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Genetic mapping of the non-nodulation phenotype of the mutant MN-1008 in tetraploid alfalfa (Medicago sativa).

Abstract. Roots of the non-nodulating Medicago sativa mutant MN-1008 neither undergo root-hair curling, cortical cell division nor any of the early molecular events that accompany nodule initiation and development following rhizobial infection or treatment with Nod factor. These observations suggested that the mutation(s) impaired a pivotal function in Nod factor perception or in the signal transduction pathway. In this paper we show that the genetic lesion conditioning the recessive non-nodulation phenotype in the tetraploid alfalfa mutant MN-1008 can be localized to a single region on LG5 of the M. sativa genetic map. This conclusion is based on genetic analyses conducted at the tetraploid level, involving both segregation analysis and genetic mapping of the trait with respect to molecular DNA markers. The genetic mapping of the Nod(-) phenotype was performed in a segregating tetraploid F2 population, taking advantage of the availability of an advanced genetic map for diploid alfalfa. Two tightly linked flanking markers have been identified which will facilitate the physical mapping and cloning of the gene(s) that underlie(s) the non-nodulation phenotype.

Chromosome Mapping↗

Port-wine stain nodules in the adult: report of 20 cases treated by CO2 laser vaporization.

BACKGROUND: Port-wine stain (PWS) is a congenital vascular malformation of the superficial dermal vessels. These vessels become progressively ectatic, with development of nodular and hypertrophic areas on the surface of the lesions. OBJECTIVE: To determine the efficacy of CO2 laser vaporization in the treatment of nodules in PWS. METHODS: Twenty adult patients with PWS who developed nodules and hypertrophy on the surface of the lesions were treated by CO2 laser vaporization. Only one pass was performed to each area of the lesions, using a continuous and defocused mode, with a power density of 10 W/cm2. When the treated lesion was very large, several sessions of treatment were necessary to vaporize its entire surface. Photographic controls were performed before and after treatment. RESULTS: The nodules and hypertrophy were removed and the smooth surface of the lesions was reestablished. The color, usually violaceous, was transformed in a slight erythema. CONCLUSION: CO2 laser is a good method for treatment of nodules and hypertrophy in PWS. With adequate precautions, excellent cosmetic results can be obtained. Other more-specific laser systems may be successively used to treat the remaining erythema.

Adult↗

Gene expression analysis reveals evidence for increased expression of cell cycle-associated genes and Gq-protein-protein kinase C signaling in cold thyroid nodules.

In contrast to the molecular etiology of autonomously functioning thyroid nodules, the molecular cause of cold thyroid nodules (CTNs), their benign, functional inactive counterparts, are so far largely unknown. Because of the partially dedifferentiated phenotype of CTNs, alterations in signaling cascades that favor proliferation, but not differentiation, are likely candidates for tumor induction and progression. The importance of RAS mutations for the development of benign nodules with follicular histology is still in question. However, differentially expressed genes in the context of their signaling cascades could define aberrant signaling in CTNs. Therefore, we investigated gene expression in 22 CTNs and their normal surrounding tissue using Affymetrix GeneChips. Most prominently, data analysis revealed an increased expression of cell cycle-associated genes and a special relevance of protein kinase C signaling, whereas no evidence of RAS-MAPK signaling in CTNs was found. Moreover, we determined 31 differentially regulated genes in CTNs, including several histone mRNAs. Taken together, these results explain recent findings showing an increased proliferation in CTNs and draw attention to protein kinase C signaling, but away from RAS-MAPK signaling, as being involved in the etiology of CTNs.

Cell Cycle↗

Disseminated peritoneal leiomyomatosis.

