The European Medicines Agency review of sacituzumab govitecan for the treatment of triple-negative breast cancer.

Sacituzumab govitecan (SG) is an antineoplastic agent which combines a humanized monoclonal antibody binding to trophoblast cell surface antigen-2 (Trop-2)-expressing cancer cells, linked with cytotoxic moiety SN-38 (govitecan) with topoisomerase I inhibitor action. On 22 November 2021, a marketing authorization valid through the European Union (EU) was issued under the European Medicines Agency (EMA)'s accelerated assessment program for SG as monotherapy for the treatment of adult patients with unresectable or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, including at least one of them for advanced disease. The assessment was based on results from an open-label, randomized, phase III trial to evaluate the safety, tolerability, pharmacokinetics and efficacy of SG versus treatment of physician's choice (TPC) in patients with mTNBC who received at least two prior treatments including at least one of them for advanced disease. The efficacy results in the overall population, based on mature data, showed a statistically significant improvement of SG over TPC in progression-free survival (PFS) and overall survival (OS). The median PFS was 4.8 months versus 1.7 months [hazard ratio (HR) = 0.43, n = 529; 95% CI 0.35-0.54; P < 0.0001] and the median OS was 11.8 months versus 6.9 months (HR = 0.51, n = 529; 95% CI 0.41-0.62; P < 0.0001). The most common (>30%) side effects of SG were diarrhea, neutropenia, nausea, fatigue, alopecia, anemia, constipation and vomiting. The aim of this manuscript is to summarize the scientific review of the application leading to regulatory approval in the EU.

The EMA assessment of pembrolizumab as monotherapy for the first-line treatment of adult patients with metastatic microsatellite instability-high or mismatch repair deficient colorectal cancer.

On 21 January 2021, the European Commission amended the marketing authorisation granted for pembrolizumab to include the first-line treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) in adults. The recommended dose of pembrolizumab was either 200 mg every 3 weeks or 400 mg every 6 weeks by intravenous infusion. Pembrolizumab was evaluated in a phase III, open-label, multicentre, randomised trial versus standard of care (SOC: FOLFOX6/FOLFIRI alone or in combination with bevacizumab/cetuximab) as first-line treatment of locally confirmed mismatch repair-deficient or microsatellite instability-high stage IV CRC. Subjects randomised to the SOC arm had the option to crossover and receive pembrolizumab once disease progressed. Both progression-free survival (PFS) and overall survival were primary endpoints. Pembrolizumab showed a statistically significant improvement in PFS compared with SOC, with a hazard ratio of 0.60 [95% confidence interval (CI): 0.45-0.80], P = 0.0002. Median PFS was 16.5 (95% CI: 5.4-32.4) versus 8.2 (95% CI: 6.1-10.2) months for the pembrolizumab versus SOC arms, respectively. The most frequent adverse events in patients receiving pembrolizumab were diarrhoea, fatigue, pruritus, nausea, increased aspartate aminotransferase, rash, arthralgia, and hypothyroidism. Having reviewed the data submitted, the European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) considered that the benefit-risk balance was positive. This is the first time the CHMP has issued an opinion for a target population defined by DNA repair deficiency biomarkers. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the European Union.

The European Medicines Agency review of the initial application of atezolizumab and the role of PD-L1 expression as biomarker for checkpoint inhibitors.

Immune checkpoint inhibitors have revolutionised cancer therapeutics. Translational research evaluating the role of biomarkers is essential to identify the ideal target population for these drugs. From a regulatory perspective, the identification of biomarkers and diagnostic assays is strongly encouraged by the European Medicines Agency (EMA). The aim of this article is to analyse the role of programmed death-ligand 1 (PD-L1) expression as a predictive biomarker in relation to the data submitted for the initial assessment of atezolizumab, a monoclonal antibody targeting human PD-L1. On 20 July 2017, atezolizumab was granted a marketing authorisation valid throughout the European Union (EU) for adult patients with (i) locally advanced or metastatic non-small-cell lung cancer (NSCLC) after chemotherapy and (ii) locally advanced or metastatic urothelial carcinoma (UC) after chemotherapy or cisplatin-ineligibility. Initially, these indications were not restricted by the level of PD-L1 expression, but preliminary data from an ongoing phase III trial in patients with UC led to a restriction in the UC indication to cisplatin-ineligible patients whose tumours have ≥5% PD-L1 expression. Still, the role of PD-L1 expression as predictive biomarker for atezolizumab therapy remains inconclusive and further research is needed. Data in this paper came from the scientific review leading to the initial regulatory approval of atezolizumab in the EU and its complementary application for indication (EMEA/H/C/004143/II/0010). The full scientific assessment report and product information are available on the EMA website (www.ema.europa.eu).

