Three-dimensional printing of patient-specific computed tomography lung phantoms: a reader study.

In modern clinical decision-support algorithms, heterogeneity in image characteristics due to variations in imaging systems and protocols hinders the development of reproducible quantitative measures including for feature extraction pipelines. With the help of a reader study, we investigate the ability to provide consistent ground-truth targets by using patient-specific 3D-printed lung phantoms. PixelPrint was developed for 3D-printing lifelike computed tomography (CT) lung phantoms by directly translating clinical images into printer instructions that control density on a voxel-by-voxel basis. Data sets of three COVID-19 patients served as input for 3D-printing lung phantoms. Five radiologists rated patient and phantom images for imaging characteristics and diagnostic confidence in a blinded reader study. Effect sizes of evaluating phantom as opposed to patient images were assessed using linear mixed models. Finally, PixelPrint's production reproducibility was evaluated. Images of patients and phantoms had little variation in the estimated mean (0.03-0.29, using a 1-5 scale). When comparing phantom images to patient images, effect size analysis revealed that the difference was within one-third of the inter- and intrareader variabilities. High correspondence between the four phantoms created using the same patient images was demonstrated by PixelPrint's production repeatability tests, with greater similarity scores between high-dose acquisitions of the phantoms than between clinical-dose acquisitions of a single phantom. We demonstrated PixelPrint's ability to produce lifelike CT lung phantoms reliably. These phantoms have the potential to provide ground-truth targets for validating the generalizability of inference-based decision-support algorithms between different health centers and imaging protocols and for optimizing examination protocols with realistic patient-based phantoms. Classification: CT lung phantoms, reader study.

PixelPrint: Three-dimensional printing of realistic patient-specific lung phantoms for validation of computed tomography post-processing and inference algorithms

BackgroundRadiomics and other modern clinical decision-support algorithms are emerging as the next frontier for diagnostic and prognostic medical imaging. However, heterogeneities in image characteristics due to variations in imaging systems and protocols hamper the advancement of reproducible feature extraction pipelines. There is a growing need for realistic patient-based phantoms that accurately mimic human anatomy and disease manifestations to provide consistent ground-truth targets when comparing different feature extraction or image cohort normalization techniques. Materials and MethodsPixelPrint was developed for 3D-printing lifelike lung phantoms for computed tomography (CT) by directly translating clinical images into printer instructions that control the density on a voxel-by-voxel basis. CT datasets of three COVID-19 pneumonia patients served as input for 3D-printing lung phantoms. Five radiologists rated patient and phantom images for imaging characteristics and diagnostic confidence in a blinded reader study. Linear mixed models were utilized to evaluate effect sizes of evaluating phantom as opposed to patient images. Finally, PixelPrints reproducibility was evaluated by producing four phantoms from the same clinical images. ResultsEstimated mean differences between patient and phantom images were small (0.03-0.29, using a 1-5 scale). Effect size assessment with respect to rating variabilities revealed that the effect of having a phantom in the image is within one-third of the inter- and intra-reader variabilities. PixelPrints production reproducibility tests showed high correspondence among four phantoms produced using the same patient images, with higher similarity scores between high-dose scans of the different phantoms than those measured between clinical-dose scans of a single phantom. ConclusionsWe demonstrated PixelPrints ability to produce lifelike 3D-printed CT lung phantoms reliably. These can provide ground-truth targets for validating the generalizability of inference-based decision-support algorithms between different health centers and imaging protocols, as well as for optimizing scan protocols with realistic patient-based phantoms.

Phenotypes in canalicular adenoma of human minor salivary glands reflect the interplay of altered secretory product, absent neuro-effector relationships and the diversity of the microenvironment.

