Whipple's disease in Spain: a clinical review of 91 patients diagnosed between 1947 and 2001.

BACKGROUND: To determine the epidemiological, clinical, diagnostic and therapeutic characteristics of Whipple s disease in Spain. PATIENTS AND METHOD: Cases of Whipple s disease reported in the Spanish literature between 1947 and 2001 which meet histological or PCR criteria are reviewed. RESULTS: 91 cases were included, 87.5% of which were male. The maximum incidence was between 40 and 60 years of age (68%). There was no family clustering or susceptibility by profession or surroundings. The most common symptoms and signs were: weight loss (80%), diarrhoea (63%), adenopathies (35%), skin problems (32%), abdominal pain (27%), fever (23%), joint problems (20%) and neurological problems (16%). Arthralgias, diarrhoea and fever were noted prior to diagnosis in 58, 18 and 13% of patients, respectively. Diagnosis was histological in all cases except two, which were diagnosed by PCR. Intestinal biopsy was positive in 94%. Adenopathic biopsies (mesenteric or peripheral) were suggestive in 13% of cases, and treatment was effective in 89%. There were nine relapses, four of which were neurological, although all occurred before the introduction of cotrimoxazole. CONCLUSIONS: Whipple s disease is not uncommon, although it requires a high degree of suspicion to be diagnosed in the absence of digestive symptoms. The most common and most sensitive diagnostic method is duodenal biopsy. PCR is beginning to be introduced to confirm the diagnosis and as a therapeutic control. Initial antibiotic treatment with drugs that cross the blood-brain barrier, such as cotrimoxazole and ceftriaxone, is key to achieving a cure and avoiding relapses.

HPLC assay for determination of amphotericin B in biological samples.

A fast and selective HPLC method for assaying amphotericin B in biological samples was developed and validated. The chromatographic separation was achieved in less than 12 min on a reverse-phase C(18) column using an acetonitrile-acetic acid-water (52:4.3:43.7, v/v/v) mixture as mobile phase. The flow rate was 1 mL/min and the effluent was monitored at 406 nm. A linear response over the concentration range 0.1-10.0 microg/mL was obtained. Intra-day and inter-day RSDs were below 5% for all the sample types. This new HPLC method was applied to assay amphotericin B in plasma and several tissue samples such as kidney, liver, spleen and bone marrow. Application of this method to pharmacokinetic studies in mice and dog is provided.

Real-time reverse transcription-PCR quantification of cytokine mRNA expression in golden Syrian hamster infected with Leishmania infantum and treated with a new amphotericin B formulation.

A real-time quantitative reverse transcription-PCR assay was developed for the quantification of cytokine mRNA expression in the golden Syrian hamster Mesocricetus auratus infected with Leishmania infantum and treated with amphotericin B (AMB) formulated in microspheres made of human serum albumin (HSA). Treatment was administered intravenously on days 69, 71, and 73 postinfection (p.i.) with 10(7) metacyclic promastigotes, at doses of 2 and 40 mg/kg of AMB. High infection levels were recorded for untreated animals by day 76 p.i., with parasite loads always about 2 log10 per gram higher in the liver than in the spleen. Treatment was highly effective with both doses, but at 40 mg/kg, almost complete parasite elimination was achieved. mRNA expression of gamma interferon (IFN-gamma) and, to a lesser extent, tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) in spleen cells was up-regulated in most animals of the untreated group. The mRNA expression of interleukin-4 was strongly down-regulated in untreated as well as treated infected animals. Treatment with the lower dose of AMB-HSA down-regulated the mRNA expression of IFN-gamma and TNF-alpha, with no effect on the deactivating cytokine TGF-beta. In contrast, treatment with the higher dose (40 mg/kg) of the formulation caused moderate up-regulation of IFN-gamma and TNF-alpha and strong suppression of TGF-beta. Treatment of noninfected animals did not alter the cytokine expression pattern with regard to untreated controls. Our results suggest that treatment of L. infantum-infected Syrian hamsters with highly effective nontoxic doses of AMB-HSA causes deactivation of the anti-inflammatory cytokine TGF-beta, which in turn results in up-regulation of the Th1 cytokines IFN-gamma and TNF-alpha.

Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis.

Transgenic mice expressing mutant forms of both amyloid-beta (Abeta) precursor protein (APP) and presenilin (PS) 2 develop severe brain amyloidosis and cognitive deficits, two pathological hallmarks of Alzheimer's disease (AD). One-year-old APP/PS2 mice with high brain levels of Abeta and abundant Abeta plaques show disturbances in spatial learning and memory. Treatment of these deteriorated mice with a systemic slow-release formulation of insulin-like growth factor I (IGF-I) significantly ameliorated AD-like disturbances. Thus, IGF-I enhanced cognitive performance, decreased brain Abeta load, increased the levels of synaptic proteins, and reduced astrogliosis associated to Abeta plaques. The beneficial effects of IGF-I were associated to a significant increase in brain Abeta complexed to protein carriers such as albumin, apolipoprotein J or transthyretin. Since levels of APP were not modified after IGF-I therapy, and in vitro data showed that IGF-I increases the transport of Abeta/carrier protein complexes through the choroid plexus barrier, it seems that IGF-I favors elimination of Abeta from the brain, supporting a therapeutic use of this growth factor in AD.

[Type III glycogen storage disease associated with hepatocellular carcinoma]. / Glucogenosis tipo III asociada a carcinoma hepatocelular.

Type III glycogen storage disease is a hereditary disorder with autosomal recessive transmission. It is characterized by accumulation of abnormal glycogen in the liver and, in 80% of patients, in muscle. The liver can also show fibrosis and sometimes cirrhosis. Until 2000, 9 cases of cirrhosis had been published, 3 of which showed associated hepatocarcinoma. We present the case of a 31-year-old woman, diagnosed in childhood with type III glycogen storage disease, who 30 years after onset developed a hepatocellular carcinoma with portal thrombosis in the context of advanced cirrhosis. This is the first case to be reported in the Spanish literature of type III glycogen storage disease associated with hepatocellular carcinoma.

The effect of solubilization on the oral bioavailability of three benzimidazole carbamate drugs.

The effect of solubilization by complexation with povidone on the oral bioavailability of three anthelmintic benzimidazole carbamate drugs: mebendazole (MBZ), albendazole (ABZ) and ricobendazole (RBZ), was studied in mice. The following in vitro characteristics of the initial raw materials and the drug-povidone complexes were evaluated: melting point (MP); mean dissolution time (MDT); solubility constants (Cs) in n-octanol, acid (pH 1.2) and neutral (pH 7.4) aqueous media; apparent partition coefficients (P) and capacity factors (k'W) determined by HPLC. The following in vivo parameters were also evaluated: AUC(0-infinity), C(max), T(max) and MRT. The possible relationship between in vitro characteristics and in vivo parameters was explored and it was found that an increase in solubility, especially in acidic medium, leads to an increase in AUC and C(max) and a decrease in T(max). Therefore, dissolution seems to be the absorption limiting step for these drugs. For the in vivo parameters related to the amount of absorbed drug (AUC and C(max)), the best correlation was obtained with the in vitro characteristics related to solubility which are Cs, MP and MDT. On the other hand, there were good linear correlations between T(max) which is an in vivo parameter related to the rate of drug absorption, and the lipophilia/hydrophilia (logP and log k'W) relation-parameters.

Clinical trials in isolated systolic hypertension in the elderly

The presence of isolated systolic hypertension in elderly subjects predisposes to the development of coronary artery disease, myocardial infarction, heart failure, cardiovascular events, stroke and cardiovascular mortality. Whether pharmacologic management of isolated systolic hypertension in the elderly is justified or not has not received attention until the recent years. In this era of the practice of evidence based medicine it is important to review the results of clinical trials about the management of isolated systolic hypertension involving thousands of elderly patients. The main trials and their results will be presented. These demonstrate a 17 per cent reduction in total mortality, 25 per cent reduction in cardiovascular mortality, 37 per cent reduction in stroke and a 25 per cent reduction in myocardial infarction for those patients under pharmacologic treatment.

