Effectiveness and tolerability of second-line therapy with vildagliptin vs. other oral agents in type 2 diabetes: a real-life worldwide observational study (EDGE).

AIM: Real-life studies are needed to confirm the clinical relevance of findings from randomised controlled trials (RCTs). This study aimed to assess the effectiveness and tolerability of vildagliptin add-on vs. other oral antihyperglycaemic drugs (OADs) added to OAD monotherapy in a real-life setting, and to explore the advantages and limitations of large-scale 'pragmatic' trials. METHODS: EDGE was a prospective, 1-year, worldwide, real-life observational study in which 2957 physicians reported on the effects of second-line OADs in 45,868 patients with T2DM not reaching glycaemic targets with monotherapy. Physicians could add any OAD, and patients entered either vildagliptin or (pooled) comparator cohort. The primary effectiveness and tolerability end-point (PEP) evaluated proportions of patients decreasing HbA(1c) > 0.3%, without hypoglycaemia, weight gain, peripheral oedema or gastrointestinal side effects. The most clinically relevant secondary end-point (SEP 3) was attainment of end-point HbA(1c) < 7% without hypoglycaemia or ≥ 3% increase in body weight. RESULTS: In this large group of T2DM patients, a second OAD was added at mean HbA(1c) of 8.2 ± 1.3%, with no baseline HbA(1c) difference between cohorts. Second-line OAD therapy attained the PEP in the majority of patients, with higher attainment in those prescribed a vildagliptin-based regimen. The adjusted odds ratio was 1.49 (95% CI: 1.42, 1.55; p < 0.001). In patients with baseline HbA(1c) ≥ 7%, SEP 3 was achieved by 35% of patients on a vildagliptin-based combination and by 23% of those receiving comparator combinations. The adjusted odds ratio was 1.96 (95% CI: 1.85, 2.07; p < 0.001). Safety events were reported infrequently and safety profiles of vildagliptin and other OADs were consistent with previous data. CONCLUSION: EDGE demonstrates that in a 'real-life' setting, vildagliptin as second OAD can lower HbA(1c) to target without well-recognised OAD side effects, more frequently than comparator OADs. In addition, EDGE illustrates that conducting large-scale, prospective, real-life studies poses challenges but yields valuable clinical information complementary to RCTs.

Phase II trial: concurrent radio-chemotherapy with weekly docetaxel for advanced squamous cell carcinoma of head and neck.

INTRODUCTION: Standard fractionation radiation therapy (RT) combined with concomitant chemotherapy (CT) based on cisplatin schemes is actually the standard treatment for locally advanced non-resectable squamous cell carcinoma of head and neck (SCCHN). The appearance of taxoids has introduced a new kind of treatment with high antitumoral power. The aim of this study is to add more information about the role of this new approach. MATERIALS AND METHODS: Twenty-six patients with locally advanced non-resectable SCCHN were recruited at six institutions in Spain, between January 2001 and January 2003. Docetaxel was administered weekly, for 6 weeks, concurrently with RT. RESULTS: The mean total delivered dose of RT was 70'2 Gy (range 64-74 Gy). The median and mean duration of time were 63 days and 61 days (range 49-103 days) respectively. After a median time control of 19 months (range 3.3-42.2 months), the response rate was 83.4%. The median time to local progression was 16.4 months (95% confidence interval [CI]=4.4-28.4 months). The median survival time was 26.9 months, with one- and two-year overall survival of 66.9% (95% CI=48.1-85.7%) and 57.5% (95% CI=37.3-77.7%) respectively. The median duration time response was 15.1 months (95% CI=3.7-26.5 months). The median time until treatment failure was 9.4 months (95% CI=4.7-14.1). Incidence of grade III-IV mucositis was 88%, neutropenia 72% and skin toxicity 92% (24% grade III-IV). The incidence of severe late toxicity (grade III and IV) due to RT/CT was 31.4%. CONCLUSIONS: Although therapeutics results are equivalent to cisplatin schemes of concurrent CT-RT, mucositis and cutaneous toxicity registered in this trial must be considered as limiting factors to application of this new approach.

