Standardized PSMA-PET Imaging of Advanced Prostate Cancer.

Imaging of advanced prostate cancer is a challenging task, as it requires longitudinal characterization of disease extent in a standardized way to enable appropriate treatment selection and evaluation of treatment efficacy. In the last years, prostate-specific membrane antigen (PSMA)-PET/CT has become the reference standard examination for patients with advanced prostate cancer. Together with the rise of PSMA-PET, standardized frameworks for the reporting of image findings have been proposed, eg, the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) and the structured reporting system for PSMA targeted PET imaging (PSMA-RADS) framework. Therefore, recent evidence on PSMA-PET derived tumor volume as useful a biomarker for outcome prognostication and related frameworks will be discussed in the article. The PROMISE framework recommends quantifying the tumor volume per-organ system, which accounts for the fact that the location of the metastases greatly influence its biological aggressiveness. In addition, changes in PSMA-PET derived tumor volume have been shown to be promising biomarkers for response assessment. Limitations of PSMA-PET will also be discussed because the tumor volume might not always be suited for response assessment. As a pitfall of PSMA-based systems, decreasing PSMA-expression might erroneously be interpreted as response to therapy. Also, especially for patients with limited disease, the tumor volume might not be ideal for response assessment. Therefore, various frameworks have been introduced to objectively measure response to therapy with PSMA-PET. Amongst these, the PSMA-PET progression (PPP) criteria and the response evaluation criteria in PSMA (RECIP) are optimized for earlier and later phenotypes of advanced prostate cancer, respectively. Variables needed to determine PPP or RECIP outcome on PSMA-PET are recorded under the umbrella of PROMISE recommendations. In this article, various reporting and response assessment frameworks are explained and discussed. Also, recent evidence for the relevance of PSMA-PET biomarkers for clinical management and outcome prognostication are shown.

Joint EANM/SNMMI guideline on radiomics in nuclear medicine : Jointly supported by the EANM Physics Committee and the SNMMI Physics, Instrumentation and Data Sciences Council.

PURPOSE: The purpose of this guideline is to provide comprehensive information on best practices for robust radiomics analyses for both hand-crafted and deep learning-based approaches. METHODS: In a cooperative effort between the EANM and SNMMI, we agreed upon current best practices and recommendations for relevant aspects of radiomics analyses, including study design, quality assurance, data collection, impact of acquisition and reconstruction, detection and segmentation, feature standardization and implementation, as well as appropriate modelling schemes, model evaluation, and interpretation. We also offer an outlook for future perspectives. CONCLUSION: Radiomics is a very quickly evolving field of research. The present guideline focused on established findings as well as recommendations based on the state of the art. Though this guideline recognizes both hand-crafted and deep learning-based radiomics approaches, it primarily focuses on the former as this field is more mature. This guideline will be updated once more studies and results have contributed to improved consensus regarding the application of deep learning methods for radiomics. Although methodological recommendations in the present document are valid for most medical image modalities, we focus here on nuclear medicine, and specific recommendations when necessary are made for PET/CT, PET/MR, and quantitative SPECT.

Author Correction: The solute carrier SLC9C1 is a Na+/H+-exchanger gated by an S4-type voltage-sensor and cyclic-nucleotide binding.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The solute carrier SLC9C1 is a Na+/H+-exchanger gated by an S4-type voltage-sensor and cyclic-nucleotide binding.

Voltage-sensing (VSD) and cyclic nucleotide-binding domains (CNBD) gate ion channels for rapid electrical signaling. By contrast, solute carriers (SLCs) that passively redistribute substrates are gated by their substrates themselves. Here, we study the orphan sperm-specific solute carriers SLC9C1 that feature a unique tripartite structure: an exchanger domain, a VSD, and a CNBD. Voltage-clamp fluorimetry shows that SLC9C1 is a genuine Na+/H+ exchanger gated by voltage. The cellular messenger cAMP shifts the voltage range of activation. Mutations in the transport domain, the VSD, or the CNBD strongly affect Na+/H+ exchange, voltage gating, or cAMP sensitivity, respectively. Our results establish SLC9C1 as a phylogenetic chimaera that combines the ion-exchange mechanism of solute carriers with the gating mechanism of ion channels. Classic SLCs slowly readjust changes in the intra- and extracellular milieu, whereas voltage gating endows the Na+/H+ exchanger with the ability to produce a rapid pH response that enables downstream signaling events.

