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CORRIGENDUMCorrigendumPublished Online:01 Jun 2009https://doi.org/10.1152/jn.z9k-9514-corr.2009MoreSectionsPDF (266 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat Volume 99, May 2008 Chen J-Y, Di Lorenzo PM. Responses to Binary Taste Mixtures in the Nucleus of the Solitary Tract: Neural Coding With Firing Rate. J Neurophysiol 99: 2144–2157, 2008. First published February 20, 2008; doi:10.1152/jn.01020.2007; http://jn.physiology.org/cgi/content/full/99/5/2144.During production, Fig. 5 was misrepresented; the double arrow underneath the raster displays is offset by about 0.5 s, that is, the arrow should indicate that the stimulus extends from 20 to 25 s, but it actually indicates 19.5 s to 24.5 s. Figure 5 is correctly shown here. FIG. 5.Raster plots of 9 repetitions of all taste stimuli for cell 7.Download figureDownload PowerPointThis article has no references to display. Download PDF Previous Back to Top FiguresReferencesRelatedInformation More from this issue > Volume 101Issue 6June 2009Pages 3341-3341 Copyright & PermissionsCopyright © 2009 the American Physiological Societyhttps://doi.org/10.1152/jn.z9k-9514-corr.2009History Published online 1 June 2009 Published in print 1 June 2009 Metrics

PTP1B Dephosphorylates N-Ethylmaleimide-sensitive Factor and Elicits SNARE Complex Disassembly during Human Sperm Exocytosis

The reversible phosphorylation of tyrosyl residues in proteins is a cornerstone of the signaling pathways that regulate numerous cellular responses. Protein tyrosine phosphorylation is controlled through the concerted actions of protein-tyrosine kinases and phosphatases. The goal of the present study was to unveil the mechanisms by which protein tyrosine dephosphorylation modulates secretion. The acrosome reaction, a specialized type of regulated exocytosis undergone by sperm, is initiated by calcium and carried out by a number of players, including tyrosine kinases and phosphatases, and fusion-related proteins such as Rab3A, alpha-SNAP, N-ethylmaleimide-sensitive factor (NSF), SNAREs, complexin, and synaptotagmin VI. We report here that inducers were unable to elicit the acrosome reaction when permeabilized human sperm were loaded with anti-PTP1B antibodies or with the dominant-negative mutant PTP1B D181A; subsequent introduction of wild type PTP1B or NSF rescued exocytosis. Wild type PTP1B, but not PTP1B D181A, caused cis SNARE complex dissociation during the acrosome reaction through a mechanism involving NSF. Unlike its non-phosphorylated counterpart, recombinant phospho-NSF failed to dissociate SNARE complexes from rat brain membranes. These results strengthen our previous observation that NSF activity is regulated rather than constitutive during sperm exocytosis and indicate that NSF must be dephosphorylated by PTP1B to disassemble SNARE complexes. Interestingly, phospho-NSF served as a substrate for PTP1B in an in vitro assay. Our findings demonstrate that phosphorylation of NSF on tyrosine residues prevents its SNARE complex dissociation activity and establish for the first time a role for PTP1B in the modulation of the membrane fusion machinery.

Prenatal US diagnosis of congenital imperforate hymen

A 32-year-old woman, gravida 1, para 0, was referred for third-trimester sonography at 34 weeks’ gestation to evaluate fetal growth. Sonography revealed a female fetus with an echogenic, midline, nonvascular pelvic mass (Fig. 1, arrow) and no associated genitourinary abnormality. Differential diagnoses included an ovarian mass, distended rectum, hydrocolpos, vaginal atresia and urogenital sinus. Postnatal US revealed an echogenic, fluid-containing midline pelvic mass (Fig. 2, black arrow) in the setting of an imperforate hymen. The cervix is marked (double white arrows). The

