A Bayesian hierarchical approach to account for left-censored and missing radiation doses prone to classical measurement error when analyzing lung cancer mortality due to γ-ray exposure in the French cohort of uranium miners.

Epidemiological data on cohorts of occupationally exposed uranium miners are currently used to assess health risks associated with chronic exposure to low doses of ionizing radiation. Nevertheless, exposure uncertainty is ubiquitous and questions the validity of statistical inference in these cohorts. This paper highlights the flexibility and relevance of the Bayesian hierarchical approach to account for both missing and left-censored (i.e. only known to be lower than a fixed detection limit) radiation doses that are prone to measurement error, when estimating radiation-related risks. Up to the authors' knowledge, this is the first time these three sources of uncertainty are dealt with simultaneously in radiation epidemiology. To illustrate the issue, this paper focuses on the specific problem of accounting for these three sources of uncertainty when estimating the association between occupational exposure to low levels of γ-radiation and lung cancer mortality in the post-55 sub-cohort of French uranium miners. The impact of these three sources of dose uncertainty is of marginal importance when estimating the risk of death by lung cancer among French uranium miners. The corrected excess hazard ratio (EHR) is 0.81 per 100 mSv (95% credible interval: [0.28; 1.75]). Interestingly, even if the 95% credible interval of the corrected EHR is wider than the uncorrected one, a statistically significant positive association remains between γ-ray exposure and the risk of death by lung cancer, after accounting for dose uncertainty. Sensitivity analyses show that the results obtained are robust to different assumptions. Because of its flexible and modular nature, the Bayesian hierarchical models proposed in this work could be easily extended to account for high proportions of missing and left-censored dose values or exposure data, prone to more complex patterns of measurement error.

[A case of amputation neuroma of the bile duct following video-laparoscopic cholecystectomy]. / A proposito di un caso di neuroma d'amputazione della via biliare dopo colecistectomia laparoscopica.

We report a case of neuroma of the common hepatic duct arising five years after cholecystectomy (laparoscopic then converted in laparotomy). A 73-years-old patient was admitted for obstructive jaundice. Ultrasonography, TC and cholangiography showed a nodular lesion of the common hepatic of 1 cm in diameter, causing a regular and important stenosis of the main bile duct. Histologic examination demonstrated neuroma. By the analysis of this and 42 other previously published cases, the following features of bile duct neuroma were outlined: 1) variable interval between cholecystectomy and the onset of jaundice (2 months to 40 years); 2) the same incidence after laparoscopic or laparotomic cholecystectomy; 3) the generally complicated postoperative course after first surgical approach; 4) the various localizations on the biliary tree (cystic, main bile duct, intrahepatic ducts); 5) the circumstances of onset are almost the same (obstructive jaundice); 6) the histologic examination is mandatory for a correct diagnosis; and 7) the best treatment is resection of the bile duct tract involved in neuroma and reconstruction of biliary tree with hepaticojejunostomy.

Aberrations induced in chromosomes of somatic cells of Drosophila melanogaster irradiated in C-metaphase.

Experiments conducted on the X irradiation of neural ganglia of Drosophila melanogaster are described. The ganglia were placed in saline containing colchicine. After two hours, they were irradiated and then samples were fixed at 5,15,25,35 minutes from the beginning of irradiation. The results obtained show that the aberration level increases with time subsequent to fixing. This increase takes place first for chromatid deletions and then for isochromatid deletions and chromatid exchanges. Gaps and subchromatid exchanges do not, on the contrary, show any increase with time. We did not observe a difference in radiosensitivity between the sexes. Some hypotheses are put forth in an attempt to explain these results.

Prolonged in vivo gene expression driven by a tyrosine hydroxylase promoter in a defective herpes simplex virus amplicon vector.

A 9.0-kb fragment of the tyrosine hydroxylase (TH) promoter, previously shown to direct tissue-specific expression in transgenic mice, was fused to an Escherichia coli LacZ reporter gene in a defective herpes simplex virus type-1 (HSV-1) amplicon vector (THlac). The HSV immediate early (IE) 4/5 promoter (HSVlac) was used as a control. LacZ gene expression was visualized by X-Gal histochemical and TH immunocytochemical analysis. Two days and 10 weeks after THlac injection into rat caudate nucleus (CN), X-Gal-stained cells were observed in the substantia nigra (SN) and locus ceruleus (LC) ipsilateral to the injection site. These blue cells were TH-positive neurons as evidenced by double labeling with immunocytochemistry. Moreover, the number of X-Gal+, TH+ (double-positive) neurons in the SN increased at 10 weeks as compared to that seen 2 days after THlac injection. In marked contrast, few double-positive nigral neurons were observed either 2 days or 10 weeks after direct injection of THlac into SN. However, neither nigral nor striatal injection of HSVlac resulted in prolonged gene expression. These results suggest that a neuronal, but not a viral, promoter in an HSV vector can produce cell-type-specific, prolonged, and stable gene expression following retrograde transport. In addition, THlac produced infrequent gene expression in TH-negative cells (CN and dorsal to SN) after THlac injection into CN and SN, respectively. Overall, these results suggest that in some in vivo contexts cell-type-preferred expression can be achieved by a cellular promoter in an amplicon vector. Moreover, they underscore the need for the careful and systematic study of neuronal promoters in HSV vectors.