Association between Weight Change and Mortality in Community Living Older People Followed for Up to 14 Years. The Hordaland Health Study (HUSK).

OBJECTIVES: To study the importance of weight change with regard to mortality in older people. DESIGN: Prospective cohort study. PARTICIPANTS: The cohort includes participants in the Hordaland Health Study, Norway, 1997-99 (N=2935, age 71-74 years) who had previously participated in a survey in 1992-93. MEASUREMENTS: Participants with weight measured at both surveys were followed for mortality through 2012. Cox proportional hazards models were used to calculate risk of death according to changes in weight. Hazard ratios (HR) with 95% confidence intervals (CIs) for people with stable weight (± <5% weight change) were compared to people who lost (≥5%) or gained (≥5%) weight. Cox regression with penalized spline was used to evaluate the association between weight change (in kg) and mortality. Analyses were adjusted for age, sex, physical activity, smoking, diabetes, hypertension, and previous myocardial infarction or stroke. Participants with cancer were excluded. RESULTS: Compared to those with stable weight, participants who lost ≥5% weight had an increased mortality risk (HR 1.59 [95% CI: 1.35-1.89]) while the group with weight gain ≥5% did not (HR 1.07 [95% CI 0.90-1.28]). Penalized spline identified those who lost more than about three kg or gained more than about 12 kg as having increased risk of death. CONCLUSION: Even a minor weight loss of ≥5% or >3 kg were significantly associated with increased risk of mortality. Thus, weight should be routinely measured in older adults.

Neutrophilic superoxide production can assess pharmacological and pharmacogenetic ß-adrenoreceptor effects.

Asthma can be controlled well in most patients by inhaled ß-adrenoreceptor (ß2 AR) agonists and steroids. Poor response to ß2 AR agonists is difficult to predict, especially in young children and by lung function testing, which may be affected by multiple influences. As an alternative approach, we analyzed ex vivo neutrophilic superoxide inhibition in response to ß2 AR stimulation. In 60 healthy volunteers, this assay was unaffected by sex, age, smoking, atopy or asthma status. Furthermore, we assessed effects of genetic variants in ß2 AR by sequencing the ADRB2 gene in our cohort and relating genotypes to ß2 AR-mediated neutrophilic superoxide inhibition. Gly16Arg genotypes correlated with minor decrease in overall adrenoresponse in this small study population. Taken together, ex vivo testing of the ß2 AR response in human neutrophils represents a robust tool with good signal-to-noise ratio at physiological ß2 AR agonist concentrations, and this assay may be useful to complement future pharmacogenetic studies in asthma.

Heterogeneity of pulmonary endothelial cyclic nucleotide response to Pseudomonas aeruginosa ExoY infection.

Here, we tested the hypothesis that a promiscuous bacterial cyclase synthesizes purine and pyrimidine cyclic nucleotides in the pulmonary endothelium. To test this hypothesis, pulmonary endothelial cells were infected with a strain of the Gram-negative bacterium Pseudomonas aeruginosa that introduces only exoenzyme Y (PA103 ΔexoUexoT::Tc pUCPexoY; ExoY(+)) via a type III secretion system. Purine and pyrimidine cyclic nucleotides were simultaneously detected using mass spectrometry. Pulmonary artery (PAECs) and pulmonary microvascular (PMVECs) endothelial cells both possess basal levels of four different cyclic nucleotides in the following rank order: cAMP > cUMP ≈ cGMP ≈ cCMP. Endothelial gap formation was induced in a time-dependent manner following ExoY(+) intoxication. In PAECs, intercellular gaps formed within 2 h and progressively increased in size up to 6 h, when the experiment was terminated. cGMP concentrations increased within 1 h postinfection, whereas cAMP and cUMP concentrations increased within 3 h, and cCMP concentrations increased within 4 h postinfection. In PMVECs, intercellular gaps did not form until 4 h postinfection. Only cGMP and cUMP concentrations increased at 3 and 6 h postinfection, respectively. PAECs generated higher cyclic nucleotide levels than PMVECs, and the cyclic nucleotide levels increased earlier in response to ExoY(+) intoxication. Heterogeneity of the cyclic nucleotide signature in response to P. aeruginosa infection exists between PAECs and PMVECs, suggesting the intracellular milieu in PAECs is more conducive to cNMP generation.

