Non-REM hypnic headache: a circadian disorder? A clinical and polysomnographic study.
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Adult↗
Biomedical subjects
G Merlino
Publications and source records attributed to G Merlino.
Reverse radial artery bone flap reconstruction of segmental metacarpal losses.
A vascularised bone segment of the distal radius was harvested as a distally based flap to treat segmental metacarpal bone loss in three patients. One reconstruction followed resection of a giant cell tumour excision and the other two were to replace traumatic bone loss. The bone defects were in the second metacarpal in two cases and in the second and third metacarpal in one case and included three shaft and one distal metacarpal reconstruction. The mean length of the metacarpal defects was 6 cm. All of the flaps survived and no complications occurred at the donor site. Clinical and radiological union was established in all cases after an average of 3 months.
Adult↗
Changes in hemodynamics during isoflurane and propofol anesthesia: a comparison study.
OBJECTIVES: Volatile anesthetics are thought to impair cerebral autoregulation more than i.v. anesthetics. However, few comparative studies have been carried out in humans. The aim of our study was to evaluate the differences in cerebral hemodynamic changes after introduction of isoflurane (a volatile anesthetic) and propofol (an i.v. anesthetic). METHODS: Eighteen consecutive patients submitted to laparoscopic cholecystectomy were selected. After the induction, anesthesia was maintained by isoflurane (one minimum alveolar anesthetic concentration) during the first part of the surgical operation, and then by propofol (5 mg/kg/hour i.v.). Ventilation was adjusted to maintain a constant end-tidal CO(2). Middle artery flow velocity was assessed by means of transcranial Doppler ultrasonography. Arterial blood pressure, heart rate (HR), capnometry, pulse oxymetry, inspired fraction of O(2), and body temperature, were monitored. RESULTS: Cerebral artery velocity, HR, and mean arterial pressure all significantly increased from baseline after the introduction of isoflurane (p<0.05); the HR and mean arterial blood pressure showed no significant difference between the isoflurane and propofol phases. Isoflurane anesthesia induced a significant increase in cerebral blood velocity. Propofol introduction led to a significant decrease in cerebral artery velocity (p<0.05). CONCLUSIONS: Propofol but not isoflurane decreased cerebral blood velocity thus restoring cerebral autoregulation and the coupling between cerebral blood flow and cerebral metabolism.
Adult↗
[Sarcoidosis and clear cell carcinoma of the kidney: the sixth case?].
The Authors report a very rare case of clear cell renal cancer associated with sarcoidosis, incidentally discovered in a 39 year-old man, admitted for a not correlated pathology (multiple left rib fractures due to automobile crash). Problems related to a proper assessment of sarcoidosis are discussed as well as potential arising of a neoplasm during the entire follow-up period: for that, it must always be complete and accurate.
Adenocarcinoma, Clear Cell↗
Overexpression of hepatocyte growth factor/scatter factor promotes vascularization and granulation tissue formation in vivo.
The effect of hepatocyte growth factor/scatter factor (HGF/SF) during wound healing in the skin was investigated, using HGF/SF-overexpressing transgenic mouse model. Histological analysis of HGF/SF transgenic mouse excisional wound sites revealed increased granulation tissue with marked vascularization. Northern blot analysis demonstrated that, relative to control, vascular endothelial growth factor (VEGF) expression in transgenic skin was significantly higher at baseline and was robustly up-regulated during wound healing. Elevated levels of VEGF protein were detected immunohistochemically, predominantly in endothelial cells and fibroblasts within the granulation tissue of HGF/SF transgenic skin. Serum levels of VEGF were also elevated in HGF/SF transgenic mice. Thus, results from our study suggest that HGF/SF has a significant effect on vascularization and granulation tissue formation during wound healing in vivo, involving with induction of VEGF.
Animals↗
Neonatal sunburn and melanoma in mice.
Retrospective epidemiological data have indicated that cutaneous malignant melanoma may arise as a consequence of intense, intermittent exposure of the skin to ultraviolet radiation, particularly in children, rather than from the cumulative lifetime exposure that is associated with other forms of skin cancer. Here we use a genetically engineered mouse model to show that a single dose of burning ultraviolet radiation to neonates, but not adults, is necessary and sufficient to induce tumours with high penetrance which are reminiscent of human melanoma. Our results provide experimental support for epidemiological evidence that childhood sunburn poses a significant risk of developing this potentially fatal disease.
Animals↗
The genetics of pancreatic adenocarcinoma: a roadmap for a mouse model.
