Association among low whole blood viscosity, haematocrit, haemoglobin and diabetic retinopathy in subjects with type 2 diabetes.

OBJECTIVES: Haemorheological variables influence endothelial function through the release of several factors. Clinical studies have described an association among blood viscosity, haematocrit, haemoglobin and macro-angiopathy. Few data are reported about the association between haemorheological variables and micro-angiopathy. The aim of the present study was to evaluate the association between these variables and retinopathy in subjects with type 2 diabetes. METHODS: 111 men, 79 postmenopausal women, and 95 healthy age- and sex-matched controls were recruited. Haematocrit and haemoglobin were measured by standard methods. Blood viscosity was calculated according to the formula (0.12× haematocrit)+(0.17× (plasma proteins-2.07)). Subjects were grouped according to the presence or absence of diabetic retinopathy, while the severity of retinopathy was classified according to the Early Treatment Diabetic Retinopathy Study scale. RESULTS: Haemoglobin, haematocrit and whole blood viscosity were significantly lower in subjects with retinopathy compared to subjects without retinopathy in both sexes. These variables significantly decreased with increasing severity of retinopathy. A multiple logistic regression analysis confirmed the independent inverse association among viscosity, haematocrit, haemoglobin and retinopathy (p<0.01). CONCLUSION: Results demonstrate the association among low viscosity, haemoglobin, haematocrit and diabetic retinopathy. The mechanisms responsible for this association can be hypothesised. Reduced haemoglobin might cause direct organ damage. Low blood viscosity, through the reduction of shear stress, might inhibit the anti-atherogenic functions of endothelial cells.

Investigational new drugs submitted to the Food and Drug Administration that are placed on clinical hold: the experience of the Office of Cellular, Tissue and Gene Therapy.

BACKGROUND: Cell and gene therapies are medical products regulated by the U.S. Food and Drug Administration (FDA) within its Center of Biologics Evaluation and Research (CBER) in the Office of Cellular, Tissue, and Gene Therapy (OCTGT). Clinical research using cell and gene therapies in the United States must be conducted under an Investigational New Drug (IND) application. After an initial, 30-day review FDA either places an IND on clinical hold or allows the IND to proceed. METHODS: We reviewed letters sent by OCTGT to IND sponsors that were placed on clinical hold. We categorized each deficiency and determined its frequency. RESULTS: We found that similar deficiencies existed across IND applications and we tabulated the most common deficiencies. DISCUSSION: We discussed the deficiencies and the resources that can help individuals avoid those deficiencies. We believe that awareness of the common deficiencies along with the applicable resources can reduce the frequency of clinical holds and allow clinical studies to proceed without delay. We also believe that this information will guide the FDA as to how to facilitate development of safe and effective cell and gene therapies.

Panitumumab a novel drug in cancer treatment.

The epidermal growth factor receptor (EGFR) is a member of the erbB family overexpressed in most of the solid tumors. In cancer cells, the overexpression of EGFR correlates with the development and the progression of tumor. Panitumumab is a fully human monoclonal antibody that blocks the extracellular domain of the EGFR and has not been associated with the formation of any antibodies directed against it. This review summarizes on the preclinical and clinical development of panitumumab in human solid tumors. As bevacizumab and cetuximab have been approved for colorectal cancer because of their improvements in progression-free survival and overall survival when associated with chemotherapy, panitumumab represents an interesting molecule which needs more phase III studies to validate its efficacy.

PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells.

The p85-associated phosphatidylinositol (PI) 3-kinase/Akt pathway mediates the oestradiol-induced S-phase entry and cyclin D1 promoter activity in MCF-7 cells. Experiments with Src, p85alpha and Akt dominant-negative forms indicate that in oestradiol-treated cells these signalling effectors target the cyclin D1 promoter. Oestradiol acutely increases PI3-kinase and Akt activities in MCF-7 cells. In NIH 3T3 cells expressing ERalpha, a dominant-negative p85 suppresses hormone stimulation of Akt. The Src inhibitor, PP1, prevents hormone stimulation of Akt and PI3-kinase activities in MCF-7 cells. In turn, stimulation of Src activity is abolished in ERalpha-expressing NIH 3T3 fibroblasts by co-transfection of the dominant-negative p85alpha and in MCF-7 cells by the PI3-kinase inhibitor, LY294002. These findings indicate a novel reciprocal cross-talk between PI3-kinase and Src. Hormone stimulation of MCF-7 cells rapidly triggers association of ERalpha with Src and p85. In vitro these proteins are assembled in a ternary complex with a stronger association than that of the binary complexes composed by the same partners. The ternary complex probably favours hormone activation of Src- and PI3-kinase-dependent pathways, which converge on cell cycle progression.

