The outcome of fistulotomy for anal fistula at 1 year: a prospective multicentre French study.

AIM: The study aimed to evaluate outcome at 1 year of one- and two-stage fistulotomy for anal fistula in a large group of patients. METHOD: A prospective multicentre observational study was designed to include patients with anal fistula treated by one- or two-stage fistulotomy. Data were collected using a self-administered questionnaire before surgery, during healing and at 1 year after surgery. RESULTS: Group A (133 patients) with a low anal fistula underwent a one-stage fistulotomy. The median Wexner scores before and after surgery were 1.0 (0-11) and 2.0 (0-18) (P = 0.032) and the median Vaizey scores were 2.0 (0-14) and 3.0 (0-21) (P = 0.055). The Wexner scores and percentage of patients before and after fistulotomy were as follows: 0-5: 88%, 86%; 6-10: 10.7%, 10.7%; 11-15: 1.0%, 2.6%; and 16-20: 0%, 2%. Eighty-seven per cent of the patients were satisfied. Group B (62 patients) underwent two-stage fistulotomy for a high transsphincteric fistula. The Wexner scores and percentage of patients before the first stage and 1 year after the second stage were as follows: 0-5: 86%, 66%; 6-10: 4.5%, 20%; 11-15: 9%, 11%; and 16-20: 0%, 2%. The median Wexner scores before the first stage and after the second stage were 1 (0-14) vs. 4 (0-19) (P < 0.001), and the median Vaizey scores were 1.5 (0-11) vs. 4 (0-20) (P < 0.001). Eighty-eight per cent of the patients were satisfied. CONCLUSION: Low transsphincteric anal fistula can be treated by fistulotomy without clinically significant continence disturbance. Treating high transsphincteric anal fistulae with two-stage fistulotomy is followed by mild continence disturbance. Satisfaction rates were high.

Sphincter-sparing anal-fissure surgery: a 1-year prospective, observational, multicentre study of fissurectomy with anoplasty.

AIM: Internal sphincterotomy is the standard surgical treatment for chronic anal fissure, but is frequently complicated by anal incontinence. Fissurectomy is proposed as an alternative technique to avoid sphincter injury. We describe 1-year outcomes of fissurectomy. METHOD: This was a prospective, multicentre, observational study. All patients with planned surgery for chronic anal fissure were included and had fissurectomy. Data were collected before surgery, at healing, and 1 year after fissurectomy. Patient self-assessed anal symptoms and quality of life (using the 36-item short-form health survey [SF-36] questionnaire). Presurgical and postsurgical variables were compared using the Wilcoxon signed-rank test for paired samples. RESULTS: Two-hundred and sixty-four patients were included (median age, 45 years; 52% women). Anoplasty was associated with fissurectomy in 83% of the 257 documented cases. The main complications were urinary retention (n = 3), local infection (n = 4) and faecal impaction (n = 1). Healing was achieved in all patients at a median of 7.5 weeks after surgery. No recurrence occurred. At 1 year, 210 (79%) questionnaires were returned. Median anal pain had dropped from 7.3/10 to 0.1/10 (P < 0.001), anal discomfort had decreased from 5.0/10 to 0.1/10 (P < 0.001) and the Knowles-Eckersley-Scott Symptom constipation score had decreased from 9/45 to 5/45 (P < 0.001). There was a nonsignificant increase in the Wexner anal incontinence score, from 1/20 to 2/20. De-novo clinically significant anal incontinence (Wexner score > 5) affected 7% of patients at 1 year, but presurgical incontinence had disappeared in 15% of patients. All SF-36 domains significantly improved. Anoplasty did not impact any result. CONCLUSION: Given its high rate of healing and low rate of de-novo anal incontinence, fissurectomy with anoplasty is a valuable sphincter-sparing surgical treatment for chronic anal fissure.

One-year outcome of haemorrhoidectomy: a prospective multicentre French study.

