The cell cycle and induction of apoptosis in a hamster fibrosarcoma cell line treated with anti-cancer drugs: Its importance to solid tumour chemotherapy*

The induction of apoptosis by anticancer drugs and its relationship to stages of the cell cycle was studied in cells derived from a solid tumour; a highly malignant hamster fibrosarcoma (Met B). Asynchronously proliferating cells were treated with a wide variety of agents such as actinomycin-D, 1--D-arabinofuranosyl cytosine, camptothecin, cisplatin, cyclophosphamide, daunorubicin, 5-flurouracil, 6-mercaptopurine, hydroxyurea, ionomycin, methotrexate and vincristine. With the exception of cyclophosphamide and hydroxyurea, a 36 h exposure to these drugs resulted in inhibition of cell growth and apart from cyclophosphamide, hydroxyurea, 6-mercaptopurine and cisplatin the induction of apoptosis. Studies using a decreased concentration of drug and exp osure time (12 h) followed by examination of cells using flow cytometry indicated that most drugs were capable of affecting cell cycle progression without induction of apoptosis. However when cells were synchronised at G₀/G₁, S and G₂/M phases and then exposed to these decreased concentrations of drug apart from 6MP an HU, apoptosis was observed and for the majority of drugs it took place in the same phase in which progression through the cell cycle was blocked by the drug. Cells synchronised in G₀/G₁ phase were more susceptible to methotrexate, whereas S-phase cells were more susceptible to camptothecin and 5-flurouracil and G₂/M phase cells more susceptible to actinomycin D, 1--D-arabinofuranosyl cytosine, daunorubicin and cisplatin. In contrast, vincristine blocked cells in G₂/M phase but exerted its apoptotic effect in S-phase cells, ionomycin had no effect on the cell cycle, but G₂/M cells appeared to be more susceptible to the effect of this drug. These data indicate that entry into apoptosis by this fibrosarcoma may occur at any point in the cell cycle. They also demonstrate a correlation between the action of some anticancer drugs on the cell cycle and the subsequent induction of apoptosis which may be useful in chemotherapeutic design.     

Prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawning: involvement of nitric oxide

The possible involvement of nitric oxide in the prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawning was investigated by measuring the concentration of NO₂- and NO₃- in the dialysate obtained with a vertical microdialysis probe implanted in the paraventricular nucleus of the hypothalamus of male rats. Either apomorphine (80 μg/kgs.c.) or oxytocin (30 ng i.c.v.) increased significantly basal NO₂- and NO₃- concentration in the paraventricular dialysate, penile erection and yawning. Morphine (1, 5 and 10mg/kg i.p.) prevented dose-dependently either apomorphine or oxytocin responses when given 15min before apomorphine or oxytocin. Prevention by morphine of apomorphine and oxytocin responses was abolished by naloxone (3mg/kg i.p.) given 15min before morphine. Morphine prevented apomorphine and oxytocin responses also when given in the lateral ventricles or directly in the paraventricular nucleus. In contrast, the selective agonist of the kappa opioid receptor subtype U-69,593 was found to be ineffective. The present results confirm previous findings showing that morphine acts through μ receptors in the paraventricular nucleus to prevent apomorphine and oxytocin-induced penile erection and yawning and suggest that this morphine effect is mediated by a decreased activity of nitric oxide in the paraventricular nucleus of the hypothalamus. Received: 30 September 1996 / Accepted: 24 January 1997     

Interactions between imidazoline compounds and sulphonylureas in the regulation of insulin secretion

