We report a case of a nocardial brain abscess following a common variable hypogammablobulinemia. The usual treatment of cerebral nocardiosis associates neurosurgery and antimicrobial agents, with a mortality of 50%. Our patient gets well again with only antibiotics.

Enzymatic activity and isoform expression of cathepsin D (cath D) were studied in 107 cytosols from various human thyroid tissues including 21 normal tissues, 12 cold benign nodules, 17 toxic adenomas, 22 samples from Graves' disease patients, and 35 thyroid carcinomas. Cath D assay was optimized for human thyroid tissues. We found that mean cath D specific activities, expressed as units per milligrams protein minus thyroglobulin, were higher in carcinomas (P = 0.0001), toxic adenomas (P = 0.0001), and specimens from Graves' disease patients (P = 0.0001) than in normal thyroid tissues. Mean cath D activity in carcinomas was also significantly different from that in cold benign nodules (P < 0.001) and Graves' disease tissues (P < 0.05) but not from that of toxic adenomas. To determine possible mechanisms by which the observed increase in cath D activity might be regulated, we used Western blotting to measure relative amounts of cath D isoforms in the various thyroid tissues. We found that the 31-kDa major processing form of cath D was significantly increased in carcinomas and toxic adenomas compared with normal tissues (P < 0.01), cold benign nodules (P < 0.05), and Graves' disease tissues (P < 0.05). A positive correlation of cath D activity with relative expression of the 31-kDa form (r = 0.67, P = 0.0001) was observed in 104 thyroid cytosols. These data demonstrate a deregulation at the protein level, with resulting increases in cath D activity. Immunogold labeling of cath D showed particle concentration in lysosomes or phagosomes in both normal follicles and papillary carcinoma cells, indicating that cath D localization was not altered by malignant transformation in human thyroid cells. TSH induced cath D synthesis and secretion in extracellular fluid of normal human thyroid cells in primary culture; TSH had little effect on intracellular cath D level. In conclusion, TSH-induced cath D synthesis may explain high cath D levels in Graves' disease tissues and toxic adenomas, because these tissues possess a permanently stimulated cAMP transduction pathway. Furthermore, the overexpression of cath D in thyroid carcinomas in comparison with normal controls adds further arguments for the potential role of cath D in tumor growth and metastasis.

OBJECTIVE:Compare various Doppler methods for the quantification of the degree of stenosis on 85 patients.METHOD:the following parameters were measured: maximal velocity (Vmax) inside the stenosis (PW), grades of spectral disturbances at the outlet of the stenosis (PW-CW), index of spectral disturbance (STI) at the outlet of the stenosis (PW-CW), ratio of velocities I(IC/CC) in internal and common carotid (PW), ratio of vessel cross section and residual lumen area (% STEN) by color Doppler. The reference method was the Grades of spectral disturbance and the index of stenosis measured post stenosis. (Method validated against angiography and pieces of endarterectomy.) The following comparisons were done; grades and STI by CW against grades and STI by PW, Vmax (PW) against grade and STI, % STEN (color) against grade and STI, % STEN (color) against Vmax (PW), I(IC/CC) (PW) against grade and STI, I(IC/CC) (PW) against Vmax.CONCLUSION:(a) grades or stenosis index : showed the best reproductibility; (b) a high correlation was found between the grades or stenosis index post stenosis measured by CW or PW; (c) Vmax was not proportional to the stenosis degree and showed large fluctuations for the same stenosis degree; (d) the I(IC/CC) showed large fluctuations for the same stenosis degree, the correlation was poor for this velocity ratio. Both Vmax and I(IC/CC) allow to detect only 2 groups of stenosis > 75% or > 90% in area; (e) color doppler over-estimate stenosis degree by approximately 20% but was more accurate and reproducible than Vmax. An appropriate procedure was designed to avoid this over estimation.

