Effect of the -420C/G variant of the resistin gene promoter on metabolic syndrome, obesity, myocardial infarction and kidney dysfunction.

OBJECTIVE: Resistin is an adipokine that has been suggested to be correlated with markers of inflammation and to be predictive of coronary atherosclerosis and type II diabetes in humans. A common single nucleotide polymorphism (SNP) (-420C/G) in the promoter of resistin is associated with increased resistin plasma levels and susceptibility to type II diabetes. The aim of this study was to investigate the association of the -420C/G polymorphism with metabolic syndrome, obesity, myocardial infarction and kidney disease. DESIGN AND RESULTS: First we studied 1542 subjects from the PLIC study (a population based cohort). GG carriers showed an higher prevalence of obesity and metabolic syndrome as well as increased plasma triglycerides levels, BMI, systolic and diastolic blood pressure and cardiovascular risk according to Framingham algorithm (P < 0.05 for all). Next we investigated the presence of the -420C/G resistin polymorphism in a case-control study that included 300 subject with myocardial infarction and 300 age and sex matched controls and then we studied the role of the -420C/G SNP in 88 patients with mild to moderate renal dysfunction. No statistically significant differences in allele frequencies between the PLIC study, the myocardial infarction (MI) cases and the subjects with renal dysfunction were observed. Pro-inflammatory gene expression profiling of peripheral blood mononuclear cells failed to detect any difference between wild type subjects and carriers of the rare allele. CONCLUSION: Our data suggest that the presence of the -420C/G SNP of the resistin gene is associated with increased obesity and metabolic syndrome, although it is not different in subjects at high cardiovascular risk such as patients with myocardial infarction or patients with renal dysfunction compared with controls.

Plasma resistin levels correlate with determinants of the metabolic syndrome.

OBJECTIVE: The role of resistin in insulin sensitivity and obesity is controversial. Some authors suggest that increased serum resistin levels are associated with obesity, visceral fat, insulin resistance, type 2 diabetes and inflammation, while others failed to observe such correlations. The aim of the present study was to investigate the relationship of plasma resistin levels with markers of the metabolic syndrome and atherosclerosis in a large population-based study. DESIGN AND PATIENTS: Plasma resistin levels were determined in 1090 subjects free of any medication selected from the PLIC study (designed to verify the presence of atherosclerotic lesions and progression intima-media thickness (IMT) in the common carotid artery in the general population) and related to the presence of obesity, metabolic syndrome, metabolic abnormalities, cardiovascular risk, and progression of IMT. RESULTS: Plasma resistin levels were highly positively correlated with triglycerides, waist circumference, waist/hip ratio, systolic blood pressure, and ApoAI/ApoB ratio, while they were inversely correlated with high density lipoprotein and ApoAI levels. This finding was gender specific (mainly in women). Plasma resistin levels were significantly higher in women with the metabolic syndrome compared with controls (4.90 (0.24) ng/ml vs 3.90 (0.11) ng/ml; P<0.01), while no difference was observed in obese subjects. Finally, plasma resistin levels were significantly correlated with cardiovascular risk calculated according to the Framingham algorithm (P<0.01). CONCLUSION: Plasma resistin levels are increased in presence of the metabolic syndrome and are associated with increased cardiovascular risk.

Liver X receptor and retinoic X receptor agonists modulate the expression of genes involved in lipid metabolism in human endothelial cells.

The cooperation of liver X receptors (LXRs) alpha and beta, and retinoic X receptor (RXR) modulate the expression of several genes involved in lipid metabolism in hepatocyte and macrophages. Using cDNA microarray technology, we have shown previously that several of these genes are also expressed in endothelial cells. In the present study, we investigated whether the activation of LXR and RXR affects the expression of genes involved in lipid metabolism in human endothelial cells. Relative expression of ABCA-1, CETP, SR-B1, EL, LPL, PLTP, ApoE and LDLR was investigated in HUVECs, human fibroblasts (hFB) and HepG2 cells by quantitative real-time PCR. For CETP and EL mRNA expression, the results were HUVECs > hFB > HEPG2; for PLTP, LDLR and LPL: hFB > HUVECs > HEPG2; for SR-B1 and ApoE: HEPG2 > HUVECs > hFB; and for ABCA-1 HEPG2: > hFB > HUVECs. Incubation of HUVECs with LXR agonists as 22-(R)-hydroxycholesterol (22-(R)-HC) or T0901317-induced ABCA1 (20.1- and 17.8-fold), LPL (3.46- and 7.03-fold) and CETP (6.34- and 3.98-fold) expression; EL, LDLR and SR-B1 expression was induced only upon incubation with T0901317 (2.40-, 2.83- and 2.19-fold, respectively) while 22-(R)-HC had no effect on EL and SR-B1 expression (0.8- and 0.9-fold) and decreased LDLR expression (0.4-fold). No effect of either 22-(R)-HC or T0901317 on PLTP and ApoE expression was observed. The RXR agonist, 9-cis retinoic acid (9CRA) alone induced the expression of CETP, LPL and SR-B1 (2.8-, 8.2- and 2.4-fold). No effect of 9CRA on ABCA-1, EL, PLTP, ApoE, and LDLR expression was observed. Association of 9CRA with 22-(R)-HC or T0901317 increased the expression of CETP and LPL while no effect on ABCA-1 or LDLR was observed. Activation of LXRs and RXRs in endothelial cells represents a new target of LXR and RXR agonist in the arterial wall. Modulation of gene expression in the endothelium should be taken into account when studying the effects of LXR and RXR agonists on lipid metabolism in the arterial wall.

