Lingual accessory mental foramen: a report of an extremely rare anatomical variation

The presence of accessory foramina and canals in the mandible is frequently overlooked in clinical procedures. It is important to note that these anatomical variations may only be pre-surgically detected on imaging exams, and such detection may directly influence therapeutic success. We describe a previously unreported case of accessory mental foramen located in the lingual cortical bone of the mandible.     

Symptomatic urinary tract infections after surgery for prolapse and/or incontinence

Introduction and hypothesis  

The purpose of our study was to estimate the frequency and risk factors for symptomatic urinary tract infection (UTI) after surgery for stress urinary incontinence (SUI) and/or pelvic organ prolapse (POP).     

The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination

Vaccines are the most effective agents to control infections. In addition to the pathogen antigens, vaccines contain adjuvants that are used to enhance protective immune responses. However, the molecular mechanism of action of most adjuvants is ill-known, and a better understanding of adjuvanticity is needed to develop improved adjuvants based on molecular targets that further enhance vaccine efficacy. This is particularly important for tuberculosis, malaria, AIDS, and other diseases for which protective vaccines do not exist. Release of endogenous danger signals has been linked to adjuvanticity; however, the role of extracellular ATP during vaccination has never been explored. Here, we tested whether ATP release is involved in the immune boosting effect of four common adjuvants: aluminum hydroxide, calcium phosphate, incomplete Freund’s adjuvant, and the oil-in-water emulsion MF59. We found that intramuscular injection is always associated with a weak transient release of ATP, which was greatly enhanced by the presence of MF59 but not by all other adjuvants tested. Local injection of apyrase, an ATP-hydrolyzing enzyme, inhibited cell recruitment in the muscle induced by MF59 but not by alum or incomplete Freund’s adjuvant. In addition, apyrase strongly inhibited influenza-specific T-cell responses and hemagglutination inhibition titers in response to an MF59-adjuvanted trivalent influenza vaccine. These data demonstrate that a transient ATP release is required for innate and adaptive immune responses induced by MF59 and link extracellular ATP with an enhanced response to vaccination.Vaccine adjuvants are used to enhance immune responses toward coadministered antigens, thereby improving vaccine potency, immunological memory, or cross-protection (1, 2). Experimental adjuvants range from simple molecules such as calcium phosphate (CaPi) to very complex mixtures such as incomplete Freund’s adjuvant (IFA), made of a water-in-oil emulsion, or complete Freund’s adjuvant, which also includes killed Mycobacteria (3). However, for human vaccines, adjuvants of highly defined properties that combine efficacy with complete safety are needed; to date, very few compounds have been licensed. Some of the safest and most efficient adjuvants licensed for human use, such as aluminum hydroxide (alum) and the oil-in-water squalene-based emulsion MF59, have been empirically identified, and their mechanism of action is still not fully understood (4, 5). A better understanding of their mechanism of action is needed to develop improved adjuvants that further enhance vaccine efficacy. This is particularly important for diseases for which protective vaccines do not exist (6).An examination of the chemical nature of four major vaccine adjuvants (alum, CaPi, IFA, and MF59) suggested they could interact with the phospholipid bilayer of cell membranes via hydrogen bonding or ionic interactions with the head groups of phospholipids/glycolipids and/or via hydrophobic interactions with the hydrocarbon chains of lipids. As vaccines are frequently administered by intramuscular (i.m.) injection, we posited that a high local concentration of adjuvant is generated in a confined portion of the muscle and that the first cell membrane they come in contact with is the sarcolemma. Because we found that the muscle injection of membrane-interacting snake phospholipase A2 myotoxin induces the release of ATP, which is contained in large amounts inside muscle fibers (7, 8), we decided to evaluate the possibility that other putative membrane-interacting agents such as the major adjuvants mentioned earlier might similarly induce ATP release. This possibility would be particularly relevant in the context of adjuvanticity, as ATP is a “danger signal” acting on a variety of purinergic P2 receptors and, as such, is a strong modulator of immune responses (9–11).     