[COX-2 inhibitors in cancer prevention]. / Inhibidores de la ciclooxigenasa-2 en la prevención del cáncer.

Chemoprevention of cancer is a reality today. Prevention of breast cancer with tamoxifen, of squamous cell skin cancer with actinic keratosis by diclofenac gel and in familial polyposis with anti-inflammatory drug (COX-2) celecoxib is considered of health care clinical use. The latter has received enormous attention by cancer investigators due to the attractiveness of its action mechanism and its possibilities of future clinical use in different neoplasms. Other anti-inflammatory drugs such as aspirin and sulindac also have a proven role in chemoprevention of cancer by cycloosygenase inhibition or of related substances. The review of the mechanisms by which these substances act gives us a clear idea of what it is and what the chemoprevention will be.

A useful experimental model of short bowel syndrome.

The short bowel syndrome is a well-known human clinical entity that produces serious metabolic disorders. This syndrome arises after a massive resection of more than 50% of the small intestine, when the intestine attempts to minimize the consequent irregularities by means of compensatory mechanisms. Many reports suggest that an exocrine and endocrine pancreatic dysfunction is associated with enterohormones and an abnormal altered nutrient flow. In this report, we present an experimental model of short bowel syndrome in rats. A massive intestine resection was performed in rats, followed by a histological study of the small intestine. We report the histological changes related to the compensatory changes that occurred in the remaining intestine. The residual intestine produces a hyperplasic response, and hypertrophy was seen in the portion proximal to the anastomosis. We believe this experimental model of short bowel syndrome could be a very useful tool for studying the enterohormonal changes related to an abnormal blood flow of nutrients.

A Useful Experimental Model of Short Bowel Syndrome.

The short bowel syndrome is a well-known human clinical entity that produces serious metabolic disorders. This syndrome arises after a massive resection of more than 50% of the small intestine, when the intestine attempts to minimize the consequent irregularities by means of compensatory mechanisms. Many reports suggest that an exocrine and endocrine pancreatic dysfunction is associated with enterohormones and an abnormal altered nutrient flow. In this report, we present an experimental model of short bowel syndrome in rats. A massive intestine resection was performed in rats, followed by a histological study of the small intestine. We report the histological changes related to the compensatory changes that occurred in the remaining intestine. The residual intestine produces a hyperplasic response, and hypertrophy was seen in the portion proximal to the anastomosis. We believe this experimental model of short bowel syndrome could be a very useful tool for studying the enterohormonal changes related to an abnormal blood flow of nutrients.

A Useful Experimental Model of Short Bowel Syndrome.

The short bowel syndrome is a well-known human clinical entity that produces serious metabolic disorders. This syndrome arises after a massive resection of more than 50% of the small intestine, when the intestine attempts to minimize the consequent irregularities by means of compensatory mechanisms. Many reports suggest that an exocrine and endocrine pancreatic dysfunction is associated with enterohormones and an abnormal altered nutrient flow. In this report, we present an experimental model of short bowel syndrome in rats. A massive intestine resection was performed in rats, followed by a histological study of the small intestine. We report the histological changes related to the compensatory changes that occurred in the remaining intestine. The residual intestine produces a hyperplasic response, and hypertrophy was seen in the portion proximal to the anastomosis. We believe this experimental model of short bowel syndrome could be a very useful tool for studying the enterohormonal changes related to an abnormal blood flow of nutrients.

Relationship between the number and impact of stressful life events and the onset of Graves' disease and toxic nodular goitre.