Objectif: comparer les methodes doppler d'evaluation du degre de stenose sur 85 patients. Methode: les parametres mesures etalent: la vitesse maximale intrastenotique (Vmax) en echo-doppler pulse (EDP), le grade de perturbation du spectre (1 a S) et l'index de stenose (STI) en sortie de stenose, en mode continu analyse spectrale (DCAS) et EDP. le rapport des vitesse intrastenotique et carotidienne primitive (Vmax/V.C.Prim) en EDR le degre de stenose en survace en Doppler couleur. Les methodes de reference etaient la classifiction des perturbations du spectre en S grades et l'index de stenose (STI). (Methodes validees sur angiographies et pieces operatoires.) Les comparaisons suivantes ont ete realisees: grades de stenose et STI en EDP versus DCAS, Vmax (EDP) versus grades et STI, Index de vitesses (Vmax/V.C.Prim) versus grades et STI, et % stenose couleur versus grades et STI. Conclusions: (a) les grades de stenose et le STI ont montre la meilleure reproductibilite;(b) une tres bonne correlation existe entre d'une part les grades de stenose et d'autre part les STI mesures en DCAS et EDP; (c) la V.max intrastenotique n'est pas proportionnelle au degre de stenose, et presente de larges fluctuations pour un meme degre de stenose tout comme le Vmax/V.C.prim; (d) la correlation Vmax et Vmax/V.C.prim avec le degre de stenose est mediocre. Ces donnees ne permettent d'evaluer les stenoses qu'en 2 classes: > 75 % ou > 90 % en surface; (e) le doppler couleur surestime le degre de stenose (env + 20%), mais est plus precis et reproductible que la V.max. Une procedure particuliere permet d'eviter cette surestimation.

Objective :compare various Doppler methods for the quantification of the degree of stenosis on 85 patients. Method:the following parameters were measured : maximal velocity (Vmax) inside the stenosis (PW), grades of spectral disturbances at the outlet of the stenosis (PW-CW), index of spectral disturbance (STI) at the outlet of the stenosis (PW-CW), ratio of velocities I(IC/CC) in internal and common carotid (PW), ratio of vessel cross section and residual lumen area (% STEN) by color Doppler. The reference method was the Grades of spectral disturbance and the index of stenosis measured post stenosis. (Method validated against angiography and pieces of endarterectomy.) The following comparisons were done: grades and STI by CW against grades and STI by PW, Vmax (PW) against grade and STI, % STEN (color) against grade and STI, % STEN (color) against Vmax (PW), I(IC/CC) (PW) against grade and STI, I(IC/CC) (PW) against Vmax. Conclusion : (a) grades or stenosis index : showed the best reproductibility; (b) a high correlation was found between the grades or stenosis index post stenosis measured by CW or PW; (c) V.max was not proportional to the stenosis degree and showed large fluctuations far the same stenosis degree: (d) the I(IC/CC) showed large fluctuations for the same stenosis degree, the correlation was poor for this velocity ratio. Both Vmax and I(IC/CC) allow to detect only 2 groups of stenosis > 75 % or > 90 % in area; (e) color doppler over-estimate stenosis degree by approximatly 20 % but was more acurate and reproducible than Vmax. An appropriate procedure was designed to avoid this over estimation.

Purpose: Benign prostatic hyperplasia (BPH) was shown to be associated with high concentrations of urinary prostate specific antigen (PSA). We investigated the serum-to-urinary PSA ratio in patients undergoing prostate biopsy to assess its efficacy in enhancing serum PSA specificity in the detection of prostate carcinoma.Materials and Methods: From November 1995 through January 1996 consecutive patients undergoing prostate biopsy were prospectively included in the study. Serum and urine PSA levels were measured at our laboratory with the Tandem-R dagger assay. Samples were drawn 24 hours before prostate biopsy and at a distance from prostatic manipulation or ejaculation.Results: We studied 73 patients with BPH and 57 with prostate cancer. Differences between BPH and prostate cancer were statistically significant considering serum PSA or serum-to-urinary PSA ratios. In the 50 patients with a serum PSA of 4.0 to 10.0 ng./ml. (35 with BPH and 15 with prostate cancer) the differences between prostate cancer and BPH were still significant only when considering serum-to-urinary PSA ratio. Receiver operating characteristic curves showed that serum-to-urinary PSA ratio was a better predictor of prostate cancer than serum PSA.Conclusions: Our results suggest that the serum-to-urinary PSA ratio may be useful in distinguishing BPH from prostate cancer, particularly in the diagnostic gray zone of serum PSA between 4.0 and 10.0 ng./ml.

