Is seminal vesicle implantation with permanent sources possible? A dose–volume histogram analysis in patients undergoing combined 103Pd implantation and external beam radiation for T3c prostate cancer

PURPOSE: Combined brachytherapy and external beam radiation therapy (EBRT) of the prostate and seminal vesicles (SVs) is evolving as a successful treatment option for high-risk prostate cancer. Dose-volume histogram (DVH) analysis of the SV was performed in patients with biopsy-positive SV who received implantation of the SV and prostate. METHODS AND MATERIALS: Fifteen consecutive patients with high-risk features (prostate-specific antigen [PSA] > or =10 ng/mL, Gleason score > or = 7, or clinical stage > or = T2b) and a positive SV biopsy were treated with a 103Pd implant of the prostate and SV followed by 45Gy of EBRT. DVHs were generated for the prostate and total SV volume (SVT). In addition, the SV was divided into 3-mm-thick volumes identified as SV1, SV2, SV3, SV4, SV5, and SV6 starting from the junction of the prostate and SV and extending distally. Delivered dose was defined as the D90 (dose delivered to 90% of the organ on DVH). RESULTS: The median number of seeds implanted into the prostate and the SVT was 59 (41-94) and 9 (4-21), respectively. The median D90 values for the prostate, SVT, SV1, SV2, SV3, SV4, SV5, and SV6 were 103.2 (87.4-137.1), 46.2 (4.0-69.4), 76.0 (31.2-147), 63.4 (25.1-145.9), 49.7 (15.3-118), 27.4 (9.3-135.1), 14.2 (2.3-100.3), and 3.9 (0-61.5) Gy, respectively. CONCLUSIONS: Implantation of the SV using a real-time intraoperative approach is technically feasible and results in higher doses to the SV than has been reported with implantation of the prostate alone. Although dose distribution in the SV can be variable and unpredictable, these doses, in combination with 45 Gy of EBRT, may be adequate to control disease spread in these organs.     

The acute effects of intranasal oxytocin administration on endocrine and sexual function in males

The role of the neuropeptide oxytocin (OT) ranges from the modulation of neuroendocrine physiological effects to the establishment of complex social and bonding behaviours. Experimental studies in animals, as well as case reports in humans, suggest that OT affects different aspects of sexual behaviour and has predominantly facilitating properties for sexual appetence and performance.

Using a previously established experimental paradigm of sexual arousal and masturbation-induced orgasm, this study investigated the acute effects of intranasal OT application (24 I.U.) on endocrine parameters and measures of sexual appetence and function in healthy men (n=10). In a double-blind, placebo-controlled, balanced cross-over design, sexual arousal, and orgasm were induced by an erotic film and masturbation. In addition to the continuous recording of endocrine (OT, cortisol, prolactin, epinephrine, norepinephrine) and cardiovascular data (heart rate), parameters of appetetive, consummatory, and refractory sexual behaviour were assessed using the acute sexual experience scale (ASES).

OT plasma levels were significantly elevated after intranasal OT throughout the whole experiment (>60 min). In addition, OT treatment induced significantly higher increases in epinephrine plasma levels during sexual activity without affecting cortisol levels, prolactin levels or heart rate. OT treatment did not alter appetitive, consummatory, and refractory sexual behaviour according to the ASES. However, when subjects were asked about their subjective perception of whether OT or placebo had been applied, eight out of 10 subjects in the OT group answered correctly, thus pointing to an altered perception of arousal.

In conclusion, intranasally administered OT leads to a marked increase in OT plasma levels together with increased secretion of catecholamines when subjects are engaged in sexual activity in a laboratory setting. As the effects of OT on sexual behaviour were equivocal, future studies should examine possible facilitating effects further by including males, females, and couples in a field setting, taking into account that OT exerts the most prominent behavioural effects in pair bond formations.     

Ursachen und Pathophysiologie der Kniegelenkinfektion

Zusammenfassung Kniegelenkinfekte k?nnen h?matogen endogen oder posttraumatisch exogen entstehen. H?matogene Infekte finden sich vor allem bei Kindern, aber auch bei Patienten mit verminderter Immunabwehr, z. B. nach Organtransplantionen. Der, posttraumatische Gelenkinfekt entsteht durch offene Verletzungen, intraartikul?re Injektionen, Operationen und fortgeleitet aus der Umgebung. Nach unfallchirurgischen und orthop?dischen Operationen sind Gelenkinfekte relativ selten. Für die Pathophysiologie sind zwei Erkenntnisse besonders wichtig: 1. Eine intraartikul?re Infektion führt innerhalb von 24 bis 48 Stunden zu Sch?den am hyalinen Knorpel. 2. Durch die reflektorische Ruhigstellung wird der Substrataustausch vermindert und der Knorpel zus?tzlich gesch?digt.