Branched-chain amino acids: Abundance of their transporters and metabolizing enzymes in adipose tissue, skeletal muscle, and liver of dairy cows at high or normal body condition.

Branched-chain amino acids (BCAA) are major components of milk protein and important precursors for nonessential AA. Thus, the BCAA transport and break-down play a key role in the metabolic adaptation to the high nutrient demands in lactation. However, in monogastrics, increased BCAA levels have been linked with obesity and certain metabolic disorders such as impaired insulin sensitivity. Our objective was to study the effect of over-conditioning at calving on plasma BCAA levels as well as the tissue abundance of the most relevant BCAA transporters and degrading enzymes in dairy cows during late pregnancy and early lactation. Thirty-eight Holstein cows were allocated 15 wk antepartum to either a normal- (NBCS) or over-conditioned (HBCS) group, receiving 6.8 or 7.2 MJ of NEL/kg of DM, respectively, during late lactation to reach the targeted differences in body condition score (BCS) and back fat thickness (BFT; NBCS: BCS <3.5, BFT <1.2 cm; HBCS: BCS >3.75, BFT >1.4 cm) until dry-off. During the dry period and next lactation, cows were fed the same diets, whereby differences in BCS and BFT were maintained: prepartum means were 3.16 ± 0.06 and 1.03 ± 0.07 cm (NBCS) vs. 3.77 ± 0.08 and 1.89 ± 0.11 cm (HBCS), postpartum means were 2.89 ± 0.06 and 0.81 ± 0.05 cm (NBCS) vs. 3.30 ± 0.06 and 1.38 ± 0.08 cm (HBCS). Blood and biopsies from liver, semitendinosus muscle, and subcutaneous adipose tissue (scAT) were sampled at d 49 antepartum, 3, 21, and 84 postpartum. Free BCAA were analyzed and the mRNA abundance of solute carrier family 1 member 5 (SLC1A5), SLC7A5, and SLC38A2 as well as branched-chain aminotransferase 2 (BCAT2), branched-chain α-keto acid dehydrogenase E1α (BCKDHA), and branched-chain α-keto acid dehydrogenase E1ß (BCKDHB) as well as the protein abundance of BCKDHA were assessed. Concentrations of all BCAA changed with time, most markedly in HBCS cows, with a nadir around calving. Apart from Ile, neither individual nor total BCAA differed between groups. The HBCS group had greater BCKDHA mRNA as well as higher prepartum BCKDHA protein abundance in scAT than NBCS cows, pointing to a greater oxidative capacity for the irreversible degradation of BCAA transamination products in scAT of over-conditioned cows. Prepartum hepatic BCKDHA protein abundance was lower in HBCS than in NBCS cows. In both groups, SLC1A5, SLC7A5, and BCAT2 mRNA were most abundant in scAT, whereas SLC38A2 was higher in scAT and muscle compared with liver, and BCKDHA and BCKDHB mRNA were greatest in liver and muscle, respectively. Our results indicate that scAT may be a major site of BCAA uptake and initial catabolism, with the former, however, being independent of BCS and time relative to calving in dairy cows.

Changes in tissue abundance and activity of enzymes related to branched-chain amino acid catabolism in dairy cows during early lactation.