BACKGROUND:In an earlier study, we demonstrated that benign prostatic hyperplasia (BPH) was associated with significantly higher urine levels of prostate-specific antigen (PSA) than in prostate cancer (PC). These early results led to the present study: we assessed, in patients undergoing a prostate biopsy, the clinical value of the PSA serum/urine ratio (PSA S/U) in patients for the differential diagnosis of PC, particularly when the pre-biopsy serum level of PSA lies between 4.0 and 10.0 ng/ml.METHODS:All patients without an indwelling drain who underwent transrectal echoguided biopsy were prospectively included in this study from November 1994 to December 1995. All serum and urine PSA measurements were done by the same laboratory using a Tandem R kit (Hybritech). Blood and urine samples were obtained during the 24 hour period prior to surgery during which all urethral or rectal manipulation was avoided.RESULTS:We studied 130 patients with BPH (n = 73) or PC (n = 57). The PSA serum levels and the PSA S/U were significantly different between the BPH and the PC groups. In the subgroup of 50 patients with a serum PSA level in the 4-10 ng/ml range, the difference between the BPH and PC patients was not significantly different except for the PSA S/U ratio. Receiver operating characteristic (ROC) curves showed that the diagnostic power of PSA S/U was greater than serum PSA.CONCLUSION:These results suggest that the PSA S/U ratio could be useful to distinguish between BPH and PC, particularly when diagnosis is uncertain in patients whose serum PSA is in the 4.0-10.0 ng/ml range.

OBJECTIVE:High concentrations of serum prostate-specific antigen (PSA) may be associated with the presence of benign prostatic hyperplasia or prostatitis. We investigated the serum-to-urinary PSA ratio in patients with or without prostate cancer to assess its efficacy in enhancing serum PSA specificity. METHODS:Patients presenting abnormal findings in digital rectal examination or documented prostate carcinoma were prospectively included in the study. A control group, with no evidence of prostate disease, hospitalized in the same time interval was included. Serum and urine PSA levels were measured in our laboratory with the Tandem R assay (Hybritech). Samples were drawn twice at 2-month intervals (M1 and M3). RESULTS:Sixty-eight patients were included in the study divided into 27 cases of benign prostatic hyperplasia, 20 of prostate carcinoma, 10 of prostatitis and 11 patients in the control group. Serum and urine PSA levels were not correlated (r < or = 0.1). There was no significant difference in any group from M1 to M3 as regards urinary PSA (p > or = 0.15). Intergroup comparison showed significantly (p < or = 0.004) high urinary PSA (mean level +/- SEM 28.3 +/- 3.4 micrograms/mmol creatinine) only in the benign prostatic hyperplasia group, mean levels in the prostate carcinoma, prostatitis and control groups being 3.7 +/- 1.1, 11 +/- 2.9 and 5.2 +/- 0.9 micrograms/mmol creatinine, respectively. Differences in urinary PSA levels between the confined prostate carcinoma and benign prostatic hyperplasia groups (p = 0.0008) were further increased when considering the serum-to-urinary PSA ratio (p = 0.0003). CONCLUSION:Our results suggest that the serum-to-urinary PSA ratio may be useful in distinguishing benign prostatic hyperplasia from prostate cancer.

