Consumption of oxygen: a mitochondrial-generated progression signal of advanced cancer.

Changes in mitochondrial genome such as mutation, deletion and depletion are common in cancer and can determine advanced phenotype of cancer; however, detailed mechanisms have not been elucidated. We observed that loss of mitochondrial genome reversibly induced overexpression and activation of proto-oncogenic Ras, especially K-Ras 4A, responsible for the activation of AKT and ERK leading to advanced phenotype of prostate and breast cancer. Ras activation was induced by the overexpression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), the rate-limiting enzyme of the mevalonate pathway. Hypoxia is known to induce proteasomal degradation of HMGR. Well differentiated prostate and breast cancer cells with high mitochondrial DNA content consumed a large amount of oxygen and induced hypoxia. Loss of mitochondrial genome reduced oxygen consumption and increased in oxygen concentration in the cells. The hypoxic-to-normoxic shift led to the overexpression of HMGR through inhibiting proteasomal degradation. Therefore, reduction of mitochondrial genome content induced overexpression of HMGR through hypoxic to normoxic shift and subsequently the endogenous induction of the mevalonate pathway activated Ras that mediates advanced phenotype. Reduction of mitochondrial genome content was associated with the aggressive phenotype of prostate cancer in vitro cell line model and tissue specimens in vivo. Our results elucidate a coherent mechanism that directly links the mitochondrial genome with the advanced progression of the disease.

Obesity as a cause of "false-positive" alcohol misuse laboratory investigations.

Three patients are reported with a prior history of alcohol misuse accompanied by abnormal liver toxicity tests and other indices of alcohol misuse. A decreased but persistently raised serum gamma-glutamyl transferase activity during subsequent abstinence or controlled drinking was interpreted incorrectly as due to continued alcohol misuse whereas obesity-related fatty liver was the probable cause. The value of serum carbohydrate deficient transferrin assays in the differential diagnosis of abnormal liver toxicity tests is emphasized.

Selecting patients for combined femorofemoral bypass grafting and iliac balloon angioplasty and stenting for bilateral iliac disease.

PURPOSE: This study examines the selection of patients for combined femorofemoral bypass (FFB) grafting and iliac balloon angioplasty (IBA) and stenting for bilateral iliac occlusive disease (successively or simultaneously) and the correlation of the length and location of stenoses of the donor iliac artery to the success of FFB grafts. METHODS: Forty-one patients with long iliac occlusion and significant contralateral iliac stenosis were treated with combined FFB grafting and IBA and stenting, which were performed simultaneously or percutaneously within 1 to 2 days before surgery. Stenting was performed for suboptimal IBAs. IBA/graft patency was evaluated by duplex scanning/ankle-brachial index at 1, 3, 6, and 12 months and every 12 months thereafter. A life-table analysis of patency was performed, according to the length of stenosis as classified by the Society of Cardiovascular Interventional Radiology (group A, < 3 cm and 3-5 cm; group B, > 5 cm). RESULTS: Indications for surgery were limb salvage (22%), rest pain (44%), and claudication (34%). The mean follow-up time was 34.1 months. Perioperative complications were 7% for group A versus 62% for group B (P = .0007) with no perioperative deaths or amputations. Stenting was needed in 12 of 13 patients (92%) in group B versus four of 28 patients (14%) in group A (P < .0001) and in 11 of 12 external iliac artery lesions versus five of 29 common iliac artery lesions (P < .0001). The overall early success rate was 100% for group A and 62% for group B (P = .0028). The primary patency rates at 1, 2, and 3 years were 96%, 85%, and 85% for group A, respectively, and for group B were 46%, 46%, and 31%, respectively (P < .01). The secondary patency rates for group A at 1, 2, and 3 years were 100%, 96%, and 87%, respectively; and for group B were 62%, 54%, and 27%, respectively (P < .001). The overall primary and secondary patency rates for common iliac and external iliac artery lesions were similar (72% and 72% versus 67% and 75%, respectively). The overall limb salvage rates were 96% for group A and 85% for group B. Seven of 13 patients (54%) of group B, in contrast with 0 of 28 patients in group A, had to undergo a revision of the procedure within 30 days (P < .01). CONCLUSION: Combined use of IBA and stenting and FFB grafting is effective and durable and can be performed simultaneously, if the donor iliac stenosis length is 5 cm or less. Percutaneous transluminal angioplasty/stenting of stenoses of 5 cm or more fail to support FFB grafting in most patients; therefore, their combination should be questioned.

Alcohol withdrawal and hypokalaemia: a case report.