Pancreatic cancer is among the leading causes of cancer death. Although a genetic profile for pancreatic cancer is emerging, many biological aspects of this disease are poorly understood. Indeed, fundamental questions regarding progenitor cell lineages, host stromal milieu, and the role of specific genetic alterations in tumor progression remain unresolved. A mouse model engineered with signature mutations would provide a powerful ally in the study of pancreatic cancer biology and may guide improved prognostic assessment and treatment for the human disease. In this review, we discuss the molecular basis for normal pancreatic development and the genetics of human pancreatic adenocarcinoma in the hope of charting a course for the development of a faithful mouse model for this lethal cancer.
Adenocarcinoma↗
Genetic dissection of melanoma pathways in the mouse.
The frequent loss of the INK4a/ARF locus, encoding for both p16(INK4a)and p19(ARF)in human melanoma, raises the question as to which INK4a/ARF gene product functions to suppress melanoma-genesis in vivo. Studies in the mouse have shown that activated RAS mutation can cooperate with INK4a(Delta 2/3)deficiency (null for both p16(INK4a)and p19(ARF)) to promote development of melanoma, and these melanomas retain wild-type p53. Given the functional link between p19(ARF)and p53, we have now shown that activated RAS can also cooperate with p53 deficiency to produce melanoma in the mouse. Moreover, genome-wide analysis of RAS-induced p53 mutant melanomas reveals alterations of key components governing RB-regulated G1/S transition, such as c-Myc. These experimental findings suggest that both RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.
Animals↗
Ulcerative proctitis, rectal prolapse, and intestinal pseudo-obstruction in transgenic mice overexpressing hepatocyte growth factor/scatter factor.
Hepatocyte growth factor/scatter factor (HGF/SF) can stimulate growth of gastrointestinal epithelial cells in vitro; however, the physiological role of HGF/SF in the digestive tract is poorly understood. To elucidate this in vivo function, mice were analyzed in which an HGF/SF transgene was overexpressed throughout the digestive tract. Nearly a third of all HGF/SF transgenic mice in this study (28 of 87) died by 6 months of age as a result of sporadic intestinal obstruction of unknown etiology. Enteric ganglia were not overtly affected, indicating that the pathogenesis of this intestinal lesion was different from that operating in Hirschsprung's disease. Transgenic mice also exhibited a rectal inflammatory bowel disease (IBD) with a high incidence of anorectal prolapse. Expression of interleukin-2 was decreased in the transgenic colon, indicating that HGF/SF may influence regulation of the local intestinal immune system within the colon. These results suggest that HGF/SF plays an important role in the development of gastrointestinal paresis and chronic intestinal inflammation. HGF/SF transgenic mice may represent a useful model for the study of molecular mechanisms associated with a subset of IBD and intestinal pseudo-obstruction. Moreover, our data identify previously unappreciated side effects that may be encountered when using HGF/SF as a therapeutic agent.
Animals↗
Immunohistochemical detection of the c-met proto-oncogene product in the congenital melanocytic nevus of an infant with neurocutaneous melanosis.
Transgenic mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF) demonstrate extensive pigmented nevi in both skin and leptomeninges of the central nervous system resembling human neurocutaneous melanosis. We immunohistochemically detected HGF/SF receptor, Met, in a congenital nevus of an infant with neurocutaneous melanosis, indicating that deregulation of HGF/SF-Met signaling in the critical period of development may lead to this fatal syndrome.
Animals↗
Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation.
The mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis are not understood. Because of the uncertainty of human cancer risk associated with peroxisome proliferators, delineating the mechanisms of carcinogenesis by these agents is of great interest. Alterations in liver growth factors were postulated to contribute to the carcinogenic effect of peroxisome proliferators. Administration of these compounds to rodents results in down-regulation of hepatocyte growth factor (HGF) and supplementing culture medium with HGF is reported to suppress cell proliferation of preneoplastic and neoplastic cells from WY-14,643-treated livers. Combined, these observations suggest that reduced levels of hepatic HGF contribute to the mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis. To determine if HGF can prevent the effects of peroxisome proliferators in liver, the short-term influence of WY-14,643 in two different lines of HGF transgenic mice was examined. Mice were fed either a control diet or one containing 0.1% WY-14-643 for one week. Hepatomegaly was found in both HGF transgenic mouse lines fed WY-14,643 compared with controls. Additionally, hepatic expression of typical mRNA markers of peroxisome proliferation including those encoding peroxisomal fatty acid metabolizing enzymes and cell cycle control proteins were all significantly elevated in HGF transgenic mice fed WY-14,643 compared with controls. Down-regulation of HGF was found to be dependent on PPARalpha since lower levels of HGF mRNA and protein were observed in wild-type mice fed WY-14,643 for 1 week and not in similarly treated PPARalpha-null mice. These results demonstrate that the early increase in hepatic mRNAs associated with peroxisome and cell proliferation induced by WY-14,643 treatment can not be prevented by overexpression of HGF in vivo.
Animals↗
[Non-parasitic splenic cysts].