Two new immunoenzymatic assays for c-erbB-2 oncoprotein and epidermal growth factor receptor (EGF-R) (Oncogene Science) in human breast cancer were validated. Correlations between these assays and some clinical and biological parameters were also studied. The repeatability and reproducibility of standard curves for the two methods gave a coefficient of variation (CV) of less than 4% and about 10% respectively. The accuracy of c-erbB-2 oncoprotein and EGF-R assays was examined by using dilution and recovery tests throughout the standard curves. The linear relations between theoretical and measured values, for these tests, had slopes close to 1 and an intercept near 0. The median value for EGF-R, measured on solubilized membranes of 290 primary tumors, was 0.12 fmol/micrograms protein, the mean value was 0.37 (range 0 to 35.7). For c-erbB-2 oncoprotein, the median value, measured using the same population, was 2.75 human neu unit/micrograms protein, the mean value was 7.85 (range 1 to 125). There was an inverse relationship between EGF-R values and those for the estrogen receptor (ER), progesterone receptor and pS2 protein as well as menopausal status. C-erbB-2 oncoprotein concentrations were positively correlated with ER, pS2 protein and cathepsin D. Furthermore, a significant positive correlation was observed between EGF-R levels and c-erbB-2 oncoprotein levels. In conclusion, immunoenzymatic assays of EGF-R and c-erbB-2 oncoprotein are easy to use, sensitive and reliable. The accurate standardisation of immunoenzymatic assays could contribute to the clinical use of EGF-R and c-erbB-2 oncoprotein as prognostic factors in breast cancer.

OBJECTIVE Most incidentally discovered adrenal tumours (‘incidentaloma’) are benign adrenocortical adenomas. It has been suggested that 131I‐6β‐iodomethylnorcholesterol (IMC) scan could specify the degree of functional autonomy of such adenomas depending on whether they prevent contralateral adrenal tracer uptake. Our purpose was to examine this hypothesis in a correlated scintigraphic and endocrine study.DESIGN Prospective study evaluating the prevalence of unilateral IMC uptake (tumour uptake with no visualization of the contralateral adrenal gland) and bilateral uptake (uptake in both the tumoral and the contralateral adrenal glands) in patients with unilateral incidentaloma. Comparison of adrenocortical function and of IMC scan after dexamethasone (DXM) in the two scintigraphic groups thus defined.PATIENTS Thirty‐five patients with a unilateral mass highly suggestive of benign adrenocortical adenoma on CT scan.MEASUREMENTS The IMC scan was performed in basal conditions (baseline scan) and after DXM (suppression scan). Adrenocortical function assessment included basal measurements of 11‐deoxycortisol, 17α‐hydroxyprogesterone (17‐OHP), dehydroepiandrosterone sulphate (DHEAS), plasma cortisol and ACTH, urinary free cortisol (UFC), overnight and low‐dose DXM suppression test, and CRH test.RESULTS The baseline scan showed 16 patients (46%) with unilateral uptake (group A) and 19 (54%) with bilateral uptake (group B). Patients in group A exhibited lower ACTH values at 0800 h (P = 0.05) and higher cortisol values after an overnight DXM suppression test (P = 0.02), than did patients in group B. In addition, 3 patients in group A failed the overnight and the low‐dose DXM suppression tests. Adrenal masses were larger in group A than group B (P = 0.04) and an inverse correlation was found in the whole population between tumour size and ACTH value at 0800 h (P = 0.05). On the suppression scan performed in 14 patients (7 in each group), patients in group A continued to exhibit unilateral tumour uptake and bilateral uptake was suppressed in 72% of patients in group B. An adrenal mass was removed in 3 patients of group A with confirmed benign adrenocortical adenomas. In the post‐surgical period, the contralateral gland was again visualized in a baseline scan and the hormonal evaluation returned to the normal range.CONCLUSION Unilateral 131I‐6β‐iodomethylnorcholesterol tumour uptake is a frequent feature in benign adrenocortical adenomas. Hormonal data and scintigraphic profiles obtained after dexamethasone, as well as hormono‐scintigraphic changes observed after surgery, provide evidence that unilateral uptake is related to functioning adenomas with various degrees of autononomy and suggest that the 131I‐6β‐iodomethylnorcholesterol scan could be a valuable tool for screening ‘subclinical’ Cushing's adenomas.

