and, in particular, cardiovascular toxicity. Consequently, development of thyroid hormone receptor agonists that are selective for the beta-isoform could lead to safe therapies for these common disorders while avoiding cardiotoxicity. We describe here the synthesis and evaluation of a series of novel TR ligands, which are selective for TRbeta(1) over TRalpha(1). These ligands could potentially be useful for treatment of various disorders as outlined above. From a series of homologous R(1)-substituted carboxylic acid derivatives, increasing chain length was found to have a profound effect on affinity and selectivity in a radioreceptor binding assay for the human thyroid hormone receptors alpha(1) and beta(1) (TRalpha(1) and TRbeta(2)) as well as a reporter cell assay employing CHOK1-cells (Chinese hamster ovary cells) stably transfected with hTRalpha(1) or hTRbeta(1) and an alkaline phosphatase reporter-gene downstream thyroid response element (TRAFalpha(1) and TRAFbeta(1)). Affinity increases in the order formic, acetic, and propionic acid, while beta-selectivity is highest when the R(1) position is substituted with acetic acid. Within this series 3,5-dibromo-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (11a) and 3,5-dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (15) were found to reveal the most promising in vitro data based on isoform selectivity and were selected for further in vivo studies. The effect of 2, 11a, and 15 in a cholesterol-fed rat model was monitored including potencies for heart rate (ED(15)), cholesterol (ED(50)), and TSH (ED(50)). Potency for tachycardia was significantly reduced for the TRbeta selective compounds 11a and 15 compared with 2, while both 11a and 15 retained the cholesterol-lowering potency of 2. This left an approximately 10-fold therapeutic window between heart rate and cholesterol, which is consistent with the action of ligands that are approximately 10-fold more selective for TRbeta(1). We also report the X-ray crystallographic structures of the ligand binding domains of TRalpha and TRbeta in complex with 15. These structures reveal that the single amino acid difference in the ligand binding pocket (Ser277 in TRalpha or Asn331 in TRbeta) results in a slightly different hydrogen bonding pattern that may explain the increased beta-selectivity of 15.

Alkaline Phosphatase↗
PubMed2006

Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best?

Given that natural selection is so powerful at optimizing complex adaptations, why does it seem unable to eliminate genes (susceptibility alleles) that predispose to common, harmful, heritable mental disorders, such as schizophrenia or bipolar disorder? We assess three leading explanations for this apparent paradox from evolutionary genetic theory: (1) ancestral neutrality (susceptibility alleles were not harmful among ancestors), (2) balancing selection (susceptibility alleles sometimes increased fitness), and (3) polygenic mutation-selection balance (mental disorders reflect the inevitable mutational load on the thousands of genes underlying human behavior). The first two explanations are commonly assumed in psychiatric genetics and Darwinian psychiatry, while mutation-selection has often been discounted. All three models can explain persistent genetic variance in some traits under some conditions, but the first two have serious problems in explaining human mental disorders. Ancestral neutrality fails to explain low mental disorder frequencies and requires implausibly small selection coefficients against mental disorders given the data on the reproductive costs and impairment of mental disorders. Balancing selection (including spatio-temporal variation in selection, heterozygote advantage, antagonistic pleiotropy, and frequency-dependent selection) tends to favor environmentally contingent adaptations (which would show no heritability) or high-frequency alleles (which psychiatric genetics would have already found). Only polygenic mutation-selection balance seems consistent with the data on mental disorder prevalence rates, fitness costs, the likely rarity of susceptibility alleles, and the increased risks of mental disorders with brain trauma, inbreeding, and paternal age. This evolutionary genetic framework for mental disorders has wide-ranging implications for psychology, psychiatry, behavior genetics, molecular genetics, and evolutionary approaches to studying human behavior.

Adaptation, Physiological↗
PubMed2005

Disorders of oxidised haemoglobin.

