Association of apolipoprotein ɛ4 allele and neuropathologic findings in patients with dementia

Apolipoprotein E (APOE) is a lipoprotein expressed in liver and brain as one of three isoforms (APOE 2, APOE 3 and APOE 4). Recent findings suggest that the presence of APOE 4 is associated with an increased risk for both familial Alzheimer's disease and late-onset Alzheimer's disease. We extended these observations by determining the frequency of APOE alleles in patients with pathologically confirmed Alzheimer's Disease (AD), Parkinson's disease (PD), diffuse Lewy Body disease (DLBD), AD with concomitant PD pathology, demented PD patients without or with concomitant AD pathology and in schizophrenics with a progressive dementia (SCHIZ+DEM). The APOE genotype was determined by restriction digestion of polymerase chain reaction-amplified DNA isolated from frozen brain samples. The frequency of the APOE 4 allele was highest among sporadic AD and DLBD patients (0.30 and 0.38, respectively) and lowest in the SCHIZ+DEM and non-demented PD patients (0.06 and 0.1, respectively). Thus, the APOE 4 allele is over-represented selectively in patients with dementias associated with plaques and tangles and/or cortical Lewy bodies, but not in demented schizophrenics or non-demented PD patients.     

The "conclusions of Pharmacy" in Nancy, at the end of the 18th century: between "synthèses" and "thèses"

A special requirement of the law for apothecaries in Nancy in 1764 imposed on the candidates for a master's degree was the written response to four questions following their practical examinations. Two documents heretofore unpublished show the results of this obligation: the Conclusions de Pharmacie by Joseph Pierson (1765) and the Conclusions de Pharmacie et de Chimie by Fran?ois Mandel (1771). The authors of the present article comment on these documents and make an attempt to place them in the confused history of "synthèses" and "thèses".     

Long-term survival after cardiac retransplantation: a twenty-year single-center experience

OBJECTIVE: To identify risk factors for survival after cardiac retransplantation and compare the survival after retransplantation with that after primary cardiac transplantation. METHODS: A retrospective analysis of 952 patients undergoing cardiac transplantation for the treatment of end-stage heart disease at a single center between 1977 and October 1997. Of these, 43 patients (4.5%) underwent cardiac retransplantation for cardiac failure resulting from transplant-related coronary artery disease, rejection, and early graft failure. RESULTS: No significant difference in actuarial patient survival was found by Kaplan-Meier analysis at 1, 2, and 5 years between patients undergoing primary transplantation and those undergoing retransplantation 76%, 71%, and 60% versus 66%, 66%, and 51%, respectively (P =.2). Multivariable analysis identified a shorter interval between transplants and an initial diagnosis of ischemic cardiomyopathy as significant risk factors for death after retransplantation (P =.04 and.03, respectively). Since 1993, when our criteria for patient selection for retransplantation were revised on the basis of earlier experience to exclude patients with allograft dysfunction as a result of primary graft failure and those with intractable acute rejection occurring less than 6 months after transplantation, the survival has been significantly better (<1993 = 45%, 45%, and 33% versus >/=1993 = 94%, 94%, and 94% at 1, 2, and 4 years, respectively, P =.003). CONCLUSION: The long-term outcome of cardiac retransplantation is comparable with that of primary transplantation, especially in patients with transplant-related coronary artery disease. Patient characteristics and other preoperative variables should assist in the rational application of retransplantation to ensure optimal use of donor organs.     

Microembolization from a carotid mural thrombus detected by transcranial Doppler

Over the last few years, many authors have described the possibility of using transcranial Doppler to demonstrate the passage of microemboli in the cerebral arteries. We report the case of a 44-year-old woman with thrombotic diathesis and thrombocytosis who was admitted twice within a short period of time (one and a half months) to a neurological department because of multiple cerebral infarctions. On the occasion of the second admission, a colour-Doppler examination of the epiaortic vessels, which had previously been negative, showed a carotid lesion due to a mural thrombus and, on the same side as the carotid lesion, transcranial Doppler detected short-duration, high-intensity signals in the middle and anterior cerebral arteries, an expression of the passage of microemboli.As already described by other authors in similar clinical situations, our case confirms that transcranial Doppler can identify the passage of microemboli in the circle of Willis.