BACKGROUND: In the last few decades, several studies have suggested a possible association between Stressful Life Events (SLEs) and the onset of Graves' Disease (GD). However, others have criticised this association and it has not yet been possible to prove it unequivocally. At present, we are not aware of studies correlating SLE and non autoimmune thyrotoxicosis. OBJECTIVE: To assess possible associations between SLEs, the onset of GD and the onset of non autoimmune thyrotoxicosis (toxic nodular goitre, TNG). DESIGN: A case-control retrospective study. PATIENTS: This study included 93 subjects, divided into three groups of 31 each: GD, TNG and control (CG). The GD and TNG patients had thyroid disease diagnosed within the last 12 months, with clinical and biochemical confirmation. In the CG, psychopathological and endocrine disturbances had been ruled out. All three groups consisted of nine males (29%) and 22 females (71%). The mean age was 38.4 +/- 10.9 years in the GD group, 48.3 +/- 11.1 years in the TNG group and 41.1 +/- 11.8 years in the CG group. SLEs were evaluated (number and impact) for the 12 months preceding the onset of symptoms of thyroid disease. MEASUREMENTS: SLE occurrences and their impact on each group of cases were measured. To assess SLEs, we used the Life Experiences Survey (LES). Our statistical analysis included descriptive techniques and parametric and/or nonparametric comparative tests. P < 0.01 was considered statistically significant. Odds ratios were also calculated. RESULTS: Patients with GD had a significantly greater number of SLEs compared to the TNG group and the CG (P < 0.001). The number and impact of negative SLEs were significantly higher in GD compared to TNG and CG (P < 0.001). The difference between TNG and CG was not significant (P > 0.01). GD had a higher impact of positive SLEs than TNG (P = 0.004), and no significant differences were found between the GD group and CG. Neutral SLEs were similar in the three groups. CONCLUSIONS: These results suggest that SLEs are a precipitating factor of the onset of GD. We also demonstrated that SLEs do not seem to have any conclusive relationship with the onset of TNG.

[Asymptomatic hepatitis induced by propylthiouracil]. / Hepatite assintomática induzida pelo propiltiouracilo.

Propylthiouracil (PTU) is widely used to treat patients with hyperthyroidism. In rare cases this drug has been found to have toxic effects on the liver. We describe the second assymptomatic case, reported in the literature, of PTU induced hepatotoxicity. Sixteen cases have been published so far, all with clinical manifestations. A 20-year-old female patient developed an elevation of AST, ALT and GGT levels after 5 months of PTU (50 mg tid) therapy for Graves disease with hyperthyroidism. The patient showed normal levels of liver aminotransferases before starting PTU. She had no risk factors for or clinical evidence of pre-existing liver disease. She didn't take any regular medication. After stopping PTU, the plasma levels of hepatic enzymes normalised within 6 weeks. Thirteen days after the reinstitution of PTU (150 mg tid), because of the recurrence of hyperthyroidism, another episode of assymptomatic hepatotoxicity was documented. AST, ALT, GGT and AP levels rose again, but bilirrubin levels remained normal, which represents a very unusual laboratory constellation in this kind of patient. The serology for hepatitis A, B, C and for EBV and CMV was negative. After stopping PTU, methimazole (MMI) was started and the liver enzymes normalised within two weeks. After 12 months of MMI therapy, the patient is assymptomatic, with normal liver enzyme levels and normal thyroid function tests. This case is the second to be described where the diagnosis was confirmed by the rechallenge of PTU, being this a major diagnostic criteria. Despite its rarity the disease should be suspected in any patient receiving PTU in whom clinical or laboratorial evidence of hepatocellular injury develops. The drug should be discontinued immediately when the hepatic injury is detected. Recovery is usually complete after the withdrawal of the drug, but there were al least, three fatalities among the 17 cases described.

[Relationship between obesity and educational level in Portuguese young males in 1990]. / Relação entre a obesidade e o nível educacional nos mancebos portugueses do sexo masculino em 1990.