1. Imidazoline α₂-antagonist drugs such as efaroxan have been shown to increase the insulin secretory response to sulphonylureas from rat pancreatic B-cells. We have investigated whether this reflects binding to an islet imidazoline receptor or whether α₂-adrenoceptor antagonism is involved.
2. Administration of (±)-efaroxan or glibenclamide to Wistar rats was associated with a transient increase in plasma insulin. When both drugs were administered together, the resultant increase in insulin levels was much greater than that obtained with either drug alone.
3. Use of the resolved enantiomers of efaroxan revealed that the ability of the compound to enhance the insulin secretory response to glibenclamide resided only in the α₂-selective-(+)-enantiomer; the imidazoline receptor-selective-(−)-enantiomer was ineffective.
4. In vitro, (+)-efaroxan increased the insulin secretory response to glibenclamide in rat freshly isolated and cultured islets of Langerhans, whereas (−)-efaroxan was inactive. By contrast, (+)-efaroxan did not potentiate glucose-induced insulin secretion but (−)-efaroxan induced a marked increase in insulin secretion from islets incubated in the presence of 6 mM glucose.
5. Incubation of rat islets under conditions designed to minimize the extent of α₂-adrenoceptor signalling (by receptor blockade with phenoxybenzamine; receptor down-regulation or treatment with pertussis toxin) abolished the capacity of (+)-and (±)-efaroxan to enhance the insulin secretory response to glibenclamide. However, these manoeuvres did not alter the ability of (±)-efaroxan to potentiate glucose-induced insulin secretion.
6. The results indicate that the enantiomers of efaroxan exert differential effects on insulin secretion which may result from binding to effector sites having opposite stereoselectivity. Binding of (−)-efaroxan (presumably to imidazoline receptors) results in potentiation of glucose-induced insulin secretion, whereas interaction of (+)-efaroxan with a second site leads to selective enhancement of sulphonylurea-induced insulin release.

     

Antiepileptic drug treatment in the nineties in The Netherlands.

In this review the state of the art of treating patients with epilepsy in the nineties in the Netherlands is presented. It describes general strategies for treatment with antiepileptic drugs and the history of development of the classical anticonvulsant drugs. Eight new drugs, including vigabatrin, lamotrigine, felbamate, oxcarbazepine, gabapentin, tiagabine, levetiracetam and topiramate are discussed. A review of their pharmacological and clinical properties is presented. Dutch experience with these drugs is included.     

The protective effect of thromboxane A2 synthetase inhibitor against ischemic liver injury

To evaluate the role of thromboxane A₂ (TXA₂) in ischemic liver injury, the serum changes in thromboxane B₂ (TXB₂) and 6-keto-prostaglandin F₁ alpha (6-K-PGF₁) following warm ischemia of the total canine liver were examined, and the protective effect of a TXA₂ synthetase inhibitor was assessed. Total liver ischemia was performed for 60 min on two groups of dogs: a control group, in which ischemia alone was performed, and an OKY-046 group, which received a TXA₂ synthetase inhibitor. A temporary active portacaval shunt was used to eliminate the effects of splanchnic venous stasis during clamping of the hepatic pedicle. Postoperative changes in liver function, assessed by the transaminase enzyme levels, and in prostaglandins were recorded and the histologic liver findings of both groups 1 week after ischemia were compared. The levels of 6-K-PGF₁ increased after reperfusion in both groups, while those of TXB₂ increased in the control group but maintained low levels in the OKY-046 group. Liver function was better and histologic changes less marked in the OKY-046 group than in the control group, suggesting the important role of TXA₂ in ischemic liver injury and the usefulness of a TXA₂ synthetase inhibitor for protecting the liver against ischemic injury.     

Munchausen syndrome by proxy and factitious illness: Symptomatology,parent-child interaction,and psychopathology of the parents

The term Munchausen syndrome by proxy is used to diagnose children presenting symptoms of an organic disorder resulting from manipulations initiated by their caretakers. Even in early infancy it happens that injuries are induced, and that drugs, poisons or medicine are administered in order to provoke and feign clinical symptoms of severe diseases. Exact data on prevalence are not available but it is obvious that Munchausen syndrome by proxy is a rare psychiatric disorder. There is a body of evidence that Munchausen syndrome by proxy is nothing but the extreme of a broader clinical entity for which the term factitious illness has been introduced. In this group children are included whose mothers invent a history of disease in order to produce symptoms without actually damaging their children. It is not well established whether such a distinction is necessary and whether there are differences in long-term outcome. Onset of symptoms is as early as three weeks up to twelve years, and mean age of diagnosis according to a more comprehensive study is 3 1/4 year. The estimated mortality rate of children with Munchausen syndrome by proxy is 9 percent. In three of the four cases of children reported here clinical presentations were dominated by symptoms of central nervous disorders. All mothers showed unsure and inconsistent parental behaviour and inefficient coping. None of them received support from their partners, if present. In interaction the children always wanted to dominate their mothers. The high amount of personality disorders observed in the caretakers might be the reason for the often reported failure of psychotherapeutic interventions.

