bluuebunny/crossref_metadata_2025 huggingface dataset:
The Ethics of Postmarketing Observational Studies of Drug Safety Under Section 505(o)(3) of the Food, Drug, and Cosmetic Act
Authors: Evans Barbara J.
Published: January 2017

In 2007, Congress granted the Food and Drug Administration (FDA) new powers to order pharmaceutical companies to conduct drug safety studies and clinical trials in the postmarketing period after drugs are approved. The methodologies include observational studies that examine patients' insurance claims data and clinical records to infer whether drugs are safe in actual clinical practice. Such studies offer a valuable tool for improving drug safety, but they raise ethical and privacy concerns because they would entail widespread use of patients' health information in commercial research by drug manufacturers. This is the first article to explore the ethics of these section 505(o)(3) observational studies, so named after the section of the Food, Drug, and Cosmetic Act that authorizes them.

Data access problems threaten to make the FDA's section 505(o)(3) study requirements unenforceable. Under existing federal privacy regulations, it appears highly unlikely that pharmaceutical companies will have reliable access to crucial data resources, such as insurance claims data and healthcare records, to use in these studies. State privacy laws present another potential barrier to data access. If pharmaceutical companies do manage to gain access to the needed data, this will raise serious privacy concerns because section 505(o)(3) observational studies do not appear to be covered by any of the major federal regulations that afford ethical and privacy protections to persons whose data are used in research.

If the FDA's program of section 505(o)(3) observational studies fails because of the above problems, this failure will have a number of bad consequences: the public will be exposed to avoidable drug safety risks; taxpayers may be forced to bear the costs of having the FDA conduct drug safety investigations that would have been funded by drug manufacturers if data had been available; and, perhaps most troubling, the FDA may be forced to order postmarketing clinical trials to answer questions that could have been answered using observational studies. Problems with access to data for section 505(o)(3) studies thus could directly imperil human research subjects by forcing a needless over-reliance on risky postmarketing drug safety trials.

This Article concludes by describing a promising new legal pathway for resolving these problems. Congress has provided the FDA a new set of powers that if skillfully exercised will allow the agency: (1) to facilitate pharmaceutical companies' appropriate access to data for use in section 505(o)(3) observational studies, (2) to impose strict ethical and privacy protections for persons whose data are used in these studies, and (3) to mobilize private-sector funding to generate much-needed evidence of the safety of FDA-approved drugs.
Paying for Prevention: Challenges to Health Insurance Coverage for Biomedical HIV Prevention in the United States
Authors: Underhill Kristen
Published: January 2017

Reducing the incidence of HIV infection continues to be a crucial public health priority in the United States, especially among populations at elevated risk such as men who have sex with men, transgender women, people who inject drugs, and racial and ethnic minority communities. Although most HIV prevention efforts to date have focused on changing risky behaviors, the past decade yielded efficacious new biomedical technologies designed to prevent infection, such as the prophylactic use of antiretroviral drugs and the first indications of an efficacious vaccine. Access to prevention technologies will be a significant part of the next decade's response to HIV, and advocates are mobilizing to achieve more widespread use of these interventions. These breakthroughs, however, arrive at a time of escalating healthcare costs; health insurance coverage therefore raises pressing new questions about priority-setting and the allocation of responsibility for public health. The goals of this Article are to identify legal challenges and potential solutions for expanding access to biomedical HIV prevention through health insurance coverage. This Article discusses the public policy implications of HIV prevention coverage decisions, assesses possible legal grounds on which insurers may initially deny coverage for these technologies, and evaluates the extent to which these denials may survive external and judicial review. Because several of these legal grounds may be persuasive, particularly denials on the basis of medical necessity, this Article also explores alternative strategies for financing biomedical HIV prevention efforts.
“Well Beyond” Permissible: How Severing the Leadership Act's Policy Requirement Affirms Our Commitment to First Amendment Values
Authors: Ullian David M.
Published: January 2017

Imagine an American physician working with Pathfinder International's Mukta Project to combat the prevalence and spread of Sexually Transmitted Infections (STIs) and HIV in Maharashtra, India. The physician provides HIV/AIDS prevention and treatment services at a health clinic as well as coordinates educational programs about STIs for local residents. A young woman approaches the physician's clinic. The woman tentatively informs the physician that she has recently entered the local sex trade and may have contracted HIV. The physician wishes she could speak freely about the realities of prostitution in India. The physician wishes she could empower her new patient to adopt behaviors that would reduce her vulnerability to HIV/AIDS. In spite of any professional or personal opinions the physician might hold on the subject of prostitution, however, she must choose her words carefully. In order to receive program funding from the United States government, Pathfinder International has reluctantly endorsed a strict anti-prostitution policy, and the physician is prohibited from engaging in any activities that are inconsistent with that policy.
Surgical Relief of Obstructive Jaundice in a District General Hospital
Authors: Al-Fallouji M A R , Collins R E C
Published: January 2017

Fifty consecutive patients with obstructive jaundice treated by operation in Canterbury & Thanet Health District hospitals under the care of one surgeon (RECC) over a 6-year period have been studied. The pathology was found to be common bile duct (CBD) stone in 22 patients (44%); pancreatic carcinoma in 15 (30%), 3 of whom also had CBD stones; chronic pancreatitis in 4 (8%); extrahepatic CBD carcinoma in 4 (8%); ampulla of Vater carcinoma in 3 (6%); primary duodenal carcinoma in 1 (2%); and portahepatis obstruction in 4 (8%). The 8 postoperative deaths (16%) were found to be associated with high preoperative levels of serum bilirubin, but all occurred in patients with malignant disease. Complications occurred in 20 patients (40%) and bile culture state was found to be intimately related to the morbidity rather than operative mortality. The study represents a careful audit of the pathology distribution and the surgical management of obstructive jaundice as seen in district hospitals.
Low-Dose Guar Improves Diabetic Control
Authors: Jones D B , Lousley S , Jelfs R , Slaughter P , Carter R D , Mann J I
Published: January 2017

