The ANKK1 Protein Associated with Addictions has Nuclear and Cytoplasmic Localization and Shows a Differential Response of Ala239Thr to Apomorphine

The TaqIA single-nucleotide polymorphism (SNP), which is the most widely studied genetic polymorphism in addictions, is located at the gene that encodes the RIP kinase ANKK1 near the gene for dopamine receptor D2. The TaqIA SNP is in strong linkage disequilibrium with the SNP rs7118900, which changes the alanine at position 239 to threonine in the ANKK1 protein (Ala239/A2; Thr239/A1). In silico analysis has predicted that this polymorphic substitution creates an additional phosphorylation site in the kinase domain of ANKK1. To investigate the contribution of ANKK1 to the pathophysiology of TaqIA-associated phenotypes, we analyzed transfected HEK293T cells with the human ANKK1-kinase^Ala239 and ANKK1-kinase^Thr239 variants tagged with GFP. We observed that the ANKK1-kinase is located in both the nucleus and the cytoplasm, suggesting that there is nucleocytoplasmic shuttling of this putative signal transducer. In addition, we found that the Ala239Thr ANKK1-kinase polymorphism exhibited strong expression differences in both the nucleus and the cytoplasm at basal level and when stimulated with the dopamine agonist apomorphine. Specifically, the ANKK1-kinase^Thr239 variant showed the highest level of basal protein expression, while ANKK1-kinase^Ala239 was 0.64-fold lower. After treatment with apomorphine, ANKK1-kinase^Ala239 showed a 2.4-fold increment in protein levels, whereas a 0.67-fold reduction was observed in ANKK1-kinase^Thr239. Thus, here we provide the first evidence of functional ANKK1 differences that are marked by TaqIA and could be associated with vulnerability to addiction.     

Carcinoma of unknown primary site: development in a single institution of a prognostic model based on clinical and serum variables

Purpose To identify clinical and biologic variables with significant impact on survival in patients with carcinomas of an unknown primary site (CUP) and to develop a simple prognostic model. Patients and methods In this retrospective study, univariate and multivariate prognostic factors analyses were conducted in a population of 100 patients with CUP. Patients with features requiring well defined treatments had previously been excluded. Results Overall survival (OS) was significantly related to the following pretreatment adverse prognostic clinical factors: a poor performance status (2 or 3), weight loss more than 10% in the last six months, the presence of liver metastases and more than two metastatic sites. Two biological parameters predicted a significantly shorter survival: elevated serum levels of alkaline phosphatase and of lactate dehydrogenase. In the multivariate analysis, only two independent adverse prognostic parameters were retained: a poor performance status and the presence of liver metastases. We developed a prognostic model for OS based on the following subgroups: good prognosis (PS 0 or 1 and absence of liver metastases), intermediate prognosis (PS≥2 or presence of liver metastases) and poor prognosis (PS≥2 or presence of liver metastases). Median OS for the three groups was 10.8, 4 and 1.9 months respectively, p<0.0001. Conclusion A simple prognostic model using performance status and presence of liver metastases was developed. It allowed the assignment of patients into three subgroups with different outcomes. Treatment strategies could be adapted for each subgroup. We think that this prognostic model could be useful and should be validated in other patient series.     

Laboratory evaluation of Vectobac as against Aedes aegypti in Monterrey,Nuevo León,Mexico

Intensive use of the organophosphate insecticide malathion against adults and temephos against larvae of Aedes aegypti in Mexico over the past 30 years has led to problems requiring the use of new larvicides. Toward this objective, Bacillus thuringiensis var. israelensis (Bti), a target-specific and environmentally safer control agent, was evaluated. Laboratory bioassays were done to determine the susceptibility of 2nd- and 3rd-stage larvae of Ae. aegypti to Vectobac 12 AS (aqueous suspension, 600 ITU/mg). A median lethal concentration of 0.0104 ppm and a 95% lethal concentration of 0.18 ppm were determined after 24 h of exposure to the agent. The values obtained were adjusted for field application and were further tested in the field by the State of Nuevo León, Mexico Vector Control Program. Suspensions of Bti were poured into pipe-water trucks and transferred to domestic 200-gal metal water drums. Larval populations were reduced during a 2-week study period. However, residents complained about a fine dusty film on the water surface. Nevertheless, these results are promising for future Bti field applications.     