Effect of the Toll-like receptor 4 (TLR-4) variants on intima-media thickness and monocyte-derived macrophage response to LPS.

OBJECTIVES: Toll-like receptor 4 (TLR-4) is believed to contribute to the initiation and progression of atherosclerosis. The association of the D299G polymorphism of the TLR-4 gene with the progression of coronary and carotid atherosclerosis, risk of cardiovascular events and myocardial infarction is controversial. We have investigated whether the presence of the D299G polymorphism and the co-segregated T399I polymorphism affects the intima-media thickness (IMT) in the general population. SUBJECTS: The PLIC study population (n = 1256) was genotyped for the D299G and the T399I polymorphisms. RESULTS: The presence of both the D299G and T399I alleles was observed in the 13.0% of the population, carriers of the T399I alone were 1.8% and of the D299G alone were 0.9%. No difference in IMT was detected within the carriers of the D299G and T399I alleles and the wild-type subjects in the PLIC population. Furthermore, we investigated whether monocyte from D299G to T399I subjects present a defective response to CD40, interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, cyclo-oxygenase (COX)-2 and PTX3 expression induced by lipopolysaccharide (LPS). When the monocyte-derived macrophages of these subjects were challenged with LPS (1 mug mL(-1)), no impact of the polymorphisms on the induction of CD40, MCP-1 and PTX3 was observed. Only IL-6 and COX-2 induction by LPS resulted reduced in the D299G/T399I carriers. CONCLUSION: The presence of the D299G and T399I polymorphisms of the TLR-4 gene does not play a major role on the progression of carotid atherosclerosis. Macrophages from the subjects carrying the polymorphisms show an impaired response to LPS limited only to a IL-6 and COX-2.

Conversion of recent-onset atrial fibrillation to sinus rhythm: effects of different drug protocols.

UNLABELLED: In a population of 417 hospitalized patients, the efficacy and safety of different drug regimens administered to convert atrial fibrillation (AF) of recent onset (< or = 7 days duration) to sinus rhythm were evaluated. All patients were in NYHA Class < or = 2, and free of heart failure. They were randomly allocated to treatment with placebo in 121 patients; i.v. amiodarone, 5 mg/kg bolus, followed by 1.8 g/24 hours in 51 patients; i.v. propafenone, 2 mg/kg bolus, followed by 0.0078 mg/kg/min in 57 patients; p.o. propafenone, 600 mg p.o. in a single dose in 119 patients; and p.o. flecainide, 300 mg p.o. in a single dose in 69 patients. All patients were continuously monitored by Holter ECG, and the number of conversions to sinus rhythm was measured at 1, 3, and 8 hours. RESULTS: (1) I.v. propafenone resulted in a higher conversion rate within 1 hour compared with the oral loading regimens of propafenone or flecainide, but the conversion rates at 3 and 8 hours were comparable, approximately 75% at 8 hours; 2) i.v. amiodarone was not different from placebo until 8 hours when it was associated with 57% of conversions; (3) conversion to sinus rhythm at 8 hours was observed in 37% of the placebo treated patients. Serious adverse effects occurred in few patients: two patients treated with flecainide and one treated with i.v. propafenone experienced left ventricular decompensation; one patient treated with placebo and two treated with flecainide had atrial flutter with rapid ventricular response. In conclusion, single-dose, oral loading with propafenone or flecainide are acceptable alternatives to conventional drug regimens in selected hospitalized patients. In addition, the measure of a placebo effect is mandatory in studies of recent-onset AF.

[Acute hepatotoxicity from amiodarone]. / Epatotossicità acuta da amiodarone.