The Authors report their experience matured during the last decade in the Institute of III Surgical Clinic of the University "La Sapienza" in Rome, relatively to 174 patients operated of splenectomy of which 8 for not parassitair benign cystic pathology. After the nosologic organization of the varied types of cystics splenopaty is examined the different symptomatology and is discussed the different treatment.
Adult↗
Accelerated ultraviolet radiation-induced carcinogenesis in hepatocyte growth factor/scatter factor transgenic mice.
The dramatic rise in incidence of malignant melanoma experienced by populations both within the United States and throughout the world over the last several decades has been attributed to enhanced exposure to the UV spectrum of sunlight radiation. This hypothesis can now be tested using genetically engineered mouse models predisposed to malignant melanoma. Here we use melanoma-prone transgenic mice inappropriately expressing hepatocyte growth factor/scatter factor (HGF/SF) in the skin as an experimental model system to ascertain the consequences of a chronic regimen of suberythemal UV radiation on melanoma genesis. HGF/SF is a multifunctional regulator capable of stimulating growth, motility, invasiveness, and morphogenetic transformation in cells, including melanocytes, expressing its receptor tyrosine kinase Met. HGF/SF transgenic mice demonstrate ectopic interfollicular localization and accumulation of melanocytes within the truncal dermis, epidermis, and junction and if untreated develop primary cutaneous melanoma with a mean onset age of approximately 21 months. Transgenic mice and their wild-type littermates subjected to UV radiation three times weekly using FS40 sunlamps (60% UVB and 40% UVA), with daily UV doses graded from 2.25 to 6.0 kJ/m2, developed skin tumors with a mean onset age of 26 and 37 weeks, respectively (P < 0.001, Kaplan-Meier log rank test). However, the repeated doses of suberythemal UV radiation used in this study failed to accelerate melanoma genesis, instead inducing the development of nonmelanoma tumors that included squamous cell carcinomas, squamous papillomas, and sarcomas. The conspicuous absence of melanocytic tumors occurred despite the immunohistochemical detection of a significant stimulation (P < 0.001) in melanocyte-specific bromodeoxyuridine incorporation in response to only 2 weeks of UV irradiation (total UV dose of 13.5 kJ/m2), resulting in 2.6- and 4.6-fold increases in the number of melanocytes in the dermis and epidermis, respectively. These data indicate that chronic suberythemal UV radiation preferentially favors the development of nonmelanocytic over melanocytic neoplasms in this transgenic animal, consistent with the pathogenesis proposed for sun exposure-associated skin cancer based on retrospective studies in the human population. Our findings suggest that the HGF/SF transgenic mouse will be useful as an experimental model for determining the consequences of exposure to various regimens of UV radiation and for elucidating the mechanisms by which such consequences are realized.
Age Factors↗
Involvement of hepatocyte growth factor/scatter factor and met receptor signaling in hair follicle morphogenesis and cycling.
HGF/SF and its receptor (Met) are principal mediators of mesenchymal-epithelial interactions in several different systems and have recently been implicated in the control of hair follicle (HF) growth. We have studied their expression patterns during HF morphogenesis and cycling in C57BL/6 mice, whereas functional hair growth effects of HGF/SF were assessed in vivo by analysis of transgenic mice and in skin organ culture. In normal mouse skin, follicular expression of HGF/SF and Met was strikingly localized: HGF/SF was found only in the HF mesenchyme (dermal papilla fibroblasts) and Met in the neighboring hair bulb keratinocytes. Both HGF/SF and Met expression peaked during the initial phases of HF morphogenesis, the stage of active hair growth (early and mid anagen), and during the apoptosis-driven HF regression (catagen). Met+ cells in the regressing epithelial strand appeared to be protected from undergoing apoptosis. Compared to wild-type controls, transgenic mice overexpressing HGF/SF under the control of the MT-1 promoter had twice as many developing HF and displayed accelerated HF development on postnatal day 3. They also showed significant catagen retardation on P17. In organ culture and in vivo, HGF/SF i.c. resulted in a significant catagen retardation. These results demonstrate an important role of HGF/SF and Met in murine hair growth control and suggest that Met-mediated signaling might be exploited for therapeutic manipulation of human hair growth disorders.-Lindner, G., Menrad, A., Gherardi, E., Merlino, G., Welker, P., Handjiski, B., Roloff, B., Paus, R. Involvement of hepatocyte growth factor/scatter factor and Met receptor signaling in hair follicle morphogenesis and cycling.
Animals↗
New options for aerodigestive tract replacement after extended pharyngolaryngectomy.
