The Trimera mouse: generating human monoclonal antibodies and an animal model for human diseases

Monoclonal antibodies of human origin may have great therapeutic value in the treatment of cancer, autoimmune disorders and viral or bacterial infections. Several methods for generating human monoclonal antibodies exist; some are based on the transplantation of a functioning human immune system into severe combined immunodeficient (scid) mice or into Trimera mice, which are mice that have been lethally irradiated and radioprotected by transplantation of bone-marrow cells from scid mice. Trimera mice could be also used to develop animal models for human diseases by transplanting infected human tissue fragments and for creating models for cell therapy.     

A new animal model for maxillary sinus floor augmentation: evaluation parameters

Stress mediators, CRF-41 and vasopressin known to be synthesized in, and released from the parvocellular neurosecretory neurons of the hypothalamic paraventricular nucleus (PVN) are essential to release adrenocorticotropin (ACTH) in response to stress. In addition, suckling-induced prolactin (PRL) release also depends on the integrity of the PVN. In the present study, ether stress-induced adrenocorticotrop hormone (ACTH) and prolactin (PRL) release was studied 2, 5 and 42 days after placing lesions in the hypothalamic paraventricular nucleus (PVN) of male rats. Ether-induced ACTH secretion was strongly inhibited 2 and 5 days after lesions whereas 6 weeks later the lesion induced inhibition was fading. In contrast, PVN lesion failed to inhibit ether-induced PRL release at any time studied. The results suggest that contrary to previous suggestions the peptidergic neurons essential for stress-induced PRL release are outside the PVN.     

Risk of melanoma in medium-sized congenital melanocytic nevi: a follow-up study

BACKGROUND: The risk of the occurrence of malignant melanoma (MM) in medium-sized (1.5 to 19.9 cm in diameter) congenital melanocytic nevi (CMN) is the subject of controversy. Universally accepted recommendations regarding the management of such lesions have not been made. OBJECTIVE: Our purpose was to assess the risk of MM arising in medium-sized CMN. METHODS: The study included 230 medium-sized CMN in 227 patients, first seen in a private dermatology practice from 1955 to 1996, who were followed up for MM arising within their CMNs. Criteria for entry into the study included (1) a clinically diagnosed medium-sized CMN, (2) minimum follow-up period of 1 year, and (3) a photograph of the lesion in the patient's medical record. RESULTS: No MM occurred in a medium-sized CMN during an average follow-up of 6.7 years (median, 5.8 years) to an average age of 25.5 years (median, 19.1 years). CONCLUSION: The results of this short-term follow-up study do not support the view that there is a clinically significantly increased risk for MM arising in banal-appearing medium-sized CMN or that prophylactic excision of all such lesions is mandatory. Lifelong medical observation seems a reasonable alternative for many medium-sized CMN.     

The canine as an animal model of human aging and dementia

Cytochemical defects in chromatin were examined by transmission electron microscopy (TEM) after the staining by alcoholic phosphotungstic acid (PTA) of normal and malformed ejaculated spermatozoa from 35 male partners of infertile couples, and in six sperm samples retrieved from the caput epididymidis of men affected by obstructive azoospermia. PTA staining was also analysed in normal ejaculates of fertile men after incubation of the washed spermatozoa with dithiothreitol (DTT) to reduce disulfides to thiols, or with DTT followed by iodoacetamide, a blocking agent for thiol groups. PTA stained 63 (27-100)% of malformed heads and 25 (10-100)% of normal sperm heads (median (range) n = 35; P = 0.0001, Wilcoxon matched pairs test). The percentage of normal heads stained by PTA was negatively correlated with the percentage of heads of normal form, with condensed chromatin and a normal acrosome (Spearman r = 0.75; P = 0.0001), and positively correlated with the percentage of malformed heads after conventional TEM analysis (Spearman r 0.60; P = 0.0001). Staining with PTA in normal heads was not correlated with the presence of non-condensed chromatin in otherwise normal sperm heads evaluated by conventional TEM analysis. In spermatozoa recovered from the caput epididymidis, 15% of normal heads were stained with PTA, significantly fewer than in ejaculated sperm samples (P = 0.014). The reduction of disulfides to thiols was associated with PTA staining of all normal heads, and this was prevented by incubation with iodoacetamide. We conclude that PTA staining of the nuclei of human ejaculated spermatozoa may indicate a defect of chromatin condensation, owing to an excess of free thiol groups. The lower percentage of normal epididymal sperm heads that stained with PTA in cases of obstructive azoospermia compared with ejaculated sperm may be related to an overoxidation of thils owing to the ageing of spermatozoa.     