The functional and histological liver alterations induced by amiodarone treatment have been well known for some time and often consist in isolated increases in transaminase levels during long-term treatment. Secondary phospholipidosis was observed in these cases, an alteration which suggests the presence of toxic damage. Reports in the literature also indicate acute liver intoxication, including a number of fatal cases. This paper reports the finding of acute alterations of laboratory parameters indicative of hepatocytonecrosis with alterations of protein synthesis capacity following the first dose of the drug and which regressed after its suspension. On the basis of a review of the literature the authors propose that, in addition to a dose-dependent toxic mechanism, immunogenic or idiosyncratic mechanisms may also play a role in the onset and manifestation of acute liver intoxication by amiodarone.

[Massive hemobilia caused by necrotic hemorrhagic cholecystitis. Report of a case]. / Emobilia massiva da colecistite necrotico-emorragica. Segnalazione di un caso.

The authors report a case of massive hematobilia due to hemorrhagic cholecystitis. Hematobilia is a rare pathology which affects the biliary tract and gallbladder. The first authors to describe hematobilia defined it as a hemorrhage of the gastroenteric tract due to the communication of blood vessels with the intra and extra-hepatic biliary tract and in some rare cases to the communication of the branches of the cystic artery within the gallbladder wall. Sandblom, in particular, specified that bleeding must be within the biliary tract and not secondary to an enterobiliary fistula. In 55% of cases the pathogenesis of hematobilia is traumatic, whereas in the remaining 45% the cause may be attributed to a variety of pathologies. Trauma include both non-surgical and surgical traumas; in the first group the most frequent cause is hepatic trauma, although it is worth taking into account the presence of post-traumatic arteriobiliary fistulas, lesions of arterial vessel walls with subsequent necrosis and rupture within the biliary vessels. Surgical traumas comprise lesions caused by therapeutic or diagnostic transparenchymal manoeuvres (PTC, biopsy). Non-traumatic causes include pathologies of vascular, cholecystic, inflammatory-infective and neoplastic origin. Symptoms are varied and take the form of anemia, massive bleeding with the onset of jaundice and pain in the hypochondrium and sometimes the epigastrium, whereas enterorrhagia is manifested by melena and more rarely hematemesis. The diagnosis must be made as quickly as possible; mortality increases with the delay in controlling hemorrhage. Differential diagnosis must take into account other causes of enterorrhagia, obstructive jaundice and anemia.(ABSTRACT TRUNCATED AT 250 WORDS)

[Sarcomatous degeneration of a giant scrotal lipoma. Presentation of a clinical case]. / Degenerazione sarcomatosa di lipoma gigante dello scroto. Presentazione di un caso clinico.

This paper presents a case of giant scrotal lipoma with areas of sarcomatous degeneration which were evident on anatomico-pathological examination; the authors considered it worth-while reporting this case given that giant lipomas with sarcomatous degenerations are rare. It is important to underline that in comparison to other malignant tumours of the scrotum the frequency of liposarcomas is very low. In addition to the liposarcoma reported here, at the level of the scrotum it is worth recalling neurofibrosarcoma and fibrosarcoma and some rare sarcomas of the spermatic cord among the malignant sarcomas of sarcomatous origin reported in the literature. Difficulties may arise from a diagnostic point of view due to the scarcity of symptoms. Among the most frequent symptoms is the presence of a hard mass on palpation of the scrotum; the volume of this mass may increase very rapidly. It is important to note that this tumour may sometimes originate as malignant and then degenerate in toto or in some isolated areas. Instrumental tests include abdominal radiography without the use of contrast medium in order to exclude the presence of herniated abdominal viscera at the level of the scrotum. Ultrasonography may also be extremely useful since it is capable of providing information regarding the presence, inside the scrotal sack, of liquid retention or solid forms. At all events histological diagnosis is carried out in the majority of cases following the removal of the operated part. The exeresis of the tumour therefore becomes both diagnostic and therapeutic. Surgery consists in the simple exeresis of the neoplasia; in some cases orchiectomy is required in addition to exeresis. Some authors also recommend the dissection of inguinal lymph nodes following extemporary anatomo-pathological tests. In other cases when histological tests confirm the malignant degeneration with a high degree of biological aggressiveness, the patient has to undergo postoperative radiotherapy and/or chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

[Squamous papillomas of the esophagus]. / I papillomi squamosi dell'esofago.

The paper reports 14 cases of squamous papilloma of the esophagus which were removed using an endoscopic method: this is a comparatively rare benign pathology of which an increasing number of cases have been recently observed. Endoscopic controls were carried out in all cases and the results of the follow-up are reported.