Pharmacological characteristics of parenteral IGF-I administration.

Insulin-like growth factor-I (IGF-I) is a naturally occurring single chain polypeptide of 7649 Da that is produced primarily in the liver. The metabolic activities of IGF-I are similar to those of insulin and its effects on growth, development, regeneration and metabolism have been widely studied. Indeed, IGF-I is currently being used clinically for the treatment of growth related disorders and its therapeutic value is also being evaluated in diabetes, IGF-I-induced neuroprotection, and in promoting bone healing. However, like many other peptides, IGF-I has a short biological half-life and is rapidly removed from circulation following systemic administration. In the vascular system, this is normally compensated for by the association of IGF-I with IGF-binding proteins (IGFBPs), that also appear to regulate the activities of IGF-I. Here, we describe the biopharmaceutical properties of different parenteral formulations of IGF-I. The pharmaceutical characteristics of conventional formulations such as aqueous IGF-I solutions are compare with new controlled release formulations such as multivesicular liposomes, osmotic minipumps, and poly (DL-lactic-co-glycolic) acid (PLGA) microspheres.

[Liver alterations due to alpha-1-antitrypsin deficiency in adults. Study of 5 patients and analysis of the cases reported in the Spanish literature]. / Alteraciones hepáticas por déficit de alfa-1-antitripsina en adultos. Estudio de 5 pacientes y análisis de los casos publicados en la bibliografía española.

BACKGROUND: To determine the epidemiological characteristics of liver disease secondary to alpha-1-antitrypsin deficiency and associated processes in the Spanish population. PATIENTS AND METHOD: We reviewed the medical records of adults with liver abnormalities due to alpha-1-antitrypsin deficiency diagnosed between 1981 and 2001 in the Hospital Donosti in San Sebastian (Spain) as well as the cases published in the literature before 1999. Diagnosis was based on clinical and biochemical data, imaging tests and/or liver biopsy and/or necroscopy together with serum values of alpha-1-antitrypsin and phenotyping. RESULTS: Fifty cases of liver disease secondary to alpha-1-antitrypsin deficiency (45 from the literature and 5 from our hospital) were included. There were 34 men and 16 women aged between 18 and 77 years. Fifteen (30%) had relatives with alpha-1-antitrypsin deficiency. Hepatitis and/or neonatal cholestasis were confirmed in 4 and alcoholism was confirmed in 17. Of the series, 8 (16%) had portal fibrosis and 29 (58%) had cirrhosis. Cirrhosis was mainly macro-micronodular and was decompensated in 48% of the cases. Of the patients with cirrhosis, 12 were ZZ homozygotes and 12 were heterozygotes, mainly MZ and SZ. The most frequent associated process was respiratory disease (emphysema and/or chronic bronchitis) in 25 of the 50 cases (50%). CONCLUSIONS: The presence of cirrhosis in alpha-1-antitrypsin deficiency is low, approximately 2.2/100,000 for ZZ homozygotes. Age at diagnosis of cirrhosis or fibrosis was more than 50 years. The male-to-female ratio was 2 to 1. In one-third of the patients alcohol could have been a coadjuvant or aggravating factor in the liver disease. No differences were found between homo- and heterozygote phenotypes in patients with cirrhosis. The most frequently associated processes were respiratory diseases due to alpha-1-antitrypsin deficiency.

Effect of two formulations of benzimidazole carbamates on the viability of cysts of Echinococcus granulosus in vivo.

Two different preparations, solution and suspension, of three benzimidazole carbamate drugs, mebendazole, albendazole and ricobendazole, were compared by analyzing their in vivo activity against Echinococcus granulosus cysts in a mouse model. Polyvinylpyrrolidone was used for the elaboration of drug solutions and these formulations manifested better results in terms of reduction of number of viable hydatid cysts in mice than the reference drug suspensions. The effect was more prominent on mebendazole-treated mice, at doses of 25-50 mg/kg. There was a correlation between ED50 and pharmacokinetical parameters of AUC0-infinity and Cmax, showing that a significant improvement on solubility affects the in vivo activity of these drugs.