AIMS: Uncertainty about the factors influencing phenotypes in salivary canalicular adenoma prompted the present investigation. METHODS AND RESULTS: Specimens of canalicular adenoma from 15 patients were examined with the use of histology, histochemistry for protein, mucosubstances and pigments, nerve staining and immunocytochemistry for cytoskeleton components. The tumours consisted largely of simple cells lining tubules that were occasionally cystic or branching and budding, and were set in loose, vascular and often haemorrhagic stroma. Other phenotypes recognized were mucous cells, apocrine-like cells, pigmented cells, microliths and stromal macrophages, detected in 26.6%, 20%, 33.3%, 20% and 53. 3% of the patients, respectively. Simple cells showed moderate levels of -SH groups and strong immunoreactivity for 'simple' epithelial phenotype cytokeratin. The simple cells lining cystic tubules showed additional immunoreactivity for 'stratified' epithelial phenotype cytokeratin, possibly an adaptation to mechanical pressure. Lumina showed variable levels of neutral and carboxylated glycoproteins, and chondroitin sulphate. Stroma showed high levels of chondroitin sulphate and hyaluronic acid. Mucous cells showed high levels of -SS- groups and nonsulphated glycoproteins. Apocrine-like cells contained lipofuscin. Pigmented cells contained haemosiderin, possibly a consequence of localized iron overload. Microliths contained mucosubstances. Macrophages often contained lipofuscin. No nerves were found in relation to the tumours. CONCLUSIONS: The results suggest that, contrary to popular belief, phenotypes in canalicular adenoma do not reflect histogenetic concepts but rather may derive from the interplay between an altered secretory product, consisting of glycosaminoglycan and an immature form of glycoprotein, the lack of neuro-effector relationships and the different microenvironments throughout the tumour.

Traumatically induced inclusion cyst secondary to shoe impingement: report of three cases.

Three cases of traumatically induced inclusion cyst affecting the dorsal aspect of the first metatarsophalangeal joint are presented. Though each case was unique, the clinical presentation was similar with patients relating discrete callus formation with a central sinus overlying an enlarging mass. In all cases, the lesion site involved the dorsal first metatarsophalangeal joint and specifically corresponded to the throatline of "pump" shoes that these patients commonly wore. Predisposing factors in these cases appeared to be forefoot equinus deformity with extensus contractor of the extensor hallucis longus tendon and use of pump shoes with a constricting throatline. The authors describe a surgical approach for treatment of this condition, which addresses underlying etiologies of inclusion cyst formation. Pathology was consistent with traumatically induced inclusion cyst. Though inclusion cysts are common in the foot, rarely is the dorsum of the foot involved, and this article, to the authors' knowledge, is the first to be reported in the podiatric literature.

Which treatments help? The patient's perspective.

In an effort to determine which specific aspects of treatment might account for patient satisfaction, the authors developed the Components of Treatment Questionnaire. This measure, which was administered to 500 adult inpatients along with the Client Satisfaction Questionnaire (CSQ-8; Larsen, Attkisson, Hargreaves, and Nguyen, 1979), asked patients to assess the helpfulness of their treatment. Convinced that patient input is pertinent to program design, the authors later surveyed 46 patients on treatments that they perceived as helpful and would like to receive. Respondents identified individual relationships and problem-focused therapies as the most helpful aspects of treatment.

A comparative study of the analgesia requirements following laparoscopic and open fundoplication in children.

