F376A/M388A-solulin, a new promising antifibrinolytic for severe haemophilia A.

INTRODUCTION: Haemophilia is a major bleeding disorder due to a deficiency of procoagulant factor VIII (type A) or IX (type B). The treatment is substitutive and based on infusion of factor concentrates. Main limitations of this therapy are cost, short factor half-life and the development of inhibitors (up to 30% of severe HA patients). An important aggravating factor of haemophilia is due to a premature fibrinolysis, directing attention to the therapeutic potential of suitable antifibrinolytics. Thrombomodulin (TM) is a key player of the coagulation cascade by activating protein C (an inhibitor of thrombin generation, thus antagonizing coagulation) and of the fibrinolytic cascade by activating thrombin activatable fibrinolysis inhibitor TAFI (thus reducing fibrinolysis). Solulin is a soluble form of TM that shows both capabilities. AIM: Here, we developed a new generation of solulin variants (F376A-, M388A- and F376A/M388A-solulin) with a decreased ability to activate protein C and a conserved capacity to activate TAFI. METHODS: We produced and characterized solulin variants in vitro. In addition, F376A/M388A-solulin was tested ex vivo, using blood samples of haemophilic A patients, with thromboelastography. RESULTS: The solulin variants (F376A, M388A and the double-mutant F376A/M388A) lost their abilities to activate protein C but are still capable to activate TAFI. Thrombelastography showed increased clot firmness and stability, that, as opposed to wild-type solulin, was maintained even at high concentrations of F376A/M388A-solulin (100 nm). CONCLUSION: In sum, these results open new opportunities for the development of specific medication for haemophilic patients.

Information Needs of Cancer Patients and Perception of Impact of the Disease, of Self-Efficacy, and Locus of Control.

The aim of our study was to investigate the relationship between information needs and cancer patients' perceptions of the impact of the disease, self-efficacy, and locus of control. Using a standardized questionnaire, we obtained data from patients who attended a series of lectures. The questionnaire included questions on their information needs, sources of information, satisfaction with information, and short questionnaires on self-efficacy, perception of the disease, and locus of control of reinforcement. Data was obtained from 185 patients. Our results showed that the sources of information that were most often used were physicians (84 %), print media (68 %), and the Internet (59 %); online fora (7.5 %), non-medical practitioners (9.7 %), and telephone-based counseling (8.6 %) were only used by a minority. Patients with a high perception of their own control over the disease more often used any source of information available to them and were more often interested in acquiring additional information. Higher self-efficacy was significantly associated with the need for information on all topics. Patients with a higher external locus of control significantly more often used sources of information and had significantly more need for additional information. By contrast, there were no associations with an internal locus of control. Neither external nor internal locus of control showed any associations with satisfaction with information. Information needs seem to be higher in patients with a high external locus of control and low self-efficacy. Physicians, other professionals, and institutions that provide information may take these relationships into consideration for tailoring their services to patients.

A lecture program on complementary and alternative medicine for cancer patients--evaluation of the pilot phase.

About half of all patients with cancer use complementary or alternative medicine (CAM). In 2013, we started a lecture program for patients, followed by evidence-based recommendations on counseling on CAM. These recommendations have been published before by this working group. The aim of the program is to provide scientific facts on the most often used CAM methods in standardized presentations which help patients discuss the topic with their oncologists and support shared decision making. The article presents the evaluation of the pilot phase. Participants received a standardized questionnaire before the start of the lecture. The questionnaire comprises four parts: demographic data, data concerning experience with CAM, satisfaction with the lecture, and needs for further information on CAM. In 2013, seven lectures on CAM were given in cooperation with regional branches of the German Cancer Society in several German states. Four hundred sixty patients and relatives took part (75% females and 16% males). Forty-eight percent formerly had used CAM. Most often named sources of information on CAM were print media (48%) and the Internet (37%). Most participants rated additional written information valuable. About one third would like to have an individual consultation concerning CAM. A standardized presentation of evidence on CAM methods most often used, together with recommendations on the self-management of symptoms, is highly appreciated. The concept of a highly interactive lecture comprising is feasible and if presented in lay terminology, adequate. In order to give additional support on the topic, written information should be provided as the first step.