Molecular determinants for the high constitutive activity of the human histamine H4 receptor: functional studies on orthologues and mutants.

BACKGROUND AND PURPOSE: Some histamine H4 receptor ligands act as inverse agonists at the human H4 receptor (hH4 R), a receptor with exceptionally high constitutive activity, but as neutral antagonists or partial agonists at the constitutively inactive mouse H4 receptor (mH4 R) and rat H4 receptor (rH4 R). To study molecular determinants of constitutive activity, H4 receptor reciprocal mutants were constructed: single mutants: hH4 R-F169V, mH4 R-V171F, hH4 R-S179A, hH4 R-S179M; double mutants: hH4 R-F169V+S179A, hH4 R-F169V+S179M and mH4 R-V171F+M181S. EXPERIMENTAL APPROACH: Site-directed mutagenesis with pVL1392 plasmids containing hH4 or mH4 receptors were performed. Wild-type or mutant receptors were co-expressed with Gαi2 and Gß1 γ2 in Sf9 cells. Membranes were studied in saturation and competition binding assays ([(3) H]-histamine), and in functional [(35) S]-GTPγS assays with inverse, partial and full agonists of the hH4 receptor. KEY RESULTS: Constitutive activity decreased from the hH4 receptor via the hH4 R-F169V mutant to the hH4 R-F169V+S179A and hH4 R-F169V+S179M double mutants. F169 alone or in concert with S179 plays a major role in stabilizing a ligand-free active state of the hH4 receptor. Partial inverse hH4 receptor agonists like JNJ7777120 behaved as neutral antagonists or partial agonists at species orthologues with lower or no constitutive activity. Some partial and full hH4 receptor agonists showed decreased maximal effects and potencies at hH4 R-F169V and double mutants. However, the mutation of S179 in the hH4 receptor to M as in mH4 receptor or A as in rH4 receptor did not significantly reduce constitutive activity. CONCLUSIONS AND IMPLICATIONS: F169 and S179 are key amino acids for the high constitutive activity of hH4 receptors and may also be of relevance for other constitutively active GPCRs. LINKED ARTICLES: This article is part of a themed issue on Histamine Pharmacology Update published in volume 170 issue 1. To view the other articles in this issue visit http://onlinelibrary.wiley.com/doi/10.1111/bph.2013.170.issue-1/issuetoc.

Impact of a stepwise protocol for treating pain on pain intensity in nursing home patients with dementia: a cluster randomized trial.

BACKGROUND: Pain is frequent and distressing in people with dementia, but no randomized controlled trials have evaluated the effect of analgesic treatment on pain intensity as a key outcome. METHODS: Three hundred fifty-two people with dementia and significant agitation from 60 nursing home units were included in this study. These units, representing 18 nursing homes in western Norway, were randomized to a stepwise protocol of treating pain (SPTP) or usual care. The SPTP group received acetaminophen, morphine, buprenorphine transdermal patch and pregabalin for 8 weeks, with a 4-week washout period. Medications were governed by the SPTP and each participant's existing prescriptions. We obtained pain intensity scores from 327 patients (intervention n = 164, control n = 163) at five time points assessed by the primary outcome measure, Mobilization-Observation-Behaviour-Intensity-Dementia-2 (MOBID-2) Pain Scale. The secondary outcome was activities of daily living (ADL). We used a linear intercept mixed model in a two-way repeated measures configuration to assess change over time and between groups. RESULTS: The SPTP conferred significant benefit in MOBID-2 scores compared with the control group [average treatment effect (ATE) -1.388; p < 0.001] at week 8, and MOBID-2 scores worsened during the washout period (ATE = -0.701; p = 0.022). Examining different analgesic treatments, benefit was conferred to patients receiving acetaminophen compared with the controls at week 2 (ATE = -0.663; p = 0.010), continuing to increase until week 8 (ATE = -1.297; p < 0.001). Although there were no overall improvements in ADL, an increase was seen in the group receiving acetaminophen (ATE = +1.0; p = 0.022). CONCLUSION: Pain medication significantly improved pain in the intervention group, with indications that acetaminophen also improved ADL function.

Albedo neutron dosimetry in Germany: regulations and performance.