Bovine hereditary cardiomyopathy: an animal model of human dilated cardiomyopathy

Bovine hereditary cardiomyopathy (bCMP) displays clinical characteristics of human idiopathic dilated cardiomyopathy (DCM). We studied isometric force of contraction in right ventricular trabeculae, plasma and tissue catecholamines, beta- and alpha 1-adrenoceptor density, Gi proteins and adenylyl cyclase activity in eight hearts with bCMP and eight control hearts (right and left atria and ventricles each). Results: Compared to control, the potency of isoprenaline in bCMP was eight-fold decreased, whereas the maximal positive inotropic effect of isoprenaline as well as the efficacy and potency of calcium were unchanged. Plasma noradrenaline was increased by 240%. Tissue noradrenaline and adrenaline were decreased by 36-63% and 58-69%, whereas dopamine was increased by 105-218%. beta-adrenoceptor density was drastically reduced by 90%, but binding affinity was unchanged. alpha-Adrenoceptor density and binding affinity were unchanged. Total PTX-substrates were increased in bCMP by 28-99%. Basal adenylyl cyclase activity was decreased by 36-47%. Similarly, stimulation by GTP, GMPPNP, isoprenaline, sodium fluoride, manganese or forskolin was attenuated by 26-62% (atria) and 45-66% (ventricles). In conclusion, we found marked activation of the sympatho-adrenergic system, downregulation of beta-adrenoceptors, upregulation of Gi proteins, global desensitization of adenylyl cyclase and selective subsensitivity to beta-adrenergic inotropic stimulation. These results closely resemble the characteristic alterations in the beta-adrenoceptor-G protein-adenylyl cyclase pathway in human heart failure, indicating that they are general features of heart failure. The similarity to human DCM, the inheritance and the availability of large tissue samples make bCMP a suitable model for human DCM.     

Rat as an animal model carrying human hepatitis B virus in hepatocytes

OBJECTIVE: To establish an experimental animal model of rat carrying human hepatitis B virus in the hepatocytes using a simple and reproducible method. MATERIALS AND METHODS: Human serum rich in hepatitis B virus was injected into portal veins and caudalis veins of young male Wistar rats. One and two months after the injection, liver biopsies were done. In situ hybridization and immunohistochemical study of liver specimens were carried out. Sera were also examined for HBV DNA by polymerase chain reaction. RESULTS: All of seven rats in this experiment were HBV DNA and HBV surface antigen (HBsAg) positive in their hepatocytes. Most HBV positive hepatocytes were distributed around the central vein and scattered in the liver lobules, and HBV DNA and HBsAg were located in cytoplasm. HBsAg exists mainly as the forms of diffuses and inclusion body. No hepatocytic damage or inflammation was observed. Neither viremia nor antigenemia was detected. CONCLUSIONS: Our studies showed for the first time that natural human HBV can enter Wistar rat liver cells through intravenous injection efficiently and express for a long period. This animal model can be used in the studies of HBV molecular biology, therapeutic regimens and prophylaxis against HBV. A possible mechanism of HBV entering rat hepatocytes is also proposed.     