Twenty diabetic outpatients (12 non-insulin-treated and 8 insulin-treated) were given guar granulate in a dose of 10 g daily for two months in order to study the effect on glycaemic control and lipid levels. Mean glycosylated haemoglobin levels (HbAlc%) fell from 11.1±2.0% pre-guar to 10.5 ± 2.2% (P< 0.001) after one month on guar and to 10.1±2.3% ( P<0.0001) after two months. Following discontinuation of guar, HbAlc% rose to 11.1±2.5% ( P<0.002). However, there were no significant changes in fasting blood glucose, 1 h postprandial blood glucose following a test meal, 24 h urinary glucose excretion or in lipid levels.

Gastrointestinal side effects occurred in 4 patients during treatment with guar. Four patients reduced their dose of insulin and 2 patients reduced their dose of sulphonylurea therapy during this time because of symptoms suggestive of hypoglycaemia. We suggest that the low dose of guar used in this study may help improve glycaemic control in diabetic patients and that this may be achieved with a low incidence of gastrointestinal side effects.
Multivariate Analysis of Glycosylated Haemoglobin in Insulin-Treated Diabetics
Authors: Child D F , Wood Jane , Hudson P R , Williams C P , Roberts D R , Smith C
Published: January 2017

Glycosylated haemoglobin (HbAl), as an assessment of overall control, was estimated in 858 insulin-treated diabetics attending for changeover to U100 insulin in North East Wales. Details of age, sex, duration of diabetes, insulin regimen and monitoring method were recorded. Multivariate analysis revealed lower HbAl in patients receiving twice-daily (mean 11.01) as compared with once-daily insulin (11.42, P=0.011), but no difference was found between urine and blood glucose testers when other variables were taken into consideration. HbAl was lower in men (mean 10.94) compared with women (mean 11.39, P=0.004) and there was a positive correlation of HbAl in men with age (P= 0.046) and in women with duration of disease (P=0.005).
Venous Ulceration: The Role of the White Blood Cell
Authors: Scott H.J. , McMullin G.M. , Smith P.D. Coleridge , Scurr J.H.
Published: January 2017

White blood cells (WBC) become trapped in the legs of patients with chronic venous insufficiency (CVI), in response to raised venous pressure. We have sampled blood from the foot and arm veins in normal patients and those with CVI. When the venous pressure in the arm was raised to 80 mmHg we demonstrated white cell trapping in both the hand and forearm, but we were unable to demonstrate WBC trapping in the foot, as opposed to the leg, in response to changes in posture. Capillary microscopy of the supra-malleolar skin of the ankle confirmed that a reduction of the number of funtional capillaries occured in response to an increase in venous pressure.
Recurrent Varicose Veins
Authors: Juhan Claude , Haupert Serge , Miltgen Gilles , Barthelemy Pierre , Eklof Bo
Published: January 2017

We report our experience of 93 patients with recurrent varicose veins.

Doppler ultrasound and ascending phlebology were routinely performed, with descending or popliteal phlebography in some patients, as a means of evaluating recurrence. Early recurrence was found in a few cases due to incorrect diagnosis. Late recurrence, in the majority of cases, was due to incorrect surgery or the overlooking of gastrocnemius vein incompetence. In some cases deep reflux, soleal arch compression or left iliac vein compression was found to be a possible cause of recurrence.

Extensive evaluation of the venous disorder and the ligation of every site of deep to superficial reflux are the first steps in preventing recurrence. The rules and pitfalls of surgical treatment are stressed. On recurrence, Doppler ultrasound is accurate in deep venous assessment and in demonstrating leaking perforators. Ascending phlebography is the method of choice in the investigation of the deep veins and in confirming perforating vein incompetence. We have used popliteal phlebography to demonstrate incompetence of the LSV junction, SSV junction, gastrocnemius vein and mid-thigh and popliteal fossa perforators. When necessary, surgery for recurrent varicose veins must be carefully carried out according to certain basic principles.
Is the ‘Normal’ Limb Normal in Unilateral Varicose Veins?
Authors: Sarin S. , Shields D. A. , Abu-Own A. , Scurr J. H. , Smith P. D. Coleridge
Published: January 2017

Objective:

To define venous function in the clinically normal limb of patients with unilateral primary varicose veins.

Design:

Prospective study using duplex scanning and photoplethysmography (PPG) as objective criteria of venous function.

Setting:

The Middlesex Hospital Vascular Laboratory, a teaching hospital centre of referral for the investigation of venous disease.

Patients:

Thirty patients with clinical unilateral primary varicose veins.

Results:

All clinically abnormal limbs had abnormalities on investigation. However, four of 30 patients (13%) also had abnormal duplex findings on the contralateral clinically normal limb, and six (20%) had abnormal PPG refilling times. A total of 26% clinically normal limbs could be demonstrated to have some abnormality of venous function using these two tests.

Conclusions:

We have shown that the contralateral, clinically normal limb cannot be assumed to be normal without full formal venous assessment.
Non-Invasive Methods of Measuring Venous Compliance
Authors: Davies A. H. , Magee T. R. , Hayward J. , Harris R. , Baird R. N. , Horrocks M.
Published: January 2017

Objective:

To compare two non-invasive methods of qualitative assessment of the long saphenous vein in terms of venous compliance.

