Geldanamycin restores a defective heat shock response in vivo.

Induced expression of heat shock proteins (Hsps) plays a central role in promoting cellular survival after environmental and physiological stress. We have previously shown that scrapie-infected mouse neuroblastoma (ScN2a) cells fail to induce the expression of Hsp72 and Hsp28 after various stress conditions. Here we present evidence that this impaired stress response is due to an altered regulation of HSF1 activity. Upon stress in ScN2a cells, HSF1 was converted into hyperphosphorylated trimers but failed to acquire transactivation competence. A kinetic analysis of HSF1 activation revealed that in ScN2a cells trimer formation after stress was efficient, but disassembly of trimers proceeded much faster than in the uninfected cell line. Geldanamycin, a Hsp90-binding drug, significantly delayed disassembly of HSF1 trimers after a heat shock and restored stress-induced expression of Hsp72 in ScN2a cells. Heat-induced Hsp72 expression required geldanamycin to be present; following removal of the drug ScN2a cells again lost their ability to mount a stress response. Thus, our studies show that a defective stress response can be pharmacologically restored and suggest that the HSF1 deactivation pathway may play an important role in the regulation of Hsp expression.

Epidemiologic implications of limited-duration seropositivity after toxoplasma infection.

In the Netherlands, the prevalence of immunoglobulin G antibodies against Toxoplasma shows a plateau at older ages. The titer distributions in the indirect fluorescent antibody (IFA) test do not change after the age of 40 years. In recent serologic studies, it has been observed that enzyme-linked immunosorbent assay of toxoplasma antibodies yields much higher seroprevalence values at older ages. These findings indicate that IFA seropositivity is not lifelong. It has been suggested in the literature that the IFA data in the older age groups reflect a dynamic balance between reversions to seronegativity and conversions to seropositivity. In this paper, the epidemiologic implications are examined by means of a mathematical model. The seroprevalence data linked to the model indicate that the mean duration of IFA seropositivity after infection is 40 years and that the annual infection risk in the reproductive age group (15-40 years) is 4-6%. A further implication of a limited duration of IFA seropositivity is that a certain fraction of IFA-seronegative persons have experienced an infection in the past. The model-based analysis indicates that the predictive value of a negative IFA test is very low at the older ages. The model is consistent with the available data, and it provides a framework for further theoretical and data-related research.

HIV infection dynamics and intervention experiments in linked risk groups.

A multigroup transmission model is described to study the spread of the human immunodeficiency virus (HIV) in linked risk groups. The model permits simultaneous investigation of the increase in the number of persons infected with HIV in three main risk groups: promiscuous homo/bisexual men (two levels of promiscuity), intravenous drug users (men and women) and promiscuous heterosexual men and women. Three modes of transmission are considered: anal and vaginal intercourse and needle sharing. The high dimensional parameter space is connected with the HIV incidence through a transmission matrix. This matrix summarizes the annual effective contact rates due to the three transmission modes. The model helps to clarify which data are needed to disentangle the relative contribution of the within- and between-group transmission routes. The model can be used to perform theoretical experiments. Given a specification of a baseline, the potential use of the model is illustrated by a simulation describing the effect of blocking the transmission through needle sharing. Reference is made to the HIV/AIDS epidemic in The Netherlands. The results of the study show that the model can play a part in the classification of HIV prevalence patterns in linked risk groups, in the study of the interaction between the main risk groups and in the theoretical evaluation of intervention measures.

Phase I/II study of recombinant interferon alpha and gamma in advanced progressive renal-cell carcinoma.