We investigated the effects of inhibitions of protein phosphatases and protein kinases on thyrotropin (TSH) stimulation of cAMP accumulation in human thyroid cells. Okadaic acid (OA) and calyculin-A (CL-A), two potent inhibitors of type-1 (PP-1) and type-2A (PP-2A) protein phosphatases, had a biphasic concentration-dependent response on cAMP formation. An inhibitory effect (41.3% and 47.2% inhibition with OA and CL-A) was first observed at 1 microM OA and 10 nM CL-A, followed by a reduction of this effect with OA (24% inhibition) or by a complete reversal of inhibition with CL-A, at 10-fold higher concentrations of both products. Addition of purified PP-1 and PP-2A to crude membranes from cells preincubated with OA, reversed OA-induced adenylyl cyclase inhibition, confirming that these protein phosphatases regulate TSH-mediated cAMP production. Levels of protein incorporation of 32P were higher with 10 microM OA than with 1 microM OA and did not correlate with the biphasic effect of OA on cAMP production. These results support a dual action of protein phosphorylation in the control of adenylyl cyclase activity stimulated by TSH. H-7, an inhibitor of nucleotide- and calcium/phospholipid-dependent protein kinase (PKC), increased by 197% the stimulation of cAMP accumulation by TSH in thyroid cells. Phorbol 12-myristate 13-acetate (PMA) counteracted the effect of H-7 on cAMP levels, which suggests that PKC is involved in the action of H-7. Moreover, KT5926, an inhibitor of calcium/calmodulin-dependent protein kinase II and myosin light chain kinase, increased basal cAMP levels rather than cAMP levels stimulated by TSH. In light of these results, we suggest that phosphorylation/dephosphorylation cycles regulate basal and TSH-stimulated adenylyl cyclase activities in human thyroid.

Background. Cathepsin D is a widely distributed lysosomal acidic endopeptidase. It is an estrogen-regulated protein that is a prognostic factor in breast cancer. The aim of this study was to measure cathepsin D concentrations in thyroid tissues and to correlate these concentrations with clinical and pathologic parameters.Methods. Cathepsin D and thyroglobulin concentrations were measured in the cytosol of normal thyroid tissues (n = 14), benign nodules (n = 6), and thyroid carcinomas (n = 32) with an immunoradiometric assay. Statistical analysis was based on the Kruskal-Wallis and Wilcoxon tests and on the Spearman rank correlation coefficient.Results. The mean level of cathepsin D, expressed as picomoles per milligram protein minus throglobulin, was higher in the 32 carcinomas, 29.1 +/- 15.5, than in the 14 normal thyroid tissues, 8.4 +/- 2.5 (p < 0.001) or in the 6 benign nodules, 11.2 +/- 7.3 (p = 0.003). Cathepsin D concentrations correlated with tumor size; Spearman rank correlation coefficient was r(s) = 0.44 (p = 0.012). No significant difference was found regarding histologic type. Cathepsin D concentrations were inversely correlated with the thyroglobulin level in the tumor; Spearman rank correlation coefficient was r(s) = -0.60 (p < 0.001).Conclusions. Cathepsin D concentration is higher in thyroid carcinoma than in normal thyroid tissue, Increased cathepsin D concentrations correlate with thyroid tumor size but not with histologic type. Further studies should be done to confirm the potential prognostic value of cathepsin D in patients with thyroid carcinomas.