[State of the art and therapeutic prospects in neuroectodermal tumours and other neuroendocrine pathologies]. / Attualità e prospettive terapeutiche nei tumori neuroectodermici e nelle altre patologie neuroendocrine.

The clinical and biological characteristics of neuroectodermal tumours (NETs) are such that their treatment is necessarily multidisciplinary. Surgery is the first therapeutic choice given that it is the only potentially curative treatment for this type of neoplasm. Medical treatment is mainly indicated in the treatment of metastatic disease and must be separated into three basic options: chemotherapy, immunotheraphy and hormone treatment. Owing to the low proliferative index generally found in NETs, chemotherapy is not very effective as a means of controlling tumour growth. Data in the literature on interferon suggest that it plays a limited role in the treatment of NETs, as do the preliminary results from studies on the association of interferon + chemotherapy. The introduction of somatostatin analogs in clinical practice represents an effective tool in the therapeutic strategy for NETs and has opened new possibilities for the management of other neoplasms. One particularly interesting aspect of the octreotide-mediated antitumour action concerns the blocking of tumour neo-angiogenesis. The majority of non-endocrine tumours also express specific somatostatin receptors and in theory it is possible to hypothesise an antiproliferative action also in tumours without these receptors mediated by the indirect antiproliferative effects of somatostatin.

Long-term outcomes of an abstinence-based, small-group pregnancy prevention program in New York City schools.

CONTEXT: Despite drops in U.S. teenage birthrates, questions continue to arise about how best to reduce the country's adolescent birthrate. School-based programs continue to be considered one of the best ways to reach adolescents at risk of early sexual activity. METHODS: A total of 312 students completed a pretest, a posttest and a follow-up one year after the posttest: 125 who had participated in a 3-4-month-long abstinence-based small-group intervention led by trained social workers, and 187 in a comparison group that received no special services. RESULTS: There were few significant differences between the intervention and comparison groups at posttest. At the one-year follow-up, however, intervention students had significantly better scores on locus of control, their relationship with their parents and (among males only) their attitudes about the appropriateness of teenage sex. Measures of depression, self-esteem, intentions to have sex, attitudes toward teenage pregnancy and various behaviors did not differ significantly between groups. By the time of the one-year follow-up, there was no difference between study groups among females in the initiation of sexual intercourse. Among the males, initiation of sexual intercourse appeared to be higher in the intervention group than in the comparison group, but the difference was not statistically significant. Positive outcomes were especially limited among students who were already sexually active at the start of the study, a finding that emphasizes the difficulties of reaching adolescents who are already at high risk for pregnancy CONCLUSIONS: A small-group abstinence-based intervention focusing on mental health can have some impact on adolescents' attitudes and relationships (particularly with their parents). Long-term evaluations are important for determining the effects of an intervention, as it is difficult to change adolescent risk behavior.

A phase I study of paclitaxel and epirubicin, without and with filgrastim, for the treatment of platinum-resistant advanced ovarian cancer.

The aim of the study was to determine the maximum tolerated dose (MTD) of epirubicin combined with a fixed dose of paclitaxel, without and with support of filgrastim, in patients with platinum resistant or refractory ovarian cancer. Paclitaxel (150 mg/m2) and epirubicin (starting dose 90 mg/m2, 15 mg/m2 escalation per level) were given on day 1, every 28 days for 4-6 cycles. Filgrastim (F) (5 microg/kg/die) was given in case of grade 4 leukopenia (levels without support) or from day 4 up to leukocyte count >10,000/mm3 after nadir (levels with support). Cohorts of 3 patients were enrolled at each level and further 3 patients were planned if 1 or 2 unacceptable toxic events (UTE) were registered. MTD was determined first without and then with filgrastim. Four levels were studied (90, 90+F, 105+F, 120+F) with 4, 6, 5 and 4 patients enrolled, respectively. UTE (grade 4 neutropenia) were observed in 3 patients at level 1. Thus, 90 mg/m2 was the MTD for epirubicin without filgrastim. MTD of epirubicin with filgrastim was not reached at 120 mg/m2. Hematological toxicity was mild. Grade 3 mucositis was reported in 1 patient. Among the 14 patients with measurable or evaluable disease, 3 objective responses were observed (1 complete and 2 partial) for an overall response rate of 21.4%. The combination of paclitaxel 150 mg/m2 and epirubicin at 120 mg/m2 with filgrastim is a feasible therapy. Grade 4 leukopenia is the dose limiting toxicity using epirubicin at 90 mg/m2 without filgrastim.

Phase II study of cisplatin and vinorelbine as first-line chemotherapy in patients with carcinoma of the uterine cervix.

