Clonal chromosomal defects in the molecular pathogenesis of refractory hyperparathyroidism of uremia

Indirect X chromosome-inactivation analyses have demonstrated that most parathyroid glands from patients with uremic refractory secondary/tertiary hyperparathyroidism are monoclonal neoplasms. However, little is known regarding the specific acquired genetic abnormalities that must underlie such clonal expansion or the molecular pathogenetic features of this disorder, compared with primary parathyroid adenomas. To address these issues in a uniquely powerful manner, both comparative genomic hybridization (CGH) and genome-wide molecular allelotyping were performed with a large group of uremia-associated parathyroid tumors. As indicated by CGH, one or more chromosomal changes were present in 24% of the tumors, which is markedly different from the value for common sporadic adenomas (72%). Two recurrent abnormalities that had not been previously described for sporadic parathyroid adenomas were noted with CGH, i.e., gains on chromosomes 7 (9%) and 12 (11%). Losses on chromosome 11 occurred in only one of the 46 uremia-associated tumors (2%); the tumor also contained a somatic mutation of the remaining MEN1 allele (221del18). A total of 13% of tumors demonstrated recurrent allelic loss on 18q, with 18q21.1-q21.2 being defined as the putative tumor suppressor-containing region. In conclusion, the powerful combination of genome-wide molecular allelotyping and CGH has identified recurrent clonal DNA abnormalities that suggest the existence and locations of genes important in uremic hyperparathyroidism. In addition, genome-wide patterns of somatic DNA alterations, including disparate roles for MEN1 gene inactivation, indicate that markedly different molecular pathogenetic processes exist for clonal outgrowth in severe uremic hyperparathyroidism versus common parathyroid adenomas.     

The voltage-gated sodium channel beta2-subunit gene and idiopathic generalized epilepsy

Recent identification of ion channel gene mutations in Mendelian epilepsies suggests that genetically driven neuronal hyperexcitability plays an important role in epileptogenesis. In this study, we tested the hypothesis that genetic variation in the human SCN2B gene confers liability to common subtypes of idiopathic generalized epilepsies (IGE). A systematic search for mutations was performed in 92 IGE patients. We detected a novel single nucleotide polymorphism (SNP), however, allele frequencies did not differ between IGE patients and controls (chi2 = 0.19, df = 1, p = 0.744). Furthermore, a missense mutation in codon 209 (Asn209Pro) was identified in one patient, but was found to be absent in an affected sibling of the index patient. Thus, our results do not suggest a major role of the SCN2B gene in the etiology of common IGE subtypes.     

Involvement of chemokine receptor CCR6 in colorectal cancer metastasis.

Various chemokine receptors, namely CXCR4, CCR6 and CCR7, have recently been shown to be involved in the regulation of metastasis in malignant tumors. However, little is known about the role of these receptors in promoting tumor metastasis of colorectal cancer (CRC) to the primary site of CRC metastasis in the liver. To investigate this issue, we analyzed the expression of the chemokine receptors CXCR4, CCR6 and CCR7 in colorectal tumors and colorectal liver metastases. In the present study, 30 human cancer samples from colorectal tissue, 30 human samples from colorectal liver metastases and the adjacent nontumorous liver tissues were screened using quantitative real-time PCR, Western blot analysis, histochemistry, microdissection and the enzyme-linked immunosorbent assay (ELISA). While an overexpression of all the chemokine receptors was found in CRC, in colorectal liver metastases only the chemokine receptors CXCR4 and CCR6 were significantly upregulated. Consequently, we investigated the expression of the corresponding ligands CXCL12/SDF1alpha, CCL20/MIP3alpha, CCL19/MIP3beta and CCL21/6Ckine in various organs, such as the stomach, esophagus, pancreas, colon and rectum, in comparison with their expression in the liver as the primary site of metastatic spread in CRC. We found that only CCL20 exhibits peak levels of expression in the liver, thus indicating that an increased production of CCL20 may contribute to the selective recruitment of CCR6-expressing cancer cells in CRC. Furthermore, we could demonstrate that CRC patients who developed liver metastases express significantly more CCL20 and CCL21 in the liver in comparison with an unaffected control group. Therefore, our findings strongly suggest an association between CCL20/CCR6 expression in human CRC and the promotion of colorectal liver metastasis.     

Induction of interleukin-6 by hepatitis C virus core protein in hepatitis C-associated mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma.

PURPOSE: Chronic hepatitis C carries the risk to develop mixed cryoglobulinemia (MC) and B-cell non-Hodgkin's lymphoma (B-NHL), possibly because viral antigens stimulate the host's inflammatory response via extracellular pattern recognition receptors (PRR). To clarify this issue, we studied whether recognition of hepatitis C virus (HCV) proteins by PRR is involved in the pathogenesis of HCV-associated MC or B-NHL. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells of patients with HCV-associated B-NHL (n = 12), MC (n = 14), uncomplicated hepatitis C (n = 12), and healthy volunteers (n = 12) were incubated with the recombinant HCV proteins E2, core, and NS3 to study induction of cytokine production, stimulation of B-cell proliferation, and immunoglobulin secretion. In addition, serum levels of interleukin-6 (IL-6) were measured by ELISA. RESULTS: HCV core was the only studied protein, which induced production of IL-6 and IL-8 in CD14(+) cells. IL-6 induction was mediated via Toll-like receptor 2 (TLR2) and lead to increased B-cell proliferation in vitro. TLR2 expression on monocytes and IL-6 serum concentrations were increased in all groups of HCV-infected patients compared with healthy controls and were highest in MC (P < 0.05). CONCLUSIONS: Increased secretion of IL-6 via stimulation of TLR2 by HCV core protein may play a role in the pathogenesis of hepatitis C-associated MC and B-NHL.     