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Zusammenfassung Die Diagnose Münchhausen Stellvertreter Syndrom wird bei Kindern gestellt, die Symptome einer organischen Erkrankung zeigen, die durch Manipulationen von Eltern oder anderen Sorgeberechtigten hervorgerufen werden. Vielfach werden bereits im frühen Kindesalter den Kindern Verletzungen beigebracht, Drogen, Gifte oder Medikamente verabreicht, um die klinischen Merkmale schwerer Erkrankungen vorzutäuschen. Obwohl genaue Angaben zur Häufigkeit fehlen, kann man insgesamt von einer seltenen Störung ausgehen. Es gibt zahlreiche Hinweise dafür, daß es sich beim Münchhausen Stellvertreter Syndrom um die seltene, aber sehr schwere Ausprägungsform in einer größeren Gruppe von Störungen gleichartigen klinischen Bildes handelt, für die man den Begriff der vorgetäuschte Störungen geprägt hat. In dieser Gruppe werden auch die Kinder erfaßt, deren Mütter ausschließlich Symptome und eine zugehörige Krankheitsgeschichte erfinden, die aber keine körperlichen Eingriffe (einschließlich Drogen- und Medikamentenverabreichung) vornehmen, um organische Symptome zu simulieren. Unklar ist, ob eine solche Unterscheidung notwendig und hilfreich ist. Bisher fehlen Hinweise auf Unterschiede in der Prognose im Langzeitverlauf zwischen den Untergruppen. Die Symptomatik eines Münchhausen Stellvertreter Syndroms konnte bereits bei Kindern im Alter von 3 Wochen beobachtet werden und wurde noch bei 12jährigen gefunden. In einer größeren Studie wurde ein mittleres Alter von 3 3/4Jahren für den Zeitpunkt der Diagnosestellung ermittelt. Die Sterblichkeitsrate wird auf 9 Prozent geschätzt. Bei den vier Kindern, über deren Symptomatik hier berichtet wird, standen bei drei zentralnervöse Störungen im Vordergrund. Drei Mütter gaben zusätzlich den Verdacht des sexuellen Mißbrauchs ihrer Kinder an. Die motivationalen Aspekte lassen deudiche Unterschiede erkennen. Bei drei Müttern bestand der Wunsch nach Schutz des Kindes vor realem oder vermeintlichem sexuellem Mißbrauch des Kindes. Alle Mütter hatten mindestens eine gescheiterte eheliche Beziehung. Im Erziehungsverhalten wirkten sie unsicher, inkompetent und inkonsistent; von ihren Partnern, sofern vorhanden, erhielten sie keine erzieherische Unterstützung. In der Mutter-Kind Interaktion vermochten die Kinder über die Mütter zu dominieren. Der hohe Anteil an Persönlichkeitsstörungen bei den hier beschriebenen Sorgeberechtigten könnte der Grund für das häufig berichtete Scheitern psychotherapeutischer Interventionen sein.

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Résumé On parle de Syndrôme de Munchausen par procuration chez des enfants, qui présentent des troubles organiques résultant de manipulations de leurs responsables éducatifs. Des blessures, l'administration de médicaments, de drogues ou de poison — même chez des enfants très jeunes — ont pour effet de provoquer et simuler un tableau clinique sévère. Il s'agit d'un désordre psychiatrique rare — les chiffres exacts de prévalence sont difficiles à évaluer. Le Syndrome est décrit chez l'enfant à partir de l'âge de trois semaines jusqu'à 12 ans. L'âge moyen est de trois ans et quart. La mortalité chez les enfants porteurs d'un syndrome de Munchausen par procuration est estimé à 9%. Dans trois des quatre cas présentés le tableau clinique est dominé par des symptômes d'ordre neurologique. De manière supplémentaire trois mères rapportent un abus sexuel de leurs enfants. Les mères se caracterisent par leur incompétence et inconséquence éducative; souvent elles sont sans soutien éducatif de leur partenaire. Dans l'interaction mère — enfant les enfants ont un comportement dominant envers leur mère. La non-efficacité des interventions psychothérapeutiques peut être liée a un pourcentage élevé de troubles de la personnalité chez les parents.

