11C]AZ10419369: a selective 5-HT1B receptor radioligand suitable for positron emission tomography (PET). Characterization in the primate brain

The 5-HT1B receptor has been implicated in several psychiatric disorders and is a potential pharmacological target in the treatment of depression. Here we report the synthesis of a novel PET radioligand, [11C]AZ10419369 (5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide), for in vivo visualization of 5-HT1B receptors in the brains of macaques and humans subjects. [11C]AZ10419369 was prepared by N-methylation of (8-(1-piperazinyl)-5-methylchrom-2-en-4-one-2-(4-morpholinophenyl) carboxamide, using carbon-11 methyl triflate. Regional brain uptake patterns of [11C]AZ10419369 were characterized by PET measurements in two macaques and a preliminary study in two human subjects. In addition, AZ10419369 was prepared in tritium labeled form for in vitro autoradiography studies in macaque brain tissue sections. The radiochemical purity of [11C]AZ10419369 was >99% and specific radioactivity was >3600 Ci/mmol. After iv injection of [11C]AZ10419369, 3-4% was in brain after 7.5 min. The regional brain distribution of radioactivity was similar in humans and macaques showing the highest uptake of radioactivity in the occipital cortex and the basal ganglia, in accord with autoradiographic studies performed using [3H]AZ10419369. Uptake was moderate in the temporal and frontal cortical regions, lower in the thalamus and lowest in the cerebellum. In macaques pre-treated with the selective 5-HT1B receptor antagonist, AR-A000002, binding was reduced in a dose-dependent manner, consistent with specific binding to 5-HT1B receptors. These data support [11C]AZ10419369 as a suitable radioligand for labeling 5-HT1B receptors in the primate brain. This radioligand may be useful in future studies evaluating drug-induced receptor occupancy and measurement of brain 5-HT1B receptor levels in patients with psychiatric disorders.     

Are sexual side effects of prolactin-raising antipsychotics reducible to serum prolactin?

OBJECTIVE: To assess the degree to which sexual side effects (SSE) are associated with prolactin-raising antipsychotics, and to what degree such SSE are reducible to serum prolactin levels. METHOD: A large sample (n=264) of patients treated for 6 weeks with prolactin-raising and prolactin-sparing antipsychotics was assessed for changes in sexual performance in terms of libido, arousal and orgasm using the Antipsychotics and Sexual Functioning Questionnaire. For men also erection and ejaculation were evaluated. At 6 weeks, prolactin levels were assessed and analyzed in relation to sexual performance. RESULTS: Men and women reported SSE (libido and orgasm) with about the same frequency. Prolactin-raising medication induced significantly more SSE than prolactin-sparing medication (adjusted OR=3.4, 95% CI: 1.8, 6.5) with 43% of emerging SSE attributable to prolactin-raising medication. When adjusted for serum prolactin, the association between prolactin-raising medication and SSE was reduced but remained significant (OR=2.1, 95% CI: 1.0, 4.5); 27% of emerging SSE remained attributable to prolactin-raising medication. For erectile and ejaculatory dysfunction in men, the attributable fraction due to prolactin-raising medication was 32% before, and 11% after adjustment for serum prolactin. CONCLUSIONS: Around 40% of emerging SSE in schizophrenia are attributable to the prolactin-raising properties of antipsychotic medication. Of this attributable fraction, around one-third to two-thirds is directly reducible to the effects of serum prolactin.     

