Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918.

A kindred was diagnosed with atypical MEN type 2B characterized by medullary thyroid cancer and mucosal neurilemmomas in multiple family members. Mutation analysis revealed a double RET germline mutation, Val804Met and Ser904Cys, in affected individuals. The clinical phenotype, the functional effect of the mutations, and the clinical implications of our findings are discussed.     

Hypogonadotropic hypogonadism: hormonal responses to low dose pulsatile administration of gonadotropin-releasing hormone

Patients with isolated gonadotropin deficiency were studied to determine whether pulsatile low dose gonadotropin-releasing hormone (GnRH) could induce the hormonal changes seen during normal puberty. Four male and two female patients with immature responses to a standard GnRH test (2.5 micrograms/kg) were given GnRH (0.025 micrograms/kg) iv every 2 h for 5 days. FSH responses varied between the sexes, and FSH concentrations in males rose continuously to 17.2 +/- 4.7 mIU/ml on day 5. In the females, FSH peaked at 13.8 and 15.8 mIU/ml on days 3-4 and then declined. The males showed increasing and the females decreasing incremental FSH responses to GnRH. LH concentrations and incremental responses to GnRH rose throughout the study in both sexes. Plasma testosterone rose slightly in the males to 0.7 +/- 0.2 ng/ml (P < 0.05), but in females estradiol increased to follicular range concentrations of 128 and 102 pg/ml. Standard GnRh tests on day 6 revealed maturation of gonadotropin responses in all patients. After termination of pulsatile GnRH, four patients were given single low dose GnRH injections on two to seven occasions over a period of 2-32 days. Initial LH responses were 2- to 14-fold greater than those seen on day 5 of pulsatile GnRH, and decreased over the next 3 weeks. FSH responses showed less initial augmentation and declined more slowly. Low dose pulsatile administration of GnRH to patients with isolated gonadotropin deficiency results in changing patterns of hormone secretion similar to those seen during puberty. Exaggerated pituitary sensitivity to GnRH may be present long after a brief period of GnRH stimulation, and may indicate previous rather than current secretion of GnRH.     

Classifying the probability of urinary incontinence in psychogeriatric nursing home patients

Urinary incontinence (UI) frequently occurs in psychogeriatric nursing home patients. In general the personnel involved in the care for these patients act on incontinence noted. Patients are not monitored or classified according to likelihood or severity of incontinence. This study was conducted to develop and validate a model for the classification of the likelihood of UI in demented nursing home patients. A multi-center cross-sectional study was conducted using data on clinical and functional status of 692 subjects. Subjects were subdivided in a Derivation set of 532 patients and a Validation set of 160 patients. The data were ascertained with questionnaires completed by physicians and nursing staff. All psychogeriatric wards (25) of four Dutch nursing homes were included. Using univariate logistic regression analysis on the derivation set we identified correlates of UI among 22 clinical and functional patient characteristics. Subsequently, we developed a classification model for prevalent UI, including independent patient characteristics by means of multivariable logistic regression. Next, we stratified patients into groups with varying likelihood's of UI based on the model developed. Subsequently, we transformed the model to an easy applicable classification rule for the identification of patient subgroups with high or low likelihood on UI. Finally, the rule was validated on the validation set. The independent multivariate factors associated with urinary incontinence were impaired ADL and mobility, diminished alertness and fecal impaction. After transforming the regression model to an easy classification rule, the scores ranged from 0 to 7. The area under the curve was 0.88 (95% Confidence Interval (CI): 0.85-0.91) in the derivation set. In the validation set a similar area under the curve was obtained (0.90 (95% CI: 0.85-0.95)). Among subjects with none of the associated factors the rule classified 0.5% as incontinent patients. In case all associated factors were present the proportion classified as incontinent increased to 91%. In conclusion, the developed classification rule provides means to stratifying nursing home patients according to their likelihood of being incontinent of urine.     

APOE1 mutation in a patient with type III hyperlipoproteinaemia: detailed genetic analysis required

We present the case of a patient with clinical features of familial dysbetalipoproteinaemia (FD) including high levels of total cholesterol, hypertriglyceridaemia and the presence of palmar xanthomas. Whereas genotype analysis identified the APOE3E3 isoform, sequence analysis revealed the presence of one APOE1 allele due to a mutation, p.Lys164Glu, which leads to loss of function of apolipoprotein E (ApoE), a rare cause of dominant FD.     

Monoclonal antibody U36, a suitable candidate for clinical immunotherapy of squamous-cell carcinoma,recognizes a CD44 isoform

At present, tumor-targeting with monoclonal antibodies (MAbs) is among the most promising novel adjuvant-therapy modalities for the treatment of patients with minimal residual disease of head-and-neck squamous-cell carcinoma (HNSCC). For this purpose we developed MAb U36, recognizing a 200-kDa antigen expressed on the outer cell surface of squamous-cell carcinomas and their normal counterparts. Clinical radioimmunoscintigraphy (RIS) and biodistribution studies have shown that the MAb-U36-defined antigen is a suitable target molecule for antibody-based therapy of head-and-neck cancer. In the present study we further characterized the antigen by cDNA cloning. The cDNA was isolated by expression cloning in COS-7 cells. Sequence analysis and database searching revealed that the MAb-U36-defined antigen is identical to the squamous-cell-specific CD44 splice variant epican. The epitope recognized by MAb U36 was mapped by screening overlapping synthetic peptides of the epican-specific region encoded by exon 7–11 (v3–v7), and appeared to be located in the v6 domain. The applicability of MAb U36 for targeting human tumors of various origin expressing the CD44v6 domain is discussed. © 1996 Wiley-Liss, Inc.