     

中药材“地区习惯用药”渐趋分化论

论述了中药材“地区习惯用药”的由来与含义,近现代和历史上的“地区习惯用药”的实例以及产生“地区习惯用药”的原因,随品种性质判明而渐趋分化等。最后提出应该积极研究,促其分化,按其本质分类处理的建议。     

Evaluation of regional haemodynamics and alterations of vascular wall of the lower limbs in hypertensive subjects

This study was designed to analyse the relationship betweenarterial hypertension and changes in arterial blood flow andvascular wall damage of the lower limbs in hypertensive patientswith various degrees of hypertension. Six hundred and fifty-four hypertensive patients (421 malesand 233 females) aged 35 to 70 years and 88 healthy subjects(63 males and 25 females) aged 39 to 60 years were studied.Strain-gauge plethysmography of the lower limbs was used tocalculate arterial calf blood flow (RF), arterial calf bloodflow after post-ischaemic hyperaemia (PF), basal and minimalvascular resistances (BVR and MVR), time to reach peak flow(tPF), time until 50% reduction of peak flow (tT) and totalrecovery time (tT). In 108 (67 males and 41 females) of the hypertensive patients,a morphological study by echo-Doppler duplex scanning of thepopliteal artery was performed to measure medial-intimal thickeningand popliteal lumen diameter. Our results indicate that regional haemodynamics of the lowerlimbs worsened in hypertensives in comparison with control subjects.In addition, the change in peripheral haemodynamics was relatedto the degree of hypertension. Moreover, medial-intimal thickeningwas significantly (P<0.05) higher in severe hypertensivesthan mild hypertensives. Popliteal lumen diameter was significantly(P<0.05) lower in severe hypertensives than moderate andmild hypertensives. In all these subjects mean blood pressurewas correlated directly (r=0.31; P<0.001) with medial-intimalthickening and inversely (r= – 0.37; P<0.001) withpopliteal lumen diameter. Multiple regression analysis indicatedthat mean blood pressure, age and serum cholesterol were independentlycorrelated to medial-intimal thickening. This relationship wasnot influenced by the diabetic patients and smokers among thegroups. Our results indicate that hypertension impairs peripheral flowand encourages the development of medial-intimal thickening.     

大鼠三叉神经本体觉中枢传导通路的电生理学证明

近年来形态学上发现了三叉神经领域本体感觉中枢通路,在此基础上,本文用电生理学方法,通过电刺激咬肌神经和压下颌,观察了由四级神经元组成的此通路的二级（三叉神经脊束核吻侧亚核背内侧部及邻接的网状结构）、三级（沿三叉神经感觉主核内缘存在的“带状区”）中继核团以及作为最后驿站的丘脑腹后内侧核等处的单位放电反应;另外又分别刺激或损毁二、三级中继核团,观察了丘脑腹后内侧核的单位放电变化,结果证明电刺激咬肌神经和压下颌,在上述核团都出现对本体觉冲动反应的单位放电,包括兴奋性反应单位、抑制性反应单位和无关单位三种类型,以兴奋性单位为主,占神经元单位放电总数的５２．９％～６７．７％．分别刺激二和三级神经元的所在核团,在丘脑腹后内侧核处发生相应的单位放电效应;损毁二和三级核团,本体觉传入冲动被阻断。本研究结果从电生理学上确证了形态学上发现的三叉神经本体感觉中枢通路的客观存在,从定性研究方面支持了定位研究的结果,并填补了以往生理学上只证明初级传入核团与丘脑腹后内侧核之间存在着一条多突触联系的本体觉传递通路但未能判断其具体行径和中继部位的空白,本研究并对方法论以及一些有关问题进行了讨论．     

Single forebrain ventricle without prosencephaly: agenesis of the corpus callosum with dehiscent fornices

Coalescence of the cerebral ventricles with formation of a single forebrain ventricle is described in an unusual case of agenesis of the corpus callosum with dehiscent fornices and severe hydrocephalus. The cerebral hemispheres were fully cleaved. The detached fornices were widely separated from the thalami. The membrana tectoria was retroverted over the midbrain and cerebellum, where it joined the fornices and merged with a curved membranous ependymal dome which, at a great distance, circumvented the thalami as it extended toward the anterior commissure. Other anomalies included arhinencephaly, multiple subependymal heterotopias, and Dandy-Walker malformation. Similar malformations have been described as interhemispheric cysts, as (holo)prosencephaly, or as midline telencephalic dysgenesis. The basic features of prosencephaly and agenesis of the corpus callosum are reviewed and compared to the present case.