[Disabled elderly people waiting for institutionalization to a hospital ward: prospective study in the administrative district of Strasbourg (France)]. / Personnes âgées dépendantes en attente d'entrée en EHPAD depuis un service hospitalier: étude prospective sur la communauté urbaine de Strasbourg, France.

OBJECTIVES: Our aim was to estimate the number of non-satisfied instutionalization requests for inpatients and to describe the strategies elaborated to compensate for the waiting time. METHODS: This prospective follow-up study concerning all requests for institution admission for inpatients aged 75 years or older hospitalized in acute care and rehabilitation wards. Descriptive data were gathered throughout the social support process conducted during the hospitalization. A three months follow-up was conducted. RESULTS: Among 5200 hospitalizations, a social support process was initiated for 270 patients aged 75 years and over. Two thirds of the sample were women (n=163). Mean age was 82 years. Fifty-two percent of the subjects met the criteria for iso-resource grades (IRG) 1 to 2 and 90% in IRG 1 to 4. The mean length of hospitalized stay (MLOS) was 56.8+/-10.2 days; the MLOS of unjustified stay of 23.5+/-5.6 (n=222). The average time before the social worker was informed of the patient's situation was 13.6+/-2.0 days; in addition, the time required to establish the administrative documents necessary for initiation of the social support progress was 15.0+/-1.8. The principal reasons for social support were physical dependence (77%), mental dependence (60%), insufficient family support (36%) and/or disease progression (21%). At three months, 104 patients were institutionalized, 128 were still on institution waiting list (in hospital: 48%; at home: 16%) and 38 had died (14%). The estimated annual institutional deficit for disabled elderly people was 512 beds. CONCLUSION: In light of demographical perspectives, an overall re-organization of the geriatric network is absolutely necessary. A simple increase in the capacity to fulfil the institutional beds deficit would be insufficient.

Trauma to the pontomesencephalic brainstem-a major clue to the prognosis of severe traumatic brain injury.

The objective of this study was to assess the significance of an injury to the pontomesencephalic brainstem in severe traumatic brain injury [Glasgow coma score (GCS) below 8]. Forty victims of severe traumatic brain injury with and with out compounding pathologies almost equally distributed among both groups were studied. The outcome (mean follow-up, 11.3 months) was assessed by means of the Glasgow outcome score (GOS) and of the Disability rating scale (DRS). Injury of the brainstem was detected by electrophysiological investigation (evoked potentials, brainstem reflexes) and magnetic resonance imaging (MRI) carried out early after trauma. Statistical analysis (Wilcoxon signed rank test for matched pairs) revealed a significantly worse initial GCS (median 5 versus 6), GOS (median 3 versus 4), and DRS score (median 6 versus 2) for the group with brainstem lesions than for the group without such lesions. Moreover, there was a significant accumulation of lesions of the corpus callosum, the basal ganglia, and the (para-)hippocampal area detected by MRI in the brainstem lesion group. In addition, the finding of an abnormal cortical component of the median nerve evoked somatosensory potential was significantly more frequent in the patients with brainstem injury. Traumatic brainstem lesions diagnosed by MRI a nd/or electrophysiological investigation are associated with injury to other 'deeply' situated parts ofthe brain. The finding of a brainstem lesion influences to the outcome of patients after severe traumatic brain injury.

[Antiviral therapy of hepatitis C]. / Antivirale Therapie der Hepatitis C.

Hepatitis C is one of the world's leading infectious diseases. The interferon-ribavirin combination therapy is the new standard for the treatment of hepatitis C in naive and relapse patients. Virological sustained response rates can be more than doubled by the IFN-ribavirin combination therapy compared to IFN-monotherapy and treatment duration can be reduced to six months in many cases. The IFN-ribavirin combination therapy has a high relative benefit in patients with unfavorable predictive parameters like high viral load, HCV genotype-1 infection and compensated liver cirrhosis. Anemia is the most important side effect of the guanosin analogue ribavirin. There are no official therapeutic recommendations for non-responder patients at present. These patients should be treated within controlled clinical trials. Monotherapy with PEG(pegylated)-interferons and combination therapies with PEG-interferons and ribavirin are the most promising future therapeutic options.

Surgery of intrinsic cerebral neoplasms in eloquent areas under local anesthesia.