A case is presented where a 25-year-old man developed a serious hypokalaemia (K(+) 2.2 mmol/l) during alcohol withdrawal, despite intravenous saline treatment and normal feeding. As hypokalaemia can be symptom-free, we want to draw attention to the combination of vomiting, malnutrition and alcohol withdrawal, as these can cause lethal complications. We therefore recommend that potassium serum level should be routinely monitored during alcohol withdrawal, even when this is being managed in the community.

Prevention and treatment of Wernicke-Korsakoff syndrome.

Wernicke's encephalopathy (WE) is both common and associated with high morbidity and mortality and yet there is evidence that appropriate and effective prophylaxis and treatment are often not given. Effective treatment and prophylaxis may only be achieved by use of parenteral vitamin supplements, since oral supplements are not absorbed in significant amounts. Although there are rare anaphylactoid reactions associated with the use of parenteral thiamine preparations, the risks and consequences of inadequate prophylaxis and treatment, in appropriately targeted groups of patients, are far greater. It is therefore proposed that all in-patient alcohol withdrawal should be covered by prophylactic use of parenteral thiamine, that there should be a low threshold for making a presumptive diagnosis of WE, and that there is a need for guidelines to assist physicians in appropriate management of this common clinical problem.

Spectral beam combining of a broad-stripe diode laser array in an external cavity.

The outputs from an 11-element, linear diode laser array with broad stripes have been beam combined into a single beam with a beam quality of ~20x diffraction limited in the plane of the junction. This beam combining was achieved by use of a common external cavity containing a grating, which simultaneously forces each array element to operate at a different, but controlled, wavelength and forces the beams from all the elements to overlap and propagate in the same direction. The power in the combined beam was 50% of the output from the bare laser array.

Diode-pumped 214.8-nm Nd:YAG /Cr4+:YAG microchip laser system for the detection of NO.

A passively Q-switched 214.8-nm Nd:YAG/Cr(4+):YAG microchip laser system for the detection of NO was designed, constructed, and tested. The system uses the fifth harmonic of the 1.074-microm transition in Nd:YAG to detect NO by laser-induced fluorescence. A significant challenge was the development of an environmentally stable coating to provide the necessary discrimination between the 1.074-microm laser line and the stronger transition at 1.064 microm. The exact position of the fifth-harmonic frequency was determined by use of NO fluorescence excitation spectra to be 46556 +/- 1.5 cm(-1). With a pulse energy of approximately 50 nJ of fifth-harmonic light, we observed a detection sensitivity for NO of approximately 15 parts per billion by volume in a simple, compact optical system.

Ascertainment of families for a linkage study of alcoholism.

Traditionally, researchers working in the field of genetics and alcoholism have used treatment centres and clinics to try and recruit suitable subjects for research purposes. The current study considered a diverse range of possible sources to recruit suitable families for a linkage study of alcoholism. These sources included the press, personal contacts and circular letters to alcohol treatment centres and members of the Substance Misuse Section of the Royal College of Psychiatrists. Only 9-14% of families contacted from any source were suitable for inclusion in the study, due to the strict selection criteria. Press contacts were found to be the most productive source of suitable families willing to participate in the study, accounting for over 50% of contacts and eventual subjects recruited. There appeared to be no bias in the affection status of subjects recruited from the different sources. For future genetic studies of alcoholism it might be worthwhile to utilize this source more fully. Reasons for exclusion from the study are also considered, with the most common reasons being non-co-operation and no family history.

Psychiatric aspects of alcohol misuse.

Alcohol and psychiatric disorder have a complicated relationship. Certain important psychiatric syndromes arise from the toxic effects of alcohol and thiamine deficiency. Liver disease and hypoglycaemia are also associated with their own psychiatric syndromes. Many psychiatric patients also turn to alcohol as an easily available 'medication'.

A survey of the current clinical practice of psychiatrists and accident and emergency specialists in the United Kingdom concerning vitamin supplementation for chronic alcohol misusers.

Although it is well known that B-vitamin deficiencies directly affecting the brain are common in alcohol misuse, no concise guidelines on the use of vitamin supplements in alcohol misusers currently exist in the UK. The purpose of this study was to assess current practice and opinion among UK physicians. Questionnaires were completed by a total of 427 physicians comprising Accident and Emergency (A&E) specialists and psychiatrists, with a response rate of 25%. The main findings were that vitamin deficiency was perceived as being uncommon amongst alcohol misusers (<25%) and there was no consensus as to which B vitamins are beneficial in treatment or the best method of administration of B-vitamin supplementation. The majority of psychiatrists favoured oral administration for prophylaxis against the Wernicke-Korsakoff syndrome in chronic alcohol misusers and parenteral therapy in patients with signs of Wernicke-Korsakoff syndrome. Whilst only just over half the A&E specialists expressed a preference, most favoured parenteral therapy in both cases. Most respondents did not currently have a unit policy/protocol on the management of vitamin supplementation in chronic alcohol misusers. Overall, the findings suggest that there is wide variation in current practice and highlight the need for guidelines in this area.