Methaemoglobinaemia arises from the production of non-functional haemoglobin containing oxidised Fe(3+) which results in reduced oxygen supply to the tissues and manifests as cyanosis in the patient. It can develop by three distinct mechanisms: genetic mutation resulting in the presence of abnormal haemoglobin, a deficiency of methaemoglobin reductase enzyme and toxin-induced oxidation of haemoglobin. The normal haemoglobin fold forms a pocket to bind the haem and stabilise its complex with molecular oxygen, simultaneously preventing spontaneous oxidation of the Fe(2+) ion chelated by the haem pyrroles and the globin histidines. In the abnormal, M forms of haemoglobin (Hb Ms) amino acid substitution in or near the haem pocket creates a propensity to form methaemoglobin instead of oxyhaemoglobin in the presence of molecular oxygen. Normally, haemoglobin continually oxidises but significant accumulation of methaemoglobin is prevented by the action of a group of methaemoglobin reductase enzymes. In the autosomal recessive form of methaemoglobinaemia there is a deficiency of one of these reductase enzymes thereby allowing accumulation of oxidised Fe(3+) in methaemoglobin. Oxidising drugs and other toxic chemicals may greatly enhance the normal spontaneous rate of methaemoglobin production and if levels exceed 70% of total haemoglobin, vascular collapse occurs resulting in coma and death. Under these conditions, if the source of toxicity can be eliminated methaemoglobin levels will return to normal. Disorders of oxidised haemoglobin are relatively easily diagnosed and in most cases, except for the presence of congenitally defective haemoglobin M, can be treated successfully.

Cytochrome-B(5) Reductase↗
PubMed1991

Estazolam treatment of insomnia in generalized anxiety disorder: a placebo-controlled study.

Estazolam, a triazolobenzodiazepine with an intermediate elimination half-life, has been shown previously to be an effective and safe hypnotic in insomniacs without concomitant psychiatric illness. Our study of the efficacy of estazolam in patients with insomnia associated with generalized anxiety disorder began when 108 patients meeting criteria for generalized anxiety disorder (mean total score of Hamilton Rating Scale for Anxiety [HAM-A] = 22.0 +/- 3.1 [SD]) and insomnia were given single-blind placebo for 7 nights. Nine patients whose anxiety and/or insomnia improved were dropped as placebo responders. The remaining 99 patients were randomly allocated (1:1) to double-blind treatment with either estazolam 2.0 mg or matching placebo for 7 nights. Hypnotic efficacy, as determined by patient-completed sleep questionnaires, was statistically significant for estazolam 2.0 mg versus placebo for all sleep indices (p less than 0.01). Patients treated with estazolam 2.0 mg showed significantly greater improvement in anxiety than those receiving placebo on the mean total score of HAM-A ([placebo, -3.4; estazolam, -7.1; p less than 0.001] and without the insomnia item [placebo, -2.7; estazolam, -5.5; p less than 0.001]). Anxiety scores on the State-Trait Anxiety Inventory showed greater improvement in the estazolam group, but without statistical significance (p = 0.237). Estazolam 2.0 mg is an effective hypnotic in patients with generalized anxiety disorder and appears to have a favorable anxiolytic action.

Adult↗
PubMed1981

The use of biofeedback techniques with school-aged children exhibiting behavioral and/or learning problems.

This article reviews 44 studies that investigated the efficacy of biofeedback techniques in treating childhood behavioral and learning disorders. Although the data suggest that children can learn voluntary control over a variety of physiological processes, methodological flaws make it impossible to specify the mechanisms responsible for such learning. Further, the data do not suggest that biofeedback techniques are superior to more conventional treatments in remediating learning or behavioral disorders. Suggestions for future research focus upon the elimination of methodological weaknesses, the use of more stringent diagnostic criteria, and the use of more sophisticated biofeedback equipment and procedures.

Adolescent↗
PubMed2005

Treatment of panic disorder.