Branched-chain α-keto acid dehydrogenase (BCKDH) complex catalyzes the irreversible oxidative decarboxylation of branched-chain α-keto acids. This reaction is considered as the rate-limiting step in the overall branched-chain amino acid (BCAA) catabolic pathway in mammals. For characterizing the potential enzymatic involvement of liver, skeletal muscle, adipose tissue (AT), and mammary gland (MG) in BCAA metabolism during early lactation, tissue and blood samples were examined on d 1, 42, and 105 after parturition from 25 primiparous Holstein cows. Serum BCAA profiles were analyzed and the mRNA and protein abundance as well as the activity in the different tissues were assessed for the BCAA catabolic enzymes, partly for the branched-chain aminotransferase and completely for BCKDH. Total BCAA concentration in serum was lowest on d 1 after parturition and increased thereafter to a steady level for the duration of the experiment. Pronounced differences between the tissues were observed at all molecular levels. The mRNA abundance of the mitochondrial isoform of branched-chain aminotransferase (BCATm) was greatest in AT as compared with the other tissues studied, indicating that AT might be an important contributor in the initiation of BCAA catabolism in dairy cows. From the different subunits of the BCKDH E1 component, only the mRNA for the ß polypeptide (BCKDHB), not for the α polypeptide (BCKDHA), was elevated in liver. The BCKDHA mRNA abundance was similar across all tissues except muscle, which tended to lower values. Highest BCKDHA protein abundance was observed in both liver and MG, whereas BCKDHB protein was detectable in these tissues but could not be quantified. Adipose tissue and muscle only displayed abundance of the α subunit, with muscle having the lowest BCKDHA protein of all tissues. We found similarities in protein abundance for both BCKDH E1 subunits in liver and MG; however, the corresponding overall BCKDH enzyme activity was 7-fold greater in liver compared with MG, allowing for hepatic oxidation of BCAA transamination products. Reduced BCKDH activity in MG associated with no measurable activity in AT and muscle may favor sparing of BCAA for the synthesis of the different milk components, including nonessential AA. Deviating from previously published data on BCAA net fluxes and isotopic tracer studies in ruminants, our observed results might in part be due to complex counter-regulatory mechanisms during early lactation.

[Erythropoietin in plastic surgery]. / Erythropoetin in der Plastischen Chirurgie.

EPO is an autologous hormone, which is known to regulate erythropoiesis. For 30 years it has been used for the therapy of diverse forms of anaemia, such as renal anaemia, tumour-related anaemias, etc. Meanwhile, a multitude of scientific publications were able to demonstrate its pro-regenerative effects after trauma. These include short-term effects such as the inhibition of the "primary injury response" or apoptosis, and mid- and long-term effects for example the stimulation of stem cell recruitment, growth factor production, angiogenesis and re-epithelialisation. Known adverse reactions are increases of thromboembolic events and blood pressure, as well as a higher mortality in patients with tumour anaemias treated with EPO. Scientific investigations of EPO in the field of plastic surgery included: free and local flaps, nerve regeneration, wound healing enhancement after dermal thermal injuries and in chronic wounds.Acute evidence for the clinical use of EPO in the field of plastic surgery is still not satisfactory, due to the insufficient number of Good Clinical Practice (GCP)-conform clinical trials. Thus, the initiation of more scientifically sound trials is indicated.

Lipid, lipoprotein and apolipoprotein profiles in European adolescents and its associations with gender, biological maturity and body fat--the HELENA Study.

BACKGROUND/OBJECTIVES: To provide a detailed lipid profile of a European adolescent population considering age, gender, biological maturity, body mass index (BMI), fat mass (FM) and percentage body fat (BF). SUBJECTS/METHODS: Within Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA), a cross-sectional study was conducted to determine fasting serum concentrations of lipids, lipoproteins and apolipoproteins in 1076 adolescents aged 12.5-17.49 years from ten European centres. RESULTS: All serum lipid concentrations were significantly higher in girls than in boys. In boys, age was negatively correlated with high-density lipoprotein (HDL)-cholesterol and total cholesterol (TC), and positively associated with triacylglycerides (TAG) (P < 0.01) whereas no significant associations were observed in girls. Biological maturity was negatively associated with TC, HDL-, low-density lipoprotein (LDL)- and non-HDL cholesterol in boys (all P<0.05) and negatively correlated with HDL-cholesterol in girls (P<0.05). BMI, FM and BF were significantly correlated with HDL-cholesterol, LDL-cholesterol, non-HDL cholesterol, apolipoprotein (apo) A1, apoB and TAG in both boys and girls. CONCLUSIONS: The lipid profile in adolescents is strongly determined by gender. Biological maturity, FM and percentage BF contribute to the variance in lipid concentrations and should be considered in future evaluations of lipid status.

Effect of quercetin on paraoxonase 1 activity--studies in cultured cells, mice and humans.