[Fasciola hepatica. study of a series of 37 patients]. / Fasciolasis hepatobiliar. Estudio de una serie de 37 pacientes.

BACKGROUND: To analyze the clinical, bacteriologic, diagnostic and therapeutic features of patients with Fasciola hepatica (FH) in our hospital. PATIENTS AND METHOD: We reviewed all the patients with a diagnosis of fascioliasis from 1975 to 1999 in the Aranzazu Hospital in San Sebastián (Guipúzcoa, Spain). Diagnosis was made by direct vision of adult parasites during surgery and/or the presence of ova in stool examinations and/or positive serologic tests in patients with symptoms consistent with parasitosis. RESULTS: Thirty-seven patients were included (23 men and 14 women), aged 19 to 71 years. Ingestion of watercress was confirmed in 27. Seven cases occurred as part of familiar outbreaks. Thirty-two were in the liver invasive stage and in 5 the biliary tree was invaded. The most common features were eosinophilia (91.8%), malaise and weight loss (75.6%), elevated alkaline phosphatase (74.2%), and abdominal pain (72.9%). Adult worms in the biliary ducts were observed in 3 patients and ova in feces were observed in 6. In 13 of 27 patients indirect hemagglutination test was ( 1/1,280. Data significant to confirmation of liver involvement were provided by laparoscopy in 12 of 13 patients and by imaging techniques in 13 of 31 patients. Four patients had cholelithiasis and of these, 2 also showed adult parasites in the common bile duct. Three patients underwent surgery. Therapy with dehydroemetine and/or bithionol was followed by complete remission in 30 patients, although 6 required repeat treatment cycles. The remaining 4 patients were cured by praziquantel. CONCLUSIONS: Most of the patients in these series reported consumption of watercress and all patients showed the symptoms typical of parasite disease. Imaging techniques proved to be of great utility in confirming the diagnosis of hepato-biliary disease. In most of the patients therapy with dehydroemetine and/or bithionol (in one or several cycles) was followed by complete remission.

[Krukenberg tumor secondary to gastric carcinoma in a woman in her eighth month of pregnancy]. / Tumor de Krukenberg secundario a carcinoma gástrico en una gestante de ocho meses.

The association of gastric cancer and pregnancy is rare. The cases reported by non-Japanese authors are unusual. Tumors tend to be in advanced stage when diagnosed since the symptoms of gastric cancer are easily presumed to be secondary to those of normal pregnancy. We report the case of a 43-year-old female with gastric carcinoma presenting as a Krukenberg's tumor in the eighth month of gestation. A healthy child was born and after delivery, partial gastrectomy was performed and adjuvant chemotherapy was administered. The patient died 12 months after diagnosis.

Genetic susceptibility to gastric cancer.

Although the incidence and mortality rates of gastric cancer not located in the cardia have been decreasing in the last decades, it still remains the second most common cancer in the world. On the other hand, adenocarcinoma of the cardia and gastroesophageal junction has been rapidly rising in many populations over the past two decades.

Lewis antigen alterations in a population at high risk of stomach cancer.

Anomalous Lewis(a) antigen and sulfomucin expression are considered as markers of progression in precursor lesions of gastric cancer. Additionally, Lewis antigen and secretor phenotype have been related to Helicobacter pylori infection and gastric epithelial damage. The two objectives of this study were to correlate Lewis antigen alterations with histochemical changes and to explore the relationship between Lewis and secretor phenotypes and gastric epithelial damage related to H. pylori infection. The study subjects were selected from a chemoprevention trial in Tachira State, Venezuela, an area with a high risk of gastric cancer. Anomalous Lewis(a) antigen expression in Lewis (a-b+) phenotype individuals was closely related to the severity of the histological lesions, especially to dysplasia and type III intestinal metaplasia lesions. A weak relationship was observed between nonsecretor individuals and more advanced lesions of IM, but this association was not statistically significant. There was no relationship between secretor phenotype and H. pylori status, atrophy, regenerative activity, erosion, or ulcer.

