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miR-122 is an important host factor for hepatitis C virus (HCV) replication. The aim of this study was to assess the safety and tolerability, pharmacokinetics, and antiviral effect of a single dose of RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated oligonucleotide that antagonises miR-122, in patients with chronic HCV infection with various genotypes.

Objective: Case reports on cervical root resorption in patients with complete cleft of the lip and palate are scarce. Moreover, cervical root resorption is sometimes diagnosed several years after a combined orthodontic and surgical therapy in patients with cleft. In this article a review of the literature is presented, and a description and the management of the cervical lesion is provided. An additional objective of this report is to advocate for alveolar bone grafting before the age of 12 years while the vulnerable cervical region of the teeth adjacent to the cleft defect is still protected by a thick layer of bone.

Recent evidence that Wnts and other genes in the Wnt signaling pathway are expressed in embryonic and adult mouse lung suggests that this pathway is important for cell fate decisions and differentiation of lung cell types. We therefore examined the expression and protein distribution of several Wnt pathway components during prenatal mouse lung development using whole-mount in situ hybridization and immunohistochemistry. Between embryonic days 10.5 and 17.5 (E10.5–E17.5), β-catenin was localized in the cytoplasm, and often also the nucleus, of the undifferentiated primordial epithelium (PE), differentiating alveolar epithelium (AE; present from E14.5 onward), and adjacent mesenchyme. Tcf1, Lef1, Tcf3, Tcf4, sFrp1, sFrp2and sFrp4were also expressed in the PE, AE, and adjacent mesenchyme in specific spatio-temporal patterns.

Background & Aims:Patients with progressive familial intrahepatic cholestasis (PFIC) type 3 have a mutation in the MDR3gene, encoding the hepatocanalicular phospholipid translocator. In general, liver failure develops within the first decade of life in these patients. Previous studies have shown that in the mdr2-knockout mouse, the animal model for this disease, the absence of phospholipids in bile causes chronic bile salt–induced damage to hepatocytes. We aimed to test the efficacy of hepatocyte transplantation and liver repopulation in this disease model. Methods:Transgenic MDR3-expressing hepatocytes as well as normal mdr2(+/+) hepatocytes were transplanted in mdr2(−/−) mice, and liver repopulation was assessed by immunohistochemistry and measurement of biliary lipid secretion. Results:Transplanted hepatocytes partially repopulated the liver, restored phospholipid secretion, and diminished liver pathology. Repopulation was stronger when hepatocellular damage was enhanced by a bile salt–supplemented diet. After 1 year, however, these animals developed multiple hepatic tumors, and biliary phospholipid secretion decreased. In transplanted animals receiving a control diet, repopulation was slower but eventually remained stable at 21%, while liver pathology was completely abrogated and tumor formation was prevented. Conclusions:These results suggest that moderate liver pathology is a safe condition for the induction of effective hepatocyte repopulation and that this therapy is potentially applicable to patients with PFIC type 3.

The interaction of organismal design with ecology, and its evolutionary development are the subject of many functional and ecomorphological studies. Many studies have shown that the morphology and mechanics of the masticatory apparatus in mammals are adapted to diet. To investigate the relations between diet and the morphological and physiological properties of the lizard jaw system, a detailed analysis of the structure of the jaw apparatus was undertaken in the insectivorous lizard Plocederma stellioand in closely related herbivorous lizards of the genus Uromastix.The morphological and physiological properties of the jaw system in P. stellioand U. aegyptiuswere studied by means of dissections, light microscopy, histochemical characterisations, and in vivo stimulation experiments. The skull of Uromastixseems to be built for forceful biting (high, short snout). Additionally, the pterygoid muscle is modified in P. stellio,resulting in an additional force component during static biting. Stimulation experiments indicate that jaw muscles in both species are fast, which is supported by histochemical stainings. However, the oxidative capacity of the jaw muscles is larger in Uromastix.Contraction characteristics and performance of the feeding system (force output) are clearly thermally dependent. We conclude that several characteristics of the jaw system (presence of extra portion of the pterygoid muscle, large oxidative capacity of jaw muscles) in Uromastixmay be attributed to its herbivorous diet. Jaw muscles, however, are still faster than expected. This is presumably the result of trade‐offs between the thermal characteristics of the jaw adductors and the herbivorous lifestyle of these animals. Anat Rec 254:496–507, 1999. © 1999 Wiley‐Liss, Inc.

