Dosimetric analysis of a compartmental model for radioligand uptake in tumor lesions.

Radioligand therapy is a targeted cancer therapy that delivers radiation to tumor cells based on the expression of specific markers on the cell surface. It has become an important treatment option in metastasized neuroendocrine tumors and advanced prostate cancer. The analysis of absorbed doses in radioligand therapies has gained much attention and remains a challenging task due to individual pharmacokinetics. As an alternative to the often used sum of exponential functions in intra-therapeutic dosimetry, a basic compartmental model for the pharmacokinetics of radioligands is described and analyzed in this paper. In its simplest version, the model behavior is determined by the uptake capacity and the association constant and can be solved analytically. The model is extended with rates for excretion from the source compartment and externalization from the lesion compartment. Numerical calculations offer an insight into the quantitative effects of the model parameters on the absorbed dose in the tumor lesion. This analysis helps understanding the importance of clinically relevant factors, e.g. the effect on absorbed doses of modified radioligands that bind to albumin. Using clinical data, the potential application in intra-therapeutic dosimetry is illustrated and compared to the bi-exponential function which lacks a mechanistical basis. While the compartmental model is found to constitute a feasible alternative in these examples, this has to be confirmed by further clinical studies.

Hepatocyte Transplantation to the Liver via the Splenic Artery in a Juvenile Large Animal Model.

Hepatocyte transplantation (HcTx) is a promising approach for the treatment of metabolic diseases in newborns and children. The most common application route is the portal vein, which is difficult to access in the newborn. Transfemoral access to the splenic artery for HcTx has been evaluated in adults, with trials suggesting hepatocyte translocation from the spleen to the liver with a reduced risk for thromboembolic complications. Using juvenile Göttingen minipigs, we aimed to evaluate feasibility of hepatocyte transplantation by transfemoral splenic artery catheterization, while providing insight on engraftment, translocation, viability, and thromboembolic complications. Four Göttingen Minipigs weighing 5.6 kg to 12.6 kg were infused with human hepatocytes (two infusions per cycle, 1.00E08 cells per kg body weight). Immunosuppression consisted of tacrolimus and prednisolone. The animals were sacrificed directly after cell infusion (n=2), 2 days (n=1), or 14 days after infusion (n=1). The splenic and portal venous blood flow was controlled via color-coded Doppler sonography. Computed tomography was performed on days 6 and 18 after the first infusion. Tissue samples were stained in search of human hepatocytes. Catheter placement was feasible in all cases without procedure-associated complications. Repetitive cell transplantations were possible without serious adverse effects associated with hepatocyte transplantation. Immunohistochemical staining has proven cell relocation to the portal venous system and liver parenchyma. However, cells were neither present in the liver nor the spleen 18 days after HcTx. Immunological analyses showed a response of the adaptive immune system to the human cells. We show that interventional cell application via the femoral artery is feasible in a juvenile large animal model of HcTx. Moreover, cells are able to pass through the spleen to relocate in the liver after splenic artery infusion. Further studies are necessary to compare this approach with umbilical or transhepatic hepatocyte administration.

Computed tomography-based survey of the vascular anatomy of the juvenile Göttingen minipig.

Over the past 50 years, image-guided procedures have been established for a wide range of applications. The development and clinical translation of new treatment regimens necessitate the availability of suitable animal models. The juvenile Göttingen minipig presents a favourable profile as a model for human infants. However, no information can be found regarding the vascular system of juvenile minipigs in the literature. Such information is imperative for planning the accessibility of target structures by catheterization. We present here a complete mapping of the arterial system of the juvenile minipig based on contrast-enhanced computed tomography. Four female animals weighing 6.13 ± 0.72 kg were used for the analyses. Imaging was performed under anaesthesia, and the measurement of the vascular structures was performed independently by four investigators. Our dataset forms a basis for future interventional studies in juvenile minipigs, and enables planning and refinement of future experiments according to the 3R (replacement, reduction and refinement) principles of animal research.

[Condylar remodelling after temporomandibular joint reconstruction with fibula free flap]. / Remodelage du condyle après reconstruction de l'articulation temporomandibulaire par lambeau libre de fibula.