[Nephrobronchial fistula]. / La fistola nefrobronchiale.

Nephrobronchial fistula is a rare pathology both in absolute terms and in relation to the complications of renal inflammatory processes. Clinical symptoms may be varied but pulmonary complications, which may mask renal symptoms, are generally predominant; cough, hemoptysis and the expectoration of calculi are rarely found. Occasionally, as in the case reported here, the most evident sign is an infective process due to the contemporaneous fistulization of subcutaneous tissues. Instrumental diagnosis is based on chest and abdomen X-ray, fistulography, retrograde pyelography and abdominal CT. CAT may be useful above all in the study of pararenal abscesses.

[Primary torsion of the omentum]. / La torsione primitiva dell'omento.

The paper reports a case of spontaneous torsion of the omentum. Following a review of the international literature on the topic, the Authors discuss the pathogenesis, clinical symptoms and surgical therapy of this pathology.

[Malignant schwannoma of the mesentery. Presentation of a clinical case and clinical and histopathological considerations]. / Schwannoma maligno del mesentere. Presentazione di un caso clinico e considerazioni cliniche ed istopatologiche.

A case of malignant schwannoma of the mesentery is described which was treated with radical surgery. The natural history, diagnosis and therapy of neoplasias of the mesentery are discussed.

Lung resection for metastatic sarcomas: total survival from primary treatment.

The results of surgical management of 63 cases of pulmonary metastases from bone and soft tissue sarcomas, admitted at the Istituto Nazionale Tumori of Milan, between 1970 and 1987, are reviewed in this paper. To estimate the relative impact of metastasectomy on the overall performance of treatment, survival curves were calculated from the time of first thoracotomy, as well as from the initial treatment of primary sarcoma. In the present series, total actuarial survival at 10 years was 37% for osteosarcoma, 27% for soft tissue sarcomas, and 24% for the other bone sarcomas, with a median survival of 48, 56, and 36 months, respectively. Five-year survival from the first pulmonary resection was influenced by the number of metastases and the length of the first disease-free interval only in osteosarcoma, while in soft tissue sarcomas a major untoward factor was represented by local recurrence at the site of the primary tumor. These data support the concept of pulmonary metastasectomy as effective salvage therapy for radically treated sarcomas; this management can rescue a significant proportion of all relapsed patients.

Lung resection as salvage treatment for metastatic osteosarcoma.

Resection of pulmonary metastases has achieved a central role in the overall management of osteosarcoma, since a number of studies have demonstrated that salvage surgery is able to cure 20 to 40% of all relapsing patients. This paper presents the results of surgical management of 27 consecutive cases of pulmonary metastases from osteosarcoma, who underwent complete resection at the Istituto Nazionale Tumori of Milan between 1975 and 1986. In the present series, overall actuarial survival at 3 years from the first thoracotomy was 47%, with a median survival of 28 months and no operative mortality. Better results were observed in patients with single lesions (68% survival) or when the interval to lung metastases exceeded 12 months (60% survival). These data support the concept of pulmonary metastasectomy as effective salvage therapy for metastatic osteosarcomas whose distant spread is confined in the lungs.

Modified Schoemacher resection for distal gastric cancer.

Between October 1979 and February 1987, 30 consecutive patients with cancer of the lower stomach underwent B1-Schoemacher resection with a tubular gastric pouch. Operative mortality was 0% and operative morbidity 10% (leak 3%, anastomotic stricture 3% and abscess 3%). After a mean follow-up of 30 months, the expected 5-year survival was 32%. The causes of death were: 7 distant relapses, 2 noncancer diseases and 1 new primary cancer. The overall incidence of postgastrectomy symptoms was 23% for the whole series and 35% for the patients harboring small tumors. Mild dyspepsia occurred in 71%. The declining concept of total gastrectomy as an essential requirement for curative resection and the recent evidence that B2 for gastric lesions is a carcinogenic operation necessitate alternative procedures. The data show that modified Schoemacher resection can be consider a valid challenge to B2.

Late results after sleeve or wedge lobectomies for non-small-cell lung carcinoma.

From January 1971 to June 1983, 35 lobectomies with bronchoplastic procedures for invasive non-small-cell lung carcinoma were performed. Sleeve lobectomy was carried out in 21 cases, wedge lobectomy in 11, and upper sleeve bilobectomy in 3. There were 23 stage I, 10 stage II, and 2 stage IIIa tumors. Completion pneumonectomy was required in 1 case for anastomotic fistula and in 2 for atelectasis of residual lung. One of these patients died later due to empyema. The 5-year probability of death with recurrence was 31.98%. The 5-year disease-free survival was 58.57%. Metastatic relapse was observed in 8 cases and loco-regional recurrence in 5. A new primary lung tumor occurred in 2 patients.