Prophylaxis against soman inhalation toxicity in guinea pigs by pretreatment alone with human serum butyrylcholinesterase

A total of 100 patients of tetralogy of Fallot aged 13 years and over were operated upon at the All India Institute of Medical Sciences, New Delhi, India between January 1991 and December 1996. There were 69 males (69%) and 31 females (31%). Age ranged from 13 years to 43 years (mean 19.66 years). Twenty % of patients had preoperative complications like haemoptysis, cerebrovascular accidents, brain abscess and infective endocarditis. Twenty-two patients had previous palliative shunts. Fifteen patients had coil embolisation of major collaterals prior to surgery. In hospital mortality rate was 4%. Follow-up ranged from 1 month to 5 years (mean 3.4 years). There was one late death due to infective endocarditis. Postoperatively 93.6% patients were in NYHA class I. Significant residual defects warranting re-operation were present in three patients. Total correction of tetralogy of Fallot in older patients can be performed with acceptable results.     

Neurogenically mediated cystitis in rats: an animal model

PURPOSE: Pseudorabies virus (PRV) is a useful tool for mapping the control circuitry of the spinal cord. In the process of mapping CNS regulatory pathways for the lower urinary tract, a hemorrhagic change in the bladder was observed that was not overtly evident in other pelvic organs. The relationship between the appearance of hemorrhagic changes in the bladder and the evolution of PRV induced changes in the spinal cord was therefore explored. MATERIALS AND METHODS: Sprague-Dawley rats were injected with PRV into the ACD tail-muscle. Bladder and CNS fixation were achieved by transcardial perfusion with formaldehyde. Multi-level sections were obtained from T8 through S4. Fixed tissue was stained and evaluated by light microscopy. Immunohistochemical stains were carried out for PRV and iNOS on spinal cord tissue. We were therefore able to evaluate the relationship between the manifestation of the hemorrhagic cystitis, appearance of the PRV in the spinal cord and evidence of CNS inflammation. RESULTS: The evolution of hemorrhagic cystitis paralleled the evidence of inflammation in the thoraco-lumbar and sacral cord. These bladders contained 5 to 9 ml. of bloody urine (a normal rat bladder contains 1 to 2 ml.). On cystomanometry (CMG) the bladders were acontractile. No PRV could be cultured in the hemorrhagic bladders. The histological changes observed in the bladder represent true inflammation. CONCLUSION: There was no obvious explanation for these changes other than the associated inflammatory changes in the spinal cord. The findings are consistent with the hypothesis that a spinal cord stress, via an unknown metabolic pathway, can result in dramatic, neurogenically mediated changes in the bladder.     

Associated factors in the prevalence of more than 50 common melanocytic nevi, atypical melanocytic nevi, and actinic lentigines: multicenter case-control study of the Central Malignant Melanoma Registry of the German Dermatological Society

Several case-control studies identified common and atypical melanocytic nevi as major risk indicators for the development of cutaneous melanoma. The present investigation was planned to detect factors associated with the prevalence of these melanoma risk markers. Whole-body examination findings and interview data of 513 melanoma patients and 498 age- and sex-matched control subjects were analyzed. Existence of more than 50 common melanocytic nevi and the presence of atypical melanocytic nevi were significantly related to age and gender, with significantly elevated relative risk for their prevalence before the age of 60 and in males. Additionally, sunburns before the age of 20 were significantly associated with both more than 50 common melanocytic nevi (relative risk = 1.7) and the presence of atypical melanocytic nevi (relative risk = 1.5). Actinic lentigines were found more frequently with increasing age, and the presence of actinic lentigines was significantly related to a tendency of freckling in adolescence (relative risk = 2.0) and to two or more sunburns after the age of 20 (relative risk = 1.6). In conclusion, sunburns before the age of 20 contribute to the development of multiple melanocytic nevi and atypical melanocytic nevi. In adulthood, this type of sun exposure is associated with the development of actinic lentigines. The relative risk of developing cutaneous melanoma increases in association with the development of these benign melanocytic lesions.     

Pathology of interstitial nephritis induced in guinea pigs by exoantigens

Histological and immunofluorescent assessment of the kidney, renal core cultures, and determination of circulating antibodies were carried out in Hartley guinea pigs with a selective delayed-type hypersensitivity state (DTH) and acute interstitial nephritis induced and elicited by exoantigens. The results show that the normal tubule-vascular structure of the kidney, the simplicity of the molecular structure of the exoantigens and the modification of the native form of the exoantigens, when it is presented to the kidney in the elicitation phase of the DTH reaction, are factors which may reduce the cellular response in the normal renal parenchyma. The cytological events over a 48-hour period are not different to those which have been described in DTH reactions in extrarenal tissues. Exoantigens can induce renal lesions evoking an acute interstitial nephritis picture in animals with selective DTH at a time when there are neither circulating antibodies nor deposition of immunoglobulins or infection in the renal parenchyma.     