There is increasing evidence that the HDL-associated enzyme paraoxonase 1 (PON1) may have a protective function in the atherosclerotic process. An enhancement of PON1 activity by dietary factors including flavonoids is therefore of interest. Quercetin, a flavonol frequently present in fruits and vegetables has been shown to induce PON1 in cultured liver cells, but the in vivo efficacy of a dietary quercetin supplementation has yet not been evaluated. To this end, we fed laboratory mice quercetin-enriched diets with quercetin concentrations ranging from 0.05 to 2 mg/g diet for 6 weeks and determined the expression of the hepatic PON1 gene and its protein levels. Since we could establish a moderate but significant induction of PON1 mRNA levels by dietary quercetin in mice, we aimed to proof whether healthy human volunteers, given graded supplementary quercetin (50, 100 or 150 mg/day) for two weeks, would respond with likewise enhanced plasma paraoxonase activities. However, PON1 activity towards phenylacetate and paraoxon was not changed following quercetin supplementation in humans. Differences between mice and humans regarding the PON1 inducing activity of quercetin may be related to differences in quercetin metabolism. In mice, unlike in humans, a large proportion of quercetin is methylated to isorhamnetin which exhibits, according to our reporter gene data in cultured liver cells, a potent PON1 inducing activity.

[Cholinesterase inhibitors and Alzheimer's disease: meta-analysis of the verification of effectiveness, origin and bias of results in published studies]. / Cholinesterase-Inhibitoren und Alzheimer-Demenz: Metaanalyse zu Wirksamkeitsnachweis, Ursprung und Ergebnisverzerrung in publizierten Studien.

BACKGROUND AND OBJECTIVE: The cholinesterase-inhibitors (AChE-I) donepezil, galantamine and rivastigmine are currently used in the symptomatic treatment of patients with Alzheimer's dementia (AD) and the associated cholinergic deficits as well as those with other forms of dementia. Three aspects were analysed: (1) data on their clinical efficacy, (2) differences between North-American and international studies, and (3) potential publication biases. METHODS: Included were data from randomized, placebo-controlled, double-blind parallel group trials on more than 100 patients who had been treated for > or =12 weeks for AD, VaD, dementia with Lewy bodies, dementia with Parkinson's disease or with mild cognitive impairment. RESULTS: These large published trials support the clinical efficacy of AChE-I in patients with mild to moderate AD and other forms of dementia with regard to cognition and global impression. there was a trend towards greater beneficial cognitive effects in North-American studies, but this was non-significant. There was no evidence of a publication bias. CONCLUSIONS: Published data provide evidence for the clinical efficacy of donepezil, galantamine and rivastigmine in patients with mild to moderate AD. There is no indication that these results are critically influenced by the origin or a bias of the publication.

Influence of three rapeseed oil-rich diets, fortified with alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid on the composition and oxidizability of low-density lipoproteins: results of a controlled study in healthy volunteers.

OBJECTIVE: To compare the individual effects of dietary alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) on low-density lipoprotein (LDL) fatty acid composition, ex vivo LDL oxidizability and tocopherol requirement. DESIGN, SETTING AND SUBJECTS: A randomized strictly controlled dietary study with three dietary groups and a parallel design, consisting of two consecutive periods. Sixty-one healthy young volunteers, students at a nearby college, were included. Forty-eight subjects (13 males, 35 females) completed the study. INTERVENTIONS: Subjects received a 2-week wash-in diet rich in monounsaturated fatty acids (21% energy) followed by experimental diets enriched with about 1% of energy of ALA, EPA or DHA for 3 weeks. The omega-3 (n-3) fatty acids were provided with special rapeseed oils and margarines. The wash-in diet and the experimental diets were identical, apart from the n-3 fatty acid composition and the tocopherol content, which was adjusted to the content of dienoic acid equivalents. RESULTS: Ex vivo oxidative susceptibility of LDL was highest after the DHA diet, indicated by a decrease in lag time (-16%, P<0.001) and an increase in the maximum amount of conjugated dienes (+7%, P<0.001). The EPA diet decreased the lag time (-16%, P<0.001) and the propagation rate (-12%, P<0.01). Tocopherol concentrations in LDL decreased in the ALA group (-13.5%, P<0.05) and DHA group (-7.3%, P<0.05). Plasma contents of tocopherol equivalents significantly decreased in all three experimental groups (ALA group: -5.0%, EPA group: -5.7%, DHA group: -12.8%). The content of the three n-3 polyunsaturated fatty acid differently increased in the LDL: on the ALA diet, the ALA content increased by 89% (P<0.001), on the EPA diet the EPA content increased by 809% (P<0.001) and on the DHA diet, the DHA content increased by 200% (P<0.001). In addition, the EPA content also enhanced (without dietary intake) in the ALA group (+35%, P<0.01) and in the DHA group (+284%, P<0.001). CONCLUSIONS: Dietary intake of ALA, EPA or DHA led to a significant enrichment of the respective fatty acid in the LDL particles, with dietary EPA preferentially incorporated. In the context of a monounsaturated fatty acid-rich diet, ALA enrichment did not enhance LDL oxidizability, whereas the effects of EPA and DHA on ex vivo LDL oxidation were inconsistent, possibly in part due to further changes in LDL fatty acid composition.