To introduce a new procedure, careful evaluation of its effects must be undertaken to assess its impact. Laparoscopic procedures in children are a relatively new phenomenon. A reduction in analgesia is a frequently quoted benefit of a laparoscopic procedure. The introduction of laparoscopic fundoplication into our surgical armoury lead us to evaluate the analgesia requirements of a laparoscopic procedure compared to conventional surgery. Comparative analysis of the analgesia requirements of 40 fundoplication procedures (20 laparoscopic, 20 open) was undertaken. All the pain-relief data was prospectively documented by a pain team as part of an ongoing hospital audit. This pain team was unaware of the comparative study, but were assessing the quality of analgesia within the hospital trust. The total amount of morphine analgesia required was similar for both laparoscopic and open surgery (0.432+/-0.28, 0.427+/-0.28 mg/kg). The period for which analgesia was required was significantly less in the laparoscopic group (1.2+/-0.46, 2.7+/-0.67 days; p = 0.03), yet the requirement for morphine during the first 24 hours was greater in the laparoscopic group (0.399+/-0.19, 0.22+0.11 mg/kg, p = 0.02) despite similar NSAID requirements (18+/-17.28, 18+/-20.16 mg/kg, respectively). The benefit of a laparoscopic over an open fundoplication would appear to be in the decreased duration of pain, as indicated by the decreased duration of analgesia following surgery.

Dendritic translocation of RC3/neurogranin mRNA in normal aging, Alzheimer disease and fronto-temporal dementia.

RC3/neurogranin is a postsynaptic protein kinase C (PKC)-/calmodulin-binding substrate implicated in long-term potentiation (LTP) forms of synaptic plasticity. Our previous digoxigenin in situ hybridization (DIG-ISH) studies detected RC3 mRNA in apical dendrites and cell bodies of neurons in the rat cerebral cortex and hippocampus. This observation suggested that RC3 mRNA is selectively translocated to dendrites, where it may be translated locally in response to synaptic activity. To test this hypothesis further, we isolated a full-length cDNA clone of the homologous human RC3 mRNA from a human cortex lambda GT11 library, determined its nucleotide and predicted amino acid sequences, and performed mRNA expression studies in cerebral cortex from normal human patients and from patients with Alzheimer disease (AD) and fronto-temporal dementia (FTD). The human cDNA clone detects a single approximately 1.3 kb mRNA whose nucleotide sequence is 73% similar to the rat nucleotide sequence and 96% similar to its amino acid sequence. DIG-ISH studies detect robust staining of RC3 mRNA in cell bodies of numerous neurons throughout Layers II-VI and in both apical and basal dendrites of pyramidal neurons in human neocortex (temporal/frontal). We conclude that dendritic targeting of RC3 mRNA is conserved in human brain. In AD neocortex tissue, there is little or no evidence for RC3 mRNA translocation to dendrites, while in FTD neocortex, targeting of RC3 mRNA to apical dendrites is preserved. Comparative studies in AD and FTD point to the potential importance of synapse integrity and the dendritic cytoskeleton in RC3 mRNA targeting in the human neocortex.

Functional studies of single-site variants in the calmodulin-binding domain of RC3/neurogranin in Xenopus oocytes.

Single-site variants in the calmodulin-binding domain of RC3/neurogranin were heterologously expressed in Xenopus oocytes to examine their effects on serotonin-evoked currents. RC3 variants serine36 -->alanine (Ser36-->Ala), serine36-->glycine (Ser36-->Gly), and phenylalanine37-->tryptophan (Phe37-->Trp), which bind calmodulin but are deficient in protein kinase C (PKC) phosphorylation, display serotonin-evoked Ca(2+)-dependent Cl- currents in oocytes similar to control oocytes. A serine36-->aspartate (Ser36-->Asp) variant, which does not bind calmodulin and mimics the PKC-phosphorylated state of RC3, significantly enhances serotonin-evoked currents in a manner similar to wild-type. The results suggest that RC3 not only regulates the availability of free calmodulin in a dendritic spine but also, when phosphorylated, independently stimulates G-protein coupled second messenger pathways that generate inositol 1,4,5-trisphosphate (IP3), diacylglycerol (DAG) and intracellular Ca2+.

Localization of RC3 (neurogranin) in rat brain subcellular fractions.