Disseminated peritoneal leiomyomatosis is an unusual condition characterized by the development of numerous nodules in the peritoneal cavity which histologically have the appearance of smooth muscle tumors. The ninth proven case of this ill-understood disorder is presented here, with comments on some of the other published instances. Most reported cases were diagnosed in pregnant women, and there is good reason to believe that endocrine factors are of importance in the development of this condition. Attention is drawn to experimental studies in which an apparently similar condition has been produced in guinea pigs by endocrine manipulation. Clinically, the condition appears to be benign and the correct diagnosis is, therefore, of great importance. In the case presented here histological involution of the leiomyomatous peritoneal nodules could be demonstrated for the first time by two biopsies at an interval of 4 months--in the absence of any therapy apart from the termination of pregnancy.

Adult↗

Thyroid dysfunction after radiotherapy in children with Hodgkin's disease.

Thyroid function was measured in 119 children, 16 years of age or less, after radiotherapy (XRT) for Hodgkin's disease. Thyroid abnormalities developed in 4 of 24 children (17%) who received 2600 rad or less, and in 74 of 95 children (78%) who received greater than 2600 rad to the cervical area, including the thyroid. The abnormality in all but three (one with hyperthyroidism and two with thyroid nodules) included the development of elevated levels of thyroid stimulating hormone (TSH). Age, sex, and administration of chemotherapy were not significant factors in the development of thyroid dysfunction. All children had lymphangiograms (LAG) and no time relationship was noted between thyroid dysfunction and LAG-XRT interval. The mean interval from radiotherapy to documented thyroid dysfunction was 18 months in the low-dose group and 31 months in the high-dose group, with most patients becoming abnormal within 3 to 5 years. Of interest was a spontaneous return of TSH to within normal limits in 20 children and substantial improvement in another 7. This study confirms the occurrence of dose-related occult hypothyroidism in children following external irradiation of the neck.

Adolescent↗

Effects of irradiation on the thyroid gland.

External irradiation to the thyroid, even at low doses, induces subsequent development of thyroid nodules and carcinomas, with an estimated incidence of five per one million people per year if they have been exposed to 1 rad. Larger doses are associated with hypothyroidism. External irradiation also induces thyroid hyperplasia and is associated with an increased incidence of thyroid autoimmunity and the development of thyroiditis and Graves' disease. 131I, used in the treatment of Graves' disease and thyroid cancer for nearly 50 years, has not been associated with an increased incidence of thyroid cancer. Nevertheless, caution is advisable in use of radioiodide therapy in adolescents. Low levels of fallout from nuclear explosions probably have minimal, if any, effect on the thyroid; but recent high-level exposure in individuals near Chernobyl is reported to be associated with the development of thyroid malignancies in children.

Adolescent↗

Accelerated cutaneous nodulosis during methotrexate therapy in a patient with rheumatoid arthritis.

Rheumatoid nodulosis is characterized by multiple small subcutaneous granulomatous nodules typically located on the elbows in approximately 20% of patients with rheumatoid arthritis. Accelerated rheumatoid nodulosis, especially involving the hands and feet, has recently been reported in patients receiving methotrexate therapy for rheumatoid arthritis. We describe a woman with seropositive, erosive rheumatoid arthritis who, on two occasions, developed nonperiarticular subcutaneous nodules and new heart murmurs during methotrexate therapy, while her arthritis remained under good control. The nodules resolved after methotrexate was discontinued and recurred after methotrexate was reintroduced. They again resolved after methotrexate was stopped and colchicine was added. Her DNA oligotyping was positive for HLA-DRB1*0401, a genetic risk factor associated with accelerated rheumatoid nodulosis. Cutaneous biopsy specimens revealed palisading granulomas and giant cells consistent with rheumatoid nodulosis.

Antirheumatic Agents↗

[Systemic sarcoidosis during interferon-alpha therapy for chronic hepatitis C virus infection].

A 62-year-old white woman with chronic hepatitis C virus infection was diagnosed with systemic sarcoidosis during treatment with interferon-alpha. Seventeen cases of sarcoidosis associated with interferon treatment have been reported, with only 8 inpatients with chronic hepatitis C virus infection. Our patient, with no past history of sarcoidosis, developed subcutaneous sarcoid nodules, arthritis, uveitis, pneumonitis and heart involvement two months after she was started on treatment with interferon-alpha. Her symptoms resolved when she began corticosteroid therapy and interferon-alpha was stopped. This case report suggests that exogenous interferon-alpha may trigger or contribute to the development of this multisystem granulomatous disorder in which interferon-gamma and CD4 + T-lymphocyte are mainly involved. Patients should be monitored during and following interferon-alpha therapy, since the autoimmune diseases induced by interferon therapy do not always improve after cessation of treatment.