How social an animal? The human capacity for caring.

We live in a social arena. Yet, in our interactions with others do we ever really care about them, or is the real target of our concern always, exclusively ourselves? For many years psychology, including social psychology, has assumed that we are social egoists, caring exclusively for ourselves. Today, the computer analogy that underlies so much thinking in cognitive and social psychology overlooks the fact that we care altogether. Recent evidence in support of the empathy-altruism hypothesis suggests a very different view. It suggests that not only do we care but also that when we feel empathy for others in need, we are capable of caring for them for their sakes and not our own. Limits on the human capacity for altruistic caring are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Infection of human cells by an endogenous retrovirus of pigs

The possible use of pig organs and tissues as xenografts in humans is actively being considered in biomedical research. We therefore examined whether pig endogenous retrovirus (PERV) genomes can be infectiously transmitted to human cells in culture. Two pig kidney cell lines spontaneously produce C-type retrovirus particles. Cell-free retrovirus produced by the PK-15 kidney cell line (PERV-PK) infected pig, mink and human kidney 293 cell lines and co-cultivation of X-irradiated PK-15 cells with human cells resulted in a broader range of human cell infection, including human diploid fibroblasts and B- and T-cell lines. Kidney, heart and spleen tissue obtained from domestic pigs contained multiple copies of integrated PERV genomes and expressed viral RNA. Upon passage in human cells PERV-PK could rescue a Moloney retroviral vector and acquired resistance to lysis by human complement.     

Transcatheter liver lobar ablation: an experimental trial in an animal model

Complete embolization of tumor tissue together with surrounding liver sufficiently prevents collateral blood supply to the tumor, offering curative treatment for hepatic malignancies. The present experiment was designed to test the feasibility of hepatic lobar ablation by means of the transcatheter chemoembolization technique. Five groups of rats (n = 6) were treated with a mixture of iodized oil/ethanol in ratios of 5:1, 4:1, 3:1, 1:1, and 1:0, which was injected selectively into the right-lobe artery until saturation during open surgery. Another group (n = 6) was studied using in vivo microscopy to observe the distribution of the mixture in the liver and changes in hepatic microcirculation. Ethiodol/ethanol mixture entered the portal vein after injection into the hepatic artery creating dual, complete arterial and portal venous embolization. Lobar ablation effects were achieved in 2 weeks in the 5:1, 4:1, and 3:1 ratio groups, indicated by the lobe/liver weight measurements (p < 0.001 vs normal liver). Hepatic arterial administration of the Ethiodol/ethanol mixture creates dual hepatic arterial and portal venous embolization, achieving a lobar ablation effect.     

Mammary tumour induction by pituitary grafting in male mice: an animal model for male breast cancer

Isologous anterior pituitary grafting, 4 each, to 3-4-month-old SHN and SLN male mice resulted in an appearance of mammary tumours from 8 months of age and the incidence at 12 months reached 53.8% in each strain. All tumours were diagnosed as type B adenocarcinomas. In association with the results, normal mammary gland growth and mouse mammary tumour virus (MMTV)-gp52 antigen levels in the submaxillary glands were stimulated by the treatment in these strains. The effect of pituitary grafting was much less in GR/A male mice in which no mammary tumours appeared.     

Immotile cilia syndrome in pigs. A model for human disease

This paper describes the ultrastructural alterations observed in the tracheal epithelium of six sibling swine suffering from porcine immotile cilia syndrome (PICS) compared with those in human immotile cilia syndrome (HICS). As in some human cases, the tracheal epithelium of these pigs was lined by cilia-lacking cells. A variety of dynein defects in other pigs suffering from PICS have been previously observed. The spectrum of defects affords evidence that the PICS is genetically heterogeneous. Available data suggests that there are many similarities between HICS and PICS. Therefore, it is proposed that PICS may prove to be a useful animal model for the human disease.     