Role of fucosyltransferases in the association between apomucin and Lewis antigen expression in normal and malignant gastric epithelium.

BACKGROUND: In normal gastric epithelium, MUC5AC is detected in superficial epithelium associated with Lewis type 1 antigens and MUC6 is detected in antral glands with Lewis type 2. Therefore, the stomach constitutes an excellent model to examine the role of glycosyltransferases in determining the specificity of apomucin glycosylation. AIMS: To determine the molecular basis of this association and to examine changes in expression of gastric and intestinal apomucins and their association with Lewis antigens during the gastric carcinogenesis process. METHODS: Fucosyltransferase (FUT1, FUT2, FUT3) and mucin (MUC5AC, MUC6) transcripts were detected using reverse transcription-polymerase chain reaction. Apomucin (MUC2, MUC4, MUC5AC, MUC6) and Lewis antigen (types 1 and 2) expression were analysed using single and double immunohistochemistry and in situ hybridisation. RESULTS: In the normal stomach, FUT1 is exclusively detected associated with MUC6; FUT2 is only detected when MUC5AC is present. This co-regulation is lost in gastric tumours, as is differential expression of MUC5AC and MUC6 in normal gastric epithelial cells. In gastric tumours, especially those with the intestinal phenotype, MUC2 and MUC4 genes are upregulated, and gastric-type and intestinal-type mucins are coexpressed. These changes are early events in the gastric carcinogenesis process, as they are detected in intestinal metaplasia. CONCLUSIONS: The glycosylation pattern found in normal gastric epithelium is dictated by the specific set of fucosyltranferases expressed by the cells rather than by the apomucin sequence. The development of intestinal metaplasia and gastric cancer is associated with the appearance of cellular phenotypes that are absent from normal epithelium.

Blood-group phenotypes, sulfomucins, and Helicobacter pylori in Barrett's esophagus.

Barrett's esophagus, morphologically analogous to gastric intestinal metaplasia, often precedes the development of esophageal adenocarcinoma. In the stomach, expression of sulfomucins and aberrant Lewis(a) (Le[a]) antigen is an excellent predictor of premalignant progression, and Helicobacter pylori infection is a crucial determinant for the development of atrophy, metaplasia, and adenocarcinoma. In the esophagus, the significance of sulfomucin expression is controversial, the aberrant expression of Le(a) has not been explored, and the role of H pylori in the evolution of preneoplastic conditions is unknown. We investigated in 155 patients referred for endoscopy the association of Barrett's esophagus with expression of sulfomucins, Lewis, secretor, and ABO phenotypes, and H pylori infection. We report a subtype of intestinal metaplasia, present in all patients with esophageal adenocarcinoma, similar to gastric intestinal metaplasia of colonic type (type III or incomplete), that expresses sulfomucins and aberrant Le(a) in goblet and columnar cells. Lewis(a+b-), nonsecretor and blood group A phenotypes, were all positively associated with esophageal adenocarcinoma, suggesting a genetic susceptibility. H pylori infection was detected in 75% of patients with esophageal adenocarcinoma.

Lewis, secretor, and ABO phenotypes, and sulfomucin expression in gastric intestinal metaplasia.

The closely interrelated Lewis, secretor, and ABO phenotypes have long been linked to the risk of peptic ulcers and gastric cancer and may modulate the interaction between Helicobacter pylori and the gastric surface epithelium. We explored the association between the expression of sulfomucins in gastric intestinal metaplasia, a known marker of preneoplastic progression, and the expression of Lewis, secretor, and ABO phenotypes, in 523 subjects from Nariño, Colombia, and 856 subjects from northern Spain. In both study populations, Lewis (a+/b-) and nonsecretor phenotypes showed a significant positive association with the expression of sulfomucins (odds ratios, 2.4 and 2.6, respectively).