Raf-1 kinase,epidermal growth factor receptors,and mutant ras proteins in colonic carcinomas

Epidermal growth factor receptors (EGFR) andras mutations are known to play a significant role in controlling cell growth and tumor promotion. Both of them transmit mitogenic signals to the nucleus by activation of Raf-1 kinase. In this study, the expression of EGFR and mutant Ras proteins, and, for the first time, the expression, phosphorylation and kinase activity of Raf-1 kinase have been determined in paired samples of colorectal cancer and mucosa. The tumor and mucosa samples did not differ significantly with regard to Raf-1 kinase content and activity. A major difference between tumors and mucosa was found, however, in the phosphorylation of Raf-1. Most of the mucosa samples (13/20), but only 1/20 of the cancer samples, contained hyperphosphorylated Raf-1. EGFR were significantly (p=0.0025) decreased in the tumors. The decreased phosphorylation of Raf-1 in colonic carcinomas could be the result of activation of Raf-1 phosphatases or inactivation of kinases phosphorylating Raf-1. New forms of treatment based on EGFR overexpression do not seem to be suitable for the majority of colonic cancers.This work was supported by the state of Baden-Württemberg (Verbundforschungsprojekt: Aufklärung von Mechanismen der Tumorentstehung und Tumorabwehr).     

Infradian biorhythms of enzymuria in man?

The temporal courses of dipeptidyl peptidase IV gamma-glutamyltransferase and alanine aminopeptidase were followed over 70 days in the morning urine of 15 healthy persons. Subsequent to basic statistical analysis a two-step procedure was performed, including spectral analysis and the fit of a cosine function by non-linear regression. The excretion of the 3 enzymes followed an infradian biorhythm with a mean period length of 10.04 for dipeptidyl peptidase IV, 13.34 for gamma-glutamyltransferase and 10.17 for alanine aminopeptidase. In addition to the basic rhythmic process described by the fitted cosine functions, in most of the enzyme patterns steap peaks of very high excretory activity appeared which was verified in repeated measurements. These infradian biorhythms with changes in the range of 100% and more, as well as their interindividual variations, have to be considered in assessing the excretion of enzymes.     

Splicing of the mitochondrial group-II intron rl1: conserved intron-exon interactions diminish splicing efficiency

The mitochondrial intron rI1 is a self-splicing group-II intron of algal mitochondria that can be transferred into chloroplasts from the green alga Chlamydomonas reinhardtii for in vivo investigations (Herdenberger et al. 1994). Thus, rI1 is a suitable system to compare in vitro and in vivo RNA processing. Interestingly, rI1 shows correct RNA splicing, although typical cis-acting exon-sequences (IBS2, δ) of group-II introns are lacking. In order to examine the effect of these exon-intron interactions on splicing, we introduced the endogenous mitochondrial IBS2 sequence in order to produce optimal IBS2-EBS2 base pairing. In addition, the first nucleotide of the 3′exon (δ′) was substituted to create an optimal δ-δ′ interaction. Neither of the two mutations, nor a combination of both, had any effect on the precision of the splice-site selection. Unexpectedly, introduction of IBS2 led to a reduction in the efficiency of the second splicing step in vitro but not in vivo. These findings lead us to conclude that trans-acting factors are present in vivo to optimize splicing efficiency. The possibility is discussed that these factors may, for example, stabilize tertiary intron structures that are a prerequisite for correct RNA processing. Furthermore, our data indicate that similar trans-acting factors promote correct intron splicing in chloroplasts and mitochondria. Received: 18 October / 4 December 1997     

rt-PA Lyse bei Patienten mit schwerer Lungenembolie und rechtskardialen Transitthromben Diagnostik und Verlaufskontrolle mit Hilfe der transösophagealen Echokardiographie