La methode micro-autoradiographique appelee methode trace-autoradiographique« met en evidence les electrons dans une emulsion photographique. L'interet de cette methode est de pouvoir estimer par microscopie optique la repartition d'un radiopharmaceutique dans un tissu. En cas d'inhomogeneite, il est possible, a partir du nombre de traces detectees, de calculer les doses absorbees au voisinage du radioisotope. Ces doses peuvent etre tres superieures aux doses moyennes absorbees au niveau tissulaire et entrainer une irradiation importante et specifique de certaines structures cellulaires qui capteraient electivement un radiopharmaceutique. Nous avons adapte cette methode a l'iode 123 et nous donnons des elements necessaires a la dosimetrie des electrons emis par l'iode 123

Background. To investigate the significance of estrogen receptors (ER) in the pathogenesis of thyroid dysplasia, the authors analyzed, by analogy with breast cancers, ER and three estrogen-regulated proteins: progesterone receptor (PR), cathepsin D, and pS2 protein, in cytosols of 42 human thyroid tissues.Methods. ER and PR were measured by an immunoenzymatic assay and cathepsin D and pS2 by an immunoradiometric assay. Tissue specimens included 7 normal tissues, 6 benign nodules, 8 toxic adenomas, 7 from patients with Graves disease, and 14 carcinomas.Results. ER was present at very low concentrations, with no statistical difference between neoplastic and nonneoplastic tissues. The mean levels of cathepsin D, expressed as pmol/mg protein minus thyroglobulin, were higher in the 14 carcinomas (P = 0.0003), the 7 specimens from patients with Graves disease (P = 0.006), and the 8 toxic adenomas (P = 0.04) than in the 7 normal thyroid tissues. A significant difference also was observed between the carcinomas (P = 0.003) and six benign nodules. Compared to TNM parameters, cathepsin D concentrations correlated with tumor size: higher cathepsin D levels were found in pT4 than in pT2 and pT3 carcinomas. All the tissues tested were negative for PR and pS2 protein.Conclusions. The results clearly indicate a significant difference between neoplastic and normal thyroid tissue in terms of the amount of cathepsin D, but not that of ER. This suggests that cathepsin D probably is not regulated by estrogen but simply is a marker of protease activity during invasion by thyroid carcinomas.

The two-step enzymatic immunoassay of free thyroxine (Imx FT4, Abbott Laboratories, Chicago, IL) was studied in three centres. The assay involved a fluorimetric measurement and took 45 minutes using a completely automated procedure. The results were compared with those from the free thyroxine two-step radioimmunoassay and with the "calculation" of free thyroxine. The analytical precision was found to be excellent if the analyser was correctly set. The IMx FT4 assay seemed unaffected by increased concentrations of albumin and of non-esterified fatty acids (oleic acid) up to 5 mmol/l. The euthyroid reference interval, defined as that including 95% of 194 control subjects, was 12-21 pmol/l. A limited overlap existed between euthyroid and hyperthyroid patients, but a larger one was seen between the euthyroid and hypothyroid population, the latter including subclinical hypothyroidism. IMx FT4 results agreed well when compared with those from two-step radioimmunoassays. The IMx FT4 technique gave rise to a low percentage of elevated results in patients being treated with heparin, but was undisturbed by autoantibodies to thyroxine and triiodothyronine which were present in one hypothyroid patient.

The two-step enzymatic immunoassay of free thyroxine (IMx FT4, Abbott Laboratories, Chicago, IL) was studied in three centres. The assay involved a fluorimetric measurement and took 45 minutes using a completely automated procedure. The results were compared with those from the free thyroxine two-step radioimmunoassay and with the "calculation" of free thyroxine. The analytical precision was found to be excellent if the analyser was correctly set. The IMx FT4 assay seemed unaffected by increased concentrations of albumin and of non-esterified fatty acids (oleic acid) up to 5 mmol/l. The euthyroid reference interval, defined as that including 95% of 194 control subjects, was 12-21 pmol/l. A limited overlap existed between euthyroid and hyperthyroid patients, but a larger one was seen between the euthyroid and hypothyroid population, the latter including subclinical hypothyroidism. IMx FT4 results agreed well when compared with those from two-step radioimmunoassays. The IMx FT4 technique gave rise to a low percentage of elevated results in patients being treated with heparin, but was undisturbed by autoantibodies to thyroxine and triiodothyronine which were present in one hypothyroid patient.