AIM: Mandibular reconstructions with fibula free flap are commonly used in maxillo-facial surgery; termino-lateral mandibulectomy with reconstruction of the ramus and condylar unit is seldom used. Consequences on the temporomandibular joint remain unclear, and the type of reconstruction is still subject to controversy. METHODS: Six patients were followed after terminal mandibulectomy, reconstructed with fibular free flap. Evaluations of the results were made on functional and radiological criteria. RESULTS: No patient presented functional disturbances due to reconstruction. Remodeling of the neocondyle extremity was weak in adults but important in children, with modification of morphology and architecture of the condyle in children. DISCUSSION: Preservation of the disc is recommended. Many techniques are described to improve congruence, preservation and remodeling of the free extremity of the fibula flap. All give similar results. It seems that the real determinant factors on the quality of the result are age, presence of the disc or not, previous surgery performed, with or without radiotherapy.

A coupled ecosystem-climate model for predicting the methane concentration in the Archean atmosphere.

A simple coupled ecosystem-climate model is described that can predict levels of atmospheric CH4, CO2, and H2 during the Late Archean, given observed constraints on Earth's surface temperature. We find that methanogenic bacteria should have converted most of the available atmospheric H2 into CH4, and that CH4 may have been equal in importance to CO2 as a greenhouse gas. Photolysis of this CH4 may have produced a hydrocarbon smog layer that would have shielded the surface from solar UV radiation. Methanotrophic bacteria would have consumed some of the atmospheric CH4, but they would have been incapable of reducing CH4 to modern levels. The rise of O2 around 2.3 Ga would have drastically reduced the atmospheric CH4 concentration and may thereby have triggered the Huronian glaciation.

Co-conservation of rRNA tetraloop sequences and helix length suggests involvement of the tetraloops in higher-order interactions.

Terminal loops containing four nucleotides (tetraloops) are common in structural RNAs, and they frequently conform to one of three sequence motifs, GNRA, UNCG, or CUUG. Here we compare available sequences and secondary structures for rRNAs from bacteria, and we show that helices capped by phylogenetically conserved GNRA loops display a strong tendency to be of conserved length. The simplest interpretation of this correlation is that the conserved GNRA loops are involved in higher-order interactions, intramolecular or intermolecular, resulting in a selective pressure for maintaining the lengths of these helices. A small number of conserved UNCG loops were also found to be associated with conserved length helices, consistent with the possibility that this type of tetraloop also takes part in higher-order interactions.

Phylogeny of marine Bacillus isolates from the Gulf of Mexico.

The phylogeny of 11 pigmented, aerobic, spore-forming isolates from marine sources was studied. Forty-two biochemical characteristics were examined, and a 16S rDNA sequence was obtained for each isolate. In a phylogenetic tree based on 16S sequencing, four isolates (NRRL B-14850, NRRL B-14904, NRRL B-14907, and NRRL B-14908) clustered with B. subtilis and related organisms; NRRL B-14907 was closely related to B. amyloliquefaciens. NRRL B-14907 and NRRL B-14908 were phenotypically similar to B. amyloliquefaciens and B. pumilus, respectively. Three strains (NRRL B-14906, NRRL B-14910, and NRRL B-14911) clustered in a clade that included B. firmus, B. lentus, and B. megaterium. NRRL B-14910 was closely related phenotypically and phylogenetically to B. megaterium. NRRL B-14905 clustered with the mesophilic round spore-producing species, B. fusiformis and B. sphaericus; the isolate was more closely related to B. fusiformis. NRRL B-14905 displayed characteristics typical of the B. sphaericus-like organisms. NRRL B-14909 and NRRL B-14912 clustered with the Paenibacillus species and displayed characteristics typical of the genus. Only NRRL B-14851, an unusually thin rod that forms very small spores, may represent a new Bacillus species.

Soft tissue complications of orthopedic emergencies.

The emergency physician encounters a diversity of potentially devastating and disabling soft tissue maladies. This article reviews the literature and approach to the compartment syndrome and Volkmann contracture, reflex sympathetic dystrophy and causalgia, fracture blisters, and gas gangrene.

Conserved gene clusters in bacterial genomes provide further support for the primacy of RNA.