Personal neutron dosimetry has been performed in Germany using albedo dosemeters for >20 y. This paper describes the main principles, the national standards, regulations and recommendations, the quality management and the overall performance, giving some examples.

Linking geology, fluid chemistry, and microbial activity of basalt- and ultramafic-hosted deep-sea hydrothermal vent environments.

Hydrothermal fluids passing through basaltic rocks along mid-ocean ridges are known to be enriched in sulfide, while those circulating through ultramafic mantle rocks are typically elevated in hydrogen. Therefore, it has been estimated that the maximum energy in basalt-hosted systems is available through sulfide oxidation and in ultramafic-hosted systems through hydrogen oxidation. Furthermore, thermodynamic models suggest that the greatest biomass potential arises from sulfide oxidation in basalt-hosted and from hydrogen oxidation in ultramafic-hosted systems. We tested these predictions by measuring biological sulfide and hydrogen removal and subsequent autotrophic CO2 fixation in chemically distinct hydrothermal fluids from basalt-hosted and ultramafic-hosted vents. We found a large potential of microbial hydrogen oxidation in naturally hydrogen-rich (ultramafic-hosted) but also in naturally hydrogen-poor (basalt-hosted) hydrothermal fluids. Moreover, hydrogen oxidation-based primary production proved to be highly attractive under our incubation conditions regardless whether hydrothermal fluids from ultramafic-hosted or basalt-hosted sites were used. Site-specific hydrogen and sulfide availability alone did not appear to determine whether hydrogen or sulfide oxidation provides the energy for primary production by the free-living microbes in the tested hydrothermal fluids. This suggests that more complex features (e.g., a combination of oxygen, temperature, biological interactions) may play a role for determining which energy source is preferably used in chemically distinct hydrothermal vent biotopes.

Hp(0.07) photon dosemeters for eye lens dosimetry: calibration on a rod vs. a slab phantom.

In recent years, several papers dealing with eye lens dosimetry have been published as epidemiological studies are implying that the induction of cataracts occurs even at eye lens doses of less than 500 mGy. For that reason, the necessity to monitor the eye lens may become more important than it was before. However, only few dosemeters for the appropriate quantity H(p)(3) are available. Partial-body dosemeters are usually designed to measure the quantity H(p)(0.07) calibrated on a rod phantom representing a finger while a slab phantom much better represents the head. Therefore, in this work it was investigated whether dosemeters designed for the quantity H(p)(0.07) calibrated on a rod phantom can also be worn on the head (close to the eyes) and still deliver correct results (H(p)(0.07) on a head). For that purpose, different types of partial-body dosemeters from routine use were irradiated at different photon energies on both a rod and a slab phantom. It turned out that their response values are within ±5% independent of the phantom if the quantity value for the respective phantom is used. Thus, partial-body dosemeters designed for the quantity H(p)(0.07) calibrated on a rod phantom may be worn on the head and used to monitor the eye lens dose due to photon radiation via the measurement of H(p)(0.07) on the head.

Histamine H1, H3 and H4 receptors are involved in pruritus.

Histamine has long been recognised as a classical inducer of pruritus. However, the specific mechanism of histamine-induced itch has still not been fully understood. The H1 and H4 receptor appear to be key components in the induction of itch. The specific role of the H3 receptor in histamine-induced itch remains unclear. The aim of our study was to investigate the role of the four known histamine receptors (H1-4) in acute itch in mice. Intradermal injection of the selective H3R inverse agonist pitolisant induced strong itch in mice. Pitolisant (50 nmol/injection)-induced pruritus could be completely blocked by a combined treatment with the H1R antagonist cetirizine (15 mg/kg) and the H4R antagonist JNJ 7777120 (15 mg/kg), whereas the H2R antagonist ranitidine (15 mg/kg) failed to inhibit the scratch response. Next, expression and function of histamine receptors on sensory neurons isolated from dorsal root ganglia of mice were investigated. As the itch sensation results from the excitation of sensory nerves in the skin, we further focused on skin specific sensory neurons. Therefore, neurons were retrograde labelled from the skin by means of a fluorescent tracer. Expression of H1R, H3R and H4R on skin innervating sensory neurons was detected. By single-cell calcium imaging, it was demonstrated that histamine induces a calcium increase in a subset of (skin-specific) sensory neurons via activation of the H1R and H4R as well as inhibition of the H3R. It is assumed that the decreased threshold in response to H3R antagonism activates H1R and H4R on sensory neurons, which in turn results in the excitation of histamine-sensitive afferents and therefore elicits the sensation of itch.