Anti-Inflammatory Agents↗

Effects of 12-O-tetradecanoylphorbol-13-acetate on carcinogen-induced mouse mammary lesions in organ culture.

Mammary glands of young female BALB/c mice develop hyperplastic nodule-like alveolar lesions (NLAL) in response to a 24-h exposure to 7,12-dimethylbenz(a)anthracene (DMBA; 2 micrograms/ml) on Day 3 during a 24-day organ culture. Experiments were conducted to determine if 12-O-tetradecanoylphorbol-13-acetate (TPA), a known tumor promoter, can influence the development of DMBA-induced NLAL in mammary gland organ culture. Mammary glands were incubated with TPA (25 ng/ml) for various periods of time in the presence of appropriate hormone combinations. Results indicated that the presence of TPA in the medium between Days 9 to 14 of the culture period enhanced both the incidence and multiplicity of DMBA-induced NLAL; however, it was ineffective when included in the medium between Days 4 to 9 or 19 to 24 of the organ culture. Toxicity of TPA was evident when it was present during the entire culture period subsequent to DMBA treatment. Computer-assisted image analysis of NLAL in the glands determined the area covered by these lesions within the gland. It was observed that 7.8% of the area was covered by NLAL in DMBA plus TPA-treated glands as compared to 2.5% by DMBA treatment alone. These results provide a model for initiation-promotion studies of mammary carcinogenesis in vitro, as well as a modified approach for quantitative analysis of structural alterations.

9,10-Dimethyl-1,2-benzanthracene↗

[Clinical pathology of the glomerulus--from phenomenon to entity. The nodular-lobular lesion].

The nodular lesion in renal glomeruli develops as a localized accentuation of mesangial volume augmentation. First described by Kimmelstiel and Wilson in 1936, it was soon accepted as the characteristic form of glomerular sclerosis in patients with long-term diabetes mellitus. It has for a long time been recognized that lesions very similar to nodular glomerulosclerosis may rarely occur in patients without diabetes. Clinical and pathological investigations of such cases have shown that glomerular nodules can also develop, 1. as a sequal to light chain deposit disease associated with plasma cell dyscrasia (e.g. myelomatosis), 2. in mesangioproliferative and membranoproliferative glomerulonephritis ("lobular" GN) and 3. in some cases of glomerular amyloid deposition. A survey is given of the characteristic light microscopy, ultrastructure and immunopathology of the glomerular nodules in these diseases. The differential diagnosis and pathogenesis is discussed.

Amyloidosis↗

The natural history of cerebellar hemangioblastomas in von Hippel-Lindau disease.

BACKGROUND AND PURPOSE: Cerebellar hemangioblastomas (HBs) are traditionally classified into different morphologic types: cystic and solid. We have observed the progression from solid to cystic and have reviewed the cases seen at the regional von Hippel-Lindau (VHL) clinic to document the frequency of this progression. METHODS: A retrospective review of the notes and images of all patients with VHL disease seen at a regional referral clinic since its inception in 1991. Sporadic HBs were not included in this study. RESULTS: In eight patients, a total of 28 tumors were detected. Fourteen of these had or developed cysts. Of the 14 cystic tumors, eight increased in size over the follow-up period. Of the 14 solid tumors, only one increased in size without cystic change. In four patients, the tumor progressed from a cerebellar nodule to an enlarging cyst with a nodule, with the subsequent development of symptoms requiring surgical excision. CONCLUSION: We have demonstrated that, in VHL, cerebellar HBs begin as nodules, and some subsequently develop enlarging cysts that cause pressure symptoms. In our patient population, tumors that remained solid were asymptomatic and well tolerated in the cerebellum.