Dopamine D2, D3, and D4 receptor mRNA levels in rat brain and pituitary during aging.

Reverse Transcriptase-Polymerase Chain Reaction technique was used to determine the levels of the mRNAs encoding different receptors belonging to the D2 family in various brain areas of 6-, 12-, 18-, and 24-month-old rats. We found a progressive, age-dependent reduction in the mRNA levels of D2 short and D2 long receptors in corpus striatum, substantia nigra, and frontal cortex. D2 short and D2 long receptor mRNA levels were unchanged in hippocampus and olfactory tubercle, while they increased in pituitary. D3 receptor mRNA levels were reduced in olfactory tubercle and unchanged in striatum. D4 receptor mRNA levels were unmodified in pituitary gland. These data suggest that the molecular mechanisms responsible for regulating the pattern of expression of the various dopamine receptors are differentially regulated by aging.

Distribution and kainate-mediated induction of the DNA mismatch repair protein MSH2 in rat brain.

DNA repair is one of the most essential systems for maintaining the inherited nucleotide sequence of genomic DNA over time. Repair of DNA damage would be particularly important in neurons, because these cells are among the longest-living cells in the body. MSH2 is one of the proteins which are involved in the recognition and repair of a specific type of DNA damage that is characterized by pair mismatches. We studied the distribution of MSH2 in rat brain by immunohistochemical analysis. We found the level of MSH2 expression in rat brain to be clearly heterogeneous. The highest intensity of staining was found in the pyramidal neurons of the hippocampus and in the entorhinal and frontoparietal cortices. Positive cells were observed in the substantia nigra pars compacta, in cerebellar granular and Purkinje cells, and in the motor neurons of the spinal cord. We investigated the possible modulation of MSH2 expression after injection of kainate. Systemic administration of kainate induces various behavioural alterations and a typical pattern of neuropathology, with cell death in the hippocampal pyramidal neurons of the CA3/CA4 fields. Kainate injection also resulted in a marked, dose-dependent increase of MSH2 immunoreactivity in the hippocampal neurons of the CA3/CA4 fields. The effect was specific, since no changes in immunoreactivity were detected in the dentate gyrus nor in other brain areas. In summary, our data suggest that a mismatch DNA repair system, of which MSH2 protein is a representative component, is heterogeneously expressed in the rat brain and specifically induced by an experimental paradigm of excitotoxicity.

Differential expression of fetal and mature tau isoforms in primary cultures of rat cerebellar granule cells during differentiation in vitro.

The molecular mechanism(s) responsible for the differential expression of various tau protein isoforms as well as their functional role in morphogenesis, neurofibrillary tangle formation and neurodegeneration have not been completely clarified. We found that the expression of tau proteins in primary cultures of cerebellar granule cells from neonatal rat brain is a developmentally regulated process affecting tau synthesis at different levels. Changes in tau RNA splicing are clearly demonstrated by PCR data showing the switching on of the mRNA containing four internal repeats by DIV 6 and the switching off of the mRNA containing three internal repeats after DIV 12. The changes in mRNA levels of the different tau isoforms during development in vitro occur in parallel with changes in tau protein expression, both qualitatively and quantitatively, as shown by Western analysis of protein extracts from granule cells at different DIV with an anti-tau polyclonal antibody. Finally, as indicated by MAP2 and tau immunocytochemistry data, the switch in tau protein expression appears to be contemporary with neurite outgrowth and cell differentiation. Our data suggest that a differential expression of various tau proteins parallels the degree of cell maturation.

ABO-incompatible bone marrow transplantation: a GITMO survey of current practice in Italy and comparison with the literature.