Design:

Thirty-five long saphenous veins were examined. Compliance measurements have been calculated using: Method A in which an AV Impulse machine (Novamedix, UK) is used to generate a pulse wave in the long saphenous vein and the measurement of transit times are performed. Method B involves duplex ultrasound and venous occlusion of the long saphenous vein. Occlusive pressure measurements are used in both methods.

Results:

The mean vein compliance ratio measured in 35 long saphenous veins with the different methods was 0.23 (0.18–0.28) and 0.26 (0.22–0.30) using method A and B respectively. (Mean and (95% confidence interval)). The results show that a good correlation r = 0.91 and this was confirmed using methods of agreement.

Conclusion:

Both techniques give comparable results, however, the method involving Duplex is easier to perform. The research and clinical implications of these techniques remain to be assessed.
The Effects of Varicose Vein Surgery on the Venous Function of the Lower Limb
Authors: Moor P. S. , Travers J. P. , Makin G. S.
Published: January 2017

Objectives:

To assess the effect of varicose vein surgery on the venous function of the lower limb and to determine the ability of strain-gauge and photoplethysmography in discriminating between normal and abnormal venous function.

Design:

Prospective randomized trial with follow-up to 1 month postoperatively.

Study group:

Fifteen patients presenting for varicose vein surgery and 10 controls with no evidence of venous insufficiency.

Interventions:

Venous investigations were carried out preoperatively and at 1 month postoperative appointments.

Main outcome measures:

The effect of varicose vein surgery on lower limb venous function and the ability of plethysmography to distinguish normal from abnormal venous function.

Results:

Significant differences were found between pre- and postoperative venous refilling times (VRT) in patients attending for varicose vein surgery ( p><0.01). Significant differences were also found between control and case preoperative VRTs. No significant differences were found between pre- and postoperative, and case/control venous outflow (VO) and venous capacitance (VC) values.

Conclusion:

Varicose vein surgery improved the venous function in all of the lower limbs investigated. Photoplethysmographic venous refilling times were found to be a useful, reproducible measure, able to distinguish normal from abnormal venous function.
Duplex Ultrasound Scanning for Chronic Venous Disease: Recurrent Varicose Veins in the Thigh after Surgery to the Long Saphenous Vein
Authors: Myers K. A. , Zeng G. H. , Ziegenbein R. W. , Matthews P. G.
Published: January 2017

Objective:

To use duplex ultrasound scanning to compare limbs with recurrent and primary varicose veins and to identify connections between deep veins and recurrences.

Setting:

A non-invasive vascular laboratory in Melbourne, Australia.

Patients:

A study of 779 limbs with recurrent varicose veins previously treated by ligation or stripping of the long saphenous vein and 1521 limbs with primary varicose veins.

Main outcome measures:

Connections between deep veins and recurrent varices, reflux in superficial and deep veins, and outward flow in perforators as demonstrated by duplex ultrasonography.

Results:

Recurrence was due to reflux in the long saphenous territory in 71.8%, short saphenous reflux alone in 14.7% or outward flow in calf perforators without saphenous reflux in 5.2%, while no source was detected in 8.3%. Limbs with recurrent veins in the long saphenous territory were compared with limbs with primary varicose veins; there was more frequent outward flow in thigh perforators (25.2% vs. 16.2%) but no difference for deep reflux (20.7% vs. 17.5%) or outward flow in calf perforators (56.8% vs. 53.1%). The source for recurrence in the long saphenous territory was from a single large connection in the groin in 46.3%, multiple smaller proximal connections in a further 46.3%, or thigh perforators in 7.4%. The destination was to an intact long saphenous vein in 33.7%, major tributaries in 28.7% or to other varices in 37.6%. Limbs known to have been treated by long saphenous ligation alone were compared with those known to be treated by long saphenous ligation and stripping; the source was more likely to be from a single large vein in the groin (60.3% vs. 39.9%) and the destination was more likely to be an intact long saphenous vein or major tributary (75.0% vs. 55.2%).

Conclusions:

Duplex ultrasound scanning detected the source of recurrent varicose veins in over 90% of patients and demonstrated whether there were single large or multiple smaller connections in the veins affected, and this helps to select the most appropriate treatment. Recurrence after stripping the long saphenous vein was more likely to be due to multiple small connections passing to scattered varices and this may allow more simple treatment by injection sclerotherapy rather than repeat surgery.
Ultrastructure of Evolving Deep Venous Collaterals
Authors: Fredericks R. K. , Raju S. , Klein M.
Published: January 2017

Objective:

To explore the structure of obstructive venous collaterals.

Design:

A total of 25 rats underwent unilateral ligation of the distal common femoral vein. Bilateral (control and test) vein segments with collaterals were harvested and studied with conventional light microscopy and electron microscopy at 2-week intervals for 10 weeks post-ligation.

Results:

Obstructive collaterals were quite unlike normal controls throughout the study. Initially, post-obstructive collateral walls showed disorganization of collagen, elastin, smooth muscle cells, and adventitia, while endothelial cells became more rounded and compact. The dense protein subendothelial deposits noted early became organized and moved more deeply into the wall at subsequent study intervals. Minimal motivation of smooth muscle cells, coalescence of elastic lamina, condensation of collagen and some organization of the wall were noted.