Adult↗

Two-color image analysis discriminates between mineralized and unmineralized bone nodules in vitro.

Functional assays of progenitor cell capacity for colony formation in vitro typically depend on the investigator's expertise with quantification. The ability to enumerate and analyze colony types with standardized criteria with no bias would be a useful tool for research and drug development. We report the development of a two-color automated analysis system for colony-forming unit-osteoblasts that is capable of reporting progenitor frequency and bone nodule number size, and type (mineralized or unmineralized). Our image analysis system was validated using the rat calvaria cell model to measure in vitro bone nodule development. With computer-aided image analysis, data on nodules can be rapidly generated with a minimum of user bias and fatigue. This novel tool will distinguish mineralized and unmineralized bone nodules, facilitates quantification, enable large-scale experimental design, allow for long-term data storage and tracking, and lead to the identification of new parameters that impact bone development.

Animals↗

Scabietic nodules: a dermatopathologic and immunofluorescent study.

Mites and their eggs were thought to be rarely found in nodular lesions of scabies. However, serial sections from 27 scabietic scrotal papules or nodules revealed mite parts in 22% (6/27). This supports the contention that scabietic nodules may result from persisting antigens of mite parts. In contrast to previous studies, vasculitis with fibrinoid degeneration was uncommon (3/27) in our series. This discrepancy may be due to the timing of the biopsies: 2 of 3 cases with vasculitis were associated with diffuse dense infiltration, and vasculitis may be a late event in the development of scabietic nodules. The specificity of immunoreactant deposits along the epidermodermal junction (EDJ) in scabies is controversial. In our study, direct immunofluorescence (DIF) was performed on 13 scabietic nodules. Four (31%) showed immunoreactants at the EDJ and two on blood vessels. Because of the relatively low positive rate, the low intensity of fluorescence, and 3 of 4 cases with positive immunoreactants having only a single class of immunoglobulin, the deposition may only be secondary to inflammation instead of a specific type II immunologic reaction to scabies.

Fluorescent Antibody Technique↗

[Expression of ras oncogene p21 product and proliferating cell nuclear antigen in liver cirrhosis and the correlation with liver cell dysplasia].

OBJECTIVE: To probe the role of ras oncogene p21 product, proliferating cell nuclear antigen (PCNA) and hepatitis B virus infection in the development of cirrhotic nodules, liver cell dysplasia and hepatocellular carcinoma (HCC). METHODS: S-P immunohistochemical technique was used to analyze the expression of p21, PCNA and HBsAg was studied in 30 cases of cirrhosis with HCC and 60 cases without HCC and 27 HCC cases. RESULTS: The positive rates for p21 in cirrhosis with or without HCC, and HCC tissue were 90%, 68.33%, and 62.96%, respectively. The positive rates for p21, PCNA and HBsAg in cirrhotic nodules with LCD were 92.45%, 73.59% and 64.92%, respectively, significantly higher than those without LCD (P<0.05). The incidence of p21 expression in hepatocytes was significantly higher in HBsAg- and PCNA positive cases than in negative ones (P<0.01). CONCLUSION: (1)The overexpression of p21 may play an important role in the early stage of the development of HCC; (2)LCD are precancerous cells which have the ability to initiate neoplastic growth and present a high risk of development of HCC especially combining HBV infection and the overexpression of p21 and PCNA. (3)The expression level of p21 in liver cirrhosis is related to HBV infection and the expression level of PCNA.

Adolescent↗

Histogenesis of diisopropanolnitrosamine (DIPN)-induced tumors of the rat thyroid gland.