In vitro studies have documented the synergistic antiviral and antiproliferative activity of recombinant interferon alpha (rIFN alpha) and rIFN gamma. Furthermore, rIFN gamma is a strong immunomodulator with optimal effects at a relative low dose (0.1 mg/m2). On the basis of these observations, we began a phase I/II study with the combination of rIFN gamma at 100 micrograms/m2 (2 x 10(6) IU/m2) and rIFN alpha 2c 6 micrograms/m2 (2 x 10(6) IU/m2), injected twice a week subcutaneously. In cases of stable or progressive disease we increased the dose of rIFN alpha 2c every 2 weeks by 6 micrograms/m2 until the maximum tolerated dose was reached. A total of 32 patients with proven progressive renal-cell carcinoma were included. Of the 31 eligible patients, 21 were male and 10 female, their average age was 57.2 years (range 35-72), 28 had had nephrectomy, their median Karnofsky performance status was 90% (70%-100%), and their tumors were localized predominantly to visceral tissue. In 2, response was complete and in 6 it was partial, for a response rate of 25%. The disease had stabilized in 5 patients and progressed in 16. The median duration of partial response was 14 months (8-16 months); of 2 cases of complete response, 1 persists (23+ months), and the other suffered a relapse after 22 months. The median time to response was 24 weeks (18-24 weeks). The maximum tolerated dose of rIFN alpha was 30 micrograms/m2 (range of 6-36 micrograms/m2). Side-effects included those known to be associated with interferon treatment. One patient developed septicemia during a period with grade 4 leukopenia. Our study permits no conclusion regarding the additional value of rIFN gamma.

Ultrasonic determination of prostatic volume: a cadaver study.

In a cadaver study we aimed to prove that the application of Hastak's technique of planimetric volumetry of the prostate, using transrectal ultrasonography, is an accurate method. We used Brüel and Kjaer equipment (type 1846 + 1850, 4 mHz) in measuring 25 prostates of cadavers (all older than 40 years). Ultrasonically and physically measured volumes were compared. Only small differences (+4 to -6 cm3) were due to measurement errors. We conclude that planimetric volumetry of the prostate by transrectal ultrasonography is accurate.

Bridges in general dental practices: a descriptive study of the types of bridges and patients.

Based on data from patient records from a random sample of Dutch general practices, a study was made of the bridge distribution pattern in different patient groups. Patient variables such as age, sex and insurance type were analysed. More women had a bridge inserted than men. However, there appeared to be no difference in the average quantity of bridges in men or women. The abutment teeth most frequently used were the cuspids in the maxilla and the second premolars and second molars in the mandible. Fourteen percent of the bridges consisted of five or more units, 14% were free-end bridges, 13% did not meet Ante's law and 16% had one or more non-vital abutment teeth.

Determination of prostatic volume by ultrasonography. A useful procedure in patients with prostatism?

Digital palpation is rather unreliable for estimating the volume of the prostate. Ultrasonographic measurements have been advocated as a more appropriate method. We examined 47 patients ultrasonographically. Of these, 34 underwent a transurethral resection of the prostate (TURP) (ultrasonographic volume 29 patients: prostate less than 60 cm3, 5 patients with cardiovascular problems: prostate greater than 60 cm3) and 13 an open prostatectomy according to Hryntschak (prostate greater than 60 cm3). In all patients ultrasonically determined volumes were compared with the operatively removed volume of prostatic tissue. If the size of the prostate had been estimated by digital palpation only, 12 patients would have undergone the wrong procedure (TURP instead of Hryntschack procedure). Ultrasonographic calculation of the prostatic volume demonstrated that all of these patients could be treated with less risk. After resection or abdominal prostatectomy some prostatic tissue remains. We concluded that there is no clear difference in the incidence of secondary prostatic obstruction (in need of re-TURP) either after abdominal prostatectomy or after TURP.

Effectiveness of ultrasound in the preoperative evaluation of patients with prostatism.

To avoid the disadvantages of intravenous urography (IVU) and urethrocystoscopy (UCS), we investigated prospectively their replacement by ultrasound, performed during one visit in the outpatient department, in the evaluation of patients with symptoms of prostatism. One hundred twenty patients (aged 44-89 years) were included in this study. All patients underwent two main diagnostic procedures: ultrasound of the kidneys and bladder and transrectal ultrasound of the prostate (procedure A1). This was compared with IVU and UCS (procedure A2). Following procedure A1, the main diagnoses made were benign prostatic hypertrophy in 84 patients, prostatitis in 24 patients, and prostatic cancer in 12 patients. By following procedure A2, the diagnosis was changed in 20 cases. Fourteen patients had a bladder neck sclerosis, and six had a urethral stricture. There was no relevant diagnostic difference between IVU and ultrasound of the kidneys and bladder. Ultrasound of the prostate gives better information on prostatic abnormalities than does IVU or UCS. A patient with prostatism can be screened completely during one visit at the outpatient department. Only for detection of bladder neck sclerosis and urethral strictures does UCS remain preferable.