Lung cancer chemoprevention with retinol palmitate. Preliminary data from a randomized trial on stage Ia non small-cell lung cancer.

On the basis of epidemiologic and experimental evidence of an anticancer activity of vitamin A, a randomized clinical trial was activated in Milan with the aim of evaluating if retinol palmitate administration (per os, 300,000 I.U. daily) after complete resection of stage Ia non small-cell lung cancer could reduce the occurrence of cancer relapses (within 3 years) and/or the occurrence of new primary tumors (beyond 3 years). By September 1987, 181 patients had entered the trial: 87 in the treatment arm and 94 in the control arm. After a median follow-up of 14 months, the interim analysis was focused on the evaluation of toxicity, compliance, and early recurrences. Although the large majority of patients were affected by skin and mucous membrane desquamation and dryness during treatment, these symptoms were generally mild and well tolerated, and never induced the patient to stop the treatment. Other side effects like headache, hair loss, itching, or dyspepsia were detected at a much lower frequency. Only in 3 patients the treatment was interrupted, because of signs or symptoms potentially related to vitamin A administration. At the time of the analysis, a total of 42 (23%) patients had relapsed; 16 (18%) in the treated arm, and 26 (28%) in the control arm. The largest difference between treated patients and controls was observed for bone metastases (2 vs. 7) and brain metastases (3 vs. 6), and for squamous histology (6 vs. 11). Only 2 cases of new primary cancer were detected, both in the control arm. These results are promising both in terms of tolerance and efficacy of treatment, but given the short median follow-up they must be very cautiously interpreted. A longer follow-up is necessary to establish whether a significant proportion of early recurrences could be prevented, or only delayed, by vitamin A administration.

Current results of esophageal cancer surgery. Time trends in operative mortality and long term survival.

This paper represents a historical analysis of the results achieved by esophageal cancer surgery over the last three decades, as they appear in the literature of the years 1954-1985, and in our own experience between 1965 and 1985, with the aim of assessing the evolution of operative mortality and long-term survival. In a review of 4930 resections reported in western literature, mean values of perioperative mortality went down from 30% to 9%, while the five-year survival increased from 8% to 19%. Similar changes were evident in Japanese and Chinese literature where the survival rose from 9% to 23% in unscreened populations and up to 90% in early cancers. In our experience, dividing the series in two decades (1965-74 and 1975-85), the overall perioperative mortality changed from 28% to 13%. The actuarial survival for the two periods was 8% vs 18% at 5 years, with a median survival of 9 and 18 months. A greater difference was evident for N0 patients where the survival rose from 15% to 35% at 5 years, with a median survival of 15 vs 38 months.

Leiomyoma of the esophagus.

A review of the clinical records from 1947 to 1984 of the Istituto Nazionale Tumori of Milan provided 20 cases (14 males and 6 females) of esophageal leiomyoma. Eighteen of the tumors were in the thoracic esophagus and 2 were at the cardiac level. The most frequent symptoms were dysphagia, slight epigastralgia and odynophagia. Differential diagnosis should be made with mediastinic neoplasms and esophageal cancer. Barium swallow and esophagoscopy are the most sensitive procedures for a correct preoperative diagnosis. Surgery is mandatory because of the tendency to a continuous endoluminal growth (in 97% of the cases) and a possible malignant transformation. However, surgery is conservative: extramucosal enucleation of the leiomyoma is the procedure of choice. The long-term results are excellent, and morbidity is acceptable.

A fifteen years' experience in the diagnosis and treatment of benign lung tumors.

Even the most sophisticated examinations, such as computerized tomography and percutaneous fine needle biopsy, often do not allow a certain preoperative diagnosis of benign lung cancer. The clinical history may also be deceiving: a smoker over 35 years of age need not necessarily have a primary lung cancer, but this event is frequent enough to justify a diagnostic thoracotomy. In our series, chest tomography proved to be useful and sometimes revealed unsuspected lesions. In contrast, bronchoscopy is useful only for centrally located lesions, and the same is true for bronchial washing and brushing. Finally, thoracotomy, possibly an axillary one with enucleation or possibly transegmentary resection, is the most frequent operation in benign lung tumors, because of the unfailing diagnosis and for the minimal functional damage to the patient. A diagnostic thoracotomy may also avoid the psychologic stress suffered by a patient with a simple but undiagnosed benign lung tumor.