Matrix metalloproteinases (MMPs) play a role in tissue remodelling and angiogenesis. We have investigated the expression and regulation of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-7 (matrilysin), MMP-9 (gelatinase B) and their inhibitors TIMP-1 and TIMP-2 in human umbilical vein, femoral vein and microvascular endothelial cells, and compared these data with those obtained with human synovial fibroblasts. Non-stimulated vein endothelial cells expressed the mRNAs for MMP-1, MMP-2, TIMP-1 and TIMP-2. MMP-3 mRNA and protein were undetectable or only weakly expressed, but could be stimulated by the inflammatory mediator tumour necrosis factor alpha (TNF alpha). The expression of MMP-3 and MMP-1 was further enhanced by phorbol 12-myristate 13-acetate (PMA). Phorbol ester also induced TIMP-1 and MMP-9, the expression of the latter being further enhanced by TNF alpha or interleukin 1 alpha (IL-1 alpha). Similar stimulatory effects were observed in microvascular endothelial cells. Hence the inflammatory mediator TNF alpha induces/enhances the production of several matrix metalloproteinases in human endothelial cells. On the other hand, MMP-2 and TIMP-2 were not affected or were affected in a variable way by TNF alpha and/or phorbol ester, suggesting a dissimilar regulation of these proteins. The cyclic AMP-enhancing agent forskolin affected the production of MMPs in a cell-type-specific way. In human vein endothelial cells it enhanced the PMA-mediated induction of MMP-9, whereas it suppressed this induction in human microvascular endothelial cells and in synovial fibroblasts. On the other hand, forskolin suppressed the PMA-mediated induction of MMP-1 and MMP-3 in synovial fibroblasts, while it enhanced or did not affect this induction in various types of human endothelial cells. These observations may have implications for future pharmacological intervention in angiogenesis.

The safety and efficacy of subgingivally‐applied2% minocycline ointment was evaluated in a randomized, double‐blind study of 103 adults with moderate to severe periodontitis. Two groups were compared; one received the test minocycline ointment and the other a vehicle control. Both groups had scaling and root planing at baseline, after which the test or control ointments were applied with an applicator into the periodontal pockets at baseline, and at 2, 4, and 6 weeks. Assessment of clinical response was made by measuring probing depth and probing attachment level and gingival bleeding. These measurements were made at baseline prior to scaling and root planing, and at weeks 4 and 12. Microbiological assessment of the subgingival flora was carried out with DNA probes at baseline, and at weeks 2, 4, 6, and 12 to identify and quantify Porphyromonas gingivalis, Prevotella intermedia, and Actinobacillus actinomycetemcomitans. Subgingival minocycline ointment resulted in statistically significantly greater reduction of P. gingivalisat weeks 2, 4, 6, and 12; P. intermediaat weeks 2, 4, 6, and 12; and A. actinomycetemcomitansat weeks 6 and 12. Probing depth reductions were seen for both groups at weeks 4 and 12; however, this reduction was statistically significantly greater in subjects treated with minocycline ointment. Reduction in gingival index and probing attachment gain were seen in both groups, however, the differences between the groups were not statistically significant. In those sites with a baseline probing depth ≥7 mm and a bleeding index >2, the minocycline treatment at 12 weeks resulted in a probing pocket depth reduction of 42% at baseline as compared to 28% at baseline in the control group (P= 0.0001). Subgingival administration of minocycline ointment was well tolerated. This study demonstrates that repeated subgingival administration of a minocycline ointment as an adjunct to scaling and root planing results in reduction of putative periodontal pathogens, and reduction in probing depth greater than that seen in the control. J Periodontal 1993; 64:637–644.

