STUDIES BASED ON A MALIGNANT TUMOR OF THE RABBIT : I. THE SPONTANEOUS TUMOR AND ASSOCIATED ABNORMALITIES.

A malignant tumor which developed at the site of a primary syphilitic lesion in the scrotum of a rabbit, about 4 years after inoculation, and eventually led to the death of the animal, has formed the basis for an extensive series of investigations beginning with the study of the spontaneous tumor. The present report contains the clinical history of the animal from the time of inoculation to its death and the results of pathological examinations. The most important events recorded may be summarized as follows: 1. A mild but persistent syphilitic infection with an occasional relapse and the eventual development of chronic inflammatory lesions in the skin associated with atypical epithelial proliferations. 2. The occurrence, at about the same time, of extensive degenerative changes in the dermis accompanied by an atypical growth of hair follicles, with the production of diffuse and nodular areas of thickening and induration (scleroderma). 3. The development of a growth in the skin of the left scrotum which recurred after removal and spread diffusely over adjacent parts of the skin, and metastasized to the regional lymph nodes and to internal organs. 4. The transplantation of the growth to other rabbits by intratesticular inoculation and the successful propagation of the growth over a period of nearly 2 years (twenty generations). 5. The development of a cachexia and of pressure phenomena from metastases involving the cervical and lumbar regions of the spinal column which eventually led to the death of the animal. 6. The discovery, post mortem, of an extensive leucoplakia of the tongue and buccal mucosa, chronic inflammatory lesions in the esophagus with atypical epithelial proliferation, and a nodular growth in the left testicle differing in character from that in the scrotum. 7. The presence of extensive degenerative changes in the vascular system, degeneration of the parenchymatous organs, atrophy of the thymus and lymphoid system, with chronic lymphadenitis, atrophy, degeneration, and necrosis of the suprarenals, and atrophy and hyperplasia of the thyroid with chronic thyroiditis. The conclusion was reached that the growth in the scrotum represented a neoplasm of epithelial origin which was composed of cells allied to those found in the bulb and root sheath of the hair. No explanation was offered for the origin or unusual malignancy displayed by the tumor pending the introduction of experimental data. It was stated, however, that the evidence presented was sufficient to warrant the assumption that the factor of foremost importance in the development of the tumor was constitutional rather than local.     

EXPERIMENTAL SYPHILIS IN THE RABBIT : VI. AFFECTIONS OF BONE,CARTILAGE, TENDONS,AND SYNOVIAL MEMBRANES. PART 1. LESIONS OF THE SKELETAL SYSTEM.

From a study of a series of rabbits inoculated with two old strains of Treponema pallidum, it was found that localized infection of bones and tendons was of frequent occurrence and led to the formation of a variety of lesions. The bones usually involved were those of the face and the feet and legs. Most often the lesions arose from the periosteum but developed also within the bone or marrow cavities and at lines of epiphyseal union. Grossly, the periosteal lesions were of two types—one being a circumscribed, indurated, and nodular mass and the other a process of a more diffuse character. Histologically, the lesions presented the typical appearance of syphilitic granulomata composed of more or less distinct layers which corresponded roughly with structural divisions of the periosteum. The composition of lesions of membrane and of cartilage bones differed somewhat in this respect, especially in the development of an osteoclastic layer. Invasion of the bone with absorption and necrosis were constant features of periosteal affections and were most marked in the case of the facial bones and the small bones of the feet. Lesions in the bone and marrow cavities were detected chiefly by radiographs or by the occurrence of bone destruction in the absence of periosteal involvement. They were characterized by a loss of structural detail in the bone, rarefication, increased fragility, necrosis, pathological fracture, and epiphyseal separation associated with more or less granulomatous reaction. Histologically, the bone lesions presented essentially the same picture as those of the periosteum, while the lesions which arose from the marrow cavities were composed chiefly of polyblastic infiltrations. In this group of affections, the most important were those which developed at the epiphyses. The destructive effects produced by all classes of lesions varied from a slight surface erosion or rarefication to extensive necrosis resulting in the formation of bony defects or in disintegration or fracture of the bone. These conditions differed very decidedly with the particular bones involved. Of especial importance in this connection was the occurrence of a peculiar form of mass necrosis which at times resulted in the destruction of considerable areas of bone even in parts where the granulomatous type of lesion was comparatively slight. The most characteristic injuries were the saddle-nose deformities and the epiphyseal separation in the small bones of the tarsus and hind feet. The marks of permanent injury were, on the whole, comparatively slight, but they also differed both with the degree of the original injury and with the bone affected. Granulomatous lesions of tendons or tendon sheaths were occasionally seen, and in a few instances, lesions of synovial cavities were demonstrated microscopically.     

THE RELATION OF THE SPLEEN TO BLOOD DESTRUCTION AND REGENERATION AND TO HEMOLYTIC JAUNDICE : V. CHANGES IN THE ENDOTHELIAL CELLS OF THE LYMPH NODES AND LIVER IN SPLENECTOMIZED ANIMALS RECEIVING HEMOLYTIC SERUM.