Myocardial glucose transporter GLUT1: translocation induced by insulin and ischemia.

Myocardial glucose transport is not only facilitated by the insulin sensitive glucose transporter (GLUT) 4 but also by GLUT1. It was recently demonstrated that ischemia induces GLUT4 translocation by a mechanism distinct from the insulin-induced signaling pathway. However, the role of ischemia-mediated GLUT1 translocation and the signaling pathway involved is not yet defined. This study investigated the effects of wortmannin, a phosphatidylinositol-3 kinase (PI3kinase) inhibitor, on basal, ischemia- and insulin-stimulated GLUT1 redistribution. PI3kinase is known to participate in insulin-mediated GLUT4 translocation. Rat hearts were perfused with Krebs-Henseleit buffer containing 10 mmol/l glucose according to Langendorff and treated with/without 1 micromol/l wortmannin, 100 nmol/l insulin and 15 min no-flow ischemia. Relative subcellular distribution of GLUT1 protein was analysed using membrane fractionation and subsequent Western blotting. Both ischemia and insulin significantly increased the relative amount of GLUT1 in the plasma membrane (PM) compared to controls (41.6+/-2.8% in controls v 46.0+/-2.3% in ischemic and 51.4+/-3.9% in insulin hearts, both P<0.05) with a concomitant decrease of GLUT1 in intracellular membranes. However, the increases were moderate in view of the more than 2-fold stimulated GLUT4 translocation shown for ischemia and insulin. Although wortmannin completely inhibited insulin-induced GLUT1 translocation (42.0+/-2.0% GLUT1 on PM), it had no effect on the ischemia-induced translocation of GLUT1 (45. 4+/-1% GLUT1 on PM). Treatment with the inhibitor alone did not influence basal GLUT1 distribution. Results show that in the perfused rat heart, PI3 kinase is involved in the insulin-induced signaling leading to GLUT1 translocation but not in the ischemia-mediated signaling and basal GLUT1 trafficking. This suggests two different pathways for ischemia- and insulin-induced GLUT1 translocation as recently shown for GLUT4.

Contribution of alpha-adrenergic and beta-adrenergic stimulation to ischemia-induced glucose transporter (GLUT) 4 and GLUT1 translocation in the isolated perfused rat heart.