28 patients with a mean age of 43.6 years were operated on for a cerebral neoplasm situated in close proximity to an eloquent area (24 speech area, 4 motor cortex) from 1996 to 1999. Preoperatively, all patients had undergone a detailed neuropsychological examination. In 10 patients aphasic disturbances could be detected. All patients underwent preoperative PET studies (methionine and (15)O-labeled water with activation during speech or finger tapping). These were performed and co-registered with MRI data to demonstrate the topographical relationship between motor or language function and the tumor borders. Anesthesia was induced with i.v. administration of propofol (150-250 mg/h). Craniotomy was performed under local infiltration anesthesia. After opening of the dura, sedation was stopped and operation was continued with the patient being alert and co-operative. With close clinical observation during electrical cortex stimulation, a speech arrest could be triggered or avoided. The motor cortex was identified by recording the phase reversal of the contralateral SEP of the median nerve and by direct cortical stimulation. As soon as aphasic or motor disturbances appeared, the tumor removal was continued with the goal of avoiding these specific regions. In 27 patients, preexisting neuropsychological and neurological deficits did not worsen. Only one patient was left postoperatively with a major permanent aphasic deficit that was present preoperatively to a minor degree. The use of local anesthesia in craniotomy for surgery of intrinsic cerebral neoplasms in eloquent areas allows for a continuous and repetitive monitoring of speech and motor function during the removal of even those tumors that were previously considered inoperable.

Characterization of microblasted and reactive ion etched surfaces on the commercially pure metals niobium, tantalum and titanium.

In surface-roughened metallic implant materials, the topography, chemistry and energy of the surfaces play an important role for the cell and tissue attachment. The highly reactive commercially pure metals niobium, tantalum and titanium were analysed after microblasting (with Al2O3 powder and consecutive shot-peening with ZrSiO2), and after additional reactive ion etching (RIE, with CF4). Scanning electron microscopy in combination with energy-dispersive X-ray analysis and surface roughness measurements showed, for all microblasted surfaces, a heterogeneous roughening (Ra about 0.7 microm), and a contamination with blasting particles. RIE resulted in a further roughening (Ra about 1.1 microm), and a total cleaning from contaminations, except for traces of aluminium. Determination of surface energy by dynamic contact angle measurements showed an increase in surface energy after microblasting, which further increased after RIE, most pronounced for commercially pure niobium. In conjunction with superior electrochemical properties, this makes niobium and tantalum promising candidates for implant purposes, at least equal to the generally used titanium.

Quantitative surface analysis by total electron yield.

When the surface of a solid sample is irradiated under vacuum by x-rays an electron emission, owing to photoabsorption, can be measured. As the electrons are detected under neglection of their kinetic energies the total electron yield (TEY) is determined. With a tuneable x-ray monochromator the TEY is measured below and above of one of the absorption edges of a given element. A jumplike increase of the TEY signal, due to the additional photoabsorptions in the corresponding atomic level, can be observed - qualitative analysis. The height of this jump can be correlateted to the concentration - quantitative analysis. It can be shown by a fundamental parameter approach for primary and secondary excitations how to use TEY for a quantitative analysis. The information depth lambda of this new method is approximately 2-400 nm depending on the chemical elements and on the original kinetic energies of Auger and photoelectrons. Thus, TEY is located between photoelectron spectrometry and x-ray fluorescence analysis.

Depth profiling by ARXPS in surface analysis.

A method of nondestructive depth profiling in near surface regions of solids is described. Models have been discussed from which algorithms for evaluation of measured data are obtained. The algorithms, based on standard profiles with free parameters, have been adjusted to the data resulting from angle resolved XPS (ARXPS) by means of least squares fits. Depth profile analyses and segregation studies were performed on Pt-Ni and Fe-S specimens.

[Pressor, renal and endocrine effects of systemic infusion of L-arginine in hypertensive patients]. / Effetti pressori, renali ed endocrini dell'infusione sistemica di L-arginina in soggetti ipertesi.