OBJECTIVE: To evaluate the relationship between the educational level, weight and obesity of young Portuguese males, aged 20 years. DESIGN: Cross-sectional study, based on the national military census files of 1990, provided by the military selection centres of Portugal (north, centre, south--including Azores and Madeira islands). SUBJECTS AND METHODS: In Portugal, all males aged 20 must present themselves to the military authorities to be submitted to a health exam in order to be screened for the armed forces. The data of 70,858 young Portuguese males aged 20 were gathered. Height and weight were measured by skilled teams. The educational level was confirmed by the presentation of educational attainment certificates. The population was divided into deciles of body mass index (BMI). The whole group was classified as obese or non-obese, according to a cut-off point of 27.8 Kg/sqm. The educational level was classified in four groups: group A--less than 5 years of schooling; group B--5 to 6 years; group C--7 to 9 years; group D--> or = 10 years. The level of education in each decile of BMI was determined and the percentage of obese subjects was calculated for each level of schooling. The odds of obesity associated with each group of schooling was determined as well as their 95% confidence intervals. Statistical significance was considered to exist when p < 0.05. RESULTS: The average BMI in the study population was 22.5 Kg/sqm. A slight increase in schooling was noticed from the lowest to the highest decile of BMI. The same result was obtained when we analysed the upper extreme of the BMI distribution in greater detail. According to our criteria for obesity, the percentages of obesity in each level of schooling were as follows: group A--4.2%; group B--5%; group C--5.1%; and group D--5.4%. The odds ratio (OR) of obesity according to each education level was higher in those with a higher level of education. In fact, those with 10 or more years of schooling presented an OR = 1.05(0.94;1.17) which was not statistically significant (ns) when compared to those with 7-9 years; while an OR = 1.08(0.97;1.21), was also ns when compared to those with 5-6 years, and, finally, an OR = 1.29(1.14;1.47) was statistically significant (p < 0.001) in comparison to those with only 0-4 years of schooling. CONCLUSIONS: As major conclusions one can say that the prevalence of obesity is low among young Portuguese males (4.9%), only 2.1% with a BMI > 30 Kg/sqm. Furthermore, our results show that, in Portugal, contrary to the results found mostly in western European countries, males aged 20 years with higher levels of education are slightly more prone to be obese than others with lower levels of schooling.

The CARICOM/FAO/IICA Caribbean Amblyomma Program.

The objective of the Caribbean Amblyomma Program is to eradicate the tropical bont tick (TBT), Amblyomma variegatum, from the Caribbean. Field activities directed to eradication of the TBT were initiated in May 1995 commencing in northern Caribbean islands. Plans have been finalized for the remaining islands to the south to start eradication activities in early 1997. The components of the program include tick control and surveillance, adaptive research, training, communications, and extension. Despite uncertain financial support, substantial progress has been made so far with strong participation by farmers and livestock owners who have been made responsible for the compulsory treatment of all ruminant livestock.

Effect of different East Coast fever control strategies on disease incidence in traditionally managed Sanga cattle in Central Province of Zambia.

A clinical trial, including five East Coast fever (ECF) control strategies (involving tick control and/or immunisation by infection-and-treatment) in five different groups of traditionally managed Sanga cattle, was conducted in Central Province of Zambia over 2.5 years between 1992 and 1995. Two groups were kept under intensive tick control by weekly acaricide treatment by hand spray; (one immunised and one non-immunised), two groups were under no tick control (one immunised and one non-immunised), and a fifth, immunised group was maintained under strategic tick control (18 sprays yr-1). ECF-specific mortality was highest in the non-immunised and non-treated group, while no difference in ECF-specific mortality could be observed between animals treated for ECF by immunisation or by tick control. Acaricide treatment and/or immunisation reduced the risk of clinical ECF by 92%. The results of an artificial challenge experiment at the end of the field trial indicated that about 60% of the animals in the control group had become infected with Theileria parva without showing clinical signs. ECF incidence in non-vaccinated cattle markedly declined six months after immunisation--suggesting that the carrier state induced by immunisation did not lead to a persistent high incidence, and might accelerate the progress to endemicity.

An outbreak of East Coast fever in a herd of Sanga cattle in Lutale, Central Province of Zambia.