Conclusion:

Inability of deep collaterals to function with normal wall properties is likely to be secondary to the disruption of connective tissue and sustained disorganization of the vein wall noted throughout the evolution of collateral formation.
Duplex Ultrasound Assessment of Neovascularization after Saphenofemoral or Sapheno-Popliteal Junction Ligation
Authors: De Maeseneer M. G. , Ongena K. P. , Van den Brande F. , Van Schil P. E. , De Hert S. G. , Eyskens E. J.
Published: January 2017

Objective:

Evaluation of neovascularization at the saphenous ligation site as a cause of recurrent varicose veins.

Design:

Prospective duplex study of a single patient group.

Setting:

Vascular clinic of a University Hospital.

Patients:

131 patients (177 limbs) were evaluated 2 and 12 months after varicose vein surgery.

Intervention:

Clinical assessment and colour duplex scanning of operated limbs.

Main outcome measures:

Limbs were classified according to the degree of neovascularization: grade 0 = no new communicating vein, grade 1 = new communicating vein with diameter <4 mm, and grade 2 = new communicating vein with diameter >4 mm and pathological reflux.

Results:

Two months postoperatively, grade 0 was observed in 173 limbs (98%) and grade 1 in four limbs (2%). Twelve months postoperatively, 152 limbs (86%) scored grade 0, 16 limbs (9%) grade 1 and nine limbs (5%) grade 2.

Conclusions:

After correctly performed previous surgery, neovascularization of varying degree may occur within 1 year, as can be demonstrated on postoperative duplex examination.
Studies on Ponstan (Mefenamic Acid): I. Gastro-Intestinal Blood Loss; II. Absorbtion and Excretion of a New Formulation
Authors: Tali A R , Mistilis S P
Published: January 2017

Using improved techniques in a study of faecal blood loss no significant change over control level occurred during administration of mefenamic acid 500 mg t.i.d. for six days. This lack of gastro-intestinal bleeding is at variance with earlier findings for this compound.

Studies of two mefenamic acid formulations (250 mg capsule and 500 mg filmseal tablet) showed no significant difference in area under blood level curves or in urinary output data, indicating equivalent total absorption. The 500 mg film-coated tablet gave significantly higher serum levels at 0·5 hours, whereas the 250 mg capsule gave significantly higher serum levels at 6 and 8 hours.
Kinetics of Analgesic Response in Man; an Example with Two Non-Steroidal Anti-Inflammatory Analgesic Drugs
Authors: Sacchetti G , Ferrati G C , Parrinello L , Salami A
Published: January 2017

A double-blind, controlled clinical trial is described in which a total of forty hospital in-patients suffering from severe post-operative pain were randomly allocated to treatment with one of two non-steroidal anti-inflammatory drugs, namely, either indoprofen which has a short half-life (two hours) or naproxen which has a long half-life (thirteen hours). The drugs were administered orally on a single-dose-only basis. The doses used in this way were 300 mg of indoprofen or 250 mg of naproxen.

Patients scored the severity of their pain on a five-point scale and these scores were recorded prior to and at fixed time intervals up to eight hours following administration of medication.

No significant differences emerged between the two test drugs and the duration of the response was also found to be similar for the two compounds despite their very different plasma half-life values.
Pipothiazine Palmitate in the Long-Term Treatment of Schizophrenia
Authors: Aref Mohamed A , El-Guindy Trandil A
Published: January 2017

Fifty patients suffering from active schizophrenic episodes were treated with electroplexy and thioproperazine for 3 weeks. Pipothiazine palmitate was then given parenterally at a dose of 100 mg at 4-week intervals over a period of 3 years. It seemed to be effective in maintaining remissions in forty-eight patients.
Post-Marketing Surveillance of the Transiderm-Nitro Patch in General Practice
Authors: Bridgman K M , Carr M , Tattersall A B
Published: January 2017

Post-Marketing Surveillance (PMS) of Transiderm-Nitro, a new transdermal form of nitroglycerin, was undertaken during the 6 months following its introduction to general practitioners in the United Kingdom. Two thousand four hundred and seventy-five record forms were received. Excluding the fourteen patients who died during the surveillance, treatment in the remaining 2461 was judged as effective in 80·6% of patients and was well tolerated, with 70·5% having no unwanted effects. The incidences of withdrawal from Transiderm-Nitro in all patients analyzed were 5·7% due to headaches, 3·6% due to other unwanted effects and only 3·1% due to the treatment being judged as ineffective. This PMS confirms that Transiderm-Nitro is an effective, well tolerated addition to the therapy of angina pectoris.
Clinical Experience with Two Twice Daily Slow Release Theophylline Preparations. Relation between Serum Theophylline Concentrations, Effectiveness, Tolerability and Compliance in Elderly Patients
Authors: Ruggeri S. , Bernocchi D. , Berte' F. , D'Anneo R. , Gramolini C.
Published: January 2017

The relation between serum theophylline concentrations, effectiveness, tolerability and compliance were evaluated in 14 hospitalized elderly patients with broncho-obstructive pathology, using a new twice daily sustained release theophylline suspension compared to standard twice daily slow release tablets. The results showed that the mean theophylline serum concentration remains within the therapeutic range with both preparations. No significant difference exists between the two treatments with regard to effectiveness. Tolerability and compliance of the theophylline suspension, however, were higher.
A Review of Combined Hyperlipidaemia and Its Treatment with Fenofibrate
Authors: Superko H. R.
Published: January 2017