The femoral hernia

BACKGROUND: We designed a study to determine the rate of intra- and postoperative complications as well as the rate of recurrences in elective operated femoral hernias treated via the laparoscopic technique. METHODS: Between 1993 and 1998, we performed 1,097 operations in our department using the laparoscopic transabdominal preperitoneal (TAPP) technique. Femoral hernias amounted to only 4.6% (51 cases) of these patients. The male/female ratio was 1:2. The data concerning the operations and pre- and postoperative treatment were recorded prospectively. The patients were followed up at 2 weeks and 1 year after the operation. RESULTS: We encountered one intraoperative bladder lesion, one subcutaneous port site infection, two postoperative hematomas that required reoperation, and two nerve irritation syndromes, which disappeared spontaneously after 6 months. Two patients developed an ileus; one required laparoscopic reintervention, and the other was treated with conventional open reoperation and intestinal resection. There were no recurrences. CONCLUSIONS: The application of the laparoscopic approach to the treatment of femoral hernias using the TAPP technique in nonemergency situations is highly effective. To date, we have seen no recurrences. Although the rate of major complications is low, current surgical techniques need to be perfected to avoid the type of complication recognized in this study.     

Functional results after laparoscopic rectopexy for rectal prolapse

We investigated the functional results after laparoscopic rectopexy for rectal prolapse in 29 patients at least 12 months postoperatively. Twenty patients were evaluated completely pre- and postoperatively (median 22 months postoperatively, range 12 to 54 months). Six patients were interviewed by telephone, two patients were lost to follow-up, and one patient died of causes unrelated to rectal prolapse. Patients underwent a proctologic examination, anoscopy, rigid sigmoidoscopy, fluoroscopic defecography, and anorectal manometry pre- and postoperatively, and an additional standardized interview postoperatively. Anorectal manometry showed a significant increase in maximum anal resting and squeeze pressures postoperatively (resting pressure 72 ±8 vs. 95 ±13 mm Hg, pre- vs. postoperatively; P = 0.046; squeeze pressure 105 ±17 vs. 142 ±19 mm Hg, pre- vs. postoperatively; P = 0.035), and continence improved postoperatively (Wexner incontinence score 6.0 ±1.0 vs. 3.9 ± 0.8 pre- vs. postoperatively, P = 0.02). Twenty (77%) of 26 patients were satisfied with the operative result, but functional morbidity was observed in four patients, with two patients complaining of severe evacuation problems. Rectal prolapse recurred in one patient 42 months postoperatively (recurrence rate 1 [3.8%] of 26 patients). Functional results were very similar to those obtained after open rectopexy, with symptoms of prolapse and incontinence improved in the great majority of patients. Presented at the Fortieth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Fla., May 16–19, 1999.     

Effects of succinylcholine and related substances administered into the medial preoptic area on the local EEG, body temperature, heart rate, galvanic skin resistance and biogenic amines

Succinylcholine (Sch) which is a cholinergic neuromuscular blocker has been known to occasionally lead to episodes of malignant hyperthermia in swine and humans. In order to find whether it produces any hyperthermic effects through action on medial preoptic area, experiments were carried on by administering intracerebrally the chemical into the medial preoptic area through an in-dwelling cannula-cum-electrode in the free moving rat. The changes in body temperature and the local EEG were studied. For comparison purpose, the effects of carbachol, atropine and phenylephrine were also studied. Further, in the curarized state of no muscular activity, the effect of SCh on the preoptic area was again tested and also the changes in the other autonomic parameters of heart rate and galvanic skin resistance (GSR) were studied. It was observed that SCh given into preoptic area caused a clear hyperthermic effect. The effect was countered by prior administration of atropine into the site. After SCh the local EEG changed into a high amplitude slow wave format. The heart rate was not altered but the GSR increased by two-fold. Carbachol caused a rise in body temperature, heart rate and also GSR. SCh also caused a reduction in noradrenaline content of the hypothalamus by 23% while no change in dopamine and serotonin occurred. Serotonin increased by 28% in the brainstem with no change in the other amines. Septum showed an increase of noradrenaline and dopamine contents by 40% and 25% respectively. Keeping in view the monoaminergic connections and thermoregulatory role of the preoptic area, one may postulate that SCh could inhibit the warm sensors and the controls of the dual sympathetic mechanism which normally leads to an increase of sudomotor activity and a decrease of vasomotor activity, the inhibition resulting in rise of body temperature.