From the Cover: Insects groom their antennae to enhance olfactory acuity

Grooming, a common behavior in animals, serves the important function of removing foreign materials from body surfaces. When antennal grooming was prevented in the American cockroach, Periplaneta americana, field emission gun scanning electron microscopy images revealed that an unstructured substance accumulated on nongroomed antennae, covering sensillar pores, but not on groomed antennae of the same individuals. Gas chromatography analysis of antennal extracts showed that over a 24-h period nongroomed antennae accumulated three to four times more cuticular hydrocarbons than groomed antennae. Moreover, nongroomed antennae accumulated significantly more environmental contaminants from surfaces (stearic acid) and from air (geranyl acetate) than groomed antennae. We hypothesized that the accumulation of excess native cuticular hydrocarbons on the antennae would impair olfactory reception. Electroantennogram experiments and single-sensillum recordings supported this hypothesis: antennae that were prevented from being groomed were significantly less responsive than groomed antennae to the sex pheromone component periplanone-B, as well as to the general odorants geranyl acetate and hexanol. We therefore conclude that antennal grooming removes excess native cuticular lipids and foreign chemicals that physically and/or chemically interfere with olfaction, and thus maintains the olfactory acuity of the antennae. Similar experimental manipulations of the German cockroach (Blattella germanica), carpenter ant (Camponotus pennsylvanicus), and the housefly (Musca domestica), which use different modes of antennal grooming, support the hypothesis that antennal grooming serves a similar function in a wide range of insect taxa.Insects, like most animals, groom themselves regularly (1), but the diverse functions of self-grooming have been scarcely investigated. Major proposed functions of grooming are to remove debris (2, 3), parasitoids (4), and pathogens (5). It has also been shown that grooming can be evoked by irritant chemicals (6, 7), but grooming-facilitated removal of environmental chemicals has not been demonstrated. Mutual grooming (allogrooming), likewise, can remove pathogens, especially from nestmates in social insects (8, 9). Self-grooming also serves to redistribute antimicrobial substances over the body surface (10), and a similar function has been suggested for redistribution of cuticular lipids (2).Paradoxically, however, insects meticulously self-groom, especially their sensory appendages (e.g., antennae), even in clean environments free of pathogens and dust. Although it is intuitively evident that sensory organs should be regularly groomed to keep them responsive to the environment, and the mechanics of these behaviors have been comprehensively described in various insect species (2, 11–17), the composition of the materials removed by regular grooming has not been analyzed and the adaptive outcomes of this behavior have not been investigated.We observed that antennae of the American cockroach, Periplaneta americana (Linnaeus) (Blattodea, Blattidae), that were immobilized for electrophysiological studies, accumulated a shiny substance on their surface (18). We hypothesized that grooming might serve to remove these excess native secretions and compared groomed and nongroomed antennae of male P. americana cockroaches using field emission gun scanning electron microscopy (FEG SEM). We also investigated the chemical nature of the accumulated material and the relationship between antennal grooming and the amount of this material on the antennae of four species representing three insect orders with different means of antennal grooming. In the American cockroach, and the German cockroach, Blattella germanica (L.) (Blattodea, Blattellidae), a foreleg serves the contralateral antenna to the mouth, which cleans the antenna from base to tip (15, 16). In the carpenter ant, Camponotus pennsylvanicus (De Geer) (Hymenoptera, Formicidae), a specialized structure on the foreleg—the basitarsal brush—grooms the ipsilateral antenna, and then the basitarsal brush is orally groomed (17). The house fly, Musca domestica (L.) (Diptera, Muscidae), does not use its mouth for antennal grooming, but instead sweeps the forelegs, and rarely the middle legs, over the head and cleans head appendages (19). By preventing antennal grooming we now demonstrate that large amounts of cuticular hydrocarbons (CHCs) accumulate on nongroomed antennae of all four species. We further tested whether grooming also removes environmental contaminants from the antennae, and using electroantennogram (EAG) and single-sensillum recordings (SSRs) we assessed whether grooming enhances the olfactory acuity of the antennae of P. americana. Our results support the notion that self-grooming physically removes excess native cuticular lipids as well as extrinsic chemicals from olfactory sensilla and thus maintains the insect’s olfactory acuity to all odorants.     