Types of patients with crowns in general dental practices.

Based on data from patient records of 9996 crowns constructed in forty general practices, it is discussed what crown types have been constructed in different patient categories. It was found that female 'crown patients' received on average more crowns than male patients. Hardly any difference was found between the average number of crowns the patients with or without reimbursement had received. In the younger patients (less than 21 years) more jacket crowns were constructed. The 21-30 year group received more full metal crowns, whereas the oldest group (greater than 51 years) had more metal-porcelain crowns. Sick-fund patients received more jacket crowns and metal-porcelain crowns on front teeth, while private patients received more full-metal crowns.

Postnatal growth and differentiation of muscle fibres in the mouse. II. A histochemical and morphometrical investigation of dystrophic muscle.

Postnatal development of three hind legs muscles, the soleus, plantaris, and gastrocnemius, of dystrophic mice (ReJ 129) was investigated with histochemical and morphometric methods. The results were compared with normal postnatal development. Especially during the second week postnatally, there was severe fibre necrosis with no apparent preference for any particular fibre type. This period of necrosis was shortly followed by a wave or regeneration during the third week that could not, however, compensate for the loss of fibres. In dystrophic animals of 4-5 months of age, the number of fibres was reduced by 40-70%. Cross sectional areas of dystrophic muscles rarely, if ever, exceeded values for normal animals 14 days of age, while body weights were also drastically reduced. Growth and differentiation of the nonaffected fibres proceeded almost normally during the first month. During the second month, the "slow' fibres in the soleus muscle, and the "fast-oxidative-glycolytic' fibres in the plantaris muscle were hypertrophied, while, incidentally, some "fast-glycolytic' fibres showed hypertrophy; but in this case the average size of the fibre type was not increased. After two months, a general fibre atrophy was observed. The fate of the regenerated fibres was difficult to trace, especially in muscles older than one month. It is assumed that a number of them were capable of developing into "adult' fibre types histochemically. During the course of the disease the percentage of "intermediate' fibres increased markedly, whereas nearly all "fast-glycolytic' fibres disappeared. Because of these shifts in fibre profiles, the plantaris and the gastrocnemius muscles obtained a rather "juvenile' and "oxidative' aspect. Changes in the histochemical character of the soleus muscle were less spectacular. In dystrophic muscles, no new fibre types were found, compared with normal muscles. Rather, fibre types were present at the wrong moment, or occurred in quantities unusual for the age concerned.

Postnatal growth and differentiation of muscle fibres in the mouse. I. A histochemical and morphometrical investigation of normal muscle.

A histochemical classification of muscle fibres based on three enzymes (ATPase, pre-inc. pH 4:35; succinic dehydrogenase and alpha-glycerol-phosphate-dehydrogenase) was used to describe postnatal growth and differentiation of muscle fibres. The m. soleus, m. plantaris and m. gastrocnemius were examined in normal mice from birth to the young adult stage. At birth, differentiation of the gastrocnemius muscle was in a more advanced stage than that of the plantaris and the soleus muscles, while the last of these was the least developed. During growth, as well as in the (young) adult, there was a distinct relation between fibre type and size, which, however, differed per muscle (region). The development of muscle fibres was a gradual process, rather than a succession of distinct stages, although a change in fibre type was often accompanied by a change in size. Differentiation of fibres already occurred perinatally, and the "adult fast' fibre types appeared during the second week postnatally, varying with the muscle region. During development, a percentage of fibres remained as a population that was histochemically and morphometrically intermediate between the fast-oxidative-glycolytic and fast-glycolytic adult fibres. A model is presented in which the most probable pathways of development are depicted.