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Sommario Negli ultimi anni è stata descritta da molti autori la possibilità di dimostrare mediante Doppler transcranico il passaggio di microemboli nelle arterie cerebrali. Riportiamo il caso di una donna di 44 anni con diatesi trombotica e trombocitosi ricoverata per due volte, a breve distanza di tempo (un mese e mezzo), in ambiente neurologico per infarti cerebrali multipli. In occasione del secondo ricovero l'esame Color-Doppler dei vasi epiaortici, che era risultato negativo in precedenza, ha evidenziato una lesione carotidea riferibile a un trombo murale e al Doppler transcranico sono stati rilevati, omolateralmente alla lesione carotidea, segnali di breve durata ed alta intensità nelle arterie cerebrali media e anteriore, espressione di passaggio di microemboli.Come già descritto da alcuni autori in situazioni cliniche simili, il nostro caso conferma la possibilità di individuare, mediante Doppler transcranico, il passaggio di microemboli nel circolo cerebrale.

     

A device to select the optimal time to replace the pacemaker activated by a lithium-iodine battery: results of 8 years of experience

The discharge curve of lithium-iodine batteries does not havefeatures which make the clinical decision to replace the pacemakereasy. The output voltage fall corresponding to the end of theirlife is evidenced by variations of the output variables (frequencyand/or length of pulse) and the time of elective replacementtime (ER) is arbitrarily established by the manufacturer, ERmay be too early or too late in relation to the threshold valueof myocardial stimulation. Furthermore, the variables indicatingend of life may be changed by troubles in the circuit components,irrespective of the state of battery. A device to detect theoptimal time for replacement (OR) of pacemaker was studied in1692 subjects with implanted LEM VVl electro-stimulators. Thisdevice consists of a resistance of 110 connected in serieswith the catheter through a magnetic switch, which is activatedby placing a magnet over the skin. The transient connectionof the resistor reduces the output voltage by an amount dependingon the resistive load between the electrodes. In a follow-up of 35 000 months the OR device revealed a verygood reliability. Pacemaker replacement, established when stimulation becomesineffective during the application of the magnet or when thespike amplitude in the standard oscilloscope rapidly declined,was necessary in 77 patients (six of them were excluded dueto a circuit blackout). The OR device was useful in 53 patients(74.6%) with a chronic myocardial threshold of more than 2.5V, useless in 18 patients with a myocardial threshold lowerthan 2.5 V; to obviate this limitation a new OR device is describedfeigning a temporary increment of battery impedance. The employmentof the OR device rather than using ER enabled the patients togain 1333 months of stimulation. The gain of pacing varied froma few months to 3 years, with an average of 18.7 months.     

Progetto ATENA,A study on the etiology of major chronic diseases in women: Design,rationale and objectives

In spite of their important impact on populations, a number of diseases - all types of cancer and coronary heart disease in women - are rare events for statistical analysis and often analyzed in designs affected by selection and information biases, such as case-control studies. Large cohort studies based on the storage of biological specimens appear to be the most suitable solution for identifying risks for those diseases.Progetto ATENA, a study on the etiology of major chronic diseases in women is based on this design. Ten thousand women, aged 30–69 years, living in the area of the city of Naples, free of cancer and cardiovascular disease, are being recruited over a four-year period. Ten per cent of the cohort is being randomly selected from the electoral roles, the rest will be volunteers.Information on dietary habits, reproductive history, familiarity for chronic disease, active smoking habits and passive smoking exposure, physical activity, and socio-demographic data are being collected. Clinical data such as blood pressure, anthropometry, and electrocardiogram are also taken. All the participants provide biological samples of blood (fasting drawing) and urine (timed morning spot). The biological samples are processed in order to explore the main areas under study (nutritional markers, metabolism, endocrinology, genetics, environmental exposure markers, thrombogenesis). The samples are stored in liquid nitrogen (–196° C) as soon as the blood and urine processing have been finished. An appropriate follow-up information system on the health status of the participants is being set up to estimate incidence and mortality rates.Corresponding author.     