Panic disorder with or without agoraphobia occurs commonly in patients in primary care settings. This article assesses multiple evidence-based reviews of effective treatments for panic disorder. Antidepressant medications successfully reduce the severity of panic symptoms and eliminate panic attacks. Selective serotonin reuptake inhibitors and tricyclic antidepressants are equally effective in the treatment of panic disorder. The choice of medication is based on side effect profiles and patient preferences. Strong evidence supports the effectiveness of cognitive behavior therapy in treating panic disorder. Family physicians who are not trained in cognitive behavior therapy may refer patients with panic disorder to therapists with such training. Cognitive behavior therapy can be used alone or in combination with antidepressants to treat patients with panic disorder. Benzodiazepines are effective in treating panic disorder symptoms, but they are less effective than antidepressants and cognitive behavior therapy.

Antidepressive Agents↗
PubMed1984

Alprazolam as treatment for a case of obsessive-compulsive disorder.

Because of the anxiety accompanying his obsessions and a prior panic attack, an obsessive-compulsive man was given alprazolam, which reduced his obsessions and eliminated his compulsions. The authors discuss links between obsessive-compulsive disorder and other psychiatric disorders.

Adult↗
PubMed1995

Venlafaxine treatment of panic disorder: a case series.

BACKGROUND: Venlafaxine inhibits the neuronal reuptake of both serotonin and norepinephrine and has been shown to be an effective antidepressant; however, its potential efficacy in treating panic disorder has not yet been evaluated. METHOD: Four consecutive patients with panic disorder were administered low doses of venlafaxine in an open-label, nonblinded trial. Outcome data were obtained at regular intervals via detailed clinical exploration and patient self-report. In no case was any depth psychotherapy or attempt at conflict resolution provided. RESULTS: Panic attacks were completely eliminated in the first four patients with panic disorder that I treated with low doses of venlafaxine. Three of these patients experienced no further panic attacks after the institution of venlafaxine therapy. The total daily maintenance doses used were between 50 and 75 mg/day, and the effective starting doses were even lower. CONCLUSION: The resolution of panic disorder in all four patients treated with low doses of venlafaxine suggests that venlafaxine might be an effective treatment for panic disorder. Moreover, the rapid, apparently immediate, disappearance of panic attacks after the initiation of venlafaxine in three of four patients raises the possibility that this agent may have an unusually fast onset of action. The efficacy of low doses of venlafaxine or the need to start treatment with very low doses in patients with panic disorder was predicted by experience with other monoamine reuptake inhibitors in this patient population. Double-blind, placebo-controlled studies of venlafaxine in panic disorder are indicated.

Adult↗
PubMed2000

[Hypoxia and memory. Specific features of nootropic agents effects and their use].

Hypoxia and hypoxic adaptation are powerful factors of controlling memory and behavior processes. Acute hypoxia exerts a differential impact on different deficits of mnestic and cognitive functions. Instrumental reflexes of active and passive avoidance, negative learning, behavior with a change in the stereotype of learning are more greatly damaged. Memory with spatial and visual differentiation and their rearrangement change to a lesser extent and conditional reflexes are not deranged. In this contract, altitude hypoxic adaptation enhances information fixation and increases the degree and duration of retention of temporary relations. Nootropic agents with an antihypoxic action exert a marked effect on hypoxia-induced cognitive and memory disorders and the magnitude of this effect depends on the ration of proper nootropic to antihypoxic components in the spectrum of the drugs' pharmacological activity. The agents that combine a prevailing antiamnestic effect and a marked and moderate antihypoxic action (mexidole, nooglutil, pyracetam, beglymin, etc.) are most effective in eliminating different hypoxia-induced cognitive and memory disorders, nootropic drugs that have a pronounced antiamnestic activity (centrophenoxine, etc.) and no antihypoxic component also restore the main types of mnestic disorders after hypoxia, but to a lesser extent.

Adaptation, Psychological↗
PubMed1988

Toward a selection of the most appropriate procedure in the treatment of complete rectal prolapse.