ABO incompatibility is not considered a contraindication for allogeneic haematopoietic stem cell transplantation (HSCT) despite its association with several immunohaematological complications. At present, there is no general agreement concerning the best methods to reduce these problems. To survey current practice related to ABO-incompatible HSCT in Italy, a questionnaire was sent to all GITMO centres. Specific questions were addressed for management in pretransplant, peritransplant and post transplant phases. A comparison was made with the experience reported in the literature. In all, 74% of GITMO centres answered the questionnaire. A high degree of heterogeneity concerning the pretransplant tests, methods to overcome infusion of ABO-incompatible marrow and post transplant transfusion policy and monitoring was evident. For many of these aspects the literature does not contain unanimous guidelines. The considerable degree of heterogeneity that reflects, at least partially, the lack of consensus in the literature demonstrates that ABO incompatibility is still an open issue in the setting of HSCT and that further studies are needed for a more rationale approach and for the production of evidence-based guidelines.

Deafferentation induces early and delayed differential changes in the pattern of expression of the various guanine nucleotide binding protein mRNAs in rat striatum.

A polymerase chain reaction-derived method was used to identify and quantitate the relative abundance of the different mRNAs encoding various isoforms of the guanine nucleotide regulatory protein Gs, Gi, and Go alpha subunits in the striata of rats unilaterally injected with 6-hydroxydopamine in the substantia nigra. Thirty days after the lesion, the mRNA levels of the G(o) and of the Gi 1 alpha subunits were increased by about 2-3 times, those of the Gi 3 decreased by about 60% and those of Gi 2 and Gs unmodified. The pattern of expression of the G(o) alpha subunits mRNA changed in a time-dependent fashion, being significant 20 days after the lesion. The decrease in Gi 3 alpha subunit mRNA levels was maximum 10 days after the lesion and tended to be reduced in magnitude with time while the changes in Gi 1 alpha subunit mRNA showed a byphasic behaviour being reduced at 10 days and increased at 30 days after the lesion. These data suggest that the expression of the various G protein alpha subunits in the striatum are continuously regulated by factors originating from afferent neurons and surrounding cells.

Therapy of acute pancreatitis in systemic lupus erythematosus with plasmapheresis and corticosteroids.

A 24-year-old woman with systemic lupus erythematosus had, after reduction of corticosteroid therapy, a severe relapse of the disease with hepatitis, nephritis and pleurisy. After admission to the hospital, she was given 60-80 mg/day of prednisone and acute pancreatitis developed on the third day. Plasmapheresis, followed by injection of 1 g of methylprednisolone, was started. This combined therapy induced a prompt and complete recovery in a few days.

Cytological analysis of X-ray-induced aberrations in spermatocytes I and the somatic ganglia of male Drosophila melanogaster.

The correlation between damage induced in somatic cells and that induced in germinal cells of the same genetic pool of individuals is important in establishing the possibility of extrapolation of this damage to the offspring. We have used Drosophila melanogaster to compare cytologically the frequency of aberrations induced in the cells of somatic ganglia and in the spermatocytes I of males irradiated with 625 R X-rays. The spermatocytes were more sensitive than the gangliar cells to radiation: the aberrations induced in the spermatocytes I were three times more frequent than those induced in the ganglia. The distribution of the aberrations was, however, similar. The most important variable element lies in our observing no symmetrical exchanges in the spermatocytes. This result seems to us to be related to the fact that in the males of D. melanogaster there is no crossing-over.

Complications of plasma-exchange.

Complications in apheresis affect on the average 40% of treated patients and 10-14% of the procedures. The mortality rate is 1/500 treated patients. The utilization of more complex techniques, central catheters, plasma infusion and even more the superimposition of different factors increase the incidence and gravity of side effects. Very influent are also the underlying pathologies and the clinical conditions; particularly at risk are patients with TTP/HUS and GBS. However, PE represents a relatively safe therapy in which prevention of complications requires a particularly diligent personnel and a careful evaluation of indications.

Apheresis and biocompatibility: complement activation.

When blood comes into contact with plastic surfaces of extracorporeal circuits activation of different biological systems occurs, among them the complement. This will be activated mainly through the alternative pathway but also through the classical one. The activation through the latter pathway occurs when antibodies directed against polymeric materials used for the production of extracorporeal circuits or substances utilized for their sterilization are produced by the patient's immunosystem. Even if complement activation occurs almost constantly during apheretic procedures the natural inhibitory mechanisms of this system attenuate and disguise this phenomenon. Important and clinical manifestations occur in particular patients or in case of technologically more complex techniques. In apheresis the complement activation may be implicated in the relatively frequent complications such as fever and chills, hypotension, as well as in the rare but severe cases of ARDS.

[Retroextraperitoneal laparoscopic nephrectomy]. / Nefrectomia laparoscopica per via retroextraperitoneale.