Naltrexone improves outcome of a controlled drinking program

Naltrexone is widely used in therapeutic programs with abstinence as a goal. However, it has been used in only a few studies aimed at reducing alcohol consumption. The purpose of this study was to evaluate the efficacy of naltrexone as an adjunct in controlled drinking programs. This was an open randomized study of 12 weeks duration that compared two therapeutic strategies: use of naltrexone in a controlled drinking program (NTX+CD) and the controlled drinking program alone (CD), without NTX. Each group comprised 30 male patients with mild alcohol dependence. During treatment, there were no differences between groups in drinking behavior, though the NTX+CD group showed significantly less craving. In the 12-month follow-up period, the NTX+CD group showed significantly fewer drinking days and heavy drinking days and less craving than the CD group. The results of this study suggest a role for naltrexone in controlled drinking programs.     

Burden of illness in irritable bowel syndrome comparing Rome I and Rome II criteria

OBJECTIVES: To evaluate the burden of illness in irritable bowel syndrome (IBS), in terms of resource utilisation (direct and indirect) and health-related quality of life (HR-QOL), in individuals with IBS who meet Rome I and Rome II criteria. METHODS: A cross-sectional study, carried out by personal interview, on a representative sample (n = 2000) of the Spanish population. Individuals with suspected IBS were identified via a screening question and subsequently given an epidemiological questionnaire to complete. The questionnaire collected information on IBS symptoms, resource utilisation, and HR-QOL [Medical Outcomes Study 36-item Short Form (SF-36)]. RESULTS: Sixty-five individuals met Rome II criteria for IBS, while 146 individuals met exclusively Rome I criteria. Of Rome II individuals, 67.7% had consulted some type of healthcare professional in the previous 12 months, compared with only 41.8% of those individuals meeting exclusively Rome I criteria (p vs 17.1%); 'drug consumption' (70.8 vs 45.2%); and 'reduced performance in main activity' (60 vs 27.4%). Compared with the general population, the study sample reported significantly worse HR-QOL scores in four dimensions of the SF-36 ('bodily pain', 'vitality', 'social functioning' and 'role-emotional'. Additionally, individuals meeting Rome II criteria reported worse HR-QOL scores than those individuals meeting exclusively Rome I criteria, especially in the 'bodily pain' and 'general health' dimensions. CONCLUSIONS: The burden of illness in IBS is important and correlated to the diagnostic criteria employed. Individuals who met Rome II criteria reported a higher level of resource utilisation and worse HR-QOL than individuals meeting exclusively Rome I criteria.     

ABO System: molecular mimicry of Ascaris lumbricoides

A. lumbricoides has been associated to the ABO System by various authors. The objective was to detect ABO System epitopes in A. lumbricoides of groups O, A, B and AB patients. 28 adult parasites were obtained from children to be used as assay material. The patients ABO blood groups were determined. Extracts of A. lumbricoides [AE] were prepared by surgical remotion of the cuticle and refrigerated mechanical rupture. Agglutination Inhibition (AI) and Hemoagglutination Kinetics (HK) tests were used with the [AE]. Of the 28 [AE], eight belonged to O group patients, 15 to A group, three to B group and the remaining two to AB children. The AI Test showed A epitopes in two [AE] of group A patients and B epitopes in two [AE] of group B patients. The HK Test showed B antigenic determiners in two [AE] of group B patients and in two [AE] of group AB patients as well as A antigenic determiners in one [AE] of A group patient. Of the 28 [AE] studied in both tests B epitopes were detected in all [AE] from B and AB patients and A epitopes in three of the 15 [AE] of group A patients. The experiments carried out suggest that A. lumbricoides might absorb A and B antigens from the host, and/or modify the cuticular carbohydrates expression as a kind of antigenic mimicry.     

