PrnB, the l-proline transporter of Aspergillus nidulans, belongs to the Amino acid Polyamine Organocation (APC) transporter family conserved in prokaryotes and eukaryotes. In silico analysis and limited biochemical evidence suggest that APC transporters comprise 12 transmembrane segments (TMS) connected with relatively short hydrophilic loops (L). However, very little is known on the structure-function relationships in APC transporters. This work makes use of the A. nidulans PrnB transporter to address structure-function relationships by selecting, constructing and analysing several prnB mutations. In the sample, most isolated missense mutations affecting PrnB function map in the borders of cytoplasmic loops with transmembrane domains. These are I119N and G120W in L2-TMS3, F278V in L6-TMS7, NRT378NRTNRT and PY382PYPY in L8-TMS9 and T456N in L10-TMS11. A single mutation (G403E) causing, however, a very weak phenotype, maps in the borders of an extracellular loop (L9-TMS10). An important role of helix TMS6 for proline binding and transport is supported by mutations K245L and, especially, F248L that clearly affect PrnB uptake kinetics. The critical role of these residues in proline binding and transport is further shown by constructing and analysing isogenic strains expressing selected prnB alleles fused to the gene encoding the Green Fluorescent Protein (GFP). It is shown that, while some prnB mutations affect proper translocation of PrnB in the membrane, at least two mutants, K245E and F248L, exhibit physiological cellular expression of PrnB and, thus, the corresponding mutations can be classified as mutations directly affecting proline binding and/or transport. Finally, comparison of these results with analogous studies strengthens conclusions concerning amino acid residues critical for function in APC transporters.

Amino Acid Sequence↗

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Human genetic variation and mental disorders.

Despite extensive research, our knowledge of structural or functional pathology of severe mental disorders such as schizophrenia and major affective disorders is limited. The only etiological factor with reasonably firm foundation is inheritance, as evidenced by family, twin and adoption studies, however, the molecular basis of this heritability is not established yet. In the absence of clear knowledge about the biological substrate for these psychiatric disorders all the genes expressed in the human brain are potential candidate genes. Association studies analyze genetic variants (polymorphisms) in genes with presumed functional significance in the pathophysiology of the disease (candidate genes). These genetic studies compare the frequency of the hypothetical risk variant in people affected by the disease and in healthy control representatives of the same population. Also, simplex families with an affected child (trios) or with discordant affected offspring (quadruplets), can be used in the association studies. This strategy constitutes a tool to identify the small and moderate effects of genes in these complex phenotypes. Likewise, these kinds of studies could be useful to explain the effect of genes in some specific traits and symptoms present in functional psychoses. Some of our own results on serotoninergic system genes and major depression are included in this chapter as an example of case-control association developed studies in mental disorders.

Journal Article↗

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[Duality of angiotensin II receptors and risk for stroke and cancer: what is the connection?].

Angiotensin II (AII) acts by 2 types of receptors: the ATI receptor which mediates its actions on vasoconstriction, renin (inhibition) and aldosterone (stimulation) secretions, cellular proliferation and angiogenesis and the non-AT1 (often called AT2) receptors. Mainly expressed in the embryon these latter may favor cellular differentiation and recruitment of collateral circulation. Angiotensin converting enzyme inhibitors (ACEI) decrease the synthesis of All and therefore the stimulation of both receptor types whereas AT1-receptor antagonists (AT1RA) block only the stimulation of these latter and increase the stimulation of AT2 receptor since they increase the production of All secondarily to the inhibition of the feedback of renin secretion by All. Experimentally ACEI and AT1RA decrease angiogenesis and cellular proliferation and favor cellular differentiation which could explain the protective effect of ACEI against cancer suggested recently in a Scotish study. Despite of their common suppressive effect on angiogenesis AT1RA may better than ACEI protect against ischemic events specially the cerebral ones because they favor the rapid recruitment of collateral circulation. This has been demonstrated for losartan in case of abrupt ligation of the carotid in the gerbil since its previous administration protects against fatal cerebral ischemia whereas its previous administration with enalapril abolishes this protection. These data may explain why, in the CAPP trial, captopril which has prevented more effectively diabetes occurrence could not be proved superior to diuretics and/or betablocker in the prevention of myocardial infarction and specially of strokes for which exist on the contrary a suspicion of a lower protection. Therefore a comparative trial between AT1RA and ACEI in the prevention of stroke recurrence should appear as a priority for Public Health and Pharmaceutical Industry Authorities.