Previous studies have shown that RC3 (neurogranin) is a postsynaptic, protein kinase C (PKC)/calmodulin-binding substrate that accumulates throughout the perikaryal and dendritic cytoplasm and is often closely associated with the postsynaptic density (PSD) in dendritic spines of neostriatal neurons. Here Western immunoblotting studies of rat brain subcellular fractions confirm that RC3 is predominantly a cytosolic protein but is found in lower amounts in membrane-enriched microsomes and synaptosomes. Solubilization of synaptosomes suggests that RC3 may only be loosely associated with the PSD.

G-protein gamma 7 subunit is selectively expressed in medium-sized neurons and dendrites of the rat neostriatum.

We used subtractive hybridization to isolate clones of gamma 7, a 68 residue G-protein gamma subunit. Northern blotting and in situ hybridization reveal that the gamma 7 subunit mRNA is expressed primarily in medium-sized neurons of the neostriatum and nucleus accumbens and neurons of the olfactory tubercle, and at low levels in the dentate gyrus of the hippocampal formation and laminae II-III, and V of the neocortex. The gamma 7 mRNA is translocated into dendrites of neurons in the neostriatum and the dentate gyrus of the hippocampus. gamma 7 is expressed at relatively very low concentrations in peripheral tissues. The selective pattern of gamma 7 expression within the brain is highly reminiscent of those of the striatum-enriched adenylyl cyclase ACST, dopamine receptors, and the alpha subunit of G(olf), suggesting that, in striatum, gamma 7 may be a subunit of a G(olf) alpha-containing G protein that couples dopamine receptors selectively to ACST.

Functional consequences of expression of the neuron-specific, protein kinase C substrate RC3 (neurogranin) in Xenopus oocytes.

RC3 (neurogranin) is a neuron-specific substrate of protein kinase C (PKC) that accumulates predominantly in dendritic spines of forebrain neurons and undergoes long-term potentiation (LTP)-associated increases in PKC-phosphorylation in hippocampal slices. Here the hypothesis that RC3 functions by modulating the IP3/DAG second messenger pathway after its phosphorylation by DAG-activated PKC was tested by heterologous expression in Xenopus oocytes. Acetylcholine-evoked inward chloride (Cl-) currents, dependent on both IP3 release and intracellular calcium (Ca2+), were 2- to 3-fold higher in RC3-injected oocytes than in uninjected control oocytes. RC3-oocytes did not exhibit enhanced currents when preincubated with the protein kinase inhibitor H-7 or when a glycine residue was substituted for serine, the PKC phosphorylation site of RC3. Activation of endogenous oocyte PKC by phorbol esters generated inward Cl- currents in RC3 oocytes but not in control oocytes. RC3-dependent Cl- currents were also elicited by phorbol ester in Ca(2+)-free media. We propose that PKC-phosphorylated RC3 is capable of enhancing the mobilization of intracellular Ca2+ in Xenopus oocytes and, by inference, may play a role in Ca2+ homeostasis in dendrites of forebrain neurons.

Identification of cortexin: a novel, neuron-specific, 82-residue membrane protein enriched in rodent cerebral cortex.

Nucleotide sequence analysis of a cDNA clone of a rat cortex-enriched mRNA identifies a novel integral membrane protein of 82 amino acids. The encoded protein is named cortexin to reflect its enriched expression in cortex. The amino acid sequence of rat cortexin and its mouse homologue are nearly identical (98% similarity), and both contain a conserved single membrane-spanning region in the middle of each sequence. Northern blot analysis shows that cortexin mRNA is brain-specific, cortex-enriched, and present at significant levels in fetal brain, with peak expression in postnatal rodent brain. In situ hybridization studies detect cortexin mRNA primarily in neurons of rodent cerebral cortex, but not in cells of the hindbrain or white matter regions. The function of cortexin may be particularly important to neurons of both the developing and adult cerebral cortex.

Tube feeding in children on chronic peritoneal dialysis.

We feel that tube feeding children on CPD is an important and useful therapy to optimize their growth. Strategies to accelerate growth in such children by using human growth hormone are interesting and await scientific confirmation with controlled trials.