The intracellular signaling mechanism of the ischemia-stimulated glucose transporter (GLUT) translocation in the heart is not yet characterized. It has been suggested that catecholamines released during ischemia may be involved in this pathway. The purpose of this study was to evaluate the contribution of alpha-adrenoceptors and beta-adrenoceptors to ischemia-mediated GLUT4 and GLUT1 translocation in the isolated, Langendorff-perfused rat heart. Additionally, GLUT translocation was studied in response to catecholamine stimulation with phenylephrine (Phy) and isoproterenol (Iso). The results were compared with myocardial uptake of glucose analogue [18F]fluorodeoxyglucose (FDG). Subcellular analysis of GLUT4 and GLUT1 protein on plasma membrane vesicles (PM) and intracellular membrane vesicles (IM) using membrane preparation and immunoblotting revealed that alpha- and beta-receptor agonists stimulated GLUT4 translocation from IM to PM (2.5-fold for Phy and 2.1-fold for Iso, P<0.05 versus control), which was completely inhibited by phentolamine (Phe) and propranolol (Pro), respectively. Plasmalemmal GLUT1 moderately rose after Iso exposure, and this was prevented by Pro. In contrast, ischemia-stimulated GLUT4 translocation (2.2-fold, P<0.05 versus control) was only inhibited by alpha-adrenergic antagonist Phe but not by beta-adrenergic antagonist Pro. Similarly, Phe but not Pro inhibited ischemia-stimulated GLUT1 translocation. GLUT data were confirmed by FDG uptake monitored using bismuth germanate detectors. The catecholamine-stimulated FDG uptake (6.9-fold for Phy and 8.9-fold for Iso) was significantly inhibited by Phe and Pro; however, only Phe but not Pro significantly reduced the ischemia-induced 2.5-fold increase in FDG uptake (P<0.05 versus ischemia). This study suggests that alpha-adrenoceptor stimulation may play a role in the ischemia-mediated increase in glucose transporter trafficking leading to the stimulation of FDG uptake in the isolated, perfused rat heart, whereas beta-adrenergic activation does not participate in this signaling pathway.

Effects of wortmannin on insulin- and ischemia-induced stimulation of GLUT4 translocation and FDG uptake in perfused rat hearts.

OBJECTIVE: Myocardial glucose transport is enhanced by hormonal and other stimuli such as ischemia and hypoxia which induce glucose transporter 4 (GLUT4) translocation. Whether insulin and ischemia share a common signaling mechanism is not yet known. This study investigated whether phosphatidylinositol 3-kinase (PI3K), a signaling intermediate of the insulin-responsible pathway, also participates in the ischemia-induced stimulation of glucose. METHODS: Isolated Langendorff-perfused Sprague-Dawley rat hearts were subjected to 100 nmol/l insulin or 15 min of no-flow ischemia with/without 1 mumol/l wortmannin, an inhibitor of PI3K. After perfusion, relative subcellular glucose transporter GLUT4 distribution was assessed by membrane fractionation and immunoblotting and compared to controls. Uptake kinetics of the glucose analog [18F]fluoro-deoxyglucose (FDG) were also studied during perfusion of rat hearts. RESULTS: GLUT4 translocation to the plasma membrane (PM) was increased by insulin 1.8-fold and by ischemia 2.4-fold (P < 0.05). FDG uptake was increased by insulin 6.0-fold and by ischemia 6.2-fold (P < 0.05). Wortmannin 1 mumol/l inhibited insulin-mediated translocation of GLUT4 and increase in FDG uptake completely. However, it did not show any effect on ischemia-stimulated GLUT4 translocation or on ischemia-induced increase in FDG utilization. A significant correlation was found between relative GLUT4 translocation and FDG uptake in hearts of the insulin series (r = 0.9, P < 0.05) and of the ischemia series (r = 0.8, P < 0.05). CONCLUSIONS: Our results demonstrate that wortmannin did not inhibit ischemia-induced stimulation of myocardial glucose transport, supporting the hypothesis of different signaling pathways for ischemia and insulin.

Increased sarcolemmal glucose transporter abundance in myocardial ischemia.

Many clinical and laboratory studies suggest that an increase in glucose uptake and metabolism by ischemic myocardium helps protect myocardial cells from irreversible injury. We have examined whether increased sarcolemmal abundance of cardiomyocyte glucose transporters plays a role in this adaptive response. We have shown that acute myocardial ischemia in perfused rat hearts results in increased sarcolemmal abundance of the major glucose transporter, GLUT4, by causing translocation of GLUT4 molecules from an intracellular compartment to the sarcolemma. In nonischemic control hearts only 18 +/- 2.8% of GLUT4 molecules were on the sarcolemma whereas in ischemic hearts this increased to 41 +/- 9.3%. Insulin also caused translocation of GLUT4 molecules to the sarcolemma, and resulted in 61 +/- 2.6% of GLUT4 molecules on the sarcolemma. The combination of ischemia and insulin did not result in additive increases in sarcolemmal GLUT4 abundance. In more persistent or chronic ischemia, the other major myocardial glucose transporter, GLUT1, appears to play an important role. The mRNA for this transporter, which is constitutively expressed on cardiomyocyte sarcolemma, was increased 2.0-fold in regions of hibernating myocardium in humans with coronary heart disease as well as in persistently hypoxic rat neonatal cardiomyocytes in primary culture. In neither of these conditions was GLUT4 mRNA expression increased. Thus, acute myocardial ischemia increases sarcolemmal glucose transporter abundance mainly by translocating previously synthesized GLUT4 molecules from an intracellular compartment, whereas more chronic ischemia also increases GLUT1 abundance via enhanced mRNA expression. Increased GLUT1 and GLUT4 abundance may participate in the augmented glucose uptake of ischemic myocardium and therefore may help protect ischemic myocardium from irreversible injury.