Angiotensin II↗

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Octreotide in acute bleeding esophageal varices: a prospective randomized study.

BACKGROUND/AIMS: To assess the value of octreotide in the control of acute bleeding esophageal varices, in a prospective randomized study. METHODOLOGY: One hundred and ninety-seven patients admitted for variceal bleeding confirmed at endoscopy were recruited and divided into two groups: group I (n = 111) with endoscopic stigmata of recent bleeding; and group II (n = 86) with active bleeding at emergency endoscopy. Patients in group I were randomized to receive a continuous infusion of octreotide (n = 58) or emergency sclerotherapy (n = 53). Patients in group II were assigned to sclerotherapy (n = 42) or to sclerotherapy plus octreotide (n = 44). At the end of the period of study (48 hours), patients were submitted to sclerotherapy or band ligation until variceal obliteration was achieved. RESULTS: In group I, octreotide was found to be as effective as sclerotherapy regarding hemostasis at 48 hours and on day 7 after the index bleeding episode. Transfusion needs were not significantly different for the two treatment modalities. In group II, the association of octreotide with sclerotherapy was significantly better than sclerotherapy alone either in controlling acute active bleeding (P < 0.001) or in achieving hemostasis at 48 hours (P < 0.01). Transfusion needs were significantly fewer in patients treated with this therapeutic association as compared to sclerotherapy alone. CONCLUSIONS: These results suggest that octreotide infusion is effective in the treatment of variceal bleeding. In patients with recent bleeding, octreotide infusion is as effective as emergency sclerotherapy. In active variceal bleeding, it is a valuable adjuvant treatment in association with emergency sclerotherapy.

Acute Disease↗

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Endoscopic injection therapy vs. multipolar electrocoagulation vs. laser vs. injection + octreotide vs. injection + omeprazole in the treatment of bleeding peptic ulcers. A prospective randomized study.

BACKGROUND/AIMS: A prospective randomized study was performed to assess the effectiveness and safety of 5 different methods of hemostasis in selected patients with high-risk bleeding peptic ulcers. METHODOLOGY: Two hundred and eight patients (n = 208; mean age: 61.6 yrs) with endoscopic stigmata of active hemorrhage, non-bleeding vessel or adherent fresh clot were randomized during emergency endoscopy to receive one of the following modalities of endoscopic therapy (with or without pharmacological therapy): I) injection of absolute alcohol (n = 44); II) multipolar electrocoagulation (BICAP; n = 42); III) Nd-YAG laser (n = 40); IV) injection of absolute ethanol + octreotide (n = 42); V) injection of absolute ethanol + omeprazole (n = 40). RESULTS: The 5 treatment groups were clinically and endoscopically comparable. The initial hemostatic success was > 90% in every group. No significant differences between groups were found in any of the following parameters assessed during hospitalization: incidence of rebleeding (I = 14.8% vs. II = 19.0% vs. III = 16.6% vs. IV = 18.1% vs. V = 20.0%; P > 0.05 mean = 17.7%); incidence of definitive hemostasis (I = 89.3% vs. II = 85.7% vs. III = 86.6% vs. IV = 84.0% vs. V = 86.6%; P > 0.05; mean = 86.5%); incidence of emergency surgery (I = 8.5% vs. II = 11.9% vs. III = 10.0% vs. IV = 6.8% vs. V = 11.1%; P > 0.05; mean = 9.6%); mortality rate (I = 4.2% vs. II = 4.7% vs. III = 3.3% vs. IV = 13.6% vs. V = 4.4%; P > 0.05; mean = 6.2%). Mean age of deceased patients was significantly higher than living patients (71.2 +/- 13.4 vs. 60.9 +/- 14.4; P < 0.05). Approximately 2/3 of the fatal cases were strongly weakened by coexistent medical diseases. The duration of hospital stay was similar for all groups. The BICAP group required less units of blood transfusion (1.9 +/- 1.8 vs. I = 3.0 +/- 2.6; III = 3.5 +/- 3.6; IV = 2.8 +/- 2.3; V = 3.1 +/- 2.5; P < 0.05), perhaps due to the higher mean value of hemoglobin of these patients at hospital admission, compared to all other groups. No significant complications were reported. CONCLUSIONS: This study provides good evidence that injection of absolute ethanol, multipolar electrocoagulation (BICAP) and Nd-YAG laser are equally safe and effective in the endoscopic therapy of acute bleeding peptic ulcers. In contrast, no additional hemostatic benefits arose from the association of pharmacological agents (octreotide or omeprazole) to sclerosis injection.

