Angiopoietin-1 and Angiopoietin-2 in metabolic disorders: therapeutic strategies to restore the highs and lows of angiogenesis in diabetes.

The morbidity and mortality of diabetes mellitus are mostly attributed to cardiovascular complications. Despite tremendous advancement in glycemic control, anti-diabetic medications have failed to revert vascular impairment once triggered by the metabolic disorder. The angiogenic growth factors, Angiopoietin-1 (Ang1) and Angiopoietin-2 (Ang2), are crucial regulators of vessel formation and maintenance starting with embryonic development and continuing through life. In mature vessels, angiopoietins control vascular permeability, inflammation and remodeling. A crucial role of angiopoietins is to drive vascular inflammation from the active to the quiescent state, enabling restoration of tissue homeostasis. The mechanism is of particular importance for healing and repair after damage, two conditions typically impaired in metabolic disorders. There is an emerging body of evidences suggesting that the imbalance of Ang1 and Ang2 regulation, leading to an increased Ang2/Ang1 ratio, represents a culprit of the vascular alterations of patients with type-2 diabetes mellitus. Pharmacological modulation of Ang1 or Ang2 actions may help prevent or delay the onset of diabetic vascular complications by restoring vessel function, favoring tissue repair and maintaining endothelial quiescence. In this review, we present a summary of the role of Ang1 and Ang2, their involvement in diabetic complications, and novel therapeutic strategies targeting angiopoietins to ameliorate vascular health in metabolic disorders.

Investigation of random telegraph signal in two junction layouts of proton irradiated CMOS SPADs.

This paper focuses on the understanding of the Random Telegraph Signal (RTS) in Single-Photon Avalanche Diodes (SPAD). We studied the RTS of two different SPAD layouts, designed and implemented in a 150-nm CMOS process, after proton irradiation. The two structures are characterized by different junction types: the first structure is constituted by a P+/Nwell junction, while the second is formed by a Pwell/Niso junction. RTS occurrence has been measured in about one thousand SPAD pixels and the differences addressed in two layouts are motivated and discussed. Hypotheses on the RTS origin are drawn by analyzing the RTS time constants and the RTS occurrence evolution as a function of the annealing temperature.

Metabolic or bariatric surgery? Long-term effects of malabsorptive vs restrictive bariatric techniques on body composition and cardiometabolic risk factors.

BACKGROUND: Obesity is an increasing health problem and surgery seems to be the only treatment effective in achieving weight loss without relapse. Among bariatric techniques, many differences exist in terms of weight loss and resolution of comorbidities. Up to now, there are no prospective studies comparing long-term effects of malabsorptive vs restrictive techniques. OBJECTIVE: In this study, cardiometabolic risk factors and body composition changes after malabsorptive biliointestinal bypass (BIBP) and restrictive laparoscopic adjustable gastric banding (LAGB) were compared during a 4-year follow-up. DESIGN: Prospective, case-control and cohort study. PATIENTS: In all, 80 obese subjects, matched for weight and age. Altogether, 40 patients underwent BIBP and 40 underwent LAGB. MEASUREMENTS: Weight, body composition, fasting and post-loading plasma glucose and insulin, homeostatic model assessment index (HOMA-I), lipid profile, blood pressure (BP), erythrocyte sedimentation rate and fibrinogen were monitored at baseline, 12 and 48 months. RESULTS: At 12 months after surgery, a significant reduction in body mass index, total fat mass (FM), trunk FM (trFM), trFM/legs FM (lFM) ratio (trFM/lFM), triglycerides, BP and inflammation markers was observed in both groups. BIBP patients showed a significant reduction in total cholesterol (Tot-C), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), whereas the LAGB group showed a significant increase of HDL-C. A further improvement of all the parameters evaluated was seen in the BIBP group at 48 months after surgery. CONCLUSIONS: Both bariatric procedures exerted positive effects on cardiometabolic risk factors and on weight loss in the population studied, but on the long-term period, HOMA-I, Tot-C/HDL-C ratio and body composition improvements were more evident after BIBP. We conclude that malabsorptive BIBP seems to be more effective than LAGB in treating visceral obesity and its metabolic complications.

Ordered interstrand and intrastrand DNA transfer during reverse transcription.

Retroviruses contain two copies of the plus stranded viral RNA genome. As a means of determining whether both of these RNA's are used in the reverse transcription reaction, cells were infected with heterozygous virus particles that varied in nucleotide sequence at two separate locations at the RNA termini. The DNA proviruses formed from a single cycle of reverse transcription were then examined. Of the 12 proviruses that were characterized, all exhibited long terminal repeats (LTR's) that would be expected to arise only if both RNA templates were used for the generation of minus strand DNA. In contrast, only a single minus strand DNA appeared to be used as template for the plus strand DNA in the generation of fully double-stranded viral DNA. These results indicate that the first strand transfer step in reverse transcription is an intermolecular event while that of the second transfer is intramolecular. Thus, retroviruses contain two functionally active RNA's, and both may be required for the generation of a single linear DNA molecule. Formation of heterozygotes during retrovirus infection would be expected to result in the efficient generation of LTR recombinants.

