Baseline characteristics in the VERIFY study: a randomized trial assessing the durability of glycaemic control with early vildagliptin-metformin combination in newly diagnosed Type 2 diabetes.

AIM: To assess the long-term clinical benefits of early combination treatment with vildagliptin-metformin vs. standard-of-care, metformin monotherapy in the ongoing VERIFY study. METHODS: We randomized 2001 participants with multi-ethnic background, aged 18-70 years, having HbA1c levels 48-58 mmol/mol (6.5-7.5%) and BMI 22-40 kg/m2 . Baseline data included HbA1c , fasting plasma glucose and homeostasis model ß-cell and insulin sensitivity. Standardized meal-tests, insulin secretion rate relative to glucose, and oral glucose insulin sensitivity were assessed in a subpopulation. RESULTS: Out of 4524 screened, data were collected from the 2001 eligible participants (53% women) across Europe (52.4%), Latin America (26.8%), Asia (17.2%), South Africa (3.1%) and Australia (0.5%). The median (interquartile range) disease duration was 3.4 (0.9, 10.2) months; mean (±SD) age 54.3±9.4 years; weight 85.5±17.5 kg and BMI 31.1±4.7 kg/m2 . Baseline HbA1c was 52±3 mmol/mol (6.9±0.3%), fasting plasma glucose 7.5±1.5 mmol/l and the median (interquartile range) of fasting insulin was 109 (75-160) mU/l. Homeostasis model ß-cell and insulin sensitivity values were 84% (60, 116) and 46% (31, 68), respectively. In those undertaking meal-tests, insulin secretion rate relative to glucose was 28±12 pmol/min/m2 /mmol/l and oral glucose insulin sensitivity was 353±57 ml/min/m2 . CONCLUSIONS: Our current, multi-ethnic, newly diagnosed VERIFY population reflects a characteristic presence of early insulin resistance in participants with increased demand for insulin associated with obesity. The VERIFY study will provide unique evidence in characterizing therapeutic intervention in a diverse population with hyperglycaemia, focusing on durability of early glycaemic control.

The cortical involvement of territorial infarcts as a risk factor for stroke-related seizures.

BACKGROUND: The cortical involvement of territorial infarcts is considered to be a significant risk factor for the development of early- as well as late-onset seizures. However, it is not known which cortical regions are more susceptible to the development of stroke-related seizures. PATIENTS AND METHODS: In this retrospective study of 687 patients with territorial infarcts, 184 with stroke-related seizures were compared to 503 without seizures. The extent and the location of the infarcts were determined by computed tomography (CT) scans and/or magnetic resonance imaging (MRI) scans of the brain. The infarcts of the seizure and the non-seizure group were compared on digital cerebral vascular maps by superimposing the CT and/or MRI slices. RESULTS: In patients with late-onset seizures, the infarcts were significantly more frequent in the temporal and parietal branches of the middle cerebral artery in comparison to the non-seizure group. In patients with early-onset seizures and in those with seizures due to a recurrent stroke, the territory of the temporal and occipital branches of the middle cerebral artery was the predilection side of the infarcts. Generalized tonic-clonic seizures occurred mainly in cases of infarction in the deep territory of the middle cerebral and of the anterior choroidal artery. Status epilepticus was significantly correlated with infarcts in the posterior temporal region. CONCLUSION: Some infarct regions are the sides of predilection for stroke-related seizures according to their type and their onset-time.

Chronic obstructive pulmonary disease as a risk factor for stroke-related seizures.

Chronic obstructive pulmonary disease (COPD) is a risk factor for cardiovascular disorders and different types of stroke. The present retrospective study investigates whether COPD is also a risk factor for the development of seizures in stroke patients. The study population consisted of 237 patients with stroke-related seizures. The control population was composed of 939 patients, admitted for a stroke between 2002 and 2004 and who did not develop epileptic spells on a follow up of 2 years. The stroke type and aetiology, and the vascular risk factors, including COPD, were compared. The seizure patients were older (P = 0.009) and had more arterial hypertension (P = 0.046) and cardiac-embolic strokes (P = 0.045) than the control group. On logistic regression only partial anterior circulation syndrome/infarct (PACS/I) and COPD (P < 0.001) emerged as independent risk factors for the development of seizures in stroke patients. The occurrence of seizures was not related to the severity of the COPD or to its type of treatment. The present study confirms that seizures occur most frequently in patients with a PACS/I. Although we were unable to demonstrate why COPD is a risk factor for seizures in stroke patients, its frequent associated nocturnal oxygen desaturation seems to be the most plausible explanation. Further prospective are needed to assess the role of COPD as a possible independent risk factor for stroke-related seizures.

Critical conditions for hyperventilation responses. The role of autonomic response propositions during emotional imagery.

