Role of cyclins D1 and D3 in vestibular schwannoma.

BACKGROUND: Vestibular schwannomas in younger patients have been observed to be larger in size and grow more quickly. OBJECTIVE: This study aimed to evaluate the expression of three important cell cycle proteins, cyclin D1, cyclin D3 and Ki-67, in vestibular schwannoma patients separated into two age groups: ≤ 40 years or > 40 years. METHOD: Immunohistochemical detection of cyclin D1, cyclin D3 and Ki-67 was undertaken in 180 surgically resected vestibular schwannomas. RESULTS: The proliferation index of vestibular schwannomas was statistically higher in the ≤ 40 years age group compared to that in the > 40 years age group (mean of 4.52 vs 3.27, respectively; p = 0.01). Overexpression of cyclin D1 and cyclin D3 was found in 68 per cent and 44 per cent of tumours, respectively. CONCLUSION: There was an increased Ki-67 proliferation index in the younger age group that appears to correlate with clinical behaviour. Vestibular schwannomas in both age groups show increased expression of cyclin D1 and cyclin D3.

[Impact of time of occurrence of liver metastases (synchronous vs. metachronous) on early postoperative outcome and long-term survival of colorectal cancer patients]. / Einfluss des Metastasierungszeitpunkts (synchron vs. metachron) im Hinblick auf das frühpostoperative Outcome sowie das Langzeitüberleben von Patienten nach Resektion kolorektaler Lebermetastasen.

BACKGROUND: Today, liver resection represents the only curative treatment option for patients with resectable colorectal liver metastases. Large studies could show that liver surgery can be performed safely in specialised centres, but most of those studies did not differentiate between resection of synchronous and metachronous metastases. The aim of this study was to evaluate the impact of the time of the occurrence of colorectal liver metastases on the early postoperative course as well as the long-term survival. PATIENTS AND METHODS: Two groups of 30 patients each who underwent liver surgery due to synchronous or metachronous colorectal liver metastases at our centre between 2000 and 2010 were included in a matched-pairs analysis. Early postoperative course as well as long-term survival were assessed and compared between both groups. Matching criteria included: age, sex, number of metastases and size of largest metastasis. RESULTS: Postoperative morbidity for the entire study cohort was 23.3 % with a mortality of 0 %. No significant difference could be shown between synchronous and metachronous metastases with regard to incidence and severity of postoperative complications (20 vs. 26.7 %, p = 0.54). The median survival of the synchronous group was 38.9 months (95 % CI 26.4-51.6) compared to 47.9 months (95 % CI 21.4-74.4 %) in the metachronous group, but no significant difference could be detected in the univariate analysis (p = 0.425). CONCLUSION: According to the present results, liver surgery can be performed safely in a specialised centre. The time of occurrence of the metastases (synchronous vs. metachronous) does not seem to have any impact on the early postoperative course as well as on the long-term survival in patients undergoing curative resection of colorectal liver metastases. However, larger studies appear necessary to confirm the results of the present study.

Viscoelasticity-based magnetic resonance elastography for the assessment of liver fibrosis in hepatitis C patients after liver transplantation.

PURPOSE: Despite advantages in antiviral therapy of hepatitis C (HCV) in recent years, progressing liver fibrosis remains a major problem for patients suffering from hepatitis C after liver transplantation. Therefore, effective non-invasive methods for the assessment of liver fibrosis are needed in order to guide treatment decisions and predict prognosis in these patients. The aim of this study was to prospectively assess the diagnostic accuracy of viscoelasticity-based magnetic resonance (MR) elastography for the assessment of liver fibrosis in HCV patients after liver transplantation. MATERIALS AND METHODS: After IRB approval, a total of 25 patients, who had received a liver graft due to chronic hepatitis C underwent both liver biopsy and MR elastography. Two viscoelastic constants, the shear elasticity µ and the powerlaw exponent α were calculated by fitting the frequency function of the complex shear modulus with the viscoelastic springpot-model. RESULTS: A strong positive correlation between shear elasticity µ and the stage of fibrosis could be found (R = 0.486, p = 0.0136). The area under the receiver operating curve (AUROC) of MR elastography based on µ for diagnosis of severe fibrosis (F ≥ 3) was 0.87 and 0.65 for diagnosis of significant fibrosis (F ≥ 2). The powerlaw exponent α did not correlate with the stage of fibrosis. CONCLUSION: MR elastography represents a promising non-invasive procedure for the assessment of higher grades of fibrosis in HCV patients after liver transplantation. The poor correlation for lower grades of fibrosis suggests unknown mechanical interactions in the transplanted liver.