Five complete bacterial genome sequences have been released to the scientific community. These include four (eu)Bacteria, Haemophilus influenzae, Mycoplasma genitalium, M. pneumoniae, and Synechocystis PCC 6803, as well as one Archaeon, Methanococcus jannaschii. Features of organization shared by these genomes are likely to have arisen very early in the history of the bacteria and thus can be expected to provide further insight into the nature of early ancestors. Results of a genome comparison of these five organisms confirm earlier observations that gene order is remarkably unpreserved. There are, nevertheless, at least 16 clusters of two or more genes whose order remains the same among the four (eu)Bacteria and these are presumed to reflect conserved elements of coordinated gene expression that require gene proximity. Eight of these gene orders are essentially conserved in the Archaea as well. Many of these clusters are known to be regulated by RNA-level mechanisms in Escherichia coli, which supports the earlier suggestion that this type of regulation of gene expression may have arisen very early. We conclude that although the last common ancestor may have had a DNA genome, it likely was preceded by progenotes with an RNA genome.

Phylogenetic position of the genus Hydrogenobacter.

The genus Hydrogenobacter consists of extremely thermophilic, obligately chemolithotrophic organisms that exhibit anaerobic anabolism but aerobic catabolism. Preliminary studies of the phylogenetic position of these organisms based on limited 16S ribosomal DNA sequence data suggested that they belong to one of the earliest branching orders of the Bacteria. In this study, the complete 16S ribosomal DNA sequences of two type strains, Hydrogenobacter thermophilus TK-6 and Calderobacterium hydrogenophilum Z-829, and another isolate, Hydrogenobacter sp. strain T3, were determined, and the phylogenetic positions of these organisms were examined. Our results revealed that the two type strains are members of a single genus, the genus Hydrogenobacter. Our results also verified the previous conclusion that the Aquifex-Hydrogenobacter complex belongs to a very early branching order, the "Aquificales." Within this order, the relationships among the various organisms are such that only a single family, the "Aquificaceae," can be recognized at this time. Given the early branching point of the "Aquificales," the characteristics of these organisms support the view that the last common ancestor of existing life was thermophilic and suggest that this ancestor may have fixed carbon chemoautotrophically.

[Pituitary dwarfism in a German shepherd dog (author's transl)]. / Hypophysärer Zwergwuchs beim Deutschen Schäferhund.

Pituitary dwarfism has been described in more than 20 German shepherd dogs. Some cases probably were caused by persistent cysts of Rathke's pouch. This is the first histopathological, immunohistochemical and endocrinological study. A 13-month-old, 7-kg, dwarf purebred German shepherd bitch with alopecia and hyperpigmentation was admitted to the clinic for euthanasia. Retardation of growth was noticed when the dog was about two months old. No littermates had this condition. Two subsequent breedings from the same parents produced normal offspring. The clinical parameters in our dog (hematology, function of liver and kidney) were normal. Grossly, the pituitary gland had small and large multiple cysts, which light microscopy showed to be exclusively within the adenohypophysis. The latter had pressure atrophy, and immunohistochemically showed only remnants of the hormone-producing cells (growth hormone-GH; prolactin-PRL; thyrotropin-TSH; luteinizing hormone-LH; adrenocorticotrophin-ACTH/MSH). The thyroid was relatively small, and histologically showed focally resting follicles without lumen. Endocrinological studies showed a surprisingly high value for serum growth hormone (cGH 4.1 ng/ml; normal range 1.8-3.8 ng/ml as determined by a specific homologous radioimmunoassay) and a pathologically low serum somatomedin (SM 0.132; normal value more than 0.50 unit/ml, determined by 35S incorporation in piglet rib cartilage). Hypothyroidism was verified by a low T4 binding value (T4 0.9 micrograms/100 ml; normal 4.1 +/- 0.9 micrograms/100 ml) and a low thyroid binding index (TBI 0.54; normal 0.61 +/- 0.05). While ACTH was lowered (ACTH less than 10 pg/ml; normal 74-210 pg/ml), cortisol was normal (0.81 micrograms/100 ml; normal 0.5-2.5 micrograms/100 ml). Pituitary dwarfism in the 13-month-old bitch can be ascribed to the persistence of one end of the ductus craniopharyngeus, Rathke's pouch. Pressure atrophy of the adenohypophysis led to the loss of most of the hormone-producing tissue. An increase in growth hormone with lowered somatomedin raises questions. We have no conclusive explanation for this, due to the present lack of knowledge of how growth is regulated. High growth hormone and low somatomedin values are found in Laron's syndrome in infants. The literature indicates that pituitary dwarfism in German shepherd dogs may be a hereditary autosomal recessive trait.