Approximately 15% of myocardial infarction survivors <60 years of age have a plasma lipid abnormality defined as combined hyperlipidaemia. Patients with this condition are at substantial risk for future cardiovascular events. Combined hyperlipidaemia involves elevations in both plasma triglycerides and low-density lipoprotein (LDL) cholesterol and may share similarities with hyperapolipoproteinaemia, LDL-pattern B and the small LDL-pattern. Treatment is directed at reduction of LDL-cholesterol and plasma triglyceride values. Nicotinic acid and the fibric acid derivatives are useful therapeutic agents. Fenofibrate is a fibric acid derivative that lowers both triglycerides and LDL-cholesterol in combined hyperlipidaemia. In combined hyperlipidaemia, fenofibrate has been shown to reduce significantly plasma triglycerides by approximately 40%, LDL-cholesterol by 6%, and to increase high-density lipoprotein cholesterol by 15%. Apoproteins are favourably altered with increases in apoprotein-A, decreases in apoprotein-E and inconsistent decreases in apoprotein-B. Fenofibrate is well tolerated with primarily dermatological side-effects.
Successful Treatment of Concomitant Acute Myeloblastic Leukaemia and Adenoid Cystic Carcinoma of the Palate
Authors: Handa H , Tamura J , Take H , Ikeda S , Matsushima T , Murakami H , Kubota K , Naruse T , Tsuchiya J
Published: January 2017

The case of a 55-year old man who was affected simultaneously by acute myeloblastic leukaemia (AML) and adenoid cystic carcinoma of the palate is reported. The carcinoma was removed after induction chemotherapy for AML and the patient subjected to consolidation therapy. No reports are evident of other cases in which acute leukaemia and other malignancies were treated simultaneously, and in which the patient was cured of both. It is suggested that this case may serve as a reference for future similar cases.
President Doe's Prisoner
Authors: Johnson-Sirleaf Ellen
Published: January 2017

‘In a Liberian prison, a soldier can come, order you out and shoot you…’.
The eunuchs are flying
Authors: Filipovic Zoran
Published: January 2017

Words from a song my mother sang to me as a boy, during the ‘Croatian Spring’ of 1971 that marked the beginning of the struggle of Croatian intellectuals for a free and independent Croatia
A once and future nation
Authors: Ashrawi Hanan
Published: January 2017

Hanan Mikhail Ashrawi was born in Nablus, Palestine in 1946. At one time a spokeswoman for the Palestinians in the Occupied Territories, and now a professor of English literature at Bir Zeit University in the West Bank, she has recently published a personal account of the Palestinian national struggle, This Side of Peace (Simon and Schuster, June 1995). She is the founder and director of the Palestinian Independent Commission for Citizens' Rights. Stephanie Genkin talked to her in Jerusalem for Index
False dawn
Authors: Xiaoming Chen
Published: January 2017

Those who set out to avoid politics end up in accord with official ideology
Doing harm
Authors: Petley Julian
Published: January 2017

The British Board of Film Classification finds itself squeezed by public opinion as the press on the role of censor
This dark night
Authors: Thukul Wiji
Published: January 2017

A ward-winning poet Wiji Thukul is currently in hiding and being sought by the police in connection with the Jakarta riots of 27 July 1996. Thukul, who chairs the People's Art Network (an organisation under the umbrella of the People's Democratic Party), left school at the age of 11 and took a variety of jobs, including selling newspapers, working as a carpenter, and as a pedicab driver, while composing his poetry. His books include Mencari Tanah Lapang ( Looking for Open Fields), Puisi Pelo ( A Lisper's Poetry), Darman dan Lain-Lain ( Darman and Others). This poem was written while in hiding
Puppets and masters
Authors: Parikeno Parno
Published: January 2017

Theatre cannot bring a government down — at least so theatre people and theatre-goers believe. The bureaucracy and security forces apparently think otherwise
The spirit of journalism
Authors: Yurtçu Ocak Isik
Published: January 2017

A former editor of the banned paper Özgür Gündem, Ocak Isik Yurtçu is currently serving 15 years in prison for charges under the anti-terror law. In December last year both Reporters Sans Frontières and the Committee to Protect Journalists gave Yurtçu awards in recognition of his work. CPJ commended his ‘extraordinary devotion to the principles of press freedom through extensive and balanced reporting of the Kurdish conflict’
Propaganda
Authors: Schechter Danny
Published: January 2017

Only with effort can the camera be forced to lie: basically it is an honest medium. And contemporary vision, the new life, is based on an honest approach to all problems, be they morals or art. False fronts to buildings, false standards in morals, subterfuges and mummery of all kinds, must be, will be scrapped.
Discerning ocean plastics: Activist, scientific, and artistic practices
Authors: Phillips Catherine
Published: January 2017

For almost 50 years scientists have been drawing attention to marine plastics, working to increase what we know about their incidence and impacts. However, how we come to know things is just as important as what we know. How do oceanic plastics become understood and how does this influence what we decide to do about them? Drawing upon discard studies and cultural geographies, this paper details processes of understanding and problematising marine debris by considering the practices of: an activist working with Indigenous communities to track and manage discarded fishing gear, a scientist investigating the influence of plastics in the lives of sea turtles, and Indigenous artists using oceanic debris as their material. Rather than categorising these knowledge as either lay or scientific, creating a sense of opposition, the concept of traces – material, immaterial, methodological – is employed to foreground the contingency and multiplicity involved. In this way, insight is gained about the materials, embodiments, affects and techniques involved in producing knowledge about oceanic plastics, as well as about how responses to this detritus become articulated and shared with wider publics.
Suppression of Adjuvant Arthritis in Rats with Chronic Bromocriptine Treatment Does not Prevent Associated Oxidative Stress
Authors: Jurčovičová J. , Švík K. , Rovenský J. , Stančíková M. , Zorad Š. , KonečNá I. , Holeček V. , Trefil L. , Racek J. , Rokyta R.
Published: January 2017