Zusammenfassung Bei Nachweis von rechtskardialen Thromben handelt es sich in den meisten F?llen um sogenannte ,,Transit-Thromben`` aus dem peripheren Venensystem, die nur kurz im rechten Herzen verweilen. Die Inzidenz von transthorakal echokardiographisch nachgewiesenen ,,Transit-Thromben`` bei Patienten mit Lungenembolie liegt bei etwa 3 – 4%. Unbehandelt ist die Letalit?tsrate dieser Patienten jedoch auf Grund der hohen Rate konsekutiver fulminanter Lungenembolien sehr hoch (30 – 40%). Bis vor einigen Jahren galt die operative Embolektomie als das Therapieverfahren der Wahl, das jedoch heute zunehmend durch die systemische, intraven?se Lysetherapie als Alternative ersetzt wird. Im Zeitraum von 1/94 bis 12/95 wurden in unserer Klinik 66 Patienten mit nachgewiesener Lungenembolie behandelt. Bei sieben dieser Patienten mit schwerer oder fulminanter Lungenembolie (10,6%; 5 M?nner, 55 – 74 Jahre alt) fanden sich rechtskardiale Thromben, die in allen F?llen mittels transthorakaler/ trans?sophagealer Echokardiographie (TEE) diagnostiziert wurden. In sechs F?llen sahen wir extrem mobile, wurmf?rmige Thromben im rechten Atrium, die zum Teil diastolisch tief in den rechten Ventrikel prolabierten. Bei einem Patienten waren die Thromben im rechten Ventrikel lokalisiert und fielen ventrikel-systolisch in den rechtsventrikul?ren Ausflu?trakt. In drei F?llen lie?en sich mittels TEE auch Thromben in der rechten Pulmonalarterie darstellen. Fünf Patienten wurden unmittelbar im Anschlu? an die TEE-Untersuchung ohne weitere angiographische Diagnostik mit einer systemischen, intraven?sen Lysetherapie mit 100 mg front-loaded rt-PA über 90 Minuten behandelt. Ein prim?r reanimationspflichtiger Patient erhielt als ,,Ultima Ratio`` 100 mg rt-PA als Bolus, eine weitere Patientin 50 mg rt-PA als Bolus gefolgt von 50 mg über 2 Stunden. Bei allen Patienten stabilisierte sich der h?modynamische Zustand innerhalb kürzester Zeit. In sechs F?llen konnte mittels TEE und einmal mittels transthorakaler Echokardiographie innerhalb von 15 Stunden die komplette Aufl?sung der rechtskardialen Thromben dokumentiert werden. Bei einem Patienten kam es zu einer intracerebralen Blutung und ein Patient verstarb nach 10 Tagen an den Folgen der protrahierten Reanimation mit hypoxischem Hirnschaden. Mittels TTE/TEE lassen sich rechtskardiale Transitthromben als koinzidenter Befund bei Patienten mit klinischen Hinweisen für eine fulminante Lungenembolie gut diagnostizieren sowie der Therapieerfolg verfolgen. In diesen F?llen ist die sofortige systemische Lysetherapie ohne weitere bildgebende Diagnostik durchzuführen, um einer weiteren Verschlechterung der klinischen Situation in Folge Transports und Umlagerung des Patienten mit der Gefahr des Abschwemmens des Transitthrombus vorzubeugen. Eingegangen: 15. Mai 1996 Akzeptiert: 23. Oktober 1996     

Serum and Cerebrospinal Fluid Pharmacokinetics of Intravenous and Oral Lamivudine in Human Immunodeficiency Virus-Infected Children

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (± standard deviation) in the children was 0.53 ± 0.19 liter/kg/h (229 ± 77 ml/min/m² of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 ± 0.18 and 2.2 ± 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% ± 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 μM for ≥8 h of 24 h on the twice daily oral dosing schedule with doses of ≥2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.     

Presence of synaptonemal complex protein 1 transversal filament-like protein in human primary spermatocytes

The synaptonemal complex (SC) is involved in the pairing of chromosomes during meiosis. We found that antibodies raised against a protein component (P1) of the mouse synaptonemal complex, mouse SCP1, also identified the SC in human primary spermatocytes. Biopsies from 18 men presented with infertility were evaluated by light-field microscopy and grouped into five categories: normal spermatogenesis, Sertoli cell-only syndrome, meiotic disturbances, spermiogenic (i.e. differentiation) disturbances, and other combined disturbances. In all the normal subjects the SCP1 antibody distinctly stained the synaptonemal complexes of primary spermatocytes, whereas Sertoli cells, spermatogonia or spermatids were never stained. In three of the groups, which had germ cells but showed spermatogenic disturbances, the staining was similar to that seen in normal subjects. In sharp contrast to this, in sections from men with Sertoli cell-only syndrome no specific staining was seen. This study demonstrates that a SCP1-related protein is also conserved in the synaptonemal complex in meiotic cells from man. Further studies will reveal to what extent the absence or the non-functionality of SCP1 contributes to male infertility.      