Modulation of BDNF and TrkB expression in rat hippocampus in response to acute neurotoxicity by diethyldithiocarbamate.

In this study, we examined the expression profile of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in adult rat hippocampus following acute administration of diethyldithiocarbamate (DDTC), a neurotoxic compound which was previously shown to induce microglia activation and cell death. Semiquantitative RT-PCR analysis detected significant variations of BDNF mRNA levels in whole hippocampus homogenates, with a peak at 24h after DDTC injection. Increased BDNF protein expression was demonstrated by immunohistochemistry in various hippocampal subfields. The most relevant increase was observed in the hilus of the dentate gyrus where BDNF levels at 120h were found to be almost four times those of basal levels. Full-length TrkB (TrkB.FL) encoding mRNA was also shown to undergo an earlier increase in the hippocampus of DDTC-treated rats. TrkB immunostaining with an antibody binding both full-length and truncated (TrkB.T) isoforms was found to increase at 120h in the hippocampal CA2 and CA3 regions. These results demonstrate that DDTC modulates the expression of BDNF and its receptor in the adult rat hippocampus and suggest a possible involvement of this neurotrophin in the protective response to DDTC-induced neuronal damage.

Neonatal submandibular sialadenitis progressing to submandibular gland abscess.

Submandibular sialadenitis is exceptionally rare in neonates. We describe a case of submandibular sialadenitis progressing to submandibular abscess in a term neonate. The aetiology, investigations and treatment for this very rare condition are discussed.

Cyclin D1 and p16INK4A expression predict reduced survival in carcinoma of the anterior tongue.

Cyclin D1 and p16INK4A are molecules with pivotal roles in cell cycle control and the development of diverse human cancers, and overexpression of cyclin D1 and loss of p16INK4A expression are common genetic events in head and neck squamous cell carcinoma. The prognostic significance of these molecular events at different sites within the head and neck, however, remains controversial. Thus, we sought to determine the relationship between cyclin D1 and/or p16INK4A expression and disease outcome in squamous cell carcinoma of the anterior tongue. Immunohistochemical detection of nuclear proteins cyclin D1, p53, and p16INK4A, and the Ki-67 labeling index was undertaken in tissue sections from 148 tongue cancers treated by surgical resection. Nuclear antigen status was analyzed in relation to pathological variables, tumor recurrence, and patient survival. Statistical significance was assessed using chi2 analysis for pathological variables and the Kaplan-Meier method, log rank test, and the Cox proportional hazards model for survival parameters. Overexpression of cyclin D1 occurred in 68% of tumors (100 of 147) and was associated with increased lymph node stage (P = 0.014), increased tumor grade (P = 0.003), and reduced disease-free (P = 0.006) and overall (P = 0.01) survival. Loss of p16INK4A expression was demonstrated in 55% of tumors (78 of 143) and was associated with reduced disease-free (P = 0.007) and overall (P = 0.014) survival. Multivariate analysis confirmed that in addition to pathological stage and regional lymph node status, cyclin D1 overexpression and loss of p16INK4A expression are independent predictors of death from tongue cancer. Loss of p16INK4A in the presence of cyclin D1 overexpression conferred a significantly worse disease-free (P = 0.011) and overall (P = 0.002) survival at 5 years. p53 nuclear accumulation and the Ki-67 labeling index were not prognostic. These data indicate that cyclin D1 overexpression and loss of p16INK4A expression predict early relapse and reduced survival in squamous cell carcinoma of the anterior tongue. Simultaneous assessment of cyclin D1 and p16INK4A protein levels define subgroups of patients at increased risk of relapse and may be of clinical utility in optimizing therapy.

BDNF and trkB mRNAs oscillate in rat brain during the light-dark cycle.

In this study, we investigated whether in basal conditions the different functional states occurring during a 24-h cycle are reflected by the expression of brain-derived neurotrophic factor (BDNF) and its receptor, trkB, in rat cerebral cortex and hippocampus. Using semiquantitative RT-PCR assay, the levels of both BDNF and trkB mRNAs were found to undergo significant variation in a 24-h period. The strongest variation was detected in the hippocampus, where the ratio between maximum and minimum levels was about 3.5 and 17.5 for BDNF and trkB, respectively. These findings provide the first evidence that, in the absence of any experimental manipulation, the expression of a neurotrophin and its receptor undergoes diurnal oscillation, possibly related to the physiological variations of the activity level.

