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Biomedical subjects

J Hardwicke

Publications and source records attributed to J Hardwicke.

At least 19 recordsLinked to original sources
PubMed1989

Interference with function of a homeobox gene in Xenopus embryos produces malformations of the anterior spinal cord.

XIHbox 1 is expressed in a narrow band across the cervical region of Xenopus embryos. The gene produces two related proteins: "long" and "short" XIHbox 1 homeodomain proteins. Injection of antibodies to the long XIHbox 1 protein into 1-cell embryos caused a phenotype in which the anterior spinal cord was morphologically transformed into a hindbrain-like structure. This alteration was restricted to the region normally expressing long XIHbox 1 protein. Injection of long protein mRNA disrupted segmentation and tissue organization without inhibiting cell proliferation. Injection of short protein mRNA into 1-cell embryos produced spinal cord malformations similar, but not identical, to those caused by the antibodies, suggesting antagonistic roles for long and short XIHbox 1 proteins. We immunostained tadpoles carrying extended hindbrains for N-CAM and consistently found defective organization of spinal nerves over the affected region.

Animals↗
PubMed1988

A gradient of homeodomain protein in developing forelimbs of Xenopus and mouse embryos.

The expression of the homeodomain protein XIHbox 1 in developing Xenopus limbs was analyzed using specific antibodies. In the forelimb bud mesoderm XIHbox 1 shows a clear antero-posterior gradient that is strongest in the anterior and proximal region of the forelimb. Hindlimb bud mesoderm is devoid of XIHbox 1, indicating an early molecular difference between arm and leg. The innermost ectodermal cell layer is positive throughout the forelimb and hindlimb bud ectoderm, but no other areas of the skin. Similar results are obtained in developing mouse limbs, suggesting that XIHbox 1 participates in forelimb development in a variety of tetrapods. In early tadpoles analyzed at stages preceding limb bud formation, the lateral plate mesoderm is positive in the region corresponding to the earliest "field" of forelimb information, but not in the hindlimb field. These results suggest a molecular link between morphogenetic fields, gradients, and homeobox genes in vertebrate development.

Animals↗
PubMed1988

Differential utilization of the same reading frame in a Xenopus homeobox gene encodes two related proteins sharing the same DNA-binding specificity.

Xenopus XlHbox 1 produces two transcripts during early development. One encodes a long open reading frame (ORF) and the other a short ORF sharing the same homeodomain, but differing by an 82 amino acid domain at the amino terminus. The long protein amino terminus is conserved with many other homeodomain proteins, and its absence from the short protein could have functional consequences. Some viral genes also utilize a single ORF to encode transcription factors of antagonistic functions. The overall organization of the homologous genes in frog and man is similar, supporting the notion that both transcripts are of functional significance. Studies on XlHbox 1 function show that the region common to the long and short proteins has a sequence-specific DNA-binding activity, and that microinjection of specific antibodies into embryos results in the loss of structures derived from cells normally expressing XlHbox 1.

Amino Acid Sequence↗
PubMed1988

Differential antero-posterior expression of two proteins encoded by a homeobox gene in Xenopus and mouse embryos.

The X.laevis XlHbox 1 gene uses two functional promoters to produce a short and a long protein, both containing the same homeodomain. In this report we use specific antibodies to localize both proteins in frog embryos. The antibodies also recognize the homologous proteins in mouse embryos. In both mammalian and amphibian embryos, expression of the long protein starts more posteriorly than that of the short protein. This difference in spatial expression applies to the nervous system, the segmented mesoderm and the internal organs. This suggests that each promoter from this gene has precisely restricted regions of expression along the anterior-posterior axis of the embryo. Because the long and short proteins share a common DNA-binding specificity but differ by an 82 amino acid domain, their differential distribution may have distinct developmental consequences.

Animals↗
PubMed1987

The glomerular tip lesion: a steroid responsive nephrotic syndrome.

The glomerular tip nephropathy is a cause of the nephrotic syndrome and has distinct pathological features. Glomerular tufts appear normal on light microscopy except for a segmental lesion invariably present in all glomeruli at the origin of the proximal tubule. Data on twenty adults whose renal biopsies demonstrated this lesion and who were followed for a mean of 7.4 years are analyzed. Eighteen patients were treated with steroids; ten of these had complete remission of proteinuria and seven a significant reduction of their proteinuria. Ten patients had moderately impaired renal function (serum creatinine greater than 120 mumol/l) at presentation, eight received steroids and achieved a reduction in serum creatinine. The prognosis was good, with no patient developing chronic renal failure requiring dialysis.

Adult↗
PubMed1986

Proteinuric glomerular disease in adults: cumulative life tables over twenty years.

Outcome in 425 patients with persistent proteinuria has been assessed over a period of five to 20 years. Nephrotics and non-nephrotics are analysed separately. Clinical and laboratory findings do not correlate with renal histology. Seventy-eight patients had minimal histological lesions and four died (only one in renal failure). Fifty-one patients had endothelial cell proliferation, and 20-year survival was 70 per cent; renal failure occurred within five years in