In an attempt to eludicate the histogenesis of thyroid carcinoma, histopathological and immunohistological studies were conducted on rat thyroid tumors induced by diisopropanolnitrosamine (DIPN). A total of 235 nodular lesions detected on serial sections of whole thyroid glands were classified into three types as follows: foci of cellular alteration at the single follicle level (type 1); multifollicular nodules considered to be malignant or potentially malignant (type 3); and multifollicular, proliferative nodules other than type 3, including both hyperplastic and neoplastic nodules (type 2). Analysis of the frequency of nodular lesions after various periods of time following exposure to DIPN revealed that the size of the nodules, their pattern of development, and their growth activity, as measured by the labeling index for bromodeoxyuridine (BrdU), showed sequential changes. Type 1 lesions appeared early; these lesions were the smallest and were considered to indicate the initial morphological change. Subsequently, type 2 nodules of intermediate size and labeling index, and finally type 3 nodules with the largest size and the highest labeling index developed; the latter type 3 nodules become more numerous during the latest phase following DIPN exposure. These observations support a multistage hypothesis of tumorigenesis.

Animals↗

32P-postlabeling analysis of DNA adducts in rats during estrogen-induced hepatocarcinogenesis and effect of tamoxifen on DNA adduct level.

DNA adduct formation in the liver, pancreas, kidneys and uterus in ethynylestradiol (EE)-induced carcinogenesis and the effect of tamoxifen (TAM) on DNA adduct formation were evaluated in female Wistar JCL rats using the 32P-postlabeling method. Hyperplastic nodules were noted in the liver of all rats 4 months after the first oral administration of 0.075 mg of EE, and hepatocellular carcinoma was detected in 8.1% of rats treated with EE for 12 months. DNA adducts increased in the liver for 4 months, reaching a level of 7.3 adducts/10(7) nucleotides and decreasing thereafter. Formation of DNA adducts was also noted in the pancreas and kidney, but the adduct levels were lower than those in the liver. TAM inhibited estrogen receptors (ER) in liver tissues and completely suppressed the development of hyperplastic nodules or hepatocellular carcinoma but did not affect DNA adduct formation in the liver. In this model, therefore, EE is considered to cause mutations of hepatocytes due to DNA adduct formation without mediation by ER and to induce initiated cells to develop into hepatocellular carcinoma in the presence of ER-mediated hormonal activities.

Animals↗

Mantle cell lymphoma involving skin: cutaneous lesions may be the first manifestation of disease and tumors often have blastoid cytologic features.

We describe five cases of mantle cell lymphoma involving skin. Three patients initially presented with skin lesions but had evidence of widespread disease at time of diagnosis or with relatively short follow-up. One patient was known to have disseminated disease before he developed skin lesions. One patient presented with a solitary skin nodule on the thigh and has developed multiple smaller nodules on the same leg, but no other sites of disease over 30 months of clinical follow-up. This case fulfills the criteria for primary cutaneous lymphoma as proposed by the European Organization for Research and Treatment of Cancer. Biopsy of the skin lesions in all cases showed predominantly dermal and focally subcutaneous lymphoid infiltrates, preferentially perivascular and periadnexal in four cases, and nodular in one case. The tumors were composed of small- to medium-sized lymphocytes with irregular nuclear contours. Four cases had blastoid and one case had typical cytologic features. Immunophenotypic studies showed that all cases were positive for CD20 and cyclin D1, and four of five were positive for CD5. Four cases, including the CD5-negative case, had evidence of the t(11;14) shown by either fluorescence in situ hybridization methods performed on skin tumors or conventional cytogenetic analysis performed on involved bone marrow. We conclude that mantle cell lymphoma can involve skin, usually as a manifestation of disseminated disease, and is often associated with blastoid cytologic features. Rare cases of mantle cell lymphoma may arise in skin.

Aged↗

An unusual tuberous sclerosis case presenting with fibrillary astrocytoma.

Tuberous sclerosis (TS) is an autosomal dominant disorder. It is characterized by hamartomatous lesions in various organs such as the brain, skin, kidneys and heart. Subependymal and parenchymal nodules occur in the cerebrum. Although giant cell astrocytoma may develop from these subependymal nodules, tumor formation is very rare in the cortical nodules. We present the clinical, computed tomography and magnetic resonance imaging findings of a fibrillary astrocytoma originating from a cortical tuber in a 4-year-old female with TS.

Astrocytoma↗