AIM: An evaluation was performed of the 1-year outcome of open haemorrhoidectomy (Milligan and Morgan alone or with posterior mucosal anoplasty [the Leopold Bellan procedure]). METHOD: A prospective, multicentre, observational study included all patients having a planned haemorrhoidectomy from January 2007 to June 2008. Data were collected before surgery, and at 3 months and 1 year after surgery. Patients assessed their anal symptoms and quality of life (SF-36). RESULTS: Six-hundred and thirty-three patients (median age = 48 years, 56.5% women) underwent haemorrhoidectomy either by the Milligan and Morgan procedure alone (n = 231, 36.5%) or together with the Leopold Bellan procedure (posterior mucosal anoplasty) for resection of a fourth haemorrhoid (n = 345, 54.5%), anal fissure (n = 56, 8.9%) or low anal fistula (n = 1, 0.16%). The median healing time was 6 weeks. Early complications included urinary retention (n = 3), bleeding (n = 11), local infection (n = 7) and faecal impaction (n = 9). At 1 year, the main complications included skin tags (n = 2) and anal stenosis (n = 23). There were three recurrences requiring a second haemorrhoidectomy. On a visual analogue scale, anal pain at 1 year had fallen from a median of 5.5/10 before treatment to 0.1/10 (p < 0.001), anal discomfort from 5.5/10 to 0.1/10 (P < 0.001) and the Knowles-Eckersley-Scott Symptom (KESS) constipation score from 9/45 to 6/45 (P < 0.001). The median Wexner score for anal incontinence was unchanged (2/20). De-novo anal incontinence (a Wexner score of >5) affected 8.5% of patients at 1 year, but preoperative incontinence disappeared in 16.7% of patients with this symptom. All physical and mental domains of quality of life significantly improved, and 88% of patients were satisfied or very satisfied. CONCLUSION: Complications of open haemorrhoidectomy were infrequent. Anal continence was not altered. Comfort and well-being were significantly improved at 1 year after surgery. Patient satisfaction was high despite residual anal symptoms.

Multicentre study of hepatitis B virus genotypes in France: correlation with liver fibrosis and hepatitis B e antigen status.

The clinical significance of hepatitis B virus (HBV) genotypes is still under debate. The aims of this study were to assess the distribution of HBV genotypes in France and to identify the associations between HBV genotypes and patient demographics, severity of liver disease and HBeAg status in patients referred to tertiary care centres. This was a French, multicentre, retrospective study on 262 patients with chronic HBV infection. HBV genotypes were determined using INNO-LiPA. Liver fibrosis damage was evaluated by histological analysis of biopsy samples. Patients were mainly male (74%), of Caucasian (65%), Asian (17%) or African (18%) ethnicity and 36% were HBeAg positive. All A-G genotypes were found, the most frequent being genotypes D (27%) and A (24%), followed by E (13%) and C (12%), and B (7%). Mixed genotypes were detected in 16% of the cases. Genotype A was associated with sexual contact (P < 0.001) and genotype D with transfusion (P < 0.001) and HBe antibody positivity (P = 0.03).The distribution of HBV genotypes differed with regard to the ethnicity, and may reflect migration patterns. Genotypes A and D were the most frequent in France. Genotype A was associated with HBeAg positivity and genotype D with HBe antibody positivity. In our European patients, we find no clear association between a given HBV genotype and liver disease severity.

Chronic MPTP treatment reproduces in baboons the differential vulnerability of mesencephalic dopaminergic neurons observed in Parkinson's disease.

Chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to baboons was shown previously to result in a motor syndrome and a pattern of striatal dopaminergic fibre loss similar to those observed in idiopathic Parkinson's disease. In the present study, tyrosine hydroxylase-immunoreactive neurons were quantified in the mesencephalon of control (n = 4) and chronically MPTP-treated (n = 3) baboons. MPTP induced a significant reduction in neuronal cell density in the substantia nigra (63.8% reduction) and the ventral tegmental area (53.1%). Within the substantia nigra, obvious mediolateral and dorsoventral gradients of neuronal cell loss were observed. First, the pars lateralis was more affected than the lateral divisions of the pars compacta (89.6% vs 73.8% cell loss), which in turn were more depleted than the medial divisions (60.1% reduction). Second, the ventral regions of the pars compacta were more degenerated than the dorsal parts (82.4 vs 51.5% decrease). This regional pattern is strikingly similar to that observed in Parkinson's disease and indicates that two subpopulations of dopaminergic neurons are distinguishable on the basis of their differential vulnerability to MPTP. Finally, the present study confirms that chronic mitochondrial complex I inhibition using MPTP in primates is sufficient to reproduce the typical dopaminergic cell loss and striatal fibre depletion observed in Parkinson's disease.