An outbreak of East Coast fever (ECF) occurred in an experimental herd of Sanga cattle maintained under a traditional rangeland grazing system at Lutale, Central Province of Zambia. Two groups of cattle had been kept under different tick-control regimens for several years prior to the introduction of the disease and epidemiological information on the outbreak were recorded. Weekly tick control was no sufficient to achieve full protection against Theileria parva infection. Systematic body temperature monitoring seems to be a good method for early detection of infection resulting in an important reduction of the case fatality rate after treatment with anti-theilerial drugs.

Secular trends of weight, height and obesity in cohorts of young Portuguese males in the District of Lisbon: 1960-1990.

OBJECTIVE: To examine the secular trend of weight, height and obesity among young Portuguese males at the time of military inspection for national conscription purposes in the region of Lisbon, during the last thirty years. DESIGN: Cross-sectional study, based on the review of military census files. SETTING: Military selection centre of Lisbon. SUBJECTS AND METHODS: In Portugal, military service is obligatory and medical inspections are carried out every year on males at the age of twenty. For study purposes, representative samples were taken from the young male population undergoing inspection for the Armed Forces on a five year basis, between 1960 and 1990 in the region of Lisbon. Weight and height were evaluated by a trained team, using standard measurement instruments and procedures. RESULTS: A progressive and significant increase in weight, height and BMI of the young male population was found between 1960 and 1990. For certain variables the increase was also statistically significant within a five-year period, as it was the case for height between 1965-1980 and for weight between 1985-1990. The increase in BMI experienced some minor fluctuation along the reference period, however, it was statistically significant between 1985-1990. The increase in weight and in BMI was greater in the highest percentiles and particularly noticeable between 1985 and 1990. The percentage of young males with BMI over 25 kg/m2 was of 8.1% in 1960 and of 18.0% in 1990, while those having a BMI over 27 kg/m2 varied between 3.6% and 6.4% in the same period, respectively. The percentage of young adult males with BMI higher than 25 kg/m2 doubled between 1960 and 1990.

A comparison of the insulin tolerance/glucagon test with the short ACTH stimulation test in the assessment of the hypothalamo-pituitary-adrenal axis in the early post-operative period after hypophysectomy.

OBJECTIVE: The insulin tolerance test (ITT) is the established reference test for assessing the hypothalamo-pituitary-adrenal (HPA) axis. Various authorities, however, have suggested that the 250 microgram short ACTH stimulation test may be used to assess the HPA axis in place of the ITT in suspected hypopituitarism, although a number of other studies have suggested that the test may be unreliable in this setting. In this study, the ITT (or glucagon test) has been compared with the 250 microgram short ACTH stimulation test in patients with pituitary tumours pre-operatively and within 2 weeks of trans-sphenoidal hypophysectomy. DESIGN: An ITT, or a glucagon test when the ITT was contraindicated, and the 250 micrograms short ACTH stimulation test, were performed in all the patients before (an ITT in 18 and a glucagon test in three patients) and within 2 weeks after trans-sphenoidal hypophysectomy (an ITT in 16 and a glucagon test in five patients). PATIENTS: Twenty-one patients with pituitary disorders (15 with acromegaly, one with a prolactinoma and five with non-functioning tumours) were studied; four had a microadenoma, two a mesoadenoma and 15 a macroadenoma. MEASUREMENTS: Serum cortisol was measured by radioimmunoassay. A normal response was defined as a rise in serum cortisol to 580 nmol/l or above for all the tests. RESULTS: Before surgery, three of 18 patients (17%) had a discrepancy between the ITT and the 30 minute short ACTH stimulation test and one of three between the glucagon test and the 30 minute short ACTH stimulation test. Combined together, pre-operatively, four of 21 patients (19%) had discrepant results. In the early post-operative period, the discrepancy between ITT and the 30 minute short ACTH stimulation test was higher with four of 16 patients (25%) showing discordant results; one of the five patients tested had a discrepancy between the glucagon test and the 30 minute short ACTH stimulation test. On combining the tests, the post-operative discrepancy was five of 21 patients (24%). CONCLUSIONS: The 250 microgram short ACTH stimulation test produces discordant results from the ITT in a clinically significant proportion of affected patients when assessing the HPA axis, although the rate of discordance varies according to the criteria used for normality for both the tests. We suggest that the ITT should remain the preferred test for assessing ACTH secretory capacity compared with the standard 250 microgram short ACTH stimulation test, both in the preoperative and in the early post-trans-sphenoidal hypophysectomy period.