Appendicitis in HIV-positive patients.

BACKGROUND: The aim of the present study was to review the experience of appendicitis in human immunodeficiency virus (HIV)-positive patients. METHODS: A retrospective analysis of all HIV-positive patients operated on for suspected acute appendicitis during a 10-year period at St Vincent's Hospital was performed. These patients were compared to a group of 60 age- and sex-matched patients with no HIV risk factors who were operated on during the same time period. RESULTS: On presentation the clinical findings were similar in both groups, with two notable exceptions. No HIV-positive patient had an elevated white cell count. The present study demonstrated a significant delay in presentation of the HIV-positive group to the Emergency Department, possibly explaining the higher appendiceal perforation rate in this group. There were no cases of HIV-related diseases mimicking acute appendicitis. There was no mortality, and morbidity was higher in the seropositive group. CONCLUSIONS: HIV-positive patients with a history suggestive of acute appendicitis should not be treated differently from the normal population. Morbidity and mortality can be minimized by prompt surgical treatment.

Granulosa cell tumors express erbB4 and are sensitive to the cytotoxic action of heregulin-beta2/PE40.

The molecular genetic events involved in the etiology of human granulosa cell (GC) tumors, which represent approximately 7% of all malignant ovarian neoplasms, are unknown. Amplification and/or overexpression of the ERBB genes are a feature of many cancer types, and overexpression of erbB2 correlates with poor prognosis in epithelial ovarian cancer. In the present study, we used immunohistochemistry to determine the level and frequency of expression of different erbB receptors in GC tumors. Ten of 12 tumors expressed erbB4 at moderate to high levels in >50% of cancer cells, whereas erbB2 (6 of 12) and erbB3 (2 of 12) were expressed less frequently. Western blot experiments showed that the only available GC tumor cell line, COV434, also expressed erbB receptors. Heregulin (HRG)-beta2, a ligand for erbB3 and erbB4 receptors, stimulated tyrosine phosphorylation of the erbB receptors, which was accompanied by activation of Erk1 and Erk2, two mitogen-activated protein kinases with a functional role in mitogenesis. Importantly, HRG increased cell proliferation in COV434 cells, and treatment with HRG/PE40, a ligand toxin shown previously to be cytotoxic against human breast cancer cells overexpressing erbB receptors, led to a dramatic and irreversible decrease in cell number. These results indicate that erbB receptor signaling pathways may be critical in the control of GC tumor cell proliferation and that HRG/PE40 is a potential therapeutic agent for the treatment of GC tumors.

Partial 9p monosomy in a girl with a tdic(9p23;13p11) translocation, minor anomalies, obesity, and mental retardation.

We report on a case with a partial monosomy for the regions 9p23 --> pter and 13p11 --> pter as a result of a de novo translocation (9p23;13p11). The patient, a 16-year-old girl, has mental deficiency, obesity, and minor anomalies, including trigonocephaly, hypertelorism and a short, broad neck. Cytogenetic and microsatellite marker analysis allowed us to assign the breakpoint to the chromosomal region 9p23, flanked by the markers D9S144 and D9S157. In an attempt to establish a phenotype-genotype correlation, the clinical manifestations present in our patient are compared to those with partial 9p monosomy and breakpoint in p23, referred to in the literature.

From Pitt-Rogers-Danks syndrome to Wolf-Hirschhorn syndrome and back?

Apparently normal chromosomes without a molecular 4p16.3 deletion were found in a patient with a Wolf-Hirschhorn syndrome (WHS) phenotype. During a 10-year-period of observation he consistently presented with typical facial appearance, moderate to severe mental retardation, normal physical development with normal head circumference. Genetic results and the relatively mild clinical manifestations suggest that a diagnosis of Pitt-Rogers-Danks syndrome (PRDS) may be more likely in this patient. If WHS and PRDS will ultimately prove to be caused by haploinsufficiency of the same gene in 4p16, non-deleted patients such as the present one will be good candidates for the search of point mutations in such putative gene.

Bacteriophage T4 gene 28.