In vivo high intrinsic efficacy of triazolam: a positron emission tomography study in nonhuman primates.

The triazolobenzodiazepine triazolam is a central-type benzodiazepine receptor (BZR) ligand that is widely prescribed as a hypnotic agent. Triazolam produces its effects through potentiation of gamma-aminobutyric acid-mediated neurotransmission. Findings reported from in vitro binding studies showed some discrepancies concerning the pharmacological characteristics of triazolam. The present study aims to characterize in vivo the biochemical properties of triazolam, i.e., cerebral pharmacokinetics, interaction with BZR, potency, and intrinsic efficacy. Triazolam was studied in living nonhuman primates using positron emission tomography. Two different studies were carried out: (a) a direct study using [11C]triazolam and (b) an indirect competition study using the radiolabeled BZR antagonist 1C]flumazenil. Results showed that, in the brain in vivo, triazolam binds specifically and competitively to the BZR. Its rapid cerebral kinetics is consistent with a hypnotic profile (maximal binding after 23 min, elimination half-life of 202 min). Triazolam is very potent in displacing [11C]flumazenil (ID50 = 28 +/- 6 micrograms/kg). Hill analysis of the displacement curve does not show obvious binding-site heterogeneity. Triazolam is 20 times more potent in displacing [11C]flumazenil and 50 times more potent in inhibiting pentylenetetrazol-induced paroxysmal activity than the full benzodiazepine agonist diazepam. Interestingly, the simultaneous use of positron emission tomography and EEG recording allowed us to show that triazolam-positive intrinsic efficacy is slightly higher (20%) than that of diazepam. An attractive hypothesis proposes that the severity of side effects of BZR ligands is proportional to their intrinsic efficacy. Therefore, our study shows that triazolam side effects, as for other benzodiazepines, may be related to its high intrinsic efficacy in vivo.

Synthesis of 3-[18F]fluoromethyl-BTCP and evaluation as a potential PET radioligand for the dopamine transporter in baboons.

In an attempt to visualize in vivo the dopamine transporter and evaluate its potential as an imaging tool for monitoring dopamine fiber degeneration by positron emission tomography, the 18F-positron-emitting analogue of 3-fluoromethyl-1-[1-(2-benzothienyl)-cyclohexyl]-piperidine, [18F]BTCP, was synthesized and tested in a primate model of hemiparkinsonism. [18F]BTCP was obtained from cyclotron-produced n.c.a. [18F]fluoride (110 min half-life) and by nucleophilic substitution from 3-bromomethyl-BTCP with a radiochemical yield of 6% (decay-corrected). After intravenous injection, the cerebral distribution of the radioactivity was observed mainly in cortical areas and cerebral structures enriched in catecholamine reuptake sites such as the caudate-putamen complex and the thalamus. The binding ratio, defined with respect to the cerebellum (taken as a region of non-specific binding), was highest in the thalamus (1.42), intermediate in the putamen (1.36) and lowest in the caudate nucleus (1.17), suggesting that some specific binding occurs in these regions. After saturation of dopamine and norepinephrine transporters by nomifensine, the binding ratio in the thalamus, putamen and caudate nucleus striatum remained essentially unchanged in the non-lesioned hemisphere. When comparing binding ratios between the intact and the dopamine-denervated striatum, there was a modest loss of binding in the denervated striatum, suggesting that degeneration of dopaminergic fibers could be detected using 3-[18F]fluoromethyl-BTCP. However due to a high non-specific binding in vivo, the interest of 3-[18F]fluoromethyl-BTCP to image the dopamine reuptake system in vivo appears rather limited.

Modeling analysis of [11C]flumazenil kinetics studied by PET: application to a critical study of the equilibrium approaches.