Lead identification and optimization of diaminopyrimidines as histamine H4 receptor ligands.

BACKGROUND: The human histamine H(4) receptor (hH(4)R) is a promising new target in the therapy of inflammatory or immune system diseases. METHODS: For the development of new hH(4)R ligands, a broad virtual screening was performed and two hits were identified. Their annelated heterocyclic core was optimized with regard to affinity and potency. RESULTS: Pharmacological characterization of the resulting diaminopyrimidines revealed different agonist and antagonist properties within the same scaffold.

Neoimmun versus Neoral: a bioequivalence study in healthy volunteers and influence of a fat-rich meal on the bioavailability of Neoimmun.

In two crossover studies with 12 (6 males/6 females) healthy young volunteers each, we compared the bioavailability of Neoimmun capsules with the microemulsion Neoral and the influence of a fat-rich breakfast on the bioavailability of Neoimmun. Each volunteer received a single dose of 200 mg cyclosporine A in each period. Blood samples were taken up to 24 h and analysed for cyclosporine A by high-performance liquid chromatography (HPLC) and photometric detection. The pharmacokinetic parameters were determined by non-compartmental analysis. The treatments were tested for bioequivalence and significant differences. The bioavailability of Neoimmun was significantly lower compared to Neoral, albeit Neoimmun met the bioequivalence criterion (90% confidence interval of AUC 0.80-0.94) or missed the criterion only marginally (90% confidence interval of c (max) 0.75-0.91). The bioavailability of Neoimmun as determined by area under the blood concentration-time curve (AUC) increased by nearly 20% after a fat-rich breakfast. However, mean peak concentrations after food were only higher in male subjects, whereas mean peak concentrations in female subjects were lower compared to fasting administration. In conclusion, our data show that Neoimmun exhibits a lower bioavailability than the microemulsion Neoral and that food has a significant but variable and sex-dependent impact on the bioavailability of Neoimmun capsules.

[Difficulties in asthma therapy]. / Therapie und Diagnostik von Asthma im Kindesalter. Werden die Leitlinien den Anforderungen gerecht?

Asthma is the most frequent chronic disease in childhood with rising prevalance worldwide. Early antiinflammatory therapy can prevent irreversible damage to the lung. Effective drugs such as nedrocromil, DNCG, leukotrienes antagonists or inhaled corticosteroids are available and recommended. But they are not used as assigned. Guidelines may help to find the right medication but they have to be adapted to the individual and his situation.

A receptor-like inositol lipid phosphatase is required for the maturation of developing cochlear hair bundles.

A screen for protein tyrosine phosphatases (PTPs) expressed in the chick inner ear yielded a high proportion of clones encoding an avian ortholog of protein tyrosine phosphatase receptor Q (Ptprq), a receptor-like PTP. Ptprq was first identified as a transcript upregulated in rat kidney in response to glomerular nephritis and has recently been shown to be active against inositol phospholipids. An antibody to the intracellular domain of Ptprq, anti-Ptprq, stains hair bundles in mice and chicks. In the chick ear, the distribution of Ptprq is almost identical to that of the 275 kDa hair-cell antigen (HCA), a component of hair-bundle shaft connectors recognized by a monoclonal antibody (mAb) that stains inner-ear hair bundles and kidney glomeruli. Furthermore, anti-Ptprq immunoblots a 275 kDa polypeptide immunoprecipitated by the anti-HCA mAb from the avian inner ear, indicating that the HCA and Ptprq are likely to be the same molecule. In two transgenic mouse strains with different mutations in Ptprq, anti-Ptprq immunoreactivity cannot be detected in the ear. Shaft connectors are absent from mutant vestibular hair bundles, but the stereocilia forming the hair bundle are not splayed, indicating that shaft connectors are not necessary to hold the stereocilia together; however, the mice show rapid postnatal deterioration in cochlear hair-bundle structure, associated with smaller than normal transducer currents with otherwise normal adaptation properties, a progressive loss of basal-coil cochlear hair cells, and deafness. These results reveal that Ptprq is required for formation of the shaft connectors of the hair bundle, the normal maturation of cochlear hair bundles, and the long-term survival of high-frequency auditory hair cells.