MANAGEMENT OF UNCONTROLLED GLAUCOMA WITH THE MOLTENO SYSTEM

In glaucomatous eyes refractory to medication, laser techniques and conventional drainage surgery, intraocular pressure is often high, and visual loss rapid. In this situation a reliable, robust artificial outflow system is required. Molteno has evolved a plastic tube and plate device combined with a fibrosis suppression medication regimen. Thirty-eight eyes of 32 patients with uncontrolled glaucoma were treated with the Molteno system. Six months after operation mean intraocular pressure had been reduced from 41.0 ± 13.6 to 16.2 ± 5.6 mmHg. Eighteen eyes had pressures of 20 mmHg or less on no hypotensive therapy, 17 on reduced treatment. Three eyes had a pressure of 21 to 35 mmHg on treatment at six months. The 13 aphakic eyes responded as well as 25 phakic eyes. Five eyes with rubeotic glaucoma demonstrated pressures of less than 20 mmHg without therapy, four eyes with traumatic glaucoma required continuing medication with three having pressures below 22 mmHg. Of the seven eyes with uveitic glaucoma, one was lost, two required maintenance therapy; five of six surviving eyes had pressures below 20 mmHg. Fifteen eyes with congenital or juvenile glaucoma achieved pressures below 20 mmHg, three of these with timolol drops, three with timolol and acetazolamide, and nine with no treatment. While seven of seven eyes with refractory primary open-angle glaucoma attained pressures below 20 mmHg. all seven needed continuing mild hypotensive therapy. Eleven eyes underwent a one-stage procedure, while 27 eyes required a two-stage operation. Twenty-eight eyes received fibrosis suppression medication after the second stage, and 24 maintained or improved their preoperative visual acuity. Results have been encouraging: in general the Molteno system is recommended as the second drainage operation in all glaucomatous eyes in which conventional therapy has failed, and as the primary surgical procedure (after laser techniques) in eyes with rubeotic and uveitic glaucoma. Ciliary body destructive procedures should be restricted to control of symptoms in blind eyes.     

Issues to debate on the Women's Health Initiative: estrogen: an instrument or the conductor of the orchestra?

Although it is well known that cyclic production of sex hormones is essential to establish reproductive function and female characteristics, distant impacts of the activity of the female endocrine system result from a concert of delicate mechanisms. Estrogen is rather an instrument than a conductor in this physiological orchestra of the female. Thus, controversies in the explanation of results from studies on hormone replacement therapy (HRT) and cardiovascular disease (CVD) prevention might be eliminated, if we analyse not only the role of estrogen but a broader spectrum of factors leading to CVD. Authors would like to hypothesize that haemorheological changes in women around menopause, such as increased blood and plasma viscosity, haematocrit and fibrinogen, are largely responsible for the increased mortality in the post-menopausal life period. We believe that a cyclic withdrawal bleeding establishes a more favourable haemorheological condition, thus, sequentially administered estrogen might be protective in post-menopausal women. Nevertheless, other factors, that decrease blood viscosity, such as daily exercise, intake of ample amount of fluids as well as ideal nutrition, are equally important. We are confident that sequential HRT, as well as healthy life style and risk prevention programmes have their proper place in the management of this issue.     

T helper cell-mediated interferon-gamma expression after human parvovirus B19 infection: persisting VP2-specific and transient VP1u-specific activity

Human parvovirus B19 is a small non-enveloped DNA virus with an icosahedral capsid consisting of proteins of only two species, the major protein VP2 and the minor protein VP1. VP2 is contained within VP1, which has an additional unique portion (VP1u) of 227 amino acids. We determined the ability of eukaryotically expressed parvovirus B19 virus-like particles consisting of VP1 and VP2 in the ratio recommended for vaccine use, or of VP2 alone, to stimulate, in an HLA class II restricted manner, peripheral blood mononuclear cells (PBMC) to proliferate and to secrete interferon gamma (IFN-gamma) and interleukin (IL)-10 cytokines among recently and remotely B19 infected subjects. PBMC reactivity with VP1u was determined specifically with a prokaryotically expressed VP1u antigen. In general, B19-specific IFN-gamma responses were stronger than IL-10 responses in both recent and remote infection; however, IL-10 responses were readily detectable among both groups, with the exception of patients with relapsed or persisting symptoms who showed strikingly low IL-10 responses. Whereas VP1u-specific IFN-gamma responses were very strong among the recently infected subjects, the VP1u-specific IFN-gamma and IL-10 responses were virtually absent among the remotely infected subjects. The disappearance of VP1u-specific IFN-gamma expression is surprising, as B-cell immunity against VP1u is well maintained.     