Greatwall is essential to prevent mitotic collapse after nuclear envelope breakdown in mammals

Greatwall is a protein kinase involved in the inhibition of protein phosphatase 2 (PP2A)-B55 complexes to maintain the mitotic state. Although its biochemical activity has been deeply characterized in Xenopus, its specific relevance during the progression of mitosis is not fully understood. By using a conditional knockout of the mouse ortholog, Mastl, we show here that mammalian Greatwall is essential for mouse embryonic development and cell cycle progression. Yet, Greatwall-null cells enter into mitosis with normal kinetics. However, these cells display mitotic collapse after nuclear envelope breakdown (NEB) characterized by defective chromosome condensation and prometaphase arrest. Intriguingly, Greatwall is exported from the nucleus to the cytoplasm in a CRM1-dependent manner before NEB. This export occurs after the nuclear import of cyclin B–Cdk1 complexes, requires the kinase activity of Greatwall, and is mediated by Cdk-, but not Polo-like kinase 1-dependent phosphorylation. The mitotic collapse observed in Greatwall-deficient cells is partially rescued after concomitant depletion of B55 regulatory subunits, which are mostly cytoplasmic before NEB. These data suggest that Greatwall is an essential protein in mammals required to prevent mitotic collapse after NEB.Greatwall was originally identified in Drosophila as a modulator of Polo activity and a protein required for DNA condensation and normal progression through mitosis (1–4). Biochemical assays in Xenopus extracts have demonstrated that Greatwall is able to inhibit PP2A–B55 phosphatase complexes by phosphorylating the cAMP-regulated phosphoprotein Arpp19 and α-endosulfine, thus participating in the maintenance of the mitotic state (5–8). The control of PP2A through the Greatwall-dependent phosphorylation of Arpp19/Ensa proteins has also been supported by genetic studies in Drosophila (9, 10). The mammalian ortholog of Greatwall, also known as microtubule-associated serine/threonine kinase-like protein (Mastl), also participates in the maintenance of the mitotic state by inhibiting PP2A phosphatases (11, 12). Inhibition of Greatwall is required for the activation of PP2A–B55α,δ complexes during mitotic exit (13), thus suggesting the relevance of this pathway in maintaining the mitotic state (4). How Greatwall activity and function is regulated is not well established. Several evidences support a role for cyclin-dependent kinase (Cdk)-dependent phosphorylation in the activation of Greatwall, and several phosphorylation sites for multiple kinases have been mapped (14, 15). In addition, although Greatwall is mostly nuclear in interphase (3, 11), the cellular and molecular basis of the control of its dynamic intracellular trafficking and its activity remains largely unknown.We show in this work that the murine Greatwall ortholog, encoded by the Mastl gene, is essential for mouse development and cell cycle progression. Greatwall-null cultures, however, display normal kinetics during the G₂/M transition, suggesting that this protein is not required for mitotic entry. Greatwall is exported to the cytoplasm before nuclear envelope breakdown (NEB) but, interestingly, this export follows nuclear import of cyclin B–Cdk1. The lack of Greatwall activity results in defects in chromosome condensation after NEB, and these defects can be rescued by concomitant ablation of B55 proteins. Our results imply that cells are subjected to a mitotic stress resulting from NEB, a moment in which nuclear chromatin becomes exposed to cytoplasmic phosphatases. We therefore propose that Greatwall shuttles to the cytoplasm before NEB and prevents mitotic collapse by inhibiting the PP2A–B55-dependent dephosphorylation of Cdk substrates.     

Prediction of type 1 diabetes among siblings of affected children and in the general population

Aims/hypothesis To compare the predictive characteristics of autoantibodies to GAD (GADA) and islet antigen 2 (IA–2A) for type 1 diabetes between siblings of affected children and children from the general population. Methods Seven-hundred and fifty-five siblings and 3,475 population-derived children were screened for GADA and IA–2A and observed for type 1 diabetes for 15 years. Sensitivity and cumulative disease risks from GADA, IA–2A and double positivity were compared between the cohorts. Results Fifty-six siblings (7.4%) tested positive for GADA, 39 (5.2%) for IA–2A and 29 (3.8%) for both autoantibodies. Thirty-four population derived participants (1.0%) had GADA, 22 (0.6%) had IA–2A and 7 (0.2%) had double positivity. Fifty-one siblings (6.8%) and 15 participants in the population cohort (0.4%) progressed to type 1 diabetes. The predictive sensitivity of GADA was 68% (95% CI 53–81%) among siblings and 50% (95% CI 23–77%) in the general population, while the corresponding values were 58 (95% CI 43–72%) and 43% (95% CI 18–71%) for IA–2A. Double-autoantibody positivity had a sensitivity of 48% (95% CI 34–63%) among siblings and 36% (95% CI 13–65%) in the population cohort. Cumulative disease risks from GADA, IA–2A and double positivity were, respectively, 61% (95% CI 48–74%), 74% (95% CI 61–88%) and 83% (95% CI 69–97%) among siblings compared with those of 24% (95% CI 9–38%), 32% (95% CI 12–51%) and 86% (95% CI 60–100%) in the general population. Conclusions/interpretation There were no significant differences in the disease-predictive sensitivity of GADA and IA–2A positivity or their combination between siblings and the population cohort, whereas, for each antibody, positivity was associated with a higher cumulative disease risk among siblings. Double-antibody positivity conferred similar cumulative disease risk both among siblings and in the general population.     

Pancreatic-fluid collections: a randomized controlled trial regarding stent removal after endoscopic transmural drainage

BACKGROUND: Endoscopic transmural drainage is obtained by creating a communication between the intestinal tract and the pancreatic-fluid collection, and then inserting 1 or more stents. Collection recurrence after therapy is noted in 10% to 30% of cases. It is not known whether leaving the stents in position reduces recurrence rates. OBJECTIVE: To test the hypothesis that patients who have undergone previous successful pancreatic-collection drainage and whose stents are retrieved have higher recurrence rates. DESIGN: Randomized controlled trial. SETTING: Tertiary referral center. PATIENTS: During a period of 27 months, 46 of 77 patients who had undergone endoscopic transmural drainage for pancreatic collections met inclusion or exclusion criteria, and 28 of these patients were randomized. INTERVENTIONS: Fifteen patients were assigned to group A, whose stents were left in place, and 13 were assigned to group B, whose stents were removed after collection resolution. The remaining 18 patients, who were not randomized, also had their stents left in place. All 46 patients were similarly followed. MAIN OUTCOME MEASUREMENT: Recurrence of the same pancreatic collection that required therapy. RESULTS: All patients were followed for a median period of 14 months (interquartile range, 8.2-22 months) after treatment. The primary end point was reached in 5 patients in group B (stent retrieval), as opposed to none in group A (P = .013). Moreover, no recurrence was observed in the remaining 18 nonrandomized patients. LIMITATIONS: Small sample size. CONCLUSIONS: In patients who underwent successful transmural drainage of pancreatic collections, stent retrieval was associated with higher recurrence rates.     

EUS-guided pancreatogastrostomy and pancreatobulbostomy for the treatment of pain in patients with pancreatic ductal dilatation inaccessible for transpapillary endoscopic therapy

BACKGROUND: EUS-guided pancreatogastrostomy (EPG) is described as an alternative to surgery for ductal decompression in symptomatic patients when endoscopic transpapillary access of the main pancreatic duct (MPD) is impossible. OBJECTIVE: To present the midterm clinical response and follow-up of a larger group of patients treated with EPG and a new transbulbar approach, EUS-guided pancreatobulbostomy (EPB). DESIGN: Retrospective case review. SETTING: Two tertiary referral centers in Brussels and Marseille. PATIENTS: From 2000 to 2004, 36 patients (51 years old; range, 14-71 years) were seen. INTERVENTION: EPG or EPB. MAIN OUTCOME MEASUREMENTS: Pain relief, technical aspects, complications, and clinical follow-up. RESULTS: Indications were chronic pancreatitis, with complete obstruction (secondary to a tight stenosis, a stone, or MPD rupture); inaccessible papilla or impossible cannulation (n = 20); anastomotic stenosis after a Whipple procedure (n = 12); complete MPD rupture after acute pancreatitis (AP); or trauma (n = 4). EPG or EPB was unsuccessful in 3 patients; 1 was lost to follow-up. Major complications occurred in 2 patients and included 1 hematoma and 1 severe AP. The median follow-up was 14.5 months (range, 4-55 months). Pain relief was complete or partial in 25 patients (69%, intention to treat). Eight patients treated had no improvement of their symptoms (4 were subsequently diagnosed with cancer). Stent dysfunction occurred in 20 patients (55%) and required a total of 29 repeat endoscopies. LIMITATIONS: Technically demanding and requires careful pretherapeutic evaluation. CONCLUSIONS: EPG or EPB appears to be an effective and relatively safe treatment for the management of pain secondary to pancreatic ductal hypertension in patients with an MPD not accessible by a transpapillary route.