A comparison of clinical and research DSM-III-R diagnoses of schizophrenia in a Finnish national birth cohort

As a prerequisite to the use of the Finnish National Hospital Discharge Register in psychiatric epidemiological research, we studied the diagnostic reliability of the register in terms of the psychiatric morbidity experienced by a national birth cohort. We investigated all entries to the register for a sample based upon the Northern Finland 1966 birth cohort at the age of 16 years (n=11017). Until the end of 1993 (age 27 years), a total of 563 subjects had a register diagnosis indicating a psychiatric illness, 37 of them being schizophrenia. When operational criteria (DSM-III-R) were applied to clinical information in the available original hospital records for cases of psychosis, personality disorder and substance abuse (n=249), 71 fulfilled criteria for schizophrenia, including all of the 37 cases in the register and an additional 34 (48% false-negatives), most frequently diagnosed in the register as schizophreniform or other psychosis. Despite the official use of DSM-III-R nomenclature, it appears that the clinical concept of schizophrenia in Finland, manifest within the register, remains very restrictive. The application of operational criteria is a necessary prerequisite for scientific research on schizophrenia.     

Rare diseases mimicking acute vertebrobasilar artery thrombosis

Acute ischaemia of the vertebrobasilar circulation leads to a variety of clinical manifestation and is mostly due to cardiogenic or artery-to-artery embolism. We describe four neurological emergency situations involving vertebrobasilar artery aclusion of other origins: basilar migraine, extrinsic compression by rheumatoid inflammatory tissue, generalized vasculitis in subacute rheumatic fever and basilar artery dissection. The differential diagnosis of acute vertebrobasilar artery occlusion may have an important impact on patient management.     

Adjunctive therapy with bromocriptine in Parkinson's disease

Patients with moderately severe Parkinson's disease complicated by the adverse effects of chronic levodopa use benefited from the addition of bromocriptine (Parlodel; Sandoz) in doses up to 26 mg daily, which allowed an approximate 30% reduction of levodopa dose. This resulted in a significant decrease in the amount of levodopa side-effects while maintaining or improving the original parkinsonian clinical stage. Increased effectiveness in these patients was not associated with increased dosage beyond 25-30 mg daily. When the doses of bromocriptine were increased slowly, the adverse reactions were minor and usually transient.     

The ileal neobladder: experience and results of more than 100 consecutive cases

The ileal neobladder produces a completely detubularized, low pressure, high capacity reservoir constructed from ileum without any valves. From April 1986 through May 1989, 113 patients underwent this procedure at our institution. Of these patients 99 underwent simultaneous radical cystectomy for bladder cancer and 14 underwent bladder augmentation. The mean postoperative followup was 14.4 months, with a range of 1 to 36 months. There was no perioperative mortality. However, 7 patients died more than 2 months postoperatively: 5 of tumor progression, 1 of pneumonia and severe metabolic acidosis, and 1 of septicemia of unknown cause. Reoperation was necessary in only 13 patients; 10 patients required urethrotomy or dilation of urethral strictures. Day and night continence was preserved in 82.1% of all patients. Stress incontinence, which must be corrected by an artificial sphincter, was found in 4 patients (4.2%) and night-time incontinence that required an external device occurred in 5 (5.3%). Eight patients (8.4%) with mild stress incontinence required no further treatment. Pressure waves exceeding 22 cm. water seldom occurred and then only at maximum capacity. Our experience with this relatively simple system without a nipple is an overwhelming success. The need for reoperation is extraordinarily low and the high reservoir capacity results in continence from the beginning in most patients. The concept is sound and offers a genuine alternative to any form of cutaneous urinary diversion with an incidence of complications not higher than after standard supravesical urinary diversion.