Mesenchymal stem cells can be recruited to wounded tissue via hepatocyte growth factor-loaded biomaterials.

Mesenchymal stem cells (MSC) are precursor cells of mesodermal tissue and, because of their trophic phenotype, they are known to play beneficial roles in wound healing. In addition, various tissue engineering strategies are based on MSC/biomaterial constructs. As the isolation and expansion of MSCs is a long-term process, a major goal is to develop an endogenous stem cell recruitment system that circumvents all ex vivo steps generally used for tissue engineering. Therefore collagen and silk fibroin were loaded with hepatocyte growth factor (HGF), a chemoattractant for MSCs. Collagen was mixed with HGF during polymerization, while silk fibroin and HGF were produced as fusion proteins by transgenic silkworms. To demonstrate release of active HGF, enzyme-linked immunosorbent assay, in vitro migration assays and animal studies were performed to demonstrate MSC migration in vivo, followed by detailed examinations of the immunological effects of the biomaterials. Hepatocyte growth factor was released burst-like, both from silk fibroin and collagen during the first 8 h and gradually for up to 168 h in vitro. Directed migration in vitro was demonstrated when MSCs were exposed to HGF. In vivo, HGF-loaded collagen and silk fibroin were tolerated as subcutaneous implants. In addition, it was proved that endogenous MSCs were recruited from the local environment. These results show for the first time recruitment of endogenous MSCs to HGF-loaded collagen (fast degradable) and silk fibroin scaffolds (long-term degradable) in vitro and in vivo. This knowledge could be applied to make off-the-shelf, readily available constructs for use in patients with chronic wound or burns. Copyright © 2016 John Wiley & Sons, Ltd.

Extensive and interrelated subcortical white and gray matter alterations in preterm-born adults.

Preterm birth is a leading cause for impaired neurocognitive development with an increased risk for persistent cognitive deficits in adulthood. In newborns, preterm birth is associated with interrelated white matter (WM) alterations and deep gray matter (GM) loss; however, little is known about the persistence and relevance of these subcortical brain changes. We tested the hypothesis that the pattern of correspondent subcortical WM and GM changes is present in preterm-born adults and has a brain-injury-like nature, i.e., it predicts lowered general cognitive performance. Eighty-five preterm-born and 69 matched term-born adults were assessed by diffusion- and T1-weighted MRI and cognitive testing. Main outcome measures were fractional anisotropy of water diffusion for WM property, GM volume for GM property, and full-scale IQ for cognitive performance. In preterm-born adults, reduced fractional anisotropy was widely distributed ranging from cerebellum to brainstem to hemispheres. GM volume was reduced in the thalamus, striatum, temporal cortices, and increased in the cingulate cortices. Fractional anisotropy reductions were specifically associated with GM loss in thalamus and striatum, with correlation patterns for both regions extensively overlapping in the WM of brainstem and hemispheres. For overlap regions, fractional anisotropy was positively related with both gestational age and full-scale IQ. Results provide evidence for extensive, interrelated, and adverse WM and GM subcortical changes in preterm-born adults. Data suggest persistent brain-injury-like changes of subcortical-cortical connectivity after preterm delivery.

Poor attention rather than hyperactivity/impulsivity predicts academic achievement in very preterm and full-term adolescents.

BACKGROUND: Very preterm (VP) children are at particular risk for attention deficit/hyperactivity disorder (ADHD) of the inattentive subtype. It is unknown whether the neurodevelopmental pathways to academic underachievement are the same as in the general population. This study investigated whether middle childhood attention or hyperactivity/impulsivity problems are better predictors of VP adolescents' academic achievement. METHOD: In a geographically defined prospective whole-population sample of VP (<32 weeks gestation) and/or very low birth weight (<1500 g birth weight) (VLBW/VP; n = 281) and full-term control children (n = 286) in South Germany, ADHD subtypes were assessed at 6 years 3 months and 8 years 5 months using multiple data sources. Academic achievement was assessed at 13 years of age. RESULTS: Compared with full-term controls, VLBW/VP children were at higher risk for ADHD inattentive subtype [6 years 3 months: odds ratio (OR) 2.8, p < 0.001; 8 years 5 months: OR 1.7, p = 0.020] but not for ADHD hyperactive-impulsive subtype (6 years 3 months: OR 1.4, p = 0.396; 8 years 5 months: OR 0.9, p = 0.820). Childhood attention measures predicted academic achievement in VLBW/VP and also full-term adolescents, whereas hyperactive/impulsive behaviour did not. CONCLUSIONS: Attention is an important prerequisite for learning and predicts long-term academic underachievement. As ADHD inattentive subtype and cognitive impairments are frequent in VLBW/VP children, their study may help to identify the neurofunctional pathways from early brain development and dysfunction to attention problems and academic underachievement.