The authors describe a new technique of laparoscopic nephrectomy; the retroextraperitoneal approach has been successfully performed in 4 patients with the following indications: 2 non functioning hydronephrotic kidneys, 2 atrophic chronic pyelonephritic kidneys. The patient was put in a proneoblique position after the retrograde placement of a ureteral catheter up to the renal pelvis, through which the contrast medium was injected. The Veress needle is inserted under fluoroscopic guidance into the perirenal fatty space which was insufflated with CO2. One 12 mm and three 10 mm Trocars were inserted into the cavity created by gas in the trapezoid area whose boundaries are: the 12th rib, the iliac crest, the posterior axillary line and the sacrospinalis muscle. The kidney was progressively dissected free with the traditional laparoscopic instruments (forceps and scissors). The artery has always been closed with clips. In two patients the vein has been stapled and cut with EndoGIA. After the section of the clipped ureter the kidney was removed en block by pulling it out through the 20 mm Kleiber Trocar in two cases and in the other two cases by extending to a length of 4 cm the port of one Trocar. The average total operating time was 4.35 hours and blood loss < 200 cc. The patients were all discharged on the fourth postoperative day. The advantages of the retroextraperitoneal approach with respect to open surgery are synthetically the following: a less traumatic and a more accurate dissection almost always bloodless; a shorter hospitalization period; an almost painless postoperative course.(ABSTRACT TRUNCATED AT 250 WORDS)

[Ligation of the internal spermatic vein through 2 laparoscopic ports]. / La legatura della vena spermatica interna attraveso due porte laparoscopiche.

Thirty-three two port laparoscopic internal spermatic vein ligations have been performed in 31 patients in our Department. The procedure carried out through two 10 mm ports in a mean time of 25 minutes decreases both the invasivity of intervention and the costs when reusable instruments are used. The technique is feasible with an operative laparoscope (working channel diameter 4 mm) through which a grasp can be maneuvered. The two port procedure is as safe as the three port procedures. Preliminary follow up indicated only one recurrence of varicocele (4%). Out of the 19 patients treated for male subfertility who have at least a 6 month follow up, eleven reported an improvement in seminal quality. All the patients but one were discharged on the first postoperative day. Laparoscopic internal spermatic vein ligation provides a real alternative to different surgical techniques decreasing postoperative pain and shortening period of convalescence with immediate return to full activity. The advantages of laparoscopic internal spermatic vein ligation are increased with the two port procedure.

[Conservative therapy in renal carcinoma: follow-up]. / Terapia conservativa nel carcinoma renale: follow up.

Due to the increasing use of sophisticated imaging techniques, up to 30% of diagnosed renal cell carcinoma (RCC) are asymptomatic and diagnosed incidentally. Getting the cue from our personal survey of conservative renal surgery for renal cell carcinoma with a cancer specific survival of 95.5% after a mean follow up of 32.7 months, a review of the literature is illustrated: numerous studies have documented the technical success rate with this approach as well as long term disease free survival, comparable to that obtained by radical nephrectomy, in patients with unilateral, small, low stage tumors and normal opposite kidney. Patient selection is of extreme importance in case of partial resection in the presence of a normal contralateral kidney. The tumor must be < 3-4 cm, solitary, well delineated on CT, without invasion of the perinephric far or pyelocaliceal system (T1 and T2), easily resectable with at least 1 cm of healthy parenchyma. Only well informed patients who agree on a careful follow up after surgery can be candidates for kidney sparing surgery. In case of imperative surgery the follow up must be strict and personified for every single patient. Those patients who underwent a partial nephrectomy in presence of a normal contralateral kidney should be monitored with a conventional follow up monitored in order to detect an eventual local recurrence: 12 monthly ultrasonography and contrast enhanced CT scan alternately every 6 months for the first five years after surgery and then lifelong once a year by echography and/or CT scan.

[Physiopathology of BPH obstruction]. / Fisiopatologia dell'ostruzione da IPB.

The underlying BPH related mechanisms of outlet obstruction are outlined (modification of the shape of the bladder neck, failure of funnel formation, geometric variations of the urethra, alpha 1 adrenoceptors mediated sympathetic hyperactivity at the level of the lower genito-urinary tract). Bladder voiding dysfunction in response to prostate obstruction is also discussed and correlated to ultrastructural patterns and clinical symptoms. Finally, a pathogenetic mechanism for detrusor overactivity in obstructed bladder is suggested.

[Alpha blockers, TUS-P and TUR-P in the treatment of benign prostatic hypertrophy. A comparison using multivariate statistical analysis]. / Alfa-litici, TUS-P, TUR-P nel trattamento dell'IPB. Confronto con analisi statistica multivariata.