We studied the effect of prolactin (PRL) inhibition by bromocriptine (BRC) in the first phase of adjuvant induced arthritis (AA), up to day 11 (BRC1-AA), and in the whole time course of AA, up to day 23 (BRC-AA), on the development of the disease in male Lewis rats. On day 24, arthritic rats showed inhibition of PRL secretion, but not PRL mRNA expression in adenopituitaries. BRC treatment suppressed PRL serum levels and PRL mRNA expression in adenopituitaries. In BRC1-AA group PRL levels and PRLmRNA were at the level of rats with AA. Serum corticosterone (CORT) was stimulated by AA from 16.9±5.8 to 59.1±8.7 ngml−1, p<0.05, to the same level in BRC-control (BRC-C) and BRC-AA group and further potentiated in BRC1-AA group (148.2<33.1 ngmr−1, p<0.05 vs. group with AA). Hind paw swelling was reduced but not completely inhibited in BRC1-AA group and totally prevented in BRC-AA rats as was the core temperature (36.5<0.1°C vs. 37.4<.0.1 °C in AA rats on day 23, p<0.01). Serum concentration of NO-2/NO−3 rose in rats with AA to 28.7±2.5 μmolL−1 against. 13.9±1.9 μmolL−1 in controls (p<0.01), remained elevated in BRC-AA group and was potentiated in BRC1-AA group (48.2±3.5 μmolL−1, p<0.01 vs. AA or BRC1-AA group) Thiobarbituric acid reactive substances (TBARS) and antioxidant capacity in the spleen were enhanced in rats with AA and to the same extent in BRC-AA or BRC1-AA groups. These results show a discrepancy between the suppression of clinical symptoms and persisting oxidative stress in AA rats after the BRC induced PRL inhibition. The potentiation of nintric oxide (NO) production after the sudden cessation of PRL inhibition during the disease may promote further joint damage.
Diagnostic and Therapeutic Iter in Chronic Urticaria Patients
Authors: Tosoni C. , Cinquini M.
Published: January 2017

We describe a diagnostic and therapeutic protocol for the management of chronic urticaria. It is derived from an extensive review of current literature, with a cost-effective evaluation of laboratory investigations and therapeutic approaches. Our protocol may not represent a cornerstone for chronic urticaria: much has in fact to be clarified on pathogenetic mechanisms and aetiological factors. Nevertheless, its application should be able, in our opinion, to identify what is useful or not in the everyday management of chronic urticaria patients.
Impact of Simulated Microgravity on Cell Cycle Control and Cytokine Release by U937 Cells
Authors: Maier J.A.M.
Published: January 2017

Previous experiments from flight- and ground-based model systems indicate unexpected alterations of human leukocytes, leading to growth retardation and depression of mitogenic activation. The response of myelomonocytic U937 cells to simulated microgravity was therefore investigated. To this purpose, U937 cells were cultured in the NASA-developed bioreactor Rotating Wall Vessel (RWV) as a device to simulate microgravity on earth. No apoptosis was detected, in part because of the up-regulation of hsp70. In agreement with results obtained in space-flown U937 cells, the cells grew more slowly in the RWV than under normal conditions and this correlated with the down-modulation of cdc25B. Marked alterations of the cytokine secretion profile and, in particular, of inflammatory chemokines, as well as a decrease of the proteasome activity, were also observed in response to microgravity.
Enhancement of Lysosomal Glycohydrolase Activity in Human Primary B Lymphocytes during Spontaneous Apoptosis
Authors: Rosati E. , Mencarelli S. , Magini A. , Sabatini R. , Tassi C. , Orlacchio A. , Coaccioli S. , Frenguelli A. , Marconi P. , Emiliani C.
Published: January 2017

It has been shown that lysosomes are involved in B cell apoptosis but lysosomal glycohydrolases have never been investigated during this event. In this study we determined the enzymatic activities of some lysosomal glycohydrolases in human tonsil B lymphocytes (TBL) undergoing in vitro spontaneous apoptosis. Fluorimetric methods were used to evaluate the activities of β-hexosaminidases, α-mannosidase, β-mannosidase, β-galactosidase, β-glucuronidase and α-fucosidase. Results show that in TBL during spontaneous apoptosis, there is a significant increase in the activity of β-hexosaminidases, α-mannosidase, β-mannosidase and β-galactosidase. Also β-glucuronidase and α-fucosidase activities increase but not in a significant manner. Further studies on β-hexosaminidases revealed that also mRNA expression of the α- and β-subunits, which constitute these enzymes, increases during spontaneous TBL apoptosis. When TBL are protected from apoptosis by the thiol molecule N-acetyl-L-cysteine (NAC), there is no longer any increase in glycohydrolase activities and mRNA expression of β-hexosaminidase α- and β-subunits. This study demonstrates for the first time that the activities and expression of some lysosomal glycohydrolases are enhanced in TBL during spontaneous apoptosis and that these increases are prevented when TBL apoptosis is inhibited.
Cyclooxygenase Isozymes in Oral Squamous Cell Carcinoma: A Real-Time RT-PCR Study with Clinic Pathological Correlations
Authors: Pannone G. , Sanguedolce F. , de Maria S. , Farina E. , Muzio L. Lo , Serpico R. , Emanuelli M. , Rubini C. , De Rosa G. , Staibano S. , Macchia L. , Bufo P.
Published: January 2017