The sense of touch: embodied simulation in a visuotactile mirroring mechanism for observed animate or inanimate touch

Previous studies have shown a shared neural circuitry in the somatosensory cortices for the experience of one's own body being touched and the sight of intentional touch. Using functional magnetic resonance imaging (fMRI), the present study aimed to elucidate whether the activation of a visuotactile mirroring mechanism during touch observation applies to the sight of any touch, that is, whether it is independent of the intentionality of observed touching agent. During fMRI scanning, healthy participants viewed video clips depicting a touch that was intentional or accidental, and occurring between animate or inanimate objects. Analyses showed equal overlapping activation for all the touch observation conditions and the experience of one's own body being touched in the bilateral secondary somatosensory cortex (SII), left inferior parietal lobule (IPL)/supramarginal gyrus, bilateral temporal-occipital junction, and left precentral gyrus. A significant difference between the sight of an intentional touch, compared to an accidental touch, was found in the left primary somatosensory cortex (SI/Brodmann's area [BA] 2). Interestingly, activation in SI/BA 2 significantly correlated with the degree of intentionality of the observed touch stimuli as rated by participants. Our findings show that activation of a visuotactile mirroring mechanism for touch observation might underpin an abstract notion of touch, whereas activation in SI might reflect a human tendency to "resonate" more with a present or assumed intentional touching agent.     

Lipid rafts and metabolic energy differentially determine uptake of anti-cancer alkylphospholipids in lymphoma versus carcinoma cells

Perifosine is a member of the class of synthetic alkylphospholipids (APLs) and is being evaluated as anti-cancer agent in several clinical trials. These single-chain APLs accumulate in cellular membranes and disturb lipid-dependent signal transduction, ultimately causing apoptosis in a variety of tumor cells. The APL prototype edelfosine was previously found to be endocytosed by S49 mouse lymphoma cells via lipid rafts. An edelfosine-resistant cell variant, S49(AR), was found to be cross-resistant to other APLs, including perifosine. This resistance was due to defective synthesis of the raft constituent sphingomyelin, which abrogated APL cellular uptake. Sensitivity of S49 cells to edelfosine was higher than perifosine, which correlated with a relatively higher uptake. Human KB epidermal carcinoma cells were much more sensitive to APLs than S49 cells. Their much higher APL uptake was highly dependent on intracellular ATP and ambient temperature, and was blocked by chlorpromazine, independent of canonical endocytic pathways. We found no prominent role of lipid rafts for APL uptake in these KB cells; contrary to S49(AR) cells, perifosine-resistant KBr cells display normal sphingomyelin synthesis, whereas APL uptake by the responsive KB cells was insensitive to treatment with methyl-beta-cyclodextrin, a cholesterol-sequestrator and inhibitor of raft-mediated endocytosis. In conclusion, different mechanisms determine APL uptake and consequent apoptotic toxicity in lymphoma versus carcinoma cells. In the latter cells, APL uptake is mainly determined by a raft- and endocytosis-independent process, but metabolic energy-dependent process, possibly by a lipid transporter.     

High number of intraepithelial CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in patients with large early-stage cervical cancer

In a prospective study, we have examined the tumor-specific immune response in a group of 59 patients with human papillomavirus (HPV) 16-positive (HPV16(+))-induced or HPV18(+)-induced cervical cancer. Local antitumor immunity was analyzed by the enumeration of tumor-infiltrating dendritic cells and CD4+, CD8+, and regulatory T cells as well as by calculation of the ratio of CD8+/CD4+ T cells and CD8+/regulatory T cells. Systemic tumor-specific immunity was assessed by determination of the HPV E6- and/or E7-specific T-cell response in the blood of these patients. Finally, these variables were evaluated with respect to known histopathologic prognostic variables, including the absence (LN-) or presence (LN+) of lymph node metastases. Stratification according to the lymph node status of patients revealed a significantly stronger CD8+ T-cell tumor infiltration, a higher CD8+/CD4+ T-cell ratio, and higher CD8+/regulatory T-cell ratio in the group of patients in which the tumor failed to metastasize to the tumor-draining lymph node. Subdivision according to the presence (IR+) or absence (IR-) of circulating HPV-specific T cells disclosed that the highest number of tumor-infiltrating CD8+ T cells was found in the group of LN- patients displaying a concomitant systemic tumor-specific immune response (LN-IR+). CD8+ T-cell infiltration in LN-IR- patients was comparable with that of LN+ patients. In cervical cancer, the absence of lymph node metastases is strongly associated with a better prognosis. Our data indicate that, especially in a subgroup of LN- patients, a strong and effective interaction between immune system and tumor exists. This subgroup of cervical cancer patients may have the best prognosis.     