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Causes and pathophysiology of the infection of the knee joint

The origin of an infection of the knee joint can be of an endogenous/hematogenous nature or, in posttraumatic cases, of an exogenous nature. Hematogenous infections are found mostly in children, but also in patients with reduced immune functions, e. g. after organ transplantations. Postraumatic joint infections are caused by open injuries, intraarticular injections, operations, or they can be transmitted from the surroundings. They are relatively rare after accident surgery and orthopedic surgery. Two statements are of special importance for pathophysiology: 1. An intraarticular infection will lead to lesions of the hyaline cartilage within a period of 24 to 48 hours. 2. The substrate exchange is reduced by the reflex immobilization which will result in a additional damage to the cartilage.

     

Morphometric estimation of regional differences in the rat lung

To provide a safe basis for the sampling of tissue in future morphometric investigations of the rat lung, we searched for quantitative regional differences in pulmonary structure at light microscopic (LM) and electron microscopic (EM) levels. The lungs of 11 male rats about 6 weeks of age were fixed by standard intratracheal instillation of glutaraldehyde in the supine position and embedded either in paraffin for LM or in epoxy resin for EM investigation. Sampling of tissue was designed to test for differences between lobes and between central and peripheral lung parenchyma. LM morphometry was performed by manual point counting and by using a version of an improved automated image analyzer, Quantimet 720. EM morphometric results were obtained by manual point and intersection counting only. LM point counting showed that the proportion of parenchyma was highly constant in all lobes, varying only between 79.9% and 81.5%. In the left lung, which was partitioned into two equal halves, the amount of parenchyma was significantly lower in the apical region (mean values, 72.6% compared to 83.1%; p less than 0.002), which regularly contained the hilum. Quantimet analysis of central and subpleural lung portions revealed intralobar differences. The volume density of interalveolar septa and the air space surface density were significantly decreased in subpleural compared to central lung regions (by 7% and 4.6%, respectively). EM morphometry demonstrated that the interalveolar septa were evenly structured in all lobes except for the harmonic mean thickness of the air-blood barrier, which was lower in upper lobes. In addition, the volume density of interstitial cells was found to be significantly increased in central compared to peripheral parenchyma. The results indicate that for quantitative LM analysis the smallest possible sampling unit is an entire lobe. For EM morphometry, the often practiced approach to consider information drawn from one lobe representative for the whole lung seems to be appropriate for most parameters. In view of the structural differences between central and peripheral lung parenchyma, however, attention has to be paid to applying a properly weighted sampling procedure. Depending on the size of the lobe, the peripheral mantle (2 mm thick) can represent up to 75% of the lobar volume.     

Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A

G2A is a G-protein-coupled receptor (GPCR) involved in immune regulation. Previous studies have shown that lysophosphatidylcholine (LPC), a bioactive lipid associated with atherosclerosis and autoimmunity, acts through G2A to induce diverse biologic effects. Production of LPC during cell apoptosis serves as a chemotactic signal for macrophage recruitment. Here we demonstrate that macrophage chemotaxis to LPC is dependent on G2A function. Wild-type but not G2A-deficient mouse peritoneal macrophages migrated toward LPC. RNAi-mediated knockdown of G2A in J774A.1 macrophages abolished LPC-induced chemotaxis, whereas overexpression of G2A significantly enhanced this process. Mutation of the conserved DRY motif of G2A resulted in loss of chemotaxis to LPC, suggesting a requirement for G-protein signaling. Unlike most GPCRs, including the chemokine receptors, coupling to G(i) is not required for LPC/G2A-mediated chemotaxis, but coupling to G(q/11) and G(12/13) is necessary as judged by inhibition with dominant negative forms of these alpha subunits or with regulators of G-protein signaling (RGS) constructs. Collectively, these data establish that pertussis toxin-insensitive G2A signaling regulates macrophage chemotaxis to LPC. Defects in this signaling pathway may be related to the pathogenesis of systemic autoimmune disease.     