Low activity of 13-cis-retinoic acid plus interferon alpha 2a in advanced renal cell carcinoma

Retinoids and interferon alpha have shown synergistic activity against metastatic renal cell carcinoma in previous preclinical and clinical studies. Based on these results, we conducted a phase II trial of 13-cis-retinoic acid (cRA) at 1 mg/kg/dose interferon alpha2a (IFN) at initial dose of 9 MU three times a week. Thirty-one patients were entered, all evaluable for toxicity and 30 evaluable for response. One patient achieved a partial response and 10 patients achieved stable disease. Toxicity was mild and primarily related to interferon. No toxic deaths were reported. Median survival time was 10 months. At the dose and schedule used, cRA and interferon-alpha2a showed low activity against metastatic renal cell carcinoma. Further studies with this combination are not recommended.     

Validation of a simplified clinical index to predict evolving patterns in Crohn's disease

BACKGROUND: Prior to this study we obtained a simple mathematical index that uses clinical variables to predict the evolution of Crohn's disease to either a stricturing or a penetrating type. This model was based on the following variables: duration of disease before diagnosis (DD), onset of symptoms (OS), anal disease (AD) and abdominal mass (AM). The aim of our study was to validate this model in an independent cohort of patients and to investigate the relationship between some of the variables and the actual pattern of Crohn's disease in the patients. MATERIAL AND METHODS: We prospectively evaluated 128 patients with Crohn's disease at the moment of diagnosis. We predicted the evolution of their disease using the mathematical model Z = -9.49 + 2.2643 (AD) - 0.0066 (DD) + 2.5282 (AM) + 1.3433 (OS). The cut-off value (reveiver operating characteristics curve) obtained in the training set of patients was P = 0.45. A value higher than this cut off discriminated patients who developed a stricturing pattern. The actual behaviour of the patients' Crohn's disease was observed after a median of 19 months from diagnosis. Of the 128 patients, 80 were classified into one of the two known patterns. Thirty-nine patients (48.8%) developed a stricturing pattern while 41 (51.2%) had a penetrating form of Crohn's disease. RESULTS: The sensitivity of the model for predicting a stricturing type was 100% and the specificity was 31.7%. A P value of < 0.45 proved to be highly reliable in predicting the evolution to a penetrating pattern (positive predictive value was 100% and negative predictive value was 58%). No statistical differences were found between stricturing-type or penetrating-type groups in terms of anal disease, abdominal mass, duration of disease or onset of symptoms. Compared to patients with the penetrating form, initial ileal location was significantly more frequent than colonic location in patients with the stricturing type of Crohn's disease. CONCLUSIONS: We have validated a simple mathematical model that is able to predict the behaviour of Crohn's disease in patients based on clinical variables collected at their initial evaluation. This model can be considered a useful tool for patient management. The anatomical location of the disease is related to the evolutive pattern.     

Is troponin I useful for predicting in-hospital risk for unstable angina patients in a community hospital? Results of a prospective study

INTRODUCTION AND OBJECTIVES: Before including troponin I detection in the daily practice of our hospital we performed a prospective study to determine its real usefulness and to establish the best cut-off point. METHODS: We studied 82 consecutive patients admitted with unstable angina to a community hospital. Troponin I was determined (> 10 h after chest pain). Patients were referred to a tertiary hospital for catheterization/revascularization if clinical events developed. RESULTS: Twenty-five patients (31%) suffered events during admission: recurrent angina in 23 cases (28%); heart failure in 5 (6%); exitus in 3 (4%); myocardial infarction in 1 (1%). The cut-off point for troponin I that best predicted events was 0.1 ng/ml. Patients with troponin I > 0.1 (34 patients, 42%) experienced more events [47 vs. 19%; OR = 3.8 (1.4-10.4); p = 0.01] and had higher rates of recurrent angina (42 vs. 19%), heart failure (12 vs. 2%) and exitus (9 vs 0%). Patients with ECG changes and troponin I > 0.1 showed a significantly higher percentage of events (63%) than those with ECG changes alone (23%) or troponin I > 0.1 alone (15%) or those without ECG changes and troponin I < 0.1 (17%) (p < 0.0001). CONCLUSIONS: Troponin I elevation is useful for predicting in-hospital risk for unstable angina patients admitted to a community hospital. A low cut-off value (0.1 ng/ml) predicts events. The association of ECG changes and high troponin I identifies a population at very high risk; however, the absence of both variables in patients with a diagnosis of unstable angina does not preclude the development of events.