Degeneration and electron microscope analysis of the synaptic glomeruli in the lateral geniculate body

Summary Optic fibers of retinal origin terminate in the lateral geniculate body exclusively in the so called glomerular synapses. They can be recognized on the basis of their unusually large irregular mitochondria having very few cristae. In the cat the structure of the optic terminal profiles is rather dense. The majority of terminals in most glomeruli originate from axons of other source. Relatively large axon terminal profiles of unusually light structure cannot be brought to degeneration by any interference with extraneous pathways. From Golgi information it becomes obvious that they originate from local Golgi 2nd type neurons. Small rather dense axonal profiles of the glomeruli can occasionally be traced back by degeneration to the occipital cortex (parastriate), although most of the descending cortical afferents of the lateral geniculate body terminate outside the glomeruli on more proximal parts of the dendrites. — Axo-axonic synapses are very frequent. If an optic terminal is involved, it appears that by structural standards it is presynaptic to the non optic. As judged, however, from the numerous axoaxonic contacts persisting after enucleation, many of the contacts are established between non optic axon terminals. — The progress of secondary degeneration and particularly the removal from the glomeruli of degeneration fragments is unexpectedly rapid. — The possible functional significance of these findings, especially also with regards to presynaptic inhibition, is discussed.     

LHRH Analogue Treatment for the Prevention of Premenstrual Attacks of Acute Porphyria

We have assessed the value of suppressing ovulation with theluteinizing hormone releasing hormone (LHRH) analogue buserelinin seven patients experiencing crises of acute intermittentporphyria related to the menstrual cycle. Clinical course, plasmaoestradiol and progesterone levels, and urinary porphyrin andprecursor excretion were monitored over a baseline period ofapproximately one year, and then for a similar period on buserelintreatment. There was a trend towards clinical improvement onbuserelin therapy. The median number of attacks fell from sevenduring the baseline period to three on treatment (p=0.06). Theresponse to buserelin varied considerably, with those patientsin whom the association between baseline attacks and the menstrualcycle was strongest gaining the most benefit. All patients becameamenorrhoeie with suppression of plasma oestradiol and progesteronelevels. Urinary aminolaevulinic acid and total porphyrin excretionfluctuated widely both before and during treatment. Our experienceindicates that ovulation suppression may be of value in themanagement of young women in whom recurrent attacks of porphyriaare related to the menstrual cycle.     

Exogenous insulin-like growth factor II enhances post-infarction regional myocardial function in swine

OBJECTIVES: Insulin-like growth factor II (IGF-II) promotes cardiac myocytegrowth and contractility in vitro. This study was designed toinvestigate the effect of exogenous IGF-II on regional myocardialfun ction at the area of infarct in the pig. METHODS: Myocardial infarction was induced in 12 female anoesthetizedpigs by affigel blue beads, embolizing microvessels of the leftanterior descending coronary artery distribution. In the experimentalgroup (n=6), IGF-II (0.12 µg. kg^–1 in two animalsand 0.6 µg. kg^–1 in four) was incorporated intothe beads and delivered by them to the infarct area. Myocardialfunction was followed echocardiographically, and the excisedheart was analysed immunohistochemically and histopathologically. RESULTS: Myocardial function in injured zones, inversely related to anechocardiographic segmental wall motion score (mean ±SEM), was similar between the two groups at baseline, but at4 weeks post-infarction was significantly (P=0.008) reducedin the control group (0.58± 0.38 vs 3.42 ± 0.84),in contrast to nearly baseline values in the experimental group(0.58 ± 0.33 vs 1.17 ± 0.42, P=0.41). Cardiacperformance in injured segments was sign better after myocardialinjury in the experimental group (P=0.04). Tissue samples fromboth groups (4 weeks post-infarction), stained with haematoxylinand eosin demonstrated pen-infarct myocyte hypertrophy, correspondingto regions selectively stained by an antibody for CD56, whichhighlights growing cardiac myocytes. By image analysis semi-quantification,staining for CD56 was significantly (P=0.04) higher in the peri-infarctregion of the experimental group, as compared with controls(106.5 ± 2.8 vs 92 ± 4.4 gray level units). Microvesselsstained for von-Willebrand factor were similar in nwnber inboth groups (P=0.8), as were mesenchymal cells stained for vimentin(P=0.7). CONCLUSIONS: Exogenous IGF-II, delivered to the infarct area amelioratesregional cardiac function in the pig, perhaps by inducing peri-infarctmyocyte growth.     