PURPOSE: To evaluate the activity and toxicity of the combination of cisplatin (80 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1 and 8) in patients with carcinoma of the uterine cervix that has not been previously treated with chemotherapy. PATIENTS AND METHODS: Fifty patients with cervical cancer were enrolled onto this study (27 stage IB-III, 23 stage IVB-recurrent). A two-stage optimal Simon design was applied. Thirteen responders of 29 treated patients were required to proceed beyond the first stage, and 28 responders were needed overall. RESULTS: Hematologic toxicity was mild, with neutropenia being the most frequent side effect. Nonhematologic toxicity was frequent but never severe; one patient had grade 3 peripheral neurotoxicity. Objective responses were recorded for 32 patients (64%): 11 patients (22%) achieved a complete response (CR) and 21 patients (42%) achieved a partial response (PR). The response rate was 81.5% in patients with IB-III stage (25.9% CR rate) and 43.5% in patients with IVB-recurrent disease (17.4% CR rate). Responses were seen both in stage IVB patients (one CR and two PRs, for an overall rate of 37.5%) and in patients with recurrent disease (three CRs + four PRs, for an overall rate of 46.7%). CONCLUSION: The combination of cisplatin and vinorelbine is an active regimen in the treatment of patients with early-stage and advanced carcinoma of the uterine cervix. The hematologic and nonhematologic toxicity of this combination is mild.

[Renal agenesis associated with homolateral ovarian dysplasia. A case report]. / Agenesia renale associata a displasia ovarica omolaterale. Descrizione di un caso.

The Authors describe a case of renal agenesis with ipsilateral ovarian dysplasia. The clinical features are abdominal mass and pain and then the treatment is laparoscopic ablation.

Medical knowledge systems: applications to telemedicine.

The application and form of electronically stored medical knowledge has a direct impact on the design of any healthcare delivery system. For those who plan for remote medical care or who work at the disaster relief level, there are specific requirements which will dictate the type of knowledge required and the vehicle best suited to deliver that information. The PC based multimedia biomedical library developed for NASA was originally intended for long-term space missions where complete isolation from each support was a distinct possibility. The library is a combination of traditional references and secondary databases structured within a primary care physician's workstation. The integration of the library and a point-of-care system allows optimal use of both resources and provides a basic building block for telemedicine networking.

Expression of potassium channels in epithelial cells depends on calcium-activated cell-cell contacts.

Harvesting MDCK cells with trypsin-EDTA reduces potassium currents (IK) to a mere 10%, presumably by hydrolysis of K+ channels, but replating at confluence restores them in 12-18 hr, through a process that requires transcription, translation and exocytic fusion of intracellular membrane vesicles to the plasma membrane (Ponce & Cereijido, 1991; Ponce et al., 1991a). In the present work we find that this restoration of IK also requires cell-cell contacts and the presence of 1.8 mM Ca2+. The role of extracellular Ca2+ may be substituted by 2.0 microM TRH, 10 nM PMA or 200 micrograms/ml DiC8. drugs that stimulate the system of phospholipase C (PLC) and protein kinase C (PKC). Conversely, the recovery of IK triggered by Ca-dependent contacts can be blocked by 110 microM neomycin, 2.0 microM H7, and 250 nM staurosporine, inhibitors of PLC and PKC. These results suggest that the expression of new K+ channels depends on Ca(2+)-activated contacts with neighboring cells and that the information is conveyed through PLC and PKC, a process in keeping with changes in its enzymatic activity and cellular distribution of PKC. Plasma membrane is also reduced and restored upon harvesting and replating, and depends on Ca(2+)-activated contracts. However, the effects of the chemicals tested on IK differ from the ones they elicit on the recovery of plasma membrane, suggesting that cells can independently regulate their population of K+ channels and the surface of their membrane.

Ensayo terapéutico con gangliosidos en la cardioneuropatía chagasica en dos poblaciones sudamericas (Venezuela y Arganetina) / Therapeutic essay with gangliosides in the chagasic cardioneurophathy in two sudamerican population (Venezuela and Argentina)

Hasta el presente no se ha encontrado un tratamiento farmacológico efetivo de la cardioneuropatía chagásica, una de las causas más frecuentes de Insuficiencia Cardíaca Congestiva y de Muerte Súbita en el mundo. Se realizó un estudio en una población de 128 adultos con serología positiva para la Enfermedad de Chagas y pruebas anormales del Sistema Nervioso Autónomo. El estudio tuvo las características de: doble ciego paralelo y placebo-controlado y se ajustó a las normas, de la FDA; requeridas para la investigación en la aplicación de una nueva droga. Se utilizó Cronassial (Mezcla de Gangliósidos) en inyecciones intramuscular por 4 a 8 semanas. Se tomaron todas las normas de seguridad durante el tratamiento y 31 casos fueron excluídos por presentar Insuficiencia Cardíaca Congestiva. En los 97 pacientes restantes se determinó: la respuesta postural, mediante los cambios de la frecuencia cardíaca, presión arterial sistólica y del doble producto como respuesta al adoptar la posición erecta; del mismo modo, los cambios en la frecuencia cardíaca inducidos por el reflejo de la tos y de la hiperventilación. El Cronassial se mostró seguro y mediante el analisis estadístico ANOVA demostró que hubo mejoría significativa de la presión sistólica (P<0.14) y del doble producto (P<0.059) al estrés postural y de la respuesta de la frecuencia cardíaca a la Hiperventilación (0.017) comparado con el placebo

Earthbound applications for NASA's physician workstation.