Functional adenosine receptors in human corpora cavernosa

We have demonstrated that adenosine has potent relaxant activity on the rabbit corpus cavernosum, acting through the A2a subtype receptor for adenosine. We now report studies on the identification and functional characterization of adenosine receptors in human penile vessels. To identify A2 receptors in human corpora cavernosa (HCC) we performed binding studies using the selective radioligand [125I]PAPA-APEC in membranes from HCC. We found the presence of a single class of high affinity (Kd= 0.23 +/- 0.06 nM), low capacity (Bmax=134 +/- 37 fmoles/mg protein) binding sites. Adenosine and CGS 21680 completely displaced [125I]PAPA-APEC binding (Kd= 146.7 +/- 64 microM and 51.52 +/- 27 nM, respectively). Accordingly, in functional studies adenosine relaxed phenylephrine precontracted HCC with an IC50=2.28 +/- 0.17 mM. The effect of adenosine was independent from nitric oxide (NO), and was counteracted by the A2 antagonist CGS 15943. In order to evaluate the in vivo effect of adenosine, increasing concentrations (6, 60, 600 microg) of adenosine or prostaglandin E1 (PGE1) (10 microg) were injected into the corpora cavernosa of four healthy volunteers. Blood flow and erectile response were evaluated at different times by duplex sonography and visual inspection, respectively. It was found that adenosine increased cavernosal peak blood flow velocity in a time- and dose-dependent manner. The highest concentrations of injected adenosine elicited a response that was not statistically different from that of PGE1 (10 microg). However, in contrast to PGE1, a full or partial erection was never obtained. To further investigate the lack of effect of adenosine on penile tumescence (despite the substantial increase in cavernosal blood flow), in vitro experiments were performed on human deep dorsal penile veins (DDPV) obtained from surgical ligation for impotence. Adenosine did not affect basal tone, but it induced almost complete relaxation in noradrenaline-precontracted vein strips with an IC50=1.6 +/- 0.22 mM. Conversely, PGE1 stimulated a sustained increase in basal tone. Therefore, the lack of effect of adenosine on penile tumescence could be due to a simultaneous relaxing activity on penile corpora cavernosa and veins. In conclusion, our study indicates that adenosine relaxes HCC as well as penile veins without affecting erection, at least at the concentrations we have used. Conversely, PGE1 relaxes corpora cavernosa as well as adenosine but strongly stimulates vein contraction, allowing penile tumescence.     

Loss of RhoB expression in human lung cancer progression.

PURPOSE: RhoB is a low molecular weight GTPase belonging to the Ras protein superfamily. Whereas most Rho proteins have been shown to have a positive role in proliferation and malignant transformation, the specific role of RhoB appears more divergent. We reported previously that RhoB inhibits cell proliferation in various human cancer cells. Here, we studied the specific role played by RhoB in human lung cancer. EXPERIMENTAL DESIGN: We analyzed the expression of RhoB protein by immunostaining in human lung tissues ranging from normal to invasive carcinoma from different histological types in two large independent studies of, respectively, 94 and 45 samples. We then studied the cellular effect of RhoB overexpression in a model of lung cancer (A549, adenocarcinoma) and tumorigenicity in nude mice. RESULTS: We showed in both studies that RhoB protein was expressed in normal lung and decreased dramatically through lung cancer progression (P < 0.01). Interestingly, RhoB expression was lost in 96% of invasive tumors and reduced by 86% in poorly differentiated tumors compared with the nonneoplastic epithelium. Moreover, the loss of expression of RhoB correlated significantly with tumor stage and proliferative index, whereas no correlation was found between RhoB and p53 or Bcl-2 expression. We then showed that ectopic expression of RhoB in lung cancer cell line A549 suppressed cell proliferation, anchorage-independent growth, and xenograft tumor growth in nude mice. CONCLUSIONS: RhoB loss of expression occurs very frequently in lung carcinogenesis, reinforcing its putative tumor suppressive activity, and raising the value of its potential use in cancer therapy.