Defecographic evaluation was performed in 30 patients with rectal prolapse to assess the effect of posterior rectopexy on rectal function and to arrive at a selection of the best procedure. Preoperative defecography revealed rectal intussusception in all patients. Postoperative control studies showed adequate rectal fixation to the anterior sacral surface. Intussusception no longer occurred. Rectal stenosis due to the surgical procedure was absent. The described technique of posterior rectopexy eliminates the prolapse mechanism without creating new disorders and is therefore a rational procedure. Advocation of new procedures should also be based on results of colorectal tests that assess the effect of the procedures on rectal function.

Adult↗
PubMed1999

Non-Alcoholic Steatohepatitis (NASH).

Non-alcoholic steatohepatitis (NASH) is an increasingly common cause of persistently abnormal liver tests. Establishing a diagnosis of NASH requires the secure exclusion of alcohol abuse and hepatitis C as an alternate cause of liver injury. The gold standard of diagnosis is liver biopsy. Unfortunately, NASH, although a common entity, is without a satisfactory treatment. Weight reduction, optimum blood glucose control, and elimination of medications implicated in causing the disorder are sensible first steps in treatment. Drug therapy should not be used unless there is histologic evidence of necro-inflammatory injury and/or fibrosis. Ursodeoxycholic acid (UDCA) has been reported to be of benefit in non-controlled trials and anecdotal case reports. Our approach is to use ursodeoxycholic acid in a dose of 15 mg/kg, and to monitor serial liver enzyme tests. Predictable normalization of liver tests often results, but relentless progression of liver injury can occur in the face of consistently normal liver tests. Close follow-up is mandatory after establishing a diagnosis of NASH. Newer, more effective drugs are needed to treat NASH in a controlled trial environment.

Journal Article↗
PubMed2003

Common genetic variation in a basal promoter element alters DDAH2 expression in endothelial cells.

Synthesis of the vasodilator nitric oxide (NO) can be inhibited by the endogenous methylarginines L-NMMA and ADMA. ADMA is elevated in a number of cardiovascular disorders in which NO availability is reduced. Elimination of ADMA from the body occurs primarily by enzymatic breakdown through the action of DDAH, of which two isoforms exist, DDAH1 and DDAH2. In this study we have identified a core promoter region of the DDAH2 gene, and transcription factor sites that play an important role in the regulation of DDAH2 expression. Using PCR-SSCP analysis we also identified six common polymorphisms. One of these polymorphisms (an insertion/deletion at position -871) within the core promoter element influenced basal transcription. The discovery of a functional polymorphism within the DDAH2 promoter suggests that there may be common, individual differences in the ability to metabolise ADMA in vivo, that in turn, might underlie susceptibility to cardiovascular disease.

Amidohydrolases↗
PubMed1997

Shoulder-arm muscle load and performance during control operation in forestry machines. Effects of changing to a new arm rest, lever and boom control system.

Three work station design studies in forestry machines were carried out with regard to shoulder/arm muscle load. (1) In an arm rest study, a movable (in the sagittal plane) arm rest was compared with a fixed one; (2) in a lever study, a mini lever with a small deflection was compared with an ordinary hand lever; (3) in a boom control study, a computer controlled boom system was compared with an ordinary boom system. In the arm rest study eight male subjects carried out lever operations in the laboratory. In the lever and boom studies, 15 male forestry students operated forwarders. Muscle load, cycle time, skill, perceived exertion, heart rate and preferred set up were recorded. The muscle loads on the upper trapezius, infraspinatus, extensor carpi ulnaris and flexor carpi radialis were recorded by electromyography. With mini lever and movable arm rest the upper trapezius load was reduced with preserved or decreased cycle time, although the grand mean of the 'static' load level was only about 2% of maximal voluntary contraction (MVC) and the effects of the new designs were small (about 0.7% MVC). The subjects preferred the lever/arm rest also giving the lowest muscle load. No differences between levers or arm rests were found in skill, perceived exertion or heart rate. It was not possible to draw any definitive conclusions regarding effects of the boom control system, due to technical problems. According to the literature, the duration of lever operation has increased considerably in forestry during recent years as part of a rationalization process. Partly due to this, it is suggested that the investigated work station improvements may not be sufficient to eliminate the risk for shoulder-neck disorders.

Arm↗