OBJECTIVES: Assess the results of a new type of reconstruction of the aerodigestive tract after extended pharyngolaryngectomy. STUDY DESIGN: Follow-up of a total of eight patients who had surgery using ileocolic free graft. METHODS: The surgical technique is described. Five patients underwent pharyngolaryngectomy/cervical esophagectomy, and three patients had total laryngectomy with subtotal pharyngectomy. Patients were monitored to assess complications and recovery of satisfactory swallowing and speech. RESULTS: The technique, thanks to the use of material from the colon, proved to be extremely useful for the reconstruction of the digestive tract. At the same time, ileal anastomosis with the tracheal stump enabled aerodigestive crossing restoration, protected by the ileocecal valve. All patients recovered good swallowing capacity and phoniatric expression, which were obtained by digital occlusion of the tracheostomy, forcing the expiratory air through the ileum and ileocecal valve. Manometric tests also showed that after a while there was a gradual synchronization of swallowing between the transplanted colic segment and the residual esophagus. CONCLUSIONS: The technique described in the present study may be regarded, also in the light of possible further applications, as a new and interesting option for the reconstruction of the aerodigestive tract.
Aged↗
The p53 response to DNA damage in vivo is independent of DNA-dependent protein kinase.
Ionizing radiation (IR) exposure causes mammalian cells to undergo p53-dependent cell cycle arrest and/or apoptosis. The in vivo role of DNA-dependent protein kinase (DNA-PK) in the transduction of the DNA damage signal to p53 remains unresolved. To determine the relationship between DNA-PK and p53, we studied the cell cycle and apoptotic responses to IR in mice deficient in DNA-PK. Using the slip mouse, which harbors an inactivating mutation of the DNA-PK catalytic subunit (DNA-PKcs), we demonstrated not only that these DNA-PKcs null mutants were highly radiosensitive but also that upon IR treatment, p53 accumulated in their cultured cells and tissue. Induced p53 was transcriptionally active and mediated the induction of p21 and Bax in slip cells. Examination of the thymic cell cycle response to IR treatment indicated that the slip G(1)/S-phase cell cycle checkpoint function was intact. We further show that slip mice exhibited a higher level of spontaneous thymic apoptosis as well as a more robust apoptotic response to IR than wild-type mice. Together, these data demonstrate that the p53-mediated response to DNA damage is intact in cells devoid of DNA-PK activity and suggest that other kinases, such as the product of the gene (ATM) mutated in ataxia telangiectasia, are better candidates for regulating IR-induced phosphorylation and accumulation of p53.
Animals↗
Disassociation of met-mediated biological responses in vivo: the natural hepatocyte growth factor/scatter factor splice variant NK2 antagonizes growth but facilitates metastasis.
Hepatocyte growth factor/scatter factor (HGF/SF) stimulates numerous cellular activities capable of contributing to the metastatic phenotype, including growth, motility, invasiveness, and morphogenetic transformation. When inappropriately expressed in vivo, an HGF/SF transgene induces numerous hyperplastic and neoplastic lesions. NK1 and NK2 are natural splice variants of HGF/SF; all interact with a common receptor, Met. Although both agonistic and antagonistic properties have been ascribed to each isoform in vitro, NK1 retains the full spectrum of HGF/SF-like activities when expressed as a transgene in vivo. Here we report that transgenic mice broadly expressing NK2 exhibit none of the phenotypes characteristic of HGF/SF or NK1 transgenic mice. Instead, when coexpressed in NK2-HGF/SF bitransgenic mice, NK2 antagonizes the pathological consequences of HGF/SF and discourages the subcutaneous growth of transplanted Met-containing melanoma cells. Remarkably, the metastatic efficiency of these same melanoma cells is dramatically enhanced in NK2 transgenic host mice relative to wild-type recipients, rivaling levels achieved in HGF/SF and NK1 transgenic hosts. Considered in conjunction with reports that in vitro NK2 induces scatter, but not other activities, these data strongly suggest that cellular motility is a critical determinant of metastasis. Moreover, our results demonstrate how alternatively structured ligands can be exploited in vivo to functionally dissociate Met-mediated activities and their downstream pathways.
Animals↗
[Hereditary nonpolyposis colorectal cancer (Lynch syndrome): a review of the literature and case reports].
The recent observation of a new HNPCC patient case induced the Authors to review their experience with the syndrome as well as to make an up to date of the problems related to diagnosis, surgical management, surveillance and genetic counselling for such patients with a lifelong high cancer risk. Patients with HNPCC and their first-degree relatives, whose risk of early colorectal carcinoma (especially in the proximal colon) as well as a variety of extracolonic cancers (particularly endometrium, ovary, stomach, small bowel, ureter and renal pelvis) is significantly higher then that of patients with sporadic carcinoma, should be properly managed with surgery and then with endoscopic examination (ideally all life long) starting--in unaffected individuals--at early age (25 years old). Problems related to genetic counselling are considered as well.
Adult↗