Pluripotential melanoblastoma, a unifying concept on malignancies arising in congenital melanocytic nevi: report of two cases

Congenital melanocytic nevi are benign lesions present at birth and considered to be caused by a maldevelopment of the neural crest. The malignant potential of the congenital melanocytic nevi have been extensively addressed by several authors, and malignant melanoma is the most frequent neoplasm arising in these lesions. The present report describes two patients with congenital melanocytic nevi in which malignant melanoma with undifferentiated areas showing rhabdomyoblastic differentiation developed. The findings suggest that these mixed neoplasms may be recapitulating the differentiation potential of the ectomesenchyme-neural crest cells. We advocate the term "melanoblastoma" when referring to them.     

Neurocutaneous melanosis: clinical features of large congenital melanocytic nevi in patients with manifest central nervous system melanosis

BACKGROUND: Patients with a large congenital melanocytic nevus (LCMN) may have associated leptomeningeal melanocytosis with or without central nervous system (CNS) melanomas. These patients are considered to have neurocutaneous melanosis, a disorder that, when symptomatic or otherwise manifest neurologically, carries a poor prognosis even in the absence of malignancy. OBJECTIVE: Our purpose was to identify typical clinical features in patients who have manifest CNS melanosis in association with LCMN. METHODS: The records of 117 patients with LCMN in the New York University Registry of LCMN and the reports of 172 cases of LCMN in the world literature were included for features that might signal a high risk for the development of manifest CNS involvement. RESULTS: Of the 289 patients with LCMN, 33 had manifest CNS melanosis. In all 33 in whom symptomatic neurocutaneous melanosis was diagnosed, the LCMNs were present in a posterior axial location on the head, neck, back, and/or buttocks. "Satellite" nevi were known to be present in 31 of the 33 patients. CONCLUSION: Patients with LCMN in a posterior axial location, especially when associated with "satellite" melanocytic nevi, are at greater risk for the development of manifest neurocutaneous melanosis than patients with LCMN limited to the extremities or those who are lacking satellite nevi.     

New method for determining eye anesthesia in an animal model

Some chemical which are injurious to the eye may also cause anesthesia. If the eye were unknowingly anesthetized, exposure to an irritant could go undected and cause injury. Techniques for determining whether the eye was anesthetized have been generally unreliable. Usually the technique consists of challenging the cornea with a probe and testing for a blink response. In a new method described herein, an indwelling subpalpebral lavage apparatus was surgically implanted in the dog. Through this apparatus, a test material was instilled into the eye without the animal's anticipation. Responses caused by the materials were monitored by electroencephalography. The normal response to an irritting material was increased frequency and decreased amplitude of the electroencephalogram tracing or a deflection of thepolygraph needle (blink response), or both. The method was evaluated with known eye anesthetic agents and appeared to be a useful way of detecting eye anesthesia.     

Periosteal migration in the growing mandible: an animal model

Migration of mandibular periosteum and attached musculature was tracked along the inferior border of the ramus in growing and nongrowing guinea pigs (Cavia porcellus) over a 6-week period. Particulate metallic growth-tracing implants were placed through the bony mandible and adjacent musculature at two anteroposterior locations and two bony reference markers were placed anteriorly. Quantification from weekly radiographs of growing animals showed marked posterior migration of the periosteum, whereas in nongrowing animals there was negligible periosteum movement. Significantly greater migration occurred in posterior (6.37 +/- 0.76 mm) implants relative to the anterior implants (3.45 +/- 0.86 mm, p < 0.001). The neutral zone, where little periosteal migration occurs, was calculated to be approximately at the anteroposterior center of the molar tooth row. Analysis of the orientation of the medial pterygoid muscle relative to the mandible showed that muscle fibers on average become more horizontal. Thus, the study found differential anteroposterior migration of the mandibular periosteum in growing animals and correlative changes in orientation of the medial pterygoid muscle.