Atrial natriuretic peptide and blood volume in patients with chronic glomerulonephritis: effects of albumin and frusemide administration

Blood volume, blood pressure, plasma concentrations of atrial natriuretic peptide (ANP), cyclic 3',5'-guanosine monophosphate (cGMP), angiotensin II, aldosterone, and arginine vasopressin (AVP), and urinary excretion rates of cGMP, sodium, and water were determined before and after infusion of human albumin 20%, 3.5 ml/kg body-weight to 12 patients with chronic glomerulonephritis and 19 healthy control subjects (Study 1); and before and after frusemide injection, 0.75 mg/kg to 15 patients with chronic glomerulonephritis and 19 healthy control subjects (Study 2). In Study 1 blood volume was expanded to the same degree in patients (8.8 and 7.5%, medians, after 90 and 180 min) and controls (8.6 and 6.1%). ANP was enhanced in the patients (5.9 to 11.0 pmol/l, P less than 0.01) and the controls (4.9 to 7.1 pmol/l, P less than 0.01), but the elevated level was protracted in the patients simultaneously with a delayed sodium excretion. Plasma cGMP increased, aldosterone decreased and AVP was unchanged in both groups, whereas angiotensin II decreased in the patients (P less than 0.01), but not in the controls. In Study 2 blood volume was reduced to a smaller extent in the patients than in the controls (8.9% versus 9.9%, P less than 0.05). ANP an cGMP decreased, and angiotensin II, aldosterone and AVP increased in both patients and controls. In conclusion, patients with glomerulonephritis respond to albumin- and frusemide induced changes in blood volume with essentially the same counter-regulatory changes in ANP, angiotensin II, aldosterone and AVP as do healthy subjects. The more protracted increase in ANP and the decrease in angiotensin II after albumin, and the smaller blood volume reduction after frusemide suggest an abnormal regulation of blood volume in glomerulonephritis.     

A phase II study of sulofenur,a novel sulfonylurea,in recurrent epithelial ovarian cancer

Summary A total of 16 patients with recurrent epithelial ovarian cancer were treated with sulofenur (LY 186641), a novel oral sulfonylurea. All subjects had received previous chemotherapy. Anaemia occurred in all 16 patients, 14 of whom required a blood transfusion, and 2/16 patients received methylene blue for breathlessness due to methaemaglobinaemia. Treatment was discontinued in 2/16 cases due to rising liver enzyme values, which reverted to normal on cessation of the drug. There was no nausea or alopecia. Only two minor responses were seen. Plasma drug levels were insufficient to result in antitumour activity as extrapolated from animal data. Further studies that attempt to increase the bioavailability and improve the therapeutic index are warranted.     

Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 6. Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies. Most recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 multiplex families was studied to test for an association to the HLA-DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) and a specific association with the HLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alleles. These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.      

Genome profiles of bilateral dysgerminomas, a unilateral gonadoblastoma, and a metastasis from a 46, XY phenotypic female

We present a case report of a 16-year-old, phenotypic female with bilateral dysgerminomas, a unilateral gonadoblastoma, and a peritoneal metastasis. The patient's constitutional karyotype was 46,XY. The chromosomal copy number, examined by the comparative genomic hybridization technique, showed 3 gains in the dysgerminoma of the right ovary, 6 gains in the dysgerminoma of the left ovary, and 2 gains and 1 loss in the gonadoblastoma of the left ovary. The metastasis showed 5 gains of which 4 were also observed in the dysgerminoma of the left ovary. The DNA ploidy classifications of the gonadoblastoma and the dysgerminoma in the right ovary were tetraploid, whereas the dysgerminoma in the left ovary and the metastasis were aneuploid. We therefore propose that the metastasis most probably developed from the dysgerminoma of the left ovary.     

Factors contributing to left ventricular diastolic dysfunction in long-term type I diabetic subjects

Although non-invasive studies in type I diabetic subjects indicate left ventricular (LV) diastolic dysfunction, the contribution of borderline or mild hypertension to such changes is obscure. Thus, digitized M-mode echocardiograms were obtained in 32 (18 men) young (less than 50 years) normotensive controls and 32 (21 men) long-term (greater than or equal to 12 years) type I diabetics with blood pressures ranging from normal to hypertensive. All diabetics were without clinical heart disease, none were previously treated for hypertension or using cardioactive drugs. Heart rate, systolic and diastolic blood pressures were higher in diabetic than control subjects. Their LV end-diastolic dimension was smaller, whereas wall thickness, LV mass index and fractional shortening were similar to controls. In diabetics, however, the normalized peak filling rate was decreased and the rapid filling period fraction of diastole increased. In multivariate analysis, diabetes and LV mass independently and inversely influenced the normalized peak filling rate, while fractional shortening did so positively. Furthermore, diabetes and systolic blood pressure independently influenced the rapid filling period fraction of diastole. This study is the first to demonstrate systolic blood pressure and LV mass as independent contributors to subclinical LV diastolic abnormalities in diabetics. These findings may therefore indicate the need to treat even mild hypertension in diabetics in an effort to delay the development of cardiopathy.     

Exaggerated natriuresis in adult polycystic kidney disease

Angiotensin II (AII), aldosterone (Aldo) arginine vasopressin (AVP) in plasma, serum osmolality (Sosm), and renal sodium excretion (UNaV) were studied before and after infusion of hypertonic sodium chloride solution in 20 patients with adult polycystic kidney disease (PKD) with normal or moderately reduced creatinine clearance (Ccr) and in 10 healthy control subjects. UNaV increased after sodium loading in all, significantly more in the PKD patients. AII and Aldo were normal before sodium loading and suppressed after saline in PKD patients and controls. The increase in VNaV correlated with Aldo in patients but not in controls. AVP before loading was increased in hypertensive PKD patients with reduced Ccr, but not in normotensive patients with normal Ccr. After hypertonic saline, Sosm increased to the same degree both in PKD and control subjects, but AVP increased more in those with PKD. The exaggerated natriuresis of PKD is probably not explained by a change in the activity of the renin-angiotensin-aldosterone system. The enhanced response of AVP to osmotic stimuli in PKD may be a compensatory reaction to a reduced renal tubular effect of AVP.     

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.      

Allergoprints in Horse Allergic Children

In order to determine the allergenic activity of five purified horse allergens, 22 children allergic to horses according to history, skin test, and leukocyte histamine release were evaluated. Washed leukocytes from all patients were tested for allergen-induced histamine release utilizing four epidermal horse allergens (Ags 6, 9, 11 , and 15) and horse serum albumin. Crossed radioimmunoelectrophoresis was carried out with a standardized horse dander extract and serum from each patient.
The results showed considerable variation in the individual allergoprints. Ag 11 had the highest mean allergenic activity. Sensitivity to horse serum albumin was demonstrated three times. Our data show that the amount of serum IgE antibodies bound by horse allergens correlates significantly with the capacity of the allergens to induce histamine release from washed leukocytes.