To evaluate the effectiveness of Alpha-blockers, TUI-P and TUR-P in the treatment of obstruction due to BPH, 50 patients, never before treated, were considered. Fifteen were treated with alfuzosin chlorhydrate 7.5 mg/day for four months, 15 were submitted to TUI-P and 20 to TUR-P. In all patients linear purr was carried out before treatment and was repeated from 60 to 90 days after intervention in surgical patients and during the fourth month of treatment in patients treated with alfuzosin. The data obtained were analyzed with the T-test both for dependent and independent samples. The results show that Alpha-blocker contain an increase in maximal flow, without decreasing bladder voiding pressures. On the contrary TUI-P and TUR-P, besides the increase in maximal flow obtain a significant reduction of bladder pressures. The conclusions are the following: maximal flow alone is not a sufficient parameter to evaluate the work of the bladder, the entity of the obstruction and the effectiveness of the therapy. The treatment with Alpha-blockers is unable to reduce the obstruction due to BPH. TUI-P and TUR-P realize an effective deobstruction. Under the same deobstructing effect TUR-P assures a better voiding performance by obtaining higher flow values.

[T1G3 of the bladder: our experience]. / T1G3 della vescica: la nostra esperienza.

From June 1991 to June 1995 we treated 20 patients affected by T1 G3 TCC of the bladder, 18 men and 2 women, with a mean age of 65.1 years (46-71). In 11 patients the disease was monofocal, with diameter of the tumor under 3.5 cms; in 5 patients monofocal with diameter of the tumor over 3.5 cms; in 1 patient multifocal and in 3 patients complex (mono or multifocal associated with CIS). The 11 patients with monofocal disease under 3.5 cms were treated with TUR-B, the other 9 (all males) were submitted to radical cystectomy with OINB diversion as first choice treatment. The mean follow up (all patients) was 3.2 years (6 months-14 years). Out of the patients of the former group only 3 did not show any relapse, the other 8 showed multiple relapses or metachronous tumors: 5 were treated with TUR-B+BCG, 3 were cystectomized. The patients submitted to cystectomy as first choice treatment did not show any progression of the disease after a mean follow-up of 19.8 months.

[100 orthotopic neobladders in men after cystectomy: a 5-year experience]. / 100 neovesciche ortotopiche nel maschio cistectomizzato: esperienza di 5 anni.

Urethral bladder substitution is traditionally suggested to good prognosis cystectomized patients. In our series this diversion was chosen for all but the salvage cystectomized men. Between the 1st of February 1991 and the 30th of April 1996, one hundred consecutive men underwent lower urinary tract reconstruction after radical cystoprostatectomy for bladder cancer. An orthotopic ileal neobladder was constructed (in 84 cases according to Kock's technique and in 16 to Studer's technique). Total early complication rate was 29% (29/100), including one perioperative death due to sepsis (mortality rate 1%). 13 patients required surgery (6 retroperitoneal hematomas, 2 wound dehiscences, 1 urinary fistula, 1 lymphocele, 1 rectal-neobladder fistula, 1 rectal-cutaneous fistula, 1 necrosis of the terminal ureter). The late complication rate was 19% (19/100); in 8 cases reparative surgery was required (1 mechanical ileus, 2 bladder neck stenoses, 3 stenoses of the ureteral anastomosis, 2 laparoceles). Four patients were lost at the follow-up; out of the 96 remaining patients only 85 were evaluable for continence: continence during the day was achieved in a period between there to six months in 78 patients (91.7%); night continence was achieved with planned awakenings in 60 patients (70.5%). Eight patients recovered potency, another 7 had successful intercourses after PGE1 intracavernous injection. Renal function based on creatinine value was mildly impaired in 5/78 evaluable patients (6.4%) (peak creatinine 2.8 mg%). In 29 patients tumour progression was observed (29%): 9 pelvic and 20 metastatic. Among the latter 2 urethral recurrences were observed (2%). Twenty-four patients died for metastatic cancer, one for primitive lung cancer, one patient for postoperative septic shock. Adjuvant chemotherapy was administered in 11 patients without complication with an indwelling catheter in the neobladder to avoid drug reabsorption. Four patients showed complete response (2 are alive after a mean of 12 months), 6 were non responders and 1 had a partial response. In our series the ileal neobladder is a feasible method of urinary diversion when urethral cancer involvement is ruled out. Early and late complications are proportionally decreasing with experience and overall continence is satisfactory. The fate of the neobladder depends on both the technique and patient's compliance. Only educated patients can cope successfully with neobladder diversion without major complications. All the patients operated for non salvage cystectomy deserve to be diverted with a continent urethral bladder substitution.