Hyperventilation is often conceived of as part of a fight-or-flight response, triggered by situations with high arousal and negative valence. However, a previous study using emotional imagery found hyperventilation responses during imagery of high-arousal scenes regardless of their valence. Those imagery scripts contained suggestions of autonomic activity, which may have partly induced or enhanced the hyperventilatory responsivity. The present study used four emotional scripts--depicting relaxing, fearful, depressive, and pleasant situations--without suggestions of autonomic or respiratory responses. After each imagery trial, participants rated their imagery for valence, arousal, and vividness. Fractional end-tidal carbon dioxide (FetCO2), inspiratory and expiratory time, tidal volume, and pulse rate were measured in a non-intrusive way. Results showed significant FetCO2 drops during the fearful and pleasant scripts. However, this effect was much smaller compared to imagery scripts with autonomic response propositions. Participants imagining scripts without autonomic response information found it harder to imagine the scripts vividly and reported lower levels of subjective arousal.

Stability of adenosine in infusion.

Using liquid chromatography the stability of adenosine in aqueous solution was investigated at five different temperatures, namely 4, 22, 37, 60 and 72 degrees C over a period of 6 months. At the three lowest temperatures, the initial concentration of the product was not altered, at the highest temperatures there was a significant decrease. From these data the shelf life (t90) at room temperature was estimated to be at least 5 years.

Differential cytotoxic effects induced after photosensitization by hypericin.

The cytotoxic effects of the natural photosensitizing agent hypericin were evaluated. A dramatic difference in the sensitivity of several different human and mouse cell lines towards photoactivated hypericin (4 J cm-2) was demonstrated using a neutral red assay (e.g. A431, IC50 = 0.14 +/- 0.02 microM; HeLa, IC50 = 0.32 +/- 0.05 microM, MCF7, IC50 = 1.84 +/- 0.22 microM). Dark cytotoxicity was absent, even at high hypericin concentration (25 microM). The differential phototoxicity of hypericin did not correlate with the expression of the epidermal growth factor (EGF) receptor nor with the expression of the P170 glycoprotein in the cell. The reduction of the intracellular glutathione content did not enhance further the cytotoxic effects of photoactivated hypericin, as investigated with the A431, HeLa and MCF7 cells. Conversely, using confocal laser microscopy, it was shown that the phototoxicity correlated well with the hypericin cellular uptake.

Human cytomegalovirus modulates the Ca2+ response to vasopressin and ATP in fibroblast cultures.

The free calcium concentrations in the nucleus ([Ca2+]n) and in cytosol ([Ca2+]c) of cultured human embryonic lung (HEL) fibroblasts were estimated by confocal laser microscopy using the Ca(2+)-indicator Indo-1. In resting HEL cells, The free cellular Ca(2+)-concentration significantly increased upon human cytomegalovirus (HCMV) infection. The ratio between [Ca2+]n and [Ca2+]c was not affected. Following stimulation by ATP or [Arg8] vasopressin (AVP), a differential Ca2+ response of the HCMV-infected HEL cells was observed. While uninfected cells were highly sensitive to AVP and only poorly sensitive to ATP, infected cells showed a high responsiveness to ATP but not to AVP. This switch in sensitivity to the agonists first observed at 24 h post infection. The Ca(2+)-rise following ATP or AVP stimulation was derived from intracellular Ca2+ stores. The magnitude of the ATP-induced Ca(2+)-rise increased upon infection. In contrast to non-infected cells where [Ca2+]n > [Ca2+]c during stimulation with AVP or ATP, no nucleo-cytosolic Ca(2+)-gradient was observed in infected cells. Furthermore, the magnitude of the Ca2+ rise in the two compartments was higher in ATP-stimulated cells. It is concluded that HCMV infection significantly interferes with Ca(2+)-homeostasis in HEL cells which could be related to the pathogenesis of the disease.

Stability of ascorbic acid in a standard total parenteral nutrition mixture.

We investigated the stability of ascorbic acid (AA) and the sum of AA plus dehydroascorbic acid (TAA) in a total parenteral nutrition (TPN) mixture that contained 1000 ml Vamin 14, 1000 ml glucose 30%, 500 ml Intralipid 20%, potassium phosphate, a multivitamin preparation (Cernevit) and trace elements. We used a spectrophotometer to measure AA and TAA. AA decreased from 42.2 (+/-0.9) mug/ml to 6.8 (+/-0.2) mug/ml in 7 days. Over the same time the concentration of TAA decreased from 42.2 (+/-0.5) mug/ml to 35.9 (+/-0.6) mug/ml, i.e. 63.3 (+/-1.2)% of the original concentration. When the solution was stored in glass bottles and saturated with nitrogen or when trace elements were omitted, the concentration decreased by only 25.2 (+/-0.2)% and 23.8 (+/-1.6)% respectively over 7 days. The influence of oxygen, lipids, trace elements and underfilling the bag was also investigated. We conclude that it is acceptable to prepare these bags in advance and to store them for 7 days at 2-4 degrees C.