T cell chemotaxis to lysophosphatidylcholine through the G2A receptor

G2A is an immunoregulatory G protein-coupled receptor predominantly expressed in lymphocytes and macrophages. Ectopic overexpression studies have implicated G2A as a receptor for the bioactive lysophospholipid, lysophosphatidylcholine (LPC). However, the functional consequences of LPC-G2A interaction at physiological levels of receptor expression, and in a cellular context relevant to its immunological role, remain largely unknown. Here, we show impaired chemotaxis to LPC of a T lymphoid cell line in which G2A expression was chronically down-regulated by RNA interference technology. Rescuing this phenotype by reconstitution of the physiological level of receptor expression further supports a functional connection between LPC-G2A interaction and cellular motility. Overexpression of G2A in the T lymphoid cell line significantly enhanced chemotaxis to LPC. It also modified migration toward the LPC-related molecule, lysophosphatidic acid, indicating the possibility of crosstalk between G2A and endogenous lysophosphatidic acid receptors. The role of G2A in LPC-mediated cell migration may be relevant to the autoimmune syndrome associated with genetic inactivation of this G protein-coupled receptor in mice. The experimental system described here can be useful for understanding the structural requirements for LPC recognition by G2A and the signaling pathways regulated by this ligand-receptor pair.     

mTORC1 and mTORC2 have largely distinct functions in Purkinje cells

The mammalian target of rapamycin (mTOR) is a key regulator of cellular growth which associates with other proteins to form two multi‐protein complexes called mTORC1 and mTORC2. Dysregulation of mTORC1 signalling in brain is implicated in neuropathological conditions such as autism spectrum or neurodegenerative disorders. Accordingly, allosteric mTOR inhibitors are currently in clinical trials for the treatment of such disorders. Here, we ablated either mTORC1 or mTORC2 conditionally in Purkinje cells of the mouse cerebellum to dissect their role in the development, function and survival of these neurons. We find that the two mouse models largely differ from each other by phenotype and cellular responses. Inactivation of mTORC2, but not of mTORC1, led to motor coordination deficits at an early age. This phenotype correlated with developmental deficits in climbing fibre elimination and impaired dendritic self‐avoidance in mTORC2‐deficient Purkinje cells. In contrast, inactivation of mTORC1, but not of mTORC2, affected social interest of the mice and caused a progressive loss of Purkinje cells due to apoptosis. This cell loss was paralleled by age‐dependent motor deficits. Comparison of mTORC1‐deficient Purkinje cells with those deficient for the mTORC1 inhibitor TSC1 revealed a striking overlap in Purkinje cell degeneration and death, which included neurofilamentopathy and reactive gliosis. Altogether, our study reveals distinct roles of mTORC1 and mTORC2 in Purkinje cells for mouse behaviour and the survival of neurons. Our study also highlights a convergence between the phenotypes of Purkinje cells lacking mTORC1 activity and those expressing constitutively active mTORC1 due to TSC1 deficiency.     

Amiodarone versus placebo and class Ic drugs for cardioversion of recent-onset atrial fibrillation: a meta-analysis

OBJECTIVES: This meta-analysis compared amiodarone with placebo and class Ic drugs for the cardioversion of recent-onset atrial fibrillation (AF), defined as lasting less than seven days. BACKGROUND: Despite the lack of trials that support its efficacy convincingly, amiodarone is widely used for conversion of recent-onset AF. METHODS: We searched Medline and EMBASE databases, as well as the Cochrane Controlled Trials Register for randomized trials on recent-onset AF comparing amiodarone to placebo or class Ic drugs. Data were combined according to a fixed effect model. The primary end point was the rate of conversion at 24 h. To study time-dependency of the drugs, efficacy at 1 to 2 h, 3 to 5 h, 6 to 8 h, and at 24 h was analyzed. RESULTS: We found six studies randomizing amiodarone versus placebo (595 patients) and seven studies versus class Ic drugs (579 patients). There was no significant difference between amiodarone and placebo at 1 to 2 h, but significant efficacy was found after 6 to 8 h (relative risk [RR] 1.23, p = 0.022) and at 24 h (RR 1.44, p < 0.001). Efficacy with amiodarone was inferior to class Ic drugs for up to 8 h (RR 0.67, p < 0.001) but no difference was seen at 24 h (RR 0.95, p = 0.50). There were no major adverse effects. CONCLUSIONS: Amiodarone is superior to placebo for cardioversion of AF, and even though the onset of conversion is delayed, its efficacy is similar at 24 h compared with class Ic drugs. These results favor amiodarone as a reasonable alternative for patients with recent AF in whom class Ic and other, more rapidly acting antiarrhythmic drugs cannot be used.