In a large proportion of dogs that have been splenectomized for periods of two weeks or more, one finds a great increase in the number of endothelial cells of the lymph nodes. In most splenectomized dogs that succumb to an injection of hemolytic immune serum within forty-eight hours, the sinuses of the lymph nodes contain large numbers of endothelial cells, phagocytic for red cells. This is not seen in normal dogs receiving hemolytic serum. Likewise a similar power of phagocytosis is seen frequently in the stellate cells of the capillaries of the liver. Both in the lymph nodes and the liver these cells appear to be formed in situ; we find no evidence that they have been transported to these organs. Such findings suggest the development of a compensatory function on the part of the lymph nodes and possibly of the liver. Normally the spleen contains cells which have the power to engulf and presumably to destroy the red blood corpuscles. In certain pathological conditions this function is frequently greatly augmented and may sometimes be shared by the lymph nodes, for example, in typhoid fever, as was first clearly shown by Mallory. Our observations suggest that in the absence of the spleen, this function of forming red blood corpuscle-phagocyting cells, normally a minor activity of the lymph nodes, becomes highly developed in the latter organs, and that these cells, and the stellate cells of the liver, thus assume, in part at least, the function of destroying red blood corpuscles by phagocytosis. In view of the somewhat limited material at our disposal, we offer this, not as definitely conclusive, but as evidence which, in connection with the work of others, is highly suggestive of the possibility of the lymph nodes assuming some of the function of the spleen. Whether this activity of the endothelial cells of the lymph nodes and the liver has any bearing on the anemia that follows splenectomy and on the occurrence of spontaneous jaundice in the late periods after splenectomy, is not yet clear.     

Influence of exclusive breastfeeding on hippocampal structure,satiety responsiveness,and weight status

Longer exclusive breastfeeding duration has been associated with differences in neural development, better satiety responsiveness, and decreased risk for childhood obesity. Given hippocampus sensitivity to diet and potential role in the integration of satiety signals, hippocampus may play a role in these relationships. We conducted a secondary analysis of 149, 7–11‐year‐olds (73 males) who participated in one of five studies that assessed neural responses to food cues. Hippocampal grey matter volume was extracted from structural scans using CAT12, weight status was assessed using age‐ and sex‐adjusted body mass index (%BMI_p85), and parents reported exclusive breastfeeding duration and satiety responsiveness (Children''s Eating Behaviour Questionnaire). Separate path models for left and right hippocampus tested: (1) the direct effect of exclusive breastfeeding on satiety responsiveness and its indirect effect through hippocampal grey matter volume; (2) the direct effect of hippocampal grey matter volume on %BMI_p85 and its indirect effect through satiety responsiveness. %BMI_p85 was adjusted for maternal education, yearly income, and premature birth while hippocampal grey matter volume was adjusted for total intercranial volume, age, and study from which data were extracted. Longer exclusive breastfeeding duration was associated with greater bilateral hippocampal grey matter volumes. In addition, better satiety responsiveness and greater left hippocampal grey matter volume were both associated with lower %BMI_p85. However, hippocampal grey matter volumes were not associated with satiety responsiveness. Although no relationship was found between breastfeeding and child weight status, these results highlight the potential impact of exclusive breastfeeding duration on the hippocampal structure.     

恩替卡韦与拉米夫定治疗HBeAg阴性慢性乙型肝炎的对照研究

Ⅱ期临床试验已经证实恩替卡韦是一种治疗HBeAg阴性慢性乙型肝炎有效和可选择的抗病毒药物。采用双盲法将648例未曾接受过核苷类药物治疗的HBeAg阴性慢性乙型肝炎随机分配进入恩替卡韦（0．5mg／d）治疗组或拉米夫定（100mg／d）治疗组，疗程至少52wk。     

Thyroid peroxidase forms thionamide-sensitive homodimers: relevance for immunomodulation of thyroid autoimmunity

Thyroid peroxidase (TPO) is the key enzyme in thyroid hormone production and a universal autoantigen in Graves’ and other autoimmune thyroid diseases. We wished to explore the expression of TPO and whether it was affected by thionamide antithyroid drugs. We studied recombinant TPO, stably expressed by a Chinese hamster ovary cell line (CHO-TPO) and transiently expressed TPO-enhanced green fluorescent protein (eGFP) and -FLAG fusion proteins. Immunoblotting of CHO-TPO cell extracts showed high-molecular weight (HMW) TPO isoforms that were resistant to reduction, as well as 110 kDa monomeric TPO. Co-immunoprecipitation and enzyme-linked-immunosorbent assay (ELISA) binding studies of FLAG- and eGFP-tagged TPO demonstrated TPO dimerisation. CHO-TPO cells cultured in methimazole (MMI) for 10 days showed a significant reduction in HMW-TPO isoforms at MMI concentrations of 1 μM and above (p < 0.01), whereas monomeric TPO expression was unchanged. We observed a similar reduction in HMW-TPO in CHO-TPO cells cultured in propylthiouracil (10 μM and above). Binding of Graves’ disease patient sera and TPO-Fabs to enzymatically active TPO that was captured onto solid phase was not abrogated by MMI. The cellular localisation of TPO in CHO-TPO cells was unchanged by MMI treatment. Our demonstration of homodimeric TPO and the reduction in HMW-TPO isoforms during thionamide treatment of CHO-TPO cells shows, for the first time, an effect of thionamides on TPO structure. This suggests a structural correlate to the effect of thionamides on TPO enzymatic activity and opens up a novel potential mechanism for thionamide immunomodulation of autoimmune thyroid disease.     