Period doubling bifurcation in a train of spontaneous activity

Introduction: It has been shown that fibrillations (FIBs) and positive sharp waves (PSWs) occur during spontaneous oscillations of the membrane potential when the threshold is reached. According to the models of excitable membranes these oscillations should be nonlinear. We wondered whether the nonlinearity of the underlying process could also be demonstrated indirectly in the pattern of spontaneous discharges that can be recorded much easier extracellularly in routine electromyography. A simple example of nonlinear behaviour is a period doubling bifurcation in a periodic system. Methods: In our clinical neurophysiology laboratory discharges are saved on hard disc and the interval between successive discharges is analyzed if there is any doubt whether the discharges occur at regular intervals. In one recording out of 32 we found a phenomenon that we believe to represent a bifurcation. The recording is from the left anterior tibial muscle of a 67 year old patient. The patient showed widespread presence of spontaneous activity and fasciculations in muscles. Neurography was normal. Thus, a motor neuron disease was suspected. The recordings were made with the commercial Neurophysiology workstation „Keypoint“ from ALPINE Biomed with concentric needle electrodes. The samples were exported in ASCII format at a sampling frequency of 24kHz and a resolution of 1µV. Discharges were selected manually and the interdischarge interval (IDI) was calculated. Results: The upper trace in Fig.1 shows the signal as recorded with the concentric needle electrode. The peaks of the discharges that were used to calculate the interdischarge intervals are marked with little circles. The lower trace shows the interdischarge intervals as a function of time. Note that the discharge intervals decrease initially, and increase slowly afterward. At the moment indicated by the double arrow two different IDIs occur that alternate. This resembles behaviour resembles very closely period doubling bifurcations that can be observed in simple nonlinear systems such as the logistic map. Discussion: The recording presented here illustrates that irregularity at the end of trains of spontaneous activity can be the result of nonlinear deterministic behaviour. Further studies have to show whether more irregular behaviour that also can be observed at the end of these trains can also be described with methods of nonlinear dynamics.

Ordered spaces, metric preimages, and function algebras

We consider the Complex Stone–Weierstrass Property (CSWP), which is the complex version of the Stone–Weierstrass Theorem. If X is a compact subspace of a product of three linearly ordered spaces, then X has the CSWP if and only if X has no subspace homeomorphic to the Cantor set. In addition, every finite power of the double arrow space has the CSWP. These results are proved using some results about those compact Hausdorff spaces which have scattered-to-one maps onto compact metric spaces.

Laminin-332 Is a Substrate for Hepsin, a Protease Associated with Prostate Cancer Progression

Hepsin, a cell surface protease, is widely reported to be overexpressed in more than 90% of human prostate tumors. Hepsin expression correlates with tumor progression, making it a significant marker and target for prostate cancer. Recently, it was reported that in a prostate cancer mouse model, hepsin up-regulation in tumor tissue promotes progression and metastasis. The underlying mechanisms, however, remain largely uncharacterized. Hepsin transgenic mice displayed reduced laminin-332 (Ln-332) expression in prostate tumors. This is an intriguing cue, since proteolytic processing of extracellular matrix macromolecules, such as Ln-332, is believed to be involved in cancer progression, and Ln-332 expression is lost during human prostate cancer progression. In this study, we provide the first direct evidence that hepsin cleaves Ln-332. Cleavage is specific, since it is both inhibited in a dose-dependent manner by a hepsin inhibitor (Kunitz domain-1) and does not occur when catalytically inactive hepsin is used. By Western blotting and mass spectrometry, we determined that hepsin cleaves the beta3 chain of Ln-332. N-terminal sequencing identified the cleavage site at beta3 Arg(245), in a sequence context (SQLR(245) LQGSCFC) conserved among species and in remarkable agreement with reported consensus target sequences for hepsin activity. In vitro cell migration assays showed that hepsin-cleaved Ln-332 enhanced motility of DU145 prostate cancer cells, which was inhibited by Kunitz domain-1. Further, hepsin-overexpressing LNCaP prostate cancer cells also exhibited increased migration on Ln-332. Direct cleavage of Ln-332 may be one mechanism by which hepsin promotes prostate tumor progression and metastasis, possibly by up-regulating prostate cancer cell motility.