Anti-Ulcer Agents↗

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[Dementia and extrapyramidal problems caused by long-term valproic acid].

Among the side-effects attributed to valproic acid (VPA), the occurrence of Parkinsonian syndromes and cognitive impairment is very uncommonly reported. We describe five cases of reversible associated Parkinsonism. These cases were observed in epileptic patients, 57 to 74 years old, two women and three men. Extrapyramidal disorders appeared after various durations of treatment (from 6 months to 10 years). Dementia characterized by an insidious onset was associated in three cases and bradypsychia in one case. Brain pseudoatrophy was present in three patients. In all cases the signs and symptoms improved some weeks or months after discontinuation of VPA. In the literature some cases, usually in young adults or children, have been reported. In a prospective study, Armon et al. found various abnormal symptoms and signs related to motor and cognitive function impairment in patients with long-term VPA therapy. These side-effects may be related to a disturbance in the gabaergic pathways in the basal ganglia system. It is of interest to consider that delta 2-valproic acid, a metabolite of VPA, is especially accumulated in selected areas of the brain: the substantia nigra, superior and inferior colliculus, hippocampus and medulla.

Aged↗

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[Non-traumatic rhabdomyolysis: clinical and laboratory diagnosis, assessment of renal complications].

PURPOSE: Non traumatic rhabdomyolysis (RML) is an infrequent and sometimes clinically silent syndrome. RML incidence is increasing in the last few years. A prospective study was performed: 1) to value the non traumatic RML incidence in patients admitted to Emergency Room; 2) to reevaluate the clinical and laboratory criteria of diagnosis; 3) to establish complications' incidence and prognosis during the recovery. PATIENTS AND METHODS: In Emergency Medical First Aid 15.301 patients were examined. To the study were admitted only patients having CK level grater than fivefold the upper normal limits and without trauma, recent surgery, heart and cerebral disease. RESULTS: During the six months study, non traumatic RML incidence was 0.1% (16 patients of 15.301). Drugs, alcohol and substance abuse acute intoxication were the commonest causes. The Acute Renal Failure (ARF) was the more frequent complication (9 patients of 16). Four patients of nine was treated only by fluid administration, the other five by dialysis. Oligoanuric-ARF appeared only in patients affected by toxic RML. These patients had no-return to normal renal functional values at the time of hospital discharge. CONCLUSIONS: Non traumatic RML should be take into account by emergency doctor in cases of acute intoxication. To prevent the complications it's necessary the right interpretation of clinical and laboratory datas and an early and adequate therapy.

Adult↗

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[Diagnostic imaging of kidney carcinomas. Our experience and review of the literature].

In the image diagnosis of renal carcinoma echotomography has played an increasingly important role over the past ten years due to its simplicity and low costs. This method is responsible, above all, for the increased number of diagnosed cases of kidney carcinoma at a pre-clinical stage, the so called "incidentaloma", for which an aggressive surgical approach may be employed with good probabilities of the patient's complete recovery Having illustrated their personal experience of the diagnosis of renal carcinoma, the Authors review currently used imaging methods.

Adenocarcinoma↗

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[Primary aneurysms of carotid bifurcation: surgical management].

From 1980 to 2005, eight patients, four male and four female, age range between 33 to 86 years (average 55.2) with the diagnosis of primary aneurysm of the carotid bifurcation, underwent surgical management. Patients with postendarterectomy pseudo-aneurysms (also rotulated as "secondary") were excluded from the study, due to different pathogenic, clinical and therapeutic features. Four aneurysms were degenerative by nature, occurring in the older patients of the series. Some other etiologies include arterial fibrodysplasia, brucellosis, Behçet's disease and penetrating wound of the neck. All patients underwent the surgical resection of the aneurysm, followed by reestablishment of the carotid continuity in 6 cases; two patient had a definite ligation of the internal and external carotid artery, respectively. There was no operative mortality nor significant morbidity. From 1 to 25 years after the operation, three patients died for different reasons, two were lost for follow up and the remaining three are found alive and well. The main features of clinical presentation, etiology, diagnosis and surgical management of this entity are presented and discussed and compared with similar experiences reported in the international literature.

Adult↗

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[A case of bladder herniation].

The Authors examine one patient with hernia of the bladder. The incidence, etiology and clinical picture are discussed.

Aged↗

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[Neuropathy caused by almitrine].

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Almitrine↗