Signal transduction by the platelet Fc receptor

We have evaluated the mechanism by which crosslinking human platelet Fc receptor (FcR) for IgG triggers platelet aggregation and the platelet release reaction. Platelet FcR was crosslinked by incubating purified human platelets with anti-FcRII monoclonal antibody and F(ab')2 anti- mouse Ig. The resultant [Ca2+]i increase, monitored by Fura-2 and measured in the absence of extracellular Ca2+, reached a peak of 750 +/- 50 nmol/L. The effects of cyclooxygenase inhibitors, aspirin and indomethacin, and a phospholipase A2 inhibitor, dibromoacetophenone, were examined. Regardless of the inhibitor, at least 25% of the [Ca2+]i increase remained. Thrombin (0.2 U/mL) stimulated an immediate [Ca2+]i increase that reached 1.95 +/- 0.8 mumol/L. The [Ca2+]i increase generated by thrombin was only slightly reduced by these inhibitors. Crosslinking the FcRII of platelets resulted in a fivefold increase in the production of [3H]inositol phosphates, (IP) which, in the absence of extracellular Ca2+ was insensitive to aspirin. The activation of a [Ca2+]i increase along with the measured increases in IP indicate that FcRII crosslinking leads to the activation of phospholipase C (PLC). In contrast to thrombin, platelet activation via FcRII depends to a large extent on arachidonic acid metabolites. However, neither cyclooxygenase nor phospholipase A2 inhibitors completely blocked FcRII-stimulated [Ca2+]i increase. These observations led us to propose that crosslinking of platelet FcRII initially activates PLC.     

The Role of Serotonin (5-HT) in Behavioral Control: Findings from Animal Research and Clinical Implications

The neurotransmitters serotonin and dopamine both have a critical role in the underlying neurobiology of different behaviors. With focus on the interplay between dopamine and serotonin, it has been proposed that dopamine biases behavior towards habitual responding, and with serotonin offsetting this phenomenon and directing the balance toward more flexible, goal-directed responding. The present focus paper stands in close relationship to the publication by Worbe et al. (2015), which deals with the effects of acute tryptophan depletion, a neurodietary physiological method to decrease central nervous serotonin synthesis in humans for a short period of time, on the balance between hypothetical goal-directed and habitual systems. In that research, acute tryptophan depletion challenge administration and a following short-term reduction in central nervous serotonin synthesis were associated with a shift of behavioral performance towards habitual responding, providing further evidence that central nervous serotonin function modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. In the present focus paper, we discuss the findings by Worbe and colleagues in light of animal experiments as well as clinical implications and discuss potential future avenues for related research.     

Peri-implantation undernutrition programs blunted angiotensin II evoked baroreflex responses in young adult sheep

An adverse environment around conception and implantation influences later fetal growth and development to term in humans and sheep. Indeed, preimplantation undernutrition of rats elevated the systolic blood pressure of the resultant adult offspring. In this study, adult cardiovascular function is examined in a slower growing, non-litter-bearing species after peri-implantation undernutrition. Eight ewes were fed to 50% equivalent food intake of 12 control ewes from 1 to 30 days (term approximately 147 days) only. Following consumption of an adequate diet to term, natural lambing, and then weaning, resting cardiovascular status and baroreflex function were examined in the resultant young adult offspring. Birth weight and postnatal growth to 1 year of age were unaffected by early undernutrition; however, nutrient-restricted sheep had increased pulse pressure, a reduced rate pressure product, and a leftward shift in their baroreflex function curve. Baroreflex sensitivity during angiotensin II infusion was also blunted in early nutrient-restricted sheep but the tachycardia following a reduction in central blood pressure appeared potentiated, relative to controls. The data suggest that peri-implantation undernutrition may program long-term cardiovascular dysfunction that ultimately increases the risk of hypertension later in life. An increase in regional angiotensin II activity during this critical early phase of development is a likely candidate mechanism for the effects observed. The data have broad implications for the health outcome of those offspring from mothers who were poorly nourished during early, often unknown pregnancy and for embryos artificially manipulated because of infertility treatment.