Invasive Endometrial Lesion in a Patient with Mental Retardation

A 46-year-old Caucasian woman with mental retardation experienced discomfort and irregular menstrual bleeding, which had been increasing for 2 years. The physician from her group home sent her to a gynecologist, where a mass prolapsing through the cervix was noted on physical examination. Cervical and endometrial biopsies were done. Both showed polypoid fragments of endometrium with complex hyperplasia with cytologic atypia and squamous metaplasia (Figure ​(Figure11). A computed tomography scan showed the mass in the uterine cavity, but everything else appeared normal. She was referred to a gynecologic oncologist. Figure 1 Endometrial curettings. A low-power view demonstrating irregular atypical glands with very little intervening stroma. Squamous differentiation is present (arrow). The patient had three risk factors for endometrial cancer: obesity (she weighed 210 pounds, and her body mass index was 36 kg/m2), nulliparity, and hypertension. Both her hypertension and a seizure disorder were well controlled with medications. It was unclear if Pap smears had been done in the past. The probability of endometrial cancer was discussed with her, and she agreed to surgery. Informed consent was obtained through her brother, her legal guardian who also had medical power of attorney. Procedures included exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oopho-rectomy, and bilateral pelvic lymph node dissection. The findings at surgery were a normal appearing uterus, ovaries, and fallopian tubes, with no evidence of obvious disease. The left external iliac vein lymph node appeared pathologically enlarged to 2 cm. The remainder of the pelvic and paraaortic lymph nodes were of normal size, and no other gross abnormalities were seen in the abdomen or pelvis. Clear surgical margins were obtained. On gross pathological examination, the uterus was 223 g and measured 12.3 ⊠ 7 ⊠ 5.3 cm. A polypoid tumor, 9.5 ⊠ 3.2 ⊠ 3.5 cm, was identified, and gross involvement of the lower uterine segment was noted. The cervix and both ovaries were free of disease, both grossly and microscopically, but a right paratubal cyst and left hydrosalpinx were found. Microscopic examination revealed endometrial adenocarcinoma of the endometrioid type (Figure ​(Figure22). Myometrial invasion of 18/20 mm of myometrial thickness was present, and the lower uterine segment was involved up to the endocervical junction. In addition, multifocal lymphovascular invasion was present (Figure ​(Figure33). Figure 2 (a) Section of endomyometrium of the hysterectomy specimen, consisting predominantly of irregular atypical glands infiltrating the myometrium. Focus of solid tumor is present. (b) A high-power view of endometrial carcinoma, endometrioid type, FIGO grade ... Figure 3 Multifocal lymphovascular invasion present within the myometrium (single arrow). The tumor invades the myometrium (double arrow). A total of 28 lymph nodes were excised from the left pelvic, right pelvic, and paraaortic regions. One lymph node in the left pelvis showed metastatic adenocarcinoma, with the largest focus 1.5 cm (Figure ​(Figure44). Figure 4 Extensive involvement of the left pelvic lymph node by metastatic endometrial adenocarcinoma. Note the thin rim of lymph node tissue at the periphery (arrow). Estrogen receptor staining (2–3+) was present in 70% of tumor nuclei; progesterone receptor (3+), 75%; and MIB1, 20% and focally 40% to 50%.

Cough-assisted maintenance of perfusion during asystole

Cough-assisted maintenance of perfusion during asystole. When asystole began, the patient was asked to cough, yielding a recorded aortic systolic blood pressure of 80 mmHg to 100 mmHg (double arrows). Following this, the patient’s native rhythm and blood pressure resumed

Retrospective Analysis of Complications and Risk Factors in Colonic Snare Polypectomies