B Vitamin deficiency and neuropsychiatric syndromes in alcohol misuse.

Alcohol misuse and alcohol withdrawal are associated with a variety of neuropsychiatric syndromes, some of which are associated with significant morbidity and mortality. B vitamin deficiency is known to contribute to the aetiology of a number of these syndromes, and B vitamin supplementation thus plays a significant part in prophylaxis and treatment. In particular, the Wernicke Korsakoff syndrome (WKS). due to thiamine deficiency, is a common condition in association with alcohol misuse, and is associated with high morbidity and mortality. Nicotinamide deficiency may result in a rarer condition, alcoholic pellagra encephalopathy, which often has a similar clinical presentation to WKS. This review considers the role of B vitamins in the aetiology and treatment of neuropsychiatric syndromes associated with alcohol misuse, with particular emphasis on WKS.

Alcohol policy and aviation safety.

Aviation provides an environment which is almost uniquely unforgiving of mistakes. Accordingly, impairment of aircrew performance by alcohol can, and occasionally does, lead to catastrophic mistakes. That such disasters are rare, is a credit to the responsibility of aircrew themselves and to the effectiveness of aviation industry policies. Similarly, maintenance of this exemplary record depends upon continued attention to alcohol policy in the future. The aviation industry thus provides a useful model for the study of alcohol policies within a safety critical environment. Surprisingly, this model appears not to have been subjected to critical research and evaluation. Based upon previous research on alcohol and aviation, and in consideration of findings from the wider field of alcohol policy, suggestions are made here as to a promising framework for future alcohol policy formation in the aviation environment.

Knowledge and experience of drug use amongst church affiliated young people.

A large and growing proportion of young people in the UK are using drugs. Research from the US suggests a protective effect of church affiliation or 'religiosity', but this has not been investigated in British young people. In the present study, the prevalence of drug use was estimated amongst 7666 church affiliated young people in the UK in 1995, using a self report questionnaire survey. In the 12-16 year old age group, 23.4% had been offered at least one of a list of drugs, and 9.7% had tried such drugs. In those aged 17-30 years the figures were 46.1% and 23.3%, respectively. These figures are perhaps slightly less than, those obtained in secular surveys. Those who gave more positive responses to questions on Christian commitment were less likely to have been offered any of the listed drugs, or to have used them, as compared with those who gave no such responses. A lifetime history of ever having smoked demonstrated a far stronger association, with smokers being 15-20 times more likely to have used one of the listed drugs.

Parenteral thiamine and Wernicke's encephalopathy: the balance of risks and perception of concern.

Wernicke's encephalopathy, a disorder with significant mortality and high morbidity, is common amongst alcohol-dependent patients. Thiamine deficiency appears to play a key role in its aetiology, and parenteral high-dose thiamine is effective in prophylaxis and treatment. Unfortunately, reports of rare anaphylactoid reactions have led to a dramatic reduction in the use of parenteral thiamine, and it is possible that this change in treatment has led, or will lead, to an increase in morbidity and mortality. There is a need for education of doctors who treat alcohol-dependent patients, in order to ensure appropriate use of parenteral thiamine in prophylaxis and treatment of this disorder.

B-complex vitamins in the prophylaxis and treatment of Wernicke-Korsakoff syndrome.

Wernicke-Korsakoff syndrome, which is associated with high morbidity and mortality, is a more common neuropsychiatric sequela of alcohol misuse than is widely realized. It is easily prevented and treated with parenteral B-complex vitamins, although this treatment is widely under-utilized.

Alcohol and aviation.

Aviation accidents due to alcohol consumption by aircrew appear to be rare, especially in commercial aviation. However, a small proportion of general aviation accidents are attributable to alcohol use by aircrew, and aircrew are not well informed about the metabolism of alcohol and its effects on performance. Furthermore, there is evidence that aircrew performance may be impaired by alcohol consumption even after their Blood Alcohol Concentration has returned to "zero" (i.e. < 5 mg/dl). Accidents caused by impairment of aircrew performance by alcohol may therefore not be attributed to alcohol use at all. Aviation safety relies upon faultless human performance and is thus highly sensitive to alcohol-related impairment of performance. This paper provides a review of research regarding aircrew alcohol consumption, impairment of aircrew performance by alcohol, incidence of aviation accidents attributable to alcohol use by aircrew, and other related subjects.