Clonal insulinoma cell line that stably maintains correct glucose responsiveness.

A number of pancreatic beta-tumor cell (beta TC) lines have been derived from insulinomas arising in transgenic mice expressing the SV40 T antigen gene under control of the insulin promoter. Some of these lines secrete insulin in response to physiological glucose concentrations. However, this phenotype is unstable. After propagation in culture, these nonclonal lines become responsive to subphysiological glucose levels and/or manifest reduced insulin release. Here we report the use of soft-agar cloning to isolate single-cell clones from a beta TC line, which give rise to sublines that maintain correct glucose responsiveness and high insulin production and secretion for > 55 passages (over a year) in culture. One of these clonal lines, denoted beta TC6-F7, was characterized in detail. beta TC6-F7 cells expressed high glucokinase and low hexokinase activity, similarly to normal islets. In addition, they expressed mRNA for the GLUT2 glucose transporter isotype and no detectable GLUT1 mRNA, as is characteristic of normal beta-cells. These results demonstrate that transformed beta-cells can maintain a highly differentiated phenotype during prolonged propagation in culture, which has implications for the development of continuous beta-cell lines for transplantation therapy of diabetes.

Subcutaneous and visceral fat distribution according to sex, age, and overweight, evaluated by computed tomography.

Subcutaneous and visceral fat distribution as related to sex, age, and overweight was studied in 130 subjects and 10 women with Cushing's disease. Fat depots were evaluated by computed tomography at one thoracic and one abdominal level. Adipose tissue (density range - 50 to 250 Hansfield units) was highlighted and the fat areas were measured by a laser planimeter. The ratio between subcutaneous and visceral fat areas (S:V ratio) was assumed as an index. Ratios of both nonobese and obese groups were significantly higher in females than in males. Ratios decreased markedly over age 60. There was a significant inverse correlation between age and S:V ratios in females (r = 0.65; p less than 0.001) and in males (r = 0.61; p less than 0.001). Statistically significant correlations were found between S:V ratios at thoracic and abdominal levels. In Cushing's patients, the S:V ratio at the abdominal level was significantly lower than in controls matched for age, sex, and body mass index.

Polymer-encapsulated Schwannoma cells expressing human nerve growth factor promote the survival of cholinergic neurons after a fimbria-fornix transection.

Many investigators have recently used genetically modified primary fibroblasts of fibroblast cell lines (e.g., 3T3, 208F, or BHK cells) to deliver recombinant nerve growth factor (NGF) into the CNS. In the current study, SCT-1 cells, a Schwannoma cell line derived from a transgenic mouse, were transfected with a human NGF (hNGF) cDNA. After selection, these cells were encased within a polymer capsule and implanted into the ventricles of fimbria-fornix lesioned rats. Encapsulated, non-transfected cells served as controls. Results demonstrated that the hNGF transgene is expressed for at least 3 weeks after implantation. Moreover, the cells did not overgrow the capsule. Recombinant hNGF was able to save > 70% of lesioned cholinergic neurons, as assessed by NGF-receptor (NGFr) and choline acetyltransferase (ChAT) immunohistochemistry, from cell death. The number of cholinergic neurons in animals that received control capsules (i.e., nontransfected SCT-1 cells) was similar to lesion only animals (i.e., approximately 27% and approximately 33% for NGFr- and ChAT-positive neurons, respectively. These results show that SCT-1 cells can be used to deliver biologically active hNGF into the lesioned rat brain.

Two PC12 pheochromocytoma lines sealed in hollow fiber-based capsules tonically release L-dopa in vitro.

Two PC12 cell-derived lines have been studied following encapsulation into polymer-based hollow fibers with respect to secreted catecholamines and their metabolites. Cellular encapsulation provides a chronic microperfusion environment within which basally secreted PC12 products can be readily measured. Encapsulated PC12 cells grown and held under the conditions specified in this report basally release amounts exceeding their total cellular stores of the dopamine precursor L-DOPA and the electrochemically active dopamine metabolites DOPAC and HVA during 45-min static incubations. Under these same conditions, these cells release less than 0.1% of their total cellular store of dopamine. Depolarizing incubations enhance dopamine secretion eightyfold and enhance secretion of L-DOPA, HVA, and DOPAC about twofold. The relative composition of products basally secreted differs between PC12-derived cell lines, and an inverse relationship exists between basal release of L-DOPA and total cellular store of dopamine. These results further indicate that selected PC12 cell lines are potentially a source of both dopamine and L-DOPA in therapeutic cellular replacement applications.

