Plasma nitrate plus nitrite changes during continuous intravenous infusion interleukin 2.

Nitric oxide (NO), a biologically active mediator generated in many cell types by the enzyme NO synthase, may play an important role in cardiovascular toxicity that is frequently observed in cancer patients during intravenous (i.v.) interleukin 2 (IL-2) therapy. The induction of NO synthase and the production of NO seem to be involved in the pathogenesis of the vascular leakage syndrome, as well as in the regulation of myocardial contractility. In the present study, we evaluated the pattern of plasmatic NO changes during multiple cycles of continuous i.v. infusion (CIVI) of IL-2 in ten advanced cancer patients (five males, five females, median age 59 years, range 33-67 years; eight affected by renal cell cancer and two affected by malignant melanoma). The patients received IL-2 at 18 MIU m-2 day-1 (14 cycles) or 9 MIU m-2 day-1 (seven cycles) for 96 h, repeated every 3 weeks. Interferon alpha (IFN alpha) was also administered subcutaneously (s.c) during the 3 week interval between IL-2 cycles. For each cycle, plasma samples were collected before treatment (t0), 24 h (t1), 48 h (t2), 72 h (t3) and 96 h (t4) after the start of IL-2 infusion, and 24 h after the end of the cycle. NO concentration was determined spectrophotometrically by measuring the accumulation of both nitrite and nitrate (after reduction to nitrite). The following observations may be drawn from data analysis: (1) plasma nitrate + nitrite significantly raised during treatment (P = 0.0226 for t0 vs t3), but statistical significance was retained only when cycles administered with IL-2 18 MIU m-2 day-1 are considered (P = 0.0329 for t0 vs t3; P = 0.0354 for t0 vs t2 vs t4) (dose-dependent pattern); (2) during subsequent cycles a significant trend toward a progressive increase of plasma nitrate + nitrite levels, with increasing cumulative dose of IL-2, was observed (linear regression coefficient r = 0.62, P = 0.0141 for t0; r = 0.80, P = 0.0003 for t1; r = 0.62, P = 0.013 for t2; r = 0.69, P = 0.045 for t3); (3) plasma nitrate + nitrite levels peaked earlier in subsequent cycles than in the first cycle; (4) all patients experienced hypotension. The mean of the systolic blood pressure values was significantly lower at the time of plasma nitrate + nitrite peak than at t0 (P = 0.0004); (5) the two cases of grade III hypotension occurred in patients with the higher mean and peak plasma nitrate + nitrite values. We conclude that determination of plasma nitrate + nitrite levels during CIVI IL-2 can usefully estimate, in a dose-dependent pattern, the degree of peripheral vascular relaxation and capillary leakage associated with cytokine action, clinically manifested as hypotension. However, isolated cardiac toxicity that continues to represent a relevant problem during IL-2 therapy, does not appear to correlate with plasma nitrate + nitrite levels; therefore, further studies are required to understand adequately the mechanisms underlying IL-2-induced cardiac toxicity.     

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     

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.     

Radiotherapy in the treatment of low-grade astrocytomas

Between 1954 and 1986 inclusive, 160 children in the North West Region of England were registered with histologically proven lowgrade astrocytomas (grade 1 or 2). Ten died before receiving any treatment, and a further seven died within 28 days of surgery, leaving 143 children whose survival in relation to treatment modality is the subject of this paper. Low-grade astrocytomas are responsive to radiation therapy. This treatment has no clear benefit to offer children with superficial tumours that can be resected completely or nearly so, but significantly improves survival rates when tumours are deep-seated and not amenable to excision.     

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.