The dream of a space probe to Mars or an astronaut colony on the moon persists. Despite years of setbacks and delays, NASA continues to lay the foundation for a new frontier in space. The necessity of a self contained health maintenance facility is an integral part of this stellar venture. As a subsystem of this health maintenance facility, the physician or astronaut workstation was envisioned as the vehicle of interface between the computer resources of the space station and the care provider. Our efforts to define and build this interface have resulted in a series of programs which can now be tested and refined using earth-based applications. The modules which have dual-use application from the NASA workstation include: patient scheduling and master patient index, pharmacy, laboratory, medical library, problem list/progress notes, and digital medical records. Our current plan is to develop these tools as objects that can be assembled in a variety of configurations. This will allow the technology to be used by the private sector where each doctor can select the starting point of his outpatient office system and add modules as he makes progress in system integration and training.

A physician's workstation designed for NASA and earth-based applications.

One of the prime missions for NASA is the safety and care of astronauts. In addressing this challenge, a tool has been developed which has great potential for earth-based applications. The multimedia physician's workstation is the result of 13 years of planning and technical revolution in the field of computer science. Today, we have the hardware and the software to make a major change in the office-based practice of physicians. By offering the online features of a medical library as well as a complete multimedia medical record system, we are now in a position to introduce advance decision support technology that can be used on a daily basis for routine outpatient care. The system supports a new platform for patient education and offers the doctor an opportunity to share his expertise with his patient and their family. Although NASA will need several more years before this technology can be applied to a remote space environment, we plan to introduce this system into the doctor's office as an initial test of its feasibility. The basic design and general specifications of this multimedia workstation/office system are described and illustrated as they currently exist.

Efficacy of hepatic computed tomography to detect iron overload in chronic hemodialysis.

The diagnostic efficacy of hepatic computed tomography density (HCTD) in comparison with serum ferritin for the detection of iron overload was investigated in uremic patients on maintenance hemodialysis (HD) and in patients with idiopathic hemochromatosis (IHC). Ten IHC patients, 38 HD patients and 40 healthy subjects underwent the CT scanning of the liver and determination of percent saturation of transferrin, serum ferritin concentration and HLA typing. Liver iron content was determined by histochemical grading and direct measurement of liver iron concentration either in IHC patients or in HD patients. Nineteen HD patients were considered to have iron overload on the basis of liver iron concentration exceeding 3.6 mumol/100 mg dry weight. The mean +/- SD values of HCTD in healthy subjects, IHC patients, HD patients with iron overload and without iron overload were 60.2 +/- 5.6, 79 +/- 5.6, 71.4 +/- 3.6, 58 +/- 3.8 Hounsfield units, respectively. HCTD showed positive correlations with liver iron concentration and serum ferritin either in IHC patients or in HD patients. The analysis of the diagnostic efficacy of HCTD in comparison with serum ferritin for the detection of excessive hepatic iron in HD patients demonstrated that HCTD had higher sensitivity, specificity, positive and negative predictive values. Cut-off points were arbitrarily fixed to 66 Hounsfield units for HCTD, 400 micrograms/liter for serum ferritin and 3.6 mumol/100 mg dry weight for liver iron concentration. Seventeen HD patients who possessed the histocompatibility antigens associated with IHC, namely HLA-A3 and/or HLA-B7 and/or HLA-B14, had liver iron concentration, serum ferritin and HCTD values higher than those of the HD patients without these "hemochromatosis alleles".(ABSTRACT TRUNCATED AT 250 WORDS)

Cervical schwannoma with intranuclear vacuoles by fine-needle sampling without aspiration.

In a 49-yr-old woman who presented with a cervical mass, a fine-needle specimen without aspiration was suggestive of paraganglioma; there were spindle-shaped cells with pseudoacinar structures and prominent intranuclear vacuoles. Subsequent examination of a mass removed from the vagus nerve clearly identified a schwannoma. The differential diagnosis is discussed, particularly in relation to the presence of intranuclear vacuoles, and it is concluded that this cytological characteristic should not in itself define the diagnosis.