In this study we compared the pressor, renal and endocrine effects of the physiological precursor of endothelial derived nitric oxide, L-arginine, with D-glucose, a substrate inactive on nitric oxide. Ten subjects with mild to moderate primary hypertension underwent infusion with either L-arginine (5 patients) or D-glucose (5 patients). The substances were infused over 25 min at equiosmolar rates, preceded and followed by a 25-min saline infusion. Blood pressure (BP) and heart rate were monitored at 3-min intervals; hormonal and humoral variables, inulin and para-aminohippurate clearance, and electrolyte excretion were measured at the end of each period at maximum diuresis. L-arginine and D-glucose brought about comparable increases in serum osmolality and similar hemodilution as compared with control saline. During L-arginine infusion, systolic and diastolic BP dropped by 16.6% and 11% respectively and recovered during the post-infusion period. Heart rate, plasma renin activity, and plasma norepinephrine did not change significantly. The percent BP decrease induced by L-arginine was significantly greater than that caused by D-glucose. Glomerular filtration rate remained stable, and renal plasma flow increased with both substances. However, only L-arginine stimulated markedly natriuresis, kaliuresis, and chloruresis. It also seemed to induce systemic acidosis, possibly as a consequence of hydrochloric acid generated during its metabolism. Circulating insulin, atrial natriuretic peptide, growth hormone, and glucagon levels increased, and plasma aldosterone remained unchanged during L-arginine infusion. During D-glucose infusion, insulin was stimulated and the other hormones were inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)

Pressor, renal and endocrine effects of L-arginine in essential hypertensives.

The pressor, renal and endocrine effect of the physiological precursor of endothelial derived nitric oxide, L-arginine was compared, with a substrate inactive on nitric oxide, hypertonic D-glucose, in hypertensive patients. Ten mild-moderate essential hypertensives were assigned to either L-arginine (n = 5) or D-glucose (n = 5). Substances were infused over 25 min at equiosmolal rates preceded and followed by saline infusion for 25 min. Blood pressure and heart rate were monitored at 3-min intervals, while hormonal and humoral variables, inulin and paraaminohippurate clearance and electrolyte excretion were measured at the end of each period under conditions of maximal diuresis. L-arginine and D-glucose increased serum osmolality comparably and caused similar haemodilution to that with control saline. During L-arginine infusion, systolic and diastolic blood pressure decreased by 16.6% and 11%, respectively, and recovered in the postinfusion period. Heart rate, plasma renin activity, and plasma noradrenaline did not change significantly. The percent blood pressure decrement induced by L-arginine was significantly greater than that by D-glucose. Glomerular filtration rate was stable and renal plasma flow was increased by both substances. However, natriuresis, kaliuresis and chloruresis were markedly stimulated only by L-arginine, which also promoted the development of systemic acidosis, possibly as a consequence of hydrochloridric acid generated during its metabolism. Circulating insulin, atrial natriuretic peptide, growth hormone and glucagon levels were increased and plasma aldosterone was unchanged during infusion of L-arginine. Insulin was stimulated and the other hormones inhibited during infusion of D-glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of vigabatrin: implications of creatinine clearance.

The pharmacokinetics of both enantiomers of vigabatrin after a single oral dose in healthy young subjects (mean creatinine clearance 120 ml/min) were compared with kinetics in two groups of elderly subjects, one group aged 60 to 75 years (mean creatinine clearance 86 ml/min) and one group aged 76 to 97 years (mean creatinine clearance 30 ml/min). At a dose of 1500 mg, the group with the eldest subjects and the lowest creatinine clearance values showed mean increases of 3.3-fold in the time to reach the maximum concentration, 2.7-fold in the maximum concentration, and 9.8-fold in the AUC; a twofold prolongation of the t1/2; and reduced urinary excretion of the biologically and pharmacologically active S(+)-enantiomer. Changes in the intermediate group were qualitatively similar but quantitatively less. Parallel observations were made for the inactive R(-)-enantiomer. Most of these changes can be related to decreased renal clearance of vigabatrin. No interference of either enantiomer in the renal clearance of the other was noted. A nonlinear relationship between renal clearance and creatinine clearance for both enantiomers is suggested. Knowledge of the patient's renal function and an appropriate dose adjustment will minimize side effects during vigabatrin therapy, especially in elderly patients.

Pseudomembranous colitis associated with ampicillin and erythromycin therapy: report of a case.

Pseudomembranous colitis has been observed increasingly often after therapy with several antibiotics. This report describes the case of a patient in whom pseudomembranous colitis developed in association with ampicillin, an extremely rare complication of this drug, and erythromycin, a drug that has not been previously reported to cause the disease. Clinical and pathologic features, pathogenesis, and management are discussed. Early diagnosis and treatment are extremely important to reduce the significant morbidity and mortality associated with this disorder.