COX-2 expression in tumour cells has been associated with carcinogenesis in many human neoplasms, including head and neck cancer, while the COX-1 isoform of the cyclooxygenase enzyme is constitutively expressed in normal tissues. We measured COX-1 and COX-2 m-RNA expression in samples of both oral cancer and matched oral mucosa from 22 patients by RealTime RT-PCR; clinic pathological data (grading, TNM staging, inflammation, follow-up) of all patients were available for statistical evaluation. Most of the tumor samples in our study expressed at least one cyclooxygenase enzyme (COX-1 or COX-2 mRNA) more than their matched normal oral mucosa (p<0.05), with no correlation with the entity of inflammation, and a significant inverse relationship was found between COX-1 and COX-2 in each sample. Higher levels of COX-2 expression were associated with poor disease-free survival (p<0.05), but not with overall survival and higher tumor stage and grade. Our results suggest that COX-1 may play a role in oral carcinogenesis, and could be regarded as a potential therapeutic target by chemo preventive drugs; moreover, COX-2 expression might be addressed as a new prognostic tool in the clinical management of OSCC.
Cutaneous Human Papillomaviruses as Recurrence Factor in Actinic Keratoses
Authors: Dianzani C. , Pierangeli A. , Chiricozzi A. , Avola A. , Degener A.M.
Published: January 2017

Actinic keratoses (AK) are common, premalignant lesions cause mainly by UV DNA damage. Progression into squamous cell carcinoma may be influenced by other several factors such as chronic chemical exposure or viral infection. A carcinogenic role of Human Papillomaviruses (HPV) in early steps of skin tumour development was recently hypothesized; moreover the presence of HPV DNA seems to be higher in cancer precursor lesions. The aim of this work is to identify the presence of HPV DNA in biopsies from Actinic Keratoses (AK) and from normal skin samples collected from dermatological healthy subjects in Italy, in order to evaluate the severity and the clinical evolution of the HPV positive lesions. The DNA test revealed 37% HPV positivity in AK patients versus 0% in the control group; many different genotypes and variants were identified by direct sequencing of PCR product. The HPV positive AK were usually clinically indistinguishable from the HPV negative. All AK lesions were removed by laser treatment, but AK lesions recurred in all HPV positive patients after a period of 45–60 days whereas the same disappeared in the HPV negative ones. These data permit to hypothesize that the presence of HPV DNA could be an aggravating factor for AK lesion severity and recurrence.
Activation of Interferon Response Genes and of Plasmacytoid Dendritic Cells in HIV-1 Positive Subjects with GB Virus C Co-Infection
Authors: Lalle E. , Sacchi A. , Abbate I. , Vitale A. , Martini F. , D'Offiz G. , Antonucci G. , Castilletti C. , Poccia F. , Capobianchi M.R.
Published: January 2017

GB virus C (GBV-C) coinfection has a protective role in Human Immunodeficiency Virus (HIV) infection, and increases the duration of suppression of HIV-1 viremia in patients under Highly Active Anti-Retroviral Therapy (HAART). Since innate antiviral response may be involved in the protection, we analyzed the possible role of GBV-C as activator of innate immunity. To this aim, we measured the extent of activation of the interferon (IFN) system and of circulating Dendritic Cells (DC) in vivo, and the ability of GBV-C to activate these functions in vitro. Activation of IFN system and of circulating DC was compared in GBV-positive and -negative HIV-1 co-infected patients with HAART-driven suppression of HIV-1 viremia. Endogenous levels of IFN-γ and RNA-dependent protein kinase (PKR) mRNA were significantly higher in peripheral blood mononuclear cells (PBMC) from GBV-C-positive when compared to GBV-C-negative patients. IFN-γ expression was correlated with all the Interferon response genes (IRGs) and with GBV-C viremia. The frequency of circulating plasmacytoid DC (pDC) expressing the CD80 activation marker was increased in GBV-C-positive patients, and was correlated with GBV-C viral load. In vitro experiments indicated that GBV-C is able to induce IFN-γ expression in PBMC. In addition, in PBMC cultures GBV-C induced an increase of CD80 expression by pDC, that was reduced by antibody to IFN-γ. Our data indicate that in HIV-positive patients GBV-C coinfection promotes the activation of IFN-γ and downstream IRG expression, as well as with the activation/maturation of circulating pDC. GBV-C-driven IFN-γ activation is, at least in part, responsible for the increased maturation of pDC. This crosstalk may suggest a role for GBV-C coinfection in boosting the innate antiviral response to HIV infection.
Resorcylic Acid Lactone L-783,277 Inhibits the Growth of the Human Adrenal Cancer Cell Line H295R in Vitro
Authors: Lawnicka H. , Kowalewicz-Kulbat M. , Sicinska P. , Altmann K.H. , Hofmann T. , Stepien H.
Published: January 2017

The resorcylic acid lactone L-783,277, isolated from a Phoma sp. (ATCC 74403), is a potent and specific inhibitor of MEK (Map kinase kinase) that exerts very interesting pharmacological activities including anti-neoplastic properties. However, the role of this compound in the regulation of endocrine-related cancer cell growth and tumor progression remains unknown. In the present study we have evaluated the effect of L-783,277 on the viability, proliferation and cell cycle of the human adrenocortical carcinoma cell line H295R. L-783,277 inhibited viability (IC50 of 22 μM) and cell proliferation (IC50 of 21 μM) of H295R. At concentrations of 10−6-10−8M this effect was associated with the accumulation of H295R cells in S-phase, whereas at concentrations of 10−9-10−10M a prolonged G1-phase and reduced transition into S-phase were observed. Our findings demonstrate for the first time the anti-proliferative action of L-783,277 on the human adrenocortical H295R cell line.
Proinflammatory Cytokine Production in HaCat Cells Treated by Eosin: Implications for the Topical Treatment of Psoriasis
Authors: Zampetti A. , Mastrofrancesco A. , Flori E. , Maresca V. , Picardo M. , Amerio P. , Feliciani C.
Published: January 2017