[Metastasectomy in renal cell cancer after neoadjuvant therapy with multi-tyrosine kinase inhibitors]. / Metastasenresektion nach neoadjuvanter Systemtherapie mit Multityrosinkinaseinhibitoren beim metastasierten Nierenzellkarzinom.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) still poses a challenge to therapists in spite of the availability of multiple innovative molecular treatment options. Complete remission is rare and in cases of partial remission it is often unclear if necrosis or vital carcinoma tissue persists. We report on a cohort of patients who underwent metastasectomy after neoadjuvant therapy with multi-tyrosine kinase inhibitors (MTKI). METHODS: In 2009 a total of 11 patients (7 male and 4 female) underwent metastasectomy after achievement of ≥ 3 months stable partial remission. All patients received either sunitinib (n=7, mean 5.5 cycles), bevacizumab and interferon (IFN)-α2a (n=2, mean 8.5 months), temsirolimus (n=1, mean 9 months) or a combination of sunitinib followed by temsirolimus (n=1). Of the patients 7 presented with retroperitoneal lymph node metastases with a mean diameter of 3.5-12 cm, 2 patients with pulmonary metastases, 1 patient with lymph node and pancreas tail metastases and 1 female patient showed residual disease in the vena cava. RESULTS: All metastases were completely resected with negative surgical margins. In 82% of the cases histologically active, Ki-67 positive renal cell cancer tissue was identified. The following adjunctive interventions were necessary: vena cava resection with vascular prosthesis and reimplantation of the renal vein (n=3), partial liver resection (n=1), splenectomy (n=1) and pancreas tail resection (n=1). There were no significant perioperative complications but 1 patient developed fascial dehiscence and underwent revision surgery and 1 patient developed clinically insignificant pancreatitis. After a median follow-up of 12 months (range 8-19 months) 5 patients had no recurrence and 6 of the patients showed liver (n=3), lung (n=2) or bone (n=1) recurrences from which 3 patients died. CONCLUSIONS: Metastasectomy of mRCC is associated with a low rate of complications in experienced centers. Surgical resection of metastatic disease is indicated to achieve complete remission with a favorable prognosis because of biologically active kidney cancer tissue. Patients with isolated and resectable metastases are ideal candidates for such a procedure.

Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists.

The antispastic agent and muscle relaxant baclofen 1 is a potent and selective agonist for bicuculline-insensitive GABAB receptors. For many years efforts to obtain superior GABAB agonists were unsuccessful. We describe the syntheses and biological properties of two new series of GABAB agonists, the best compounds of which are more potent than baclofen in vitro and in vivo. They were obtained by replacing the carboxylic acid group of GABA or baclofen derivatives with either the phosphinic acid or the methylphosphinic acid residue. Surprisingly, ethyl- and higher alkylphosphinic acid derivatives of GABA yielded novel GABAB antagonists, which are described in part 2 of this series. Structure-activity relationships of the novel GABAB agonists are discussed with respect to their affinities to GABAB receptors as well as to their effects in many functional tests in vitro and in vivo providing new muscle relaxant drugs with significantly improved side effect profiles.

CGP 36742: the first orally active GABAB blocker improves the cognitive performance of mice, rats, and rhesus monkeys.

The learning capacity of experimental animals in cognitive tests can be improved by blockade of the GABAB receptors. After treatment with the GABAB antagonist CGP 36742, mice performed better in a passive-avoidance test; rats did likewise in a partner-recognition test, and rhesus monkeys also in a "conditional spatial color" task. The effects demonstrated in these three different species and covering diverse manifestations of learning and memory give reason to hope that this new active principle may prove therapeutically useful.

Brofaromine: a monoamine oxidase-A and serotonin uptake inhibitor.

Brofaromine is a tight-binding, reversible inhibitor of monoamine oxidase-A (MAO-A), with concomitant serotonin (5-HT) uptake-inhibiting properties. In psychopharmacologic investigations, the compound shows the properties expected of an MAO inhibitor, antagonizing the effects of reserpine, tetrabenazine, and 5-hydroxytryptophan in rats and mice, and suppressing rapid eye movement sleep in cats. Brofaromine showed antidepressant-like activity in a rat social conflict test. In radioligand binding assays, brofaromine exhibited weak or no interaction with alpha 1- and alpha 2-noradrenergic, 5-HT1, 5-HT2, 5-HT3, cholinergic, histamine H1 and H2, mu-opiate, GABAA, benzodiazepine, adenosine, neurotensin, and substance P receptors. Comparison of in vitro and in vivo potencies to inhibit 5-HT uptake with those of reference drugs, and direct evidence in patients and volunteers suggest that 5-HT uptake inhibition plays a role in the clinical profile of brofaromine.

Behavioral effects and general pharmacology of 4-(5-chloro-benzofuranyl-2)-1-methylpiperidine HC1, an antidepressant inhibiting both monoamine oxidase A and 5-hydroxytryptamine uptake.

In psychopharmacological tests in rats and mice, 4-(5-chloro-benzofuranyl-2)-1-methylpiperidine HC1 (CGP 4718 A) was found to exert behavioral effects typical of both monoamine oxidase (MAO)-A and 5-hydroxytryptamine (5-HT) uptake inhibitors (reserpine antagonism, L-5-HTP potentiation, antiaggressive activity in isolated mice). The potential antidepressant activity of the drug was indicated in rats by antagonism of reserpine and its effect in the social-conflict test. CGP 4718 A did not impair motor coordination and had no influence on locomotor activity up to high doses in mice and rats. In monkeys, it increased directed individual activities, including sex-related behaviors and diminished locomotor activity and passivity. Electroencephalographic studies in cats revealed a significant decrease in paradoxical sleep after treatment with CGP 4718 A. In isolated organs, no significant antagonism of norepinephrine, 5-HT, acetylcholine or histamine was found. Cardiovascular studies in cats showed only transient effects on blood pressure and no effect on heart rate. In conscious dogs no cardiovascular effects were found. No potentiation of the pressor effect of tyramine in rats was detectable after repeated doses of up to 300 mg/kg p.o. A weak cardiodepressant effect was seen in isolated guinea pig atria. In conclusion, in animal experiments CGP 4718 A combines an interesting spectrum of antidepressant, activating and antiaggressive properties with a lack of cardiovascular and tyramine-potentiating effects.