Spatiotemporal analysis of organelle and macromolecular complex inheritance

Following mitosis, daughter cells must inherit a functional set of essential proteins and organelles. We applied a genetic tool to simultaneously monitor the kinetics and distribution of old and new proteins marking all intracellular compartments in budding yeasts. Most organelles followed a general pattern whereby preexisting proteins are symmetrically partitioned followed by template-based incorporation of new proteins. Peroxisomes belong to this group, supporting a model of biogenesis by growth and division from preexisting peroxisomes. We detected two exceptions: the nuclear pore complex (NPC) and the spindle pole body (SPB). Old NPCs are stably inherited during successive generations but remained separated from new NPCs, which are incorporated de novo in mother and daughter cells. Only the SPB displayed asymmetrical distribution, with old components primarily inherited by daughter cells and new proteins equally incorporated in both cells. Our analysis resolves conflicting models (peroxisomes, NPC) and reveals unique patterns (NPC, SPB) of organelle inheritance.     

Management of diverticulitis: results of a survey among gastroenterologists and surgeons

Aim The study aimed to investigate current management strategies for left‐sided diverticulitis and compare them with current international guidelines. Differences between surgeons and gastroenterologists and between gastrointestinal and nongastrointestinal surgeons were assessed. Method A web‐based survey of treatment options for uncomplicated and complicated diverticulitis was carried out among surgeons and gastroenterologists in the Netherlands. Only surgeons were asked about surgical strategy. Results A total of 292 surgeons and 87 gastroenterologists responded, representing 92% of all surgical and 46% of all gastroenterology departments. Ninety per cent of respondents treated mild diverticulitis without antibiotics. About one‐fifth (18% gastroenterologists; 19% surgeons) regarded a CT scan as mandatory in the initial assessment. Most surgeons and gastroenterologists used some form of bowel rest, would consider outpatient treatment and would perform a colonoscopy on follow up. For Hinchey Stage 3, 78% of surgeons would consider resection and primary anastomosis and laparoscopic lavage was viewed as a valid alternative by 30% of gastrointestinal and 2% of nongastrointestinal surgeons. For Hinchey stage 4, 46% of gastrointestinal and 72% of nongastrointestinal surgeons would always perform Hartmann’s procedure. Conclusion The treatment of diverticulitis in the Netherlands shows major differences when compared with guidelines for all stages of disease.     

Long-term outcome after 1822 operatively treated ankle fractures: A systematic review of the literature

The aim of this literature review is to systematically gather the highest level of available evidence on the long-term outcome after operatively treated ankle fractures in the English, German and Dutch literature. A search term with Boolean operators was constructed. The search was limited to humans and adults and the major databases were searched from 1966 to 2008 to identify studies relating to functional outcome, subjective outcome and radiographic evaluation at least 4 years after an operatively treated ankle fracture. Of the 42 initially relevant papers, 18 met our inclusion criteria. A total of 1822 fractures were identified. The mean sample-size weighted follow-up was 5.1 years. The initial number of patients that were included in the studies was 2724, which results in a long-term follow-up success rate of 66.9%. Regarding the fracture reduction we found 4 papers reporting on 106 fractures. Of the fractures that were classified according to Danis-Weber, 736 were eligible for correlation with the long-term outcome. In 442 fractures a comparison was possible between supination-external rotation stage 2 and 4 of the Lauge-Hansen classification. Only one study reported on the influence of initial cartilage lesions on the outcome. Regarding the involvement of the posterior malleolus, two studies reported on the long-term outcome. None of the studies addressed the influence of hindfoot varus or valgus on the long-term outcome after ankle fracture. Only 79.3% of the optimally reduced fractures show good to excellent long-term outcome. The Weber A type fractures do not show a better long-term outcome than Weber B type fractures. Recommendations for future research were formulated.