Psoriasis is a multifactorial skin dermatosis characterized in its classical form by erythematous and hyperkeratotic plaques on extensor surfaces of the body, that in most cases can be managed therapeutically by topical agents. Hyperproliferation and a marked inflammation in both epidermis and dermis are thought to be driven by interaction of activated type-1 T lymphocytes and antigen-presenting cells and keratinocytes that release several proinflammatory and immunomodulating molecules. The aim of this study is to investigate whether tetrabromofluorecin, commonly know as eosin, a classical compound traditionally topically used in psoriasis for its presumed anti-inflammatory activities, is able to modulate the production of TNF-α, IL-6 and IL-8 that are recognized as the most active and characterized cytokines in the pathogenesis of this skin disorder. HaCaT cell line was used to verify the effects on epidermal inflammation by eosin at scalar doses after testing the viability of cells. Two different population of cells, one stimulated by IFNγ and one non-stimulated, were cultivated in presence of tolerable concentrations. The expression and release of IL-6, IL-8, IL10, and TNF-alpha were analysed by RT-PCR and ELISA, respectively. Our results show that tolerable concentrations of eosin were 0.05%, 0.02%, and 0.01%. The expression and production of TNFα, IL-8 and IL-6 were dramatically reduced in presence of eosin 0.05% and 0.02% and the action of eosin was more pronounced on TNF-α. In agreement with clinical data, our results show that in presence of tolerable concentrations, eosin seems to influence remarkably the production of three important cytokines involved in the hyperproliferation and inflammatory process, giving a specific explanation of its efficacy and supporting its topical use in the clinical setting.
Morphine-Sparing Effect by COX-1 Inhibitor Sustains Analgesic Function without Compromising Antigen-Specific Immunity and Antitumor Effect of Naked DNA Vaccine
Authors: Sun W-Z. , Chang M-C. , Hsiao P-N. , Chen C-A. , Hsu Y-T. , Hsieh C-Y. , Cheng W-F.
Published: January 2017

Morphine and ketorolac, two analgesics with different mechanisms, have been widely used in controlling cancer pain and postoperative pain in surgery. Our previous study revealed that morphine could suppress the anti-tumor effect of antigen-specific DNA vaccine. In this study, we further evaluated and compared another analgesic drug, ketorolac, with morphine for its analgesic functions and the antitumor immunities of antigen-specific DNA vaccine. We first observed that ketorolac-treated mice did not enhance tumorigenesis nor suppress the anti-tumor effects of antigen-specific (calreticulin linked to HPV16 E7) CRT/E7 DNA vaccine. We then demonstrated that ketorolac was less potent in inducing apoptosis of T lymphocytes and the generation of reactive oxygen species, in reducing mitochondrial membrane potentials, and leading to the activation of caspases 3 and 7 in T lymphocytes than morphine. When CRT/E7 DNA vaccinated mice treated with ketorolac, the declines of frequencies of E7-specific IFN-γ-secreting CD8+ T cell precursors were slower in the morphine-treated group. CRT/E7 DNA vaccinated mice, treated with a mixture of morphine and ketorolac, could maintain the analgesic function without experiencing a decrease in the anti-tumor effects. CRT/E7 DNA vaccine with the opioid-sparing effect of ketorolac could provide potent anti-tumor effects and good analgesic function.
Nad(P)H Oxidase and Pro-Inflammatory Response during Maximal Exercise: Role of C242T Polymorphism of the P22PHOX Subunit
Authors: Izzicupo P. , Di Valerio V. , D'Amico M.A. , Di Mauro M. , Pennelli A. , Falone S. , Alberti G. , Amicarelli F. , Miscia S. , Gallina S. , Di Baldassarre A.
Published: January 2017

Intense exercise induces a pro-inflammatory status through a mechanism involving the NAD(P)H oxidase system. We focused our attention on p22phox, a subunit of the NAD(P)H oxidase, and on its allelic polymorphism C242T, which is known to affect the functional activity of the enzyme. We investigated whether the p22phox C242T variants exhibit systemic effects in healthy subjects by analyzing the proinflammatory and cardiocirculatory responses to physical exercise in endurance athletes. The group of study consisted of 97 long distance runners, 37±4.4 yrs of age, with similar training history. The subjects underwent a maximal stress test during which both inflammatory and cardiopulmonary parameters were monitored. Our results demonstrate that T allele deeply influences the neutrophil activation in response to intense exercise, since T carriers were characterized by significantly lower release of myeloperoxidase (MPO), a classical leukocyte derived pro-inflammatory cytokine. In addition, the presence of T allele was associated with a higher cardiopulmonary efficiency as evidenced by a significantly lower Heart Rate (HR) at the peak of exercise and, when a dominant model was assumed, by a higher maximal oxygen uptake (VO2 max). On the other hand, no effects of 242T mutation on the plasmatic total antioxidant capacity (TAC) and on the cortisol responses to the physical exercise were detected. In conclusion, our data support a systemic role for p22phox C242T polymorphism that, modifying the intensity of the inflammatory response, can influence the cardiovascular adaptations elicited by aerobic training. These results contribute to support the hypothesis of a systemic effect for the C242T polymorphism and of its possible functional rebound in healthy subjects.