The effects of photodynamic treatment (PDT) on venules include vascular leakage accompanied by oedema formation, vasoconstriction and blood flow stasis. The goal of this study was to gain insight into the mechanism underlying these vascular events by studying one of the earliest observations after PDT, granulocyte adhesion, in an in vitro model. For this purpose human umbilical vein endothelial cells (HUVECs) preincubated with Photofrin II (PII) were illuminated with red light and incubated with neutrophils. PDT led to a dramatic change in the morphology of the endothelial cells. Clearly, neutrophils adhered to the subendothelial matrix and their adherence coincided with an increase in the percentage of exposed subendothelial matrix by the gradual contraction of endothelial cells. Furthermore, the increase in adherence was dependent on drug dose, illumination time and the time delay after PDT. The neutrophil adherence could be inhibited by anti-beta2-integrin antibodies, which suggests that the alphaL-, alphaM- or alphaX-beta2 receptors of the neutrophil mediated this phenomenon. At 4 degrees C or by preincubation of the neutrophils with staurosporin, their adherence to the subendothelial matrix exposed by PDT of endothelial cells could be prevented. Apparently, activation of the beta2-integrin receptor by interaction with the subendothelial matrix is necessary for the increased binding of neutrophils. Taken together, these in vitro findings suggest that the PDT-induced contraction of the endothelial cells permits neutrophil adherence to the subendothelial matrix. It is conceivable that a similar mechanism contributes to the initial adherence of granulocytes to the vessel wall as observed after PDT in vivo.

We wanted to examine whether a relation between foraging strategy, morphology, the mechanics of tongue protrusion, and prey chemical detection and discrimination exists in agamid lizards. Tongue‐flick behavior was observed in two species of this family: Uromastix acanthinurusand Plocederma stellio. Potential prey chemical discrimination by means of tongue flicking was examined by using applicator tests. Tongue flicks were subsequently recorded by high‐speed video in combination with the electrical activity of a number of jaw and hyolingual muscles. The kinematics of jaws and tongue and the muscle activity patterns were quantified. To investigate if the observed differences in tongue‐flick behavior (mainly in the frequency of use) are translated into corresponding differences in tongue morphology, the tongues of both species were examined by light and scanning electron microscopy. The species differed mainly in the surface morphology of the foretongue and in the abundance and distribution of taste buds on the tongue and oral cavity. These differences can be related to behavioural observations; whereas U. acanthinurusreadily uses tongue flicks to detect and discriminate between food items, P. stelliodoes not. However, differences in tongue‐flick mechanics (kinematics, electromyograms) between both species were minor. Based on the data gathered in this study and from previously published data, an evolutionary transformation series leading to the complex tongue‐flick cycles as observed in snakes is proposed. The required morphological and mechanical changes that accompany such an evolutionary sequence are discussed. Anat. Rec. 252:102–116, 1998. © 1998 Wiley‐Liss, Inc.

We report a case of a triplet heterotopic pregnancy consisting of an intrauterine monozygous twin pregnancy and a tubal pregnancy after replacement of only two embryos in an in-vitro fertilization cycle with donor spermatozoa. This case demonstrates that sonographic demonstration of two intrauterine pregnancies after transfer of two embryos does not exclude the presence of an ectopic pregnancy. As both heterotopic pregnancy and spontaneous monozygotic twinning are more frequent after the use of assisted reproductive techniques, this combination, although extremely rare, must be kept in mind, especially in older patients with pre-existing tubal damage.Keywords:assisted reproduction/heterotopic pregnancy/monozygotic twinning

We report a case of a triplet heterotopic pregnancy consisting of an intrauterine monozygous twin pregnancy and a tubal pregnancy after replacement of only two embryos in an in-vitro fertilization cycle with donor spermatozoa. This case demonstrates that sonographic demonstration of two intrauterine pregnancies after transfer of two embryos does not exclude the presence of an ectopic pregnancy. As both heterotopic pregnancy and spontaneous monozygotic twinning are more frequent after the use of assisted reproductive techniques, this combination, although extremely rare, must be kept in mind, especially in older patients with pre-existing tubal damage.

Springhares, Pedetes capensis, are adapted for nocturnal life in arid and semiarid regions. Their large orbits and acoustic apparatus differ greatly from the primitive conditions for rodents. Herein, the masticatory apparatus of springhares is compared with the scarce data available for protrogomorph, myomorph, and hystricomorph rodents. The muscles of the zygomasseteric complex are of the hystricomorphous type and show an extremely strong development (87.5% of the total mass of the adductor muscles) compared to the hystricognathous hystricomorphous rodents (66.4% in Cavia). The digastric muscle and the medial pterygoid, in contrast, are of the sciurognathous type. Within each evolutionary line the musculature differs only in detail, whereas masticatory movement patterns vary significantly. Apparently, skeletal elements of the masticatory apparatus significantly affect the movement pattern of the lower jaw during the power stroke during which the molar teeth come into occlusion.