Sustainable tick and tickborne disease control in livestock improvement in developing countries.

Tick and tickborne disease (TTBD) control is a major component of animal health programmes protecting livestock, thereby enhancing global food security. The present methods for TTBD control are reviewed and an integrated use of the tools is recommended with a broader view of how to link TTBD control to the control of other parasitic diseases. The work of FAO in this field is presented and it is advocated that, although there are still areas that need further investigation, a stage has been reached where robust integrated TTBD control schemes, based on ecological and epidemiological knowledge of ticks and their associated diseases, can be promoted and implemented. Major challenges are the implementation of these policies in the field through the continuation of the present on-going programme in Africa and support to Latin America and Asia. The importance of involving all parties, governments, international and private organisations and the agrochemical industry in developing sustainable, cost-efficient control programmes is stressed and a global strategy is proposed. The main thrust should now be to convince policy makers on the adoption of the strategies and veterinarians and farmers on their implementation.

Long-term studies on the economic impact of ticks on Sanga cattle in Zambia.

Three different tick control policies were tested in groups of traditionally managed Sanga cattle in the Central Province of Zambia over a period of 3 years. One group was given strategic tick control using 12 pyrethroid acaricide spray applications between the onset and the end of the wet season (October to March). The productivity of this herd was compared with that of a group with no tick control and a group under an intensive tick control regimen of spraying every week in the wet season and every 2 weeks in the dry season (36 applications per year). The highest output was associated with intensive tick control, followed by strategic control and then no tick control policies. However, when the costs of tick control were taken into account, the strategic tick control policy produced the best economic result, followed by the intensive and then the no tick control policies. Neither the strategic nor the intensive tick control policy was sufficient to prevent the transmission of East Coast fever (ECF) infection when this disease was introduced to the area.

Effect of different East Coast Fever control strategies on fertility, milk production and weight gain of Sanga cattle in the Central Province of Zambia.

Five different East Coast Fever (ECF) (Theileria parva infection) control strategies, based on tick control and/or ECF immunization, were tested in groups of traditionally managed Sanga cattle in the Central Province of Zambia over a period of 2.5 years. Two groups were kept under intensive tick control (sprayed weekly), one group immunized and one non-immunized. Two further groups were under no tick control, one group immunized and one non-immunized, while a fifth group was immunized against ECF and maintained under strategic tick control (18 sprays per year). Tick control increased milk production and weight gain but not fertility. Immunization had neither marked detrimental nor beneficial effects on the cattle productivity. The combination of strategic tick control and immunization resulted in the highest level of production and at the same time reduced the potential risk from other tick-borne diseases.

Host resistance to ticks (Acari: Ixodidae) in different breeds of cattle at Bako, Ethiopia.

European cattle breeds are being introduced into Ethiopia in an effort to improve the productivity of indigenous breeds. The Ethiopian cattle breeds Horro and Boran were compared for tick burdens with their crosses with Friesian, Jersey and Simmental. Horro animals had the lowest tick burdens and the Horro x Friesian the highest. Adaptation to their environment and long-term natural selection for tick resistance in Horro cattle is the most likely explanation. Repeatability of tick burdens in all animals considered as one herd were only statistically significant for Boophilus decoloratus, the most abundant tick species. Statistically significant correlations between burdens of female B. decoloratus, Amblyomma cohaerens and Rhipicephalus praetextatus were observed and the addition of the males resulted in all inter-species correlations becoming significant. Care should be taken when crossing Ethiopian with more productive European cattle breeds in order not to lower their tick and disease resistance.