Purpose: Endoscopic removal of colorectal polyps is frequent. The aim of this study was to evaluate adverse events from snare polypectomy. Methods: We retrospectively analyzed the rate of complications of 1687 snare polypectomies carried out in 8447 patients submitted to colonoscopies between 2001 and 2007 at two Medical Institutions. Two hundred three polyps were larger than 2 cm in diameter. Student t test was used for statistical analysis of mean and chi-square to compare absolute numbers. A significant P-value was defined as < 0.05. Results: Of the 1687 colonoscopic polypectomies 203 were performed in polyps larger than 2 cm in diameter (range 2–5 cm). In this group 24 (11.8%) had immediate bleeding, against 1 (0.07%) smaller than 2 cm P < 0.01. Only one, larger than 2 cm, needed surgery to control bleeding episode (0.49%) P < 0.01. Delayed bleeding occurred in 7 (0.4%), presented only in the larger ones P < 0.01. Perforation occurred in 6 (0.35%), being all of than in the cecum and ascending colon. None required surgery. The age group for bleeding post-polypectomy did not differ, being 59.8 ± 6.7 for immediate bleeding, 60 ± 9.8 for delayed and 63.8 ± 16.3 for no bleeding P > 0.05. Post-polypectomy syndrome occurred in 6 patients (0.35%). In polyps larger than 2 cm, piecemeal resection was performed more often in sessile than in pedunculated ones (89/116,77%) versus (11/87,13%) P < 0.01. In one patient (0.05%) we had a fracture of the snare with entrapment of the basket, managed by using a second endoscope for cutting the pedicle with a Huibregtse papilotome. Invasive carcinoma was present in the adenoma in 40 polyps larger than 2 cm (19.7%). Conclusion: Snare polypectomy are safe procedures, being bleeding the most common complication, related with polyp size mainly with its base, treated most of the time endoscopically. Perforation of the colon being the next, treated too without the necessity of surgery We have no disclosure to make.Figure: Colonoscopy showed erythematous areas and aphthous ulcers throughout the colon (arrows). Pathology revealed intraepithelial lymphocytes (arrows), preserved crypt architecture, and thickened collagen band (double head arrows).

Coordination of Actin Filament and Microtubule Dynamics during Neurite Outgrowth

Although much evidence suggests that axon growth and guidance depend on well-coordinated cytoskeletal dynamics, direct characterization of the corresponding molecular events has remained a challenge. Here, we address this outstanding problem by examining neurite outgrowth stimulated by local application of cell adhesion substrates. During acute outgrowth, the advance of organelles and underlying microtubules was correlated with regions of attenuated retrograde actin network flow in the periphery. Interestingly, as adhesion sites matured, contractile actin arc structures, known to be regulated by the Rho/Rho Kinase/myosin II signaling cascade, became more robust and coordinated microtubule movements in the growth cone neck. When Rho Kinase was inhibited, although growth responses occurred with less of a delay, microtubules failed to consolidate into a single axis of growth. These results reveal a role for Rho Kinase and myosin II contractility in regulation of microtubule behavior during neuronal growth.

Left superior vena cava, a remnant of embryological development

A 46-year-old Brugada syndrome patient underwent insertion of a dual-chamber implantable cardioverter- defibrillator (ICD), revealing a left-sided superior vena cava (SVC), (figure 1), running, characteristically, left from the sternum and flowing into the great cardiac vein. Following this course, the atrial lead was placed in the right atrium (RA) (figure 2, arrow, note dorsal position). The ventricular lead was inserted through the connecting anonymous vein between left and right SVC (figure 1, double arrow), into the right SVC and right ventricle (RV). The presence of a left superior vena cava results from the persistence of the embryonic left anterior cardinal vein. This anomaly is present in approximately 0.5% of the general population and in 3 to 5% of persons with other congenital heart defects, as established by autopsy.

Cholesterol Substitution Increases the Structural Heterogeneity of Caveolae

Caveolin-1 binds cholesterol and caveola formation involves caveolin-1 oligomerization and cholesterol association. The role of cholesterol in caveolae has so far been addressed by methods that compromise membrane integrity and abolish caveolar invaginations. To study the importance of sterol specificity for the structure and function of caveolae, we replaced cholesterol in mammalian cells with its immediate precursor desmosterol by inhibiting 24-dehydrocholesterol reductase. Desmosterol could substitute for cholesterol in maintaining cell growth, membrane integrity, and preserving caveolar invaginations. However, in desmosterol cells the affinity of caveolin-1 for sterol and the stability of caveolin oligomers were decreased. Moreover, caveolar invaginations became more heterogeneous in dimensions and in the number of caveolin-1 molecules per caveola. Despite the altered caveolar structure, caveolar ligand uptake was only moderately inhibited. We found that in desmosterol cells, Src kinase phosphorylated Cav1 at Tyr(14) more avidly than in cholesterol cells. Taken the role of Cav1 Tyr(14) phosphorylation in caveolar endocytosis, this may help to preserve caveolar uptake in desmosterol cells. We conclude that a sterol C24 double bond interferes with caveolin-sterol interaction and perturbs caveolar morphology but facilitates Cav1 Src phosphorylation and allows caveolar endocytosis. More generally, substitution of cholesterol by a structurally closely related sterol provides a method to selectively modify membrane protein-sterol affinity, structure and function of cholesterol-dependent domains without compromising membrane integrity.