Bilateral Pancoast syndrome in a patient with metachronous primary lung cancer.

A rare case of double Pancoast tumor in a patient with metachronous primary cancer of the lung was treated with irradiation and operation. Both tumors were managed with pulmonary wedge resection and excision of involved chest wall. Six years after the first operation the patient is doing well without pain and respiratory failure.

Importance of auditory brainstem responses in the CT diagnosis of traumatic brainstem lesions.

Changes in brainstem auditory-evoked potential response were serially investigated in 20 head-injury patients with neurologic and computed tomographic signs of brainstem lesion. The reliability of computed tomography in the evaluation of indirect signs of brainstem lesion from the image was investigated with elaboration of the brainstem auditory-evoked potential response. The measurement of auditory brainstem response is thought to be useful in detecting the severity and predicting possible recovery in posttraumatic brainstem injury. Brainstem deformity on computed tomography was a bad prognostic sign, indicating irreversible structural change.

Morbidity, mortality, and survival after bronchoplastic procedures for lung cancer.

OBJECTIVE: Bronchoplastic procedures represent an effective surgical therapy for benign lesions, tumors of low-grade malignancy and also bronchogenic carcinoma in patients with a limited pulmonary function. We analyzed our experience in order to verify the mortality, morbidity, and long term survival in our patients. METHODS: From 1980 to 1994, 217 patients underwent bronchoplastic procedures. We performed 92 bronchoplasties, 94 bronchial sleeves, and 31 tracheo-bronchial sleeves. Histologic examination revealed 133 epidermoid carcinomas, 28 adenocarcinomas, 11 small cells lung cancers, 5 large cells carcinomas, 2 adenosquamous carcinomas, 29 bronchial carcinoids, 6 adenoidocistic carcinomas, and 3 mucoepidermoid tumors. Regarding nodal status, 99 patients had N0 disease, 64 patients had N1 disease, and 54 patients had N2 disease. Thirty-six patients had preoperative irradiation and 181 patients had no preoperative irradiation. In 63 patients we used a perianastomotic pedicled flap; in 154 we did not use it. We considered all the 217 patients for the analysis of 30-day mortality and morbidity; of the 217 patients we analyzed long-term survival only in 179 because we excluded 38 patients with low grade malignant neoplasm. RESULTS: Twenty-seven patients (12.5%) had postoperative complications. The 30-day mortality was 6.2% (14 patients). Survival at 5 and 10 years for all patients but those with low grade malignant neoplasm was 49 and 38%, respectively. For patients with N0 status 5- and 10-year survival was 72.4 and 59.4%; for patients with N1 status these rates were 35.7 and 26.8%; for patients with N2 status, 5- and 10-year survival was 22 and 14.4%. Postoperative complication rates for patients with or without pedicled flap are not significantly different; however, the rates for patients with or without preoperative irradiation are significantly different. CONCLUSIONS: Bronchoplastic procedures are a safe and effective therapy for selected patients with pulmonary malignancy. Tracheo-bronchial sleeves are associated with high postoperative mortality and complication rates and these procedures should be limited to patients without N2 disease. Preoperative irradiation increases significantly the mortality and morbidity. A multivariate analysis shows that only the nodal status affects long-term survival (P = 0.0002).

Production of prostaglandins in homogenates of kidney medullae and cortices of spontaneously hypertensive rats fed menhaden oil.

Menhaden oil (MO), whose polyunsaturated fatty acids consist mainly of (n-3) fatty acids, was fed to spontaneously hypertensive rats to determine the effect of (n-3) fatty acid on the in vitro production of prostaglandins produced from arachidonic acid (20:4[n-6]). Capacity to form PGE2 and PGF2 alpha was impaired in homogenates of kidney medullae and cortices from rats fed the MO diet compared to rats fed the control diet. The lower amounts of diene prostaglandins produced corresponded to the decrease in the amount of 20:4 (n-6) in the tissue. Possibly changes produced in tissue lipids by dietary fatty acids affect prostaglandin production by reducing the availability of substrate in tissue lipids.

Spontaneous ("erosive") cerebrospinal rhinorrhea, with pneumococcal meningitis from anterior optic glioma. Case report.

A 6-year-old girl, operated upon for an optic nerve astrocytoma (resection limited to the intraorbital portion of the nerve), developed 3 years later symptoms and signs of chiasmatic invasion. Nine years after surgery (1980), she suffered from pneumococcal meningitis, due to cerebrospinal rhinorrhea that had been present in the last few years. A repeated neuroradiological investigation showed the site of the fistula and cerebral ventricles of normal size. The case is argued for bulb-to-chiasm resection of an optic nerve glioma: a spontaneous cerebrospinal rhinorrhea with its potential dangers of meningitis seems to be one more complication of a limited resection of these tumors. It is felt that this is an unusual instance of spontaneous rhinorrhea from direct tumoral erosion. The diagnostic value of metrizamide cisternography for the assessment of presence and site of the fistulous leak is confirmed.