The complete nucleotide sequence of bacteriophage T4D gene 28 has been determined. Gene 28 product is a structural component of the viral baseplate for which an enzymatic activity has also been proposed.

Molecular biology of hepatocellular carcinoma and hepatitis B virus association.

The involvement of the hepatitis B virus in the pathogenesis of hepatocellular carcinoma was initially suggested on the basis of epidemiological studies. In recent years several kinds of experimental evidence have supported this hypothesis; however, the role played by hepatitis B virus in hepatocarcinogenesis still needs to be elucidated. Several groups of researchers are presently involved in establishing whether hepatitis B virus makes a specific genetic contribution to carcinogenesis or predisposes to neoplastic transformation by causing chronic inflammation and cell regeneration. A comprehensive examination of the data available in the literature suggests that the two hypotheses may not be mutually exclusive.

Molecular study of parental origin of extra chromosome 21 in regular and de novo translocation trisomies.

The parental origin of the extra chromosome 21 (or extra 21q) was determined in seven informative families with a Down syndrome (DS) child by using molecular polymorphisms. Five DS patients had regular trisomy, one a de novo 14/21 translocation and another a de novo 21/21 translocation or isochromosome 21q. In four families with regular trisomy, the extra chromosome was of maternal origin, and in one family it was paternally derived. In the two families with a de novo aberration, both the 14/21 translocation and 21/21 rearrangement originated during maternal meiosis. For a better evaluation of the stage of meiotic error and the occurrence of crossovers between nondisjoined chromosomes, the regional map position of four of the nine informative DNA markers, used in this study, was refined, leading to useful localizations in both centromeric and distal regions. Recombination events were found in two families with regular trisomy, one occurring between chromosomes 21 that failed to disjoin at maternal meiosis I, the other prior to a paternal meiosis II nondisjunction.

Acrocentric chromosome double NOR is not a risk factor for Down syndrome.

Jackson-Cook et al. (American Journal of Human Genetics 37:1049-1061, 1985) predicted a high risk of Down syndrome (DS) children for parents carrying a double NOR on acrocentric chromosomes. Hassold et al. (Human Genetics 76:381-384, 1987) could not confirm Jackson-Cook et al.'s findings, thus casting doubts on their conclusions. We studied the NORs of 1) 60 parents of 30 unselected DS subjects; 2) 30 unselected healthy subjects without trisomic offspring, who asked for chromosome analysis; and 3) 100 slides randomly chosen among 1,000 prepared by routine standard techniques and belonging to subjects who were chromosomally normal. By applying rigorously established techniques and scoring criteria we found 4 subjects (6.7%) with strictly defined double NORs (dNORs) in the DS parents sample, 2 subjects (6.7%) in the first control sample, and 3 (3%) in the second control sample. No significant difference among the observed frequencies of dNORs in the 3 samples could be demonstrated. Therefore, our data do not support Jackson-Cook et al.'s statements on the association of dNOR carrier status with DS offspring and on a highly increased risk of meiotic nondisjunction of chromosome 21 for a dNOR carrier parent. A tentative interpretation of the apparently contrasting cytogenetic findings would indicate that sampling and assignment biases are the main causes of this discrepancy.

Pericentric inversion of chromosome 9: prevalence in 300 Down syndrome families and molecular studies of nondisjunction.

The incidence of Down syndrome (DS) families where one of the parents is an heterozygous carrier of pericentric inversion of the heterochromatic region of chromosome 9-inv(9) (qh) - was determined in 3 independent groups of 100 families each. The total number of 17 such families found in the sample is significantly greater than the expected number of 5.73 for a sample of non-DS families of equal size. Consequently, the statistical association of the presence of inv (9) (qh) in one parent with the birth of a DS offspring, and the correlative 3-fold increased risk of a DS child for such families, seem to be demonstrated. A study of the origin of nondisjunction, using restriction fragment length polymorphism (RFLP) segregation analysis with a sufficient number of chromosome 21 specific probes, has provided complete information in 7 of 8 available families. Although the statistical interpretation of the results is not straightforward, due to the small size of the sample, the observed data do not contradict the assumption that the presence of inv (9) (qh) in a parent increases, by a factor of about 3, the chance that the offspring will inherit an extra chromosome 21 from that parent. Nevertheless, gathering further data appears desirable because stronger evidence would have relevance both for clinical implications and for the understanding of the function of heterochromatin, particularly with respect to meiotic and mitotic processes.