Specific activation of the mu opioid receptor (MOR) by endomorphin 1 and endomorphin 2

The recently discovered endomorphin 1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin 2 (Tyr-Pro-Phe-Phe-NH2) were investigated with respect to their direct receptor-binding properties, and to their ability to activate G proteins and to inhibit adenylyl cyclase in both cellular and animal models. Both tetrapeptides activated G proteins and inhibited adenylyl cyclase activity in membrane preparations from cells stably expressing the mu opioid receptor, an effect reversed by the mu receptor antagonist CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2), but they had no influence on cells stably expressing the delta opioid receptor. To further establish the selectivity of these peptides for the mu opioid receptor, brain preparations of mice lacking the mu opioid receptor gene were used to study their binding and signalling properties. Endomorphin 2, tritiated by a dehalotritiation method resulting in a specific radioactivity of 1.98 TBq/mmol (53.4 Ci/mmol), labelled the brain membranes of wild-type mice with a Kd value of 1.77 nM and a Bmax of 63.33 fmol/mg protein. In membranes of mice lacking the mu receptor gene, no binding was observed, and both endomorphins failed to stimulate [35S]guanosine-5'-O-(3-thio)triphosphate ([35S]GTPgammaS) binding and to inhibit adenylyl cyclase. These data show that endomorphins are capable of activating G proteins and inhibiting adenylyl cyclase activity, and all these effects are mediated by the mu opioid receptors.     

Heat- and 4-hydroperoxy-ifosfamide-induced apoptosis in B cell precursor leukaemias.

In the group of high risk childhood acute lymphoblastic leukaemia (ALL), very early and early relapses have a very poor prognosis with conventional chemotherapy alone. Remission induction in these patients is often hindered by drug resistance. Thus, intensifying chemotherapy strategies are required. Application of hyperthermia enhances efficacy of certain anti-neoplastic drugs such as ifosfamide. In this study, effects and molecular mechanisms of ifosfamide - and hyperthermia-induced apoptosis are investigated in a B cell precursor leukaemia cell line (REH) and in primary patient-derived B cell progenitor leukaemic blasts. Both 4OOH-IFA and hyperthermia are able to induce cell death in leukaemic cells, mainly by induction of caspase-dependent apoptosis. However, completely different kinetics of caspase-3, -8 and -9 activation are found for both stimuli. In addition, activation of caspase-1 is only observed following stimulation with hyperthermia. Combined application of ifosfamide and hyperthermia reveals increased cytotoxicity in both the leukaemia cell line and in 5/8 of the patient-derived leukaemic blast samples. In conclusion, hyperthermia and ifosfamide mediate cytotoxicity in B precursor leukaemic blasts by different kinetics of caspase activation. This might explain the additive effects of 4OOH-IFA and heat on leukaemic cell death. Therefore, whole body thermochemotherapy could be considered as a treatment option in relapsed leukaemic patients.     

Neoadjuvante Therapiekonzepte beim Zervixkarzinom

Bei vielen Organentitäten ist das neoadjuvante Konzept mittlerweile etablierter Bestandteil der Therapie. Die neoadjuvante Therapie scheint auch in speziellen Situationen für Zervixkarzinompatientinnen interessant. Dieser Artikel soll einen Überblick über die aktuell diskutierten Einsatzgebiete in der Neoadjuvanz beim Zervixkarzinom darlegen, die verschiedenen Optionen werden besprochen. Als Grundlage für diesen Artikel dient die S3-Leitlinie Diagnostik, Therapie und Nachsorge der Patientin mit Zervixkarzinom AWMF(Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften)-Registernummer 032/033OL in der Version von 2014. Diese wurde durch die Literatur zur Update-Recherche der Neufassung der Leitlinie erweitert. Die NACT(neoadjuvante Chemotherapie)-Ansprechrate liegt bei 84 %, das progressionsfreie Überleben (PFS) über 5 Jahre und das Gesamtüberleben (OS) betragen 61,9 und 72,8 %. Das Ansprechen auf eine NACT korreliert mit einem besseren Langzeitüberleben. In einer Cochrane-Analyse von 2012 wurde gezeigt, dass eine neoadjuvante Chemotherapie vor geplanter Operation zu einer Verbesserung des PFS (HR [Hazard Ratio] 0,75, 95 %-KI [Konfidenzintervall] 0,61–0,93, p = 0,008) und des Gesamtüberlebens (HR 0,77, 95 %-KI 0,62–0,96, p = 0,02) führt. Unter Berücksichtigung des Random-Effekt-Modells war der Effekt aber nicht mehr signifikant (OR [Odds Ratio] 0,60, 95 %-KI 0,32–1,12, p = 0,11). Bei makroinvasiven Karzinomen in der Schwangerschaft vor einer möglichen Entbindung ist die NACT fester Bestandteil der Therapie. Die Datenlage zum Einsatz der neoadjuvanten Therapie beim Zervixkarzinom ist unklar. Die neoadjuvante Therapie ist aktuell kein Standard in der Behandlung des Zervixkarzinoms. Ungeklärt ist auch die Rolle des operativen Stagings und positiver Lymphknoten nach der neoadjuvanten Therapie. In verschiedenen Metaanalysen konnte gezeigt werden, dass die neoadjuvante Therapie das PFS und das OS verbessert. Dies gilt insbesondere für Frauen, die auf die neoadjuvante Therapie angesprochen haben.