Chondropathia patellae and knee muscle control. An electromyographic study.

The activity of knee-related muscles was registered via exercising on a bicycle ergometer by 17 patients with clinically diagnosed chondropathia patellae. M. quadriceps activity was shorter and the hamstring activity longer in the chondropathy group compared with a matched healthy control group. The changes in m. quadriceps occurred to an almost equal extent in lateral and medial sections. In five patients with unilateral complaints, the electromyographic changes were nevertheless noted on both sides. The study shows that chondropathia patellae involves a change in muscle control affecting not only the knee extensors but also the hamstrings. Through the changed innervation pattern the coactivation phase, i.e. the phase of simultaneous activation of knee flexors and extensors at the end of the extension phase, takes place at a higher angle of flexion. Physiotherapy should involve all knee-related muscles and should include not only isometric but also dynamic exercises.

[Scintigraphic evaluation of the ischemically damaged myocardium in patients with reduced left ventricular function. From clinical aspects to the cell]. / Szintigraphische Beurteilung ischämisch geschädigten Myokards bei Patienten mit eingeschränkter linksventrikulärer Funktion. Von der Klinik zur Zelle.

Identification of viable myocardium in patients with impaired left ventricular function, who are possible candidates for revascularization, represents an important clinical question. Modern methods of revascularization provide a therapeutic alternative to conventional pharmacological therapy even in patients with advanced ischemic heart disease. Modern diagnostic techniques make it possible to assess not only the extent of ischemia under exercise conditions, but also the presence of viable tissue in patients with severe coronary artery disease and impaired ventricular function. Currently, the most accurate methods for scintigraphic quantification of viable myocardial tissue are metabolic investigations with positron emission tomography (PET). Because of the limited availability of PET other methods like thallium-201-scintigraphy play an important clinical role. Modifications of thallium-201-scintigraphy, for example the introduction of reinjection protocols have improved the recognition of viable tissue and decreased the diagnostic difference to PET. We recommend as standard diagnostic procedure for assessment of tissue viability thallium-201-scintigraphy with reinjection. In patients with severely depressed left ventricular function and equivocal thallium-201-scintigraphy findings, PET should be considered as further diagnostic test. Low dose dobutamine-echocardiography is emerging as alternative test for evaluation of contractile reserve in dysfunctioning left ventricular segments. Its clinical role, however, remains to be determined. Besides the clinical application of these methods, newly developed radiotracers, together with PET, may provide insights into the mechanism of metabolic adaptations in patients with repeated episodes of ischemia. Furthermore, correlation of clinical data with in vitro histological and biological tissue analysis in the same patients may provide a better understanding of metabolic alterations observed in chronic ischemic heart disease.

Psychiatric interviewing techniques. IV. Experimental study: Four contrasting styles.

The development and definition of four contrasting interview styles is described. The four styles were designed using different permutations of techniques which, on the basis of an earlier naturalistic study, appeared to be most effective in eliciting either factual information or feelings. A 'sounding board' style utilized a minimal activity approach; an 'active psychotherapy' style actively sought to explore feelings and to bring out emotional links and meanings; a 'structured' style adopted an active cross-questioning approach, and a 'systematic exploratory' style aimed to combine a high use of both fact-oriented and feeling-oriented techniques. Quantitative measures based on video-tape and audio-tape analysis showed that two experienced interviewers could be trained to adopt these four very different styles and yet remain feeling and appearing natural. An experimental design to compare the four styles is described.

Alcoholism: a controlled trial of "treatment" and "advice".

Two groups of alcoholics received either one counseling session or several months of in- and outpatient treatment. One year later there were no significant differences in outcome between the two groups.