The multi-injection modeling approach was used for the in vivo quantitation of benzodiazepine receptors in baboon brain using positron emission tomography (PET) and [11C]flumazenil (RO 15-1788) as a specific ligand. The model included three compartments (plasma, free, and bound ligand) and five parameters (including the benzodiazepine receptor concentration). The plasma concentration after correction for the metabolites was used as the input function. The experimental protocol consisted of four injections of labeled and/or unlabeled ligand. This protocol allows the evaluation, from a single experiment, of the five model parameters in various regions of interest. For example, in the temporal cortex, the concentration of receptor sites available for binding (B'max) and the equilibrium dissociation constant (Kd) were estimated to be 70 +/- 15 pmol/ml and 15.8 +/- 2.2 nM, respectively. The validity of the equilibrium approach, which is the most often used quantitation method, has been studied from simulated data calculated using these model parameters. The equilibrium approaches consist of reproducing in PET studies the experimental conditions that permit the use of the usual in vitro methods such as Scatchard analysis. These approaches are often open to criticism because of the difficulty of defining the notion of equilibrium in in vivo studies. However, it appears that the basic relation of Scatchard analysis is valid over a broader range of conditions than those normally used, such as the requirement of a constant bound/free ratio. Simulations showed that the values of the receptor concentration (B'max) and the equilibrium dissociation constant (Kd) found using Scatchard analysis are always underestimated. These simulations also suggest an explanation concerning the dependency of B'max and Kd on the time point employed for the Scatchard analysis, a phenomenon found by several authors. To conclude, we propose new protocols that allow the estimation of the B'max and Kd parameters using a Scatchard analysis but based on a protocol including only one or two injections. These protocols being entirely noninvasive, it thus becomes possible to investigate possible changes in receptor density and/or affinity in patients.

Stable parkinsonian syndrome and uneven loss of striatal dopamine fibres following chronic MPTP administration in baboons.

The progressive degeneration of dopamine neurons observed in idiopathic Parkinson's disease was mimicked by injecting low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to baboons, on a chronic basis. Five Papio papio baboons were treated on two different regimens (chronic intravenous administration at weekly intervals for 20-21 months or, daily MPTP treatment for five days followed five to six months later by chronic weekly injections for 5-21.5 months). All animals were assessed for motor symptoms during and after neurotoxic treatment. Both regimens invariably resulted in the appearance of a progressive and irreversible syndrome characterized by action and resting tremor, cogwheel rigidity, postural impairments, hypokinesia and bradykinesia. In some animals, symptoms of resting tremor and rigidity initially restricted to one side of the body became bilateral within a few months of treatment. Subtle abnormalities that may be found in idiopathic Parkinson's disease such as alterations of the blink reflex response were also noted. Neuropathological examination of caudate nucleus, putamen, substantia nigra and ventral tegmental area in brain sections stained for tyrosine hydroxylase showed a typical uneven striatal dopamine fibre loss and a neuronal depletion in the dopaminergic mesencephalic cell groups that reproduce those observed in idiopathic Parkinson's disease. Immunocytochemical observations and behavioural data show that chronic rather than acute MPTP injection regimens can replicate most of the neuropathological and the clinical features typical of idiopathic Parkinson's disease, possibly by increasing the ability of this neurotoxin to target specific subpopulations of mesencephalic dopaminergic neurons.

In vivo visualization of central muscarinic receptors using [11C]quinuclidinyl benzilate and positron emission tomography in baboons.

The muscarinic antagonist, quinuclidinyl benzilate (QNB), labeled with carbon 11 was used as a radioligand to visualize in vivo by positron emission tomography (PET) the central muscarinic acetylcholine receptors (mAChR) in baboons (Papio papio). The binding characteristics of [11C]QNB showed its specific binding to central mAChR. [11C]QNB brain uptake was high in cerebral cortex and striatum, areas that are rich in mAChR, whereas it decreased rapidly in cerebellum, evidencing non-specific binding in this structure that is almost devoid of mAChR. These results are consistent with the known cerebral distribution of mAChR in primates. [11C]QNB specific cerebral binding was enhanced by pretreatment with methyl-QNB, a peripherally acting muscarinic antagonist. Specifically labeled binding sites alone were blocked by prior administration of dexetimide, a muscarinic antagonist. Specific radioactivity was driven out from mAChR-rich regions by atropine and dexetimide, drugs with high affinity for mAChR. This competition was stereospecific since only dexetimide, the pharmacologically active isomer of benzetimide, was able to compete with the radioligand on its binding sites. A relationship between the occupancy of [11C]QNB-labeled receptors by atropine or dexetimide and the concomitant induction of a pharmacological effect was also detected by simultaneous PET scanning and electroencephalographic recording. Since mAChR form an important part of choline receptors in the central nervous system, [11C]QNB appears to be a suitable radiotracer to monitor cerebral physiological or pathological phenomena linked to the cholinergic system in living subjects.