Diagnosis of cerebral venous angioma by rapidly enhanced CT scan.

A case is presented of cerebral venous angioma demonstrated by cerebral angiography and by CT scans in the axial and coronal projections after contrast enhancement with high, rapidly administered doses of contrast medium. The respective advantages of the two examinations in the diagnosis of cerebral vascular hamartomas with a slow blood flow are discussed.

Rheumatoid nodules and cyclosporin A treatment.

The authors describe the appearance of rheumatoid nodules during cyclosporin A (CsA) therapy for RA. Their course was evaluated by sonography that revealed an increase in number and size of rheumatoid nodules. The relationship between CsA treatment and the onset of nodulosis is not clear and further studies are needed to assess the role of CsA treatment in the extra-articular manifestations of rheumatoid arthritis such as rheumatoid nodules.

Adrenocortical oncocytoma: case report and review of the literature.

Only 9 oncocytic neoplasms of true adrenal origin have been described to date. It therefore seemed of interest to study the histochemical and ultrastructural features of a non-functioning monolateral adrenocortical oncocytoma which was incidentally detected by ultrasonography and magnetic resonance imaging in a 28-year-old woman. The tumor was round, well encapsulated and weighed 73 g. It consisted of islets of eosinophilic cells, and did not display any sign of necrosis. The proliferation rate (as evaluated by mitotic index and percentage of MIB-1 Ki67 positive cells) was low, and atypic mitoses were absent; some rare cells with nuclear atypias were observed and the capsule was focally invaded by oncocytes. Immunocytochemistry did not show expression of vimentin or cytokeratin. The oncocytes had an abundant cytoplasm packed with mitochondria containing plate-like cristae. Smooth endoplasmic reticulum was virtually absent, while rough endoplasmic reticulum cisternae and free ribosomes were abundant. Although the classic histological approach clearly indicates the benign nature of the tumor, the immunocytochemical and ultrastructural features of oncocytes may suggest their potential for malignant behavior.

[Diagnostic problems in hydantoin immunopathy. Review of the literature and description of 3 cases]. / Problemi diagnostici dell'immunopatia idantoinica. Revisione della letteratura e descrizione di tre casi.

During phenytoin therapy, a male patient showed hypertermia, myalgias and mediastinal and abdominal lymphadenopathy. Despite the impossibility of histological diagnosis, he was treated with antiblastic polychemotherapy with little benefit. Another female patient on the same therapy showed splenomegaly with pancytopenia. The spleen and some abdominal lymph nodes were removed; they revealed a pattern of tubercular-like gigantocellular-epithelioid chronic flogosis. As in the first patient, the suspension of therapy gave a disease-free period. A third female patient on diphenylhydantoin therapy undervent some hemolytic crysis and, finally, SLE with cardiac involvement. We point out the complexity of the pathogenesis of hydantoinic immunologic syndromes, the polymorphism of the clinical patterns and the difficulty to make a correct diagnosis, mostly on presence exclusively deep involvement.

Cervical rib syndrome: a neurosurgical experience with a series of 38 cases.

A series of 38 patients with thoracic outlet syndrome caused by a cervical rib is reviewed after a postoperative follow-up period of 3 to 24 years. The outcome of the operation (anterior scalenotomy and partial to subtotal removal of the cervical rib) is not considered wholly satisfactory; three causes for this were identified: excessive duration of symptoms (mean almost 6 years), insufficient patient work-up and inadequacy of the incomplete removal of the cervical rib. In the presence of a cervical rib, other possible causes of compression of the neurovascular supply to the upper limb should always be considered.

MR imaging of transverse myelitis using Gd-DTPA.

A patient with subacute transverse myelitis (TM) had MRI studies, including scans after Gd-DTPA administration. The enhancement, with its intensity and persistence, seems to herald residual cord deficits. TM remains a clinical diagnosis of exclusion whereas MRI plays a valuable role in the assessment of the different abnormalities which may produce this syndrome and also defines accurately the location and extent of the intramedullary pathology.

[Description of two cases of retrobrachiocephalic thymus gland]. / Descrizioni di due casi di timo retrobrachiocefalico.

We report two rare cases of thymus gland found behind the left brachiocephalic vein, in young women undergoing thymectomy for myasthenia gravis. Our observations are included among the thymic anatomical variants. After a review of the literature on the subject, we discuss both the diagnostic role of new radiological techniques (CT, NRM) and the choice of surgical approach to these variants.