Tiling of R7 Axons in the Drosophila Visual System Is Mediated Both by Transduction of an Activin Signal to the Nucleus and by Mutual Repulsion

The organization of neuronal wiring into layers and columns is a common feature of both vertebrate and invertebrate brains. In the Drosophila visual system, each R7 photoreceptor axon projects within a single column to a specific layer of the optic lobe. We refer to the restriction of terminals to single columns as tiling. In a genetic screen based on an R7-dependent behavior, we identified the Activin receptor Baboon and the nuclear import adaptor Importin-alpha3 as being required to prevent R7 axon terminals from overlapping with the terminals of R7s in neighboring columns. This tiling function requires the Baboon ligand, dActivin, the transcription factor, dSmad2, and retrograde transport from the growth cone to the R7 nucleus. We propose that dActivin is an autocrine signal that restricts R7 growth cone motility, and we demonstrate that it acts in parallel with a paracrine signal that mediates repulsion between R7 terminals.

Severe local vancomycin induced skin necrosis

Vancomycin is a glycopeptide antibiotic with activity against gram-positive bacteria, used in the treatment of endocarditis, as an alternative to penicillin in the case of allergy and is the drug of choice for the treatment of infections due to methicillin-resistant staphylococci (MRSA). With the increase of MRSA infections, the use of vancomycin is on the rise. Vancomycin use is estimated at 3.5/100 admissions in the Netherlands [1]. Vancomycin has been documented to cause a variety of adverse reactions that can be roughly divided into two groups. The first is related to an acute release of histamine and is also called vancomycin pseudo-allergic reaction [2]. A well-known example is the Red Men Syndrome (RMS) with an incidence 1–10%. Clinical signs are erythematous or maculopapular rash on face, upper body and extremities, in some cases accompanied by hypotension [3, 4]. The causative mechanism is related to a direct release of histamine by vancomycin or coproducts. This reaction is not IgE mediated. RMS is often associated with the speed of the infusion. Antihistamines, epinephrine and corticosteroids can reduce this reaction. Desensitization is an option for these pseudo-allergic reactions like RMS, IgA dermatosis and Stevens–Johnson syndrome if no other therapy is available [5, 6]. The second group of adverse reactions is related to a hypersensitivity reaction caused by IgE mediated histamine release and can occur in up to 5% of patients [6, 7]. The third group of adverse reactions consists of a heterogeneous mix which include ototoxicity, nephrotoxicity, drug-induced fever, neurological, haematological, gastrointestinal and various dermatological reactions [8]. The mechanism of these reactions is not clear but some may be due to impurities in the vancomycin. We would like to describe a new adverse effect of vancomycin. A 63 year old woman was admitted to the ICU after an emergency laparotomy for an anastomotic leakage after hemicolectomy. Peritoneal cultures became positive for Enterococcus faecium for which intravenous vancomycin therapy was started, using an IV line in the dorsum of the left foot due to difficulty in obtaining peripheral venous access. After 48 h, a progressive skin lesion was noted in the regional vascular bed of the IV line and the left leg was swollen and red (Figure 1). An ischaemic lesion developed after 72 h. The line was tested for patency, working appropriately and not running subcutaneously. No other drugs were given over the IV line and a 0.9% saline drip was running. After discontinuation of the vancomycin and removal of the IV line the lesions regressed and recovered gradually over several weeks. Four weeks later vancomycin administered through a subclavian central venous catheter did not cause any adverse effects. Figure 1 Left foot with ischaemic lesions after vancomycin infusion in the flow area of the vein. Double arrow venous access point Phlebitis can occur in up to 3–13% in patients with a peripheral venous line. Vancomycin is an irritating drug most likely because of its low pH (2.8–4.5), which has a direct irritant effect on the vascular wall [9]. Therefore, the most likely cause of the skin necrosis was a leakageof the i.v. line or capillary leakage, with drug extravasation causing necrosis. An allergic or generalized reaction did not occur after rechallenge of vancomycin. This adds to the likelihood of a local irritant aetiology. In addition, although drug-induced bullous dermatosis and more generalized toxic epidermal necrolysis have been related to vancomycin use, local nonbullous vancomycin-induced skin necrosis as encountered in our patient has not been reported before [10, 11]. If vancomycin is administered via a peripheral line, regular checks for phlebitis and skin necrosis are advised.

Liver Failure in Mitochondrial DNA Depletion Syndrome: The Importance of Serial Neuroimaging in Liver Transplantation Evaluation

Liver Failure in Mitochondrial DNA Depletion Syndrome: The Importance of Serial Neuroimaging in Liver Transplantation Evaluation

Drug-Eluting Stent-Induced Left Anterior Descending Coronary Artery Aneurysm: Repair by Pericardial Patch—Where Are We Headed?

Deployment of drug-eluting stents has been associated with late thrombosis and restenosis on withdrawal of antiplatelet agents. We report a complication of inflammation and localized coronary artery aneurysms immediately adjacent to the stent after 4 years of implantation. Late chronic inflammatory responses may evolve for up to 4 years after sirolimus-eluting stent implantation and can cause weakening, erosion, and aneurysms of the coronary arteries.

Pesticide Exposure Exacerbates α-Synucleinopathy in an A53T Transgenic Mouse Model

The factors initiating or contributing to the pathogenesis of Parkinson's disease and related neurodegenerative synucleinopathies are still largely unclear, but environmental factors such as pesticides have been implicated. In this study, A53T mutant human alpha-synuclein transgenic mice (M83), which develop alpha-synuclein neuropathology, were treated with the pesticides paraquat and maneb (either singly or together), and their effects were analyzed. Immunohistochemical and biochemical analyses showed that chronic treatment of M83 transgenic mice with both pesticides (but not with either pesticide alone) drastically increased neuronal alpha-synuclein pathology throughout the central nervous system including the hippocampus, cerebellum, and sensory and auditory cortices. alpha-Synuclein-associated mitochondrial degeneration was observed in M83 but not in wild-type alpha-synuclein transgenic mice. Because alpha-synuclein inclusions accumulated in pesticide-exposed M83 transgenic mice without a motor phenotype, we conclude that alpha-synuclein aggregate formation precedes disease onset. These studies support the notion that environmental factors causing nitrative damage are closely linked to mechanisms underlying the formation of alpha-synuclein pathologies and the onset of Parkinson's-like neurodegeneration.

Proteomorphous Objects from Abiotic Backbones.

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Ultrastructure of Bone Cells in Paget's Disease of Bone

Ultrastructure of Bone Cells in Paget's Disease of Bone

Protein kinase B/Akt phosphorylation of PDE3A and its role in mammalian oocyte maturation

cGMP-inhibited cAMP phosphodiesterase 3A (PDE3A) is expressed in mouse oocytes, and its function is indispensable for meiotic maturation as demonstrated by genetic ablation. Moreover, PDE3 activity is required for insulin/insulin-like growth factor-1 stimulation of Xenopus oocyte meiotic resumption. Here, we investigated the cAMP-dependent protein kinase B (PKB)/Akt regulation of PDE3A and its impact on oocyte maturation. Cell-free incubation of recombinant mouse PDE3A with PKB/Akt or cAMP-dependent protein kinase A catalytic subunits leads to phosphorylation of the PDE3A protein. Coexpression of PDE3A with constitutively activated PKB/Akt (Myr-Akt) increases PDE activity as well as its phosphorylation state. Injection of pde3a mRNA potentiates insulin-dependent maturation of Xenopus oocytes and rescues the phenotype of pde3(-/-) mouse oocytes. This effect is greatly decreased by mutation of any of the PDE3A serines 290-292 to alanine in both Xenopus and mouse. Microinjection of myr-Akt in mouse oocytes causes in vitro meiotic maturation and this effect requires PDE3A. Collectively, these data indicate that activation of PDE3A by PKB/Akt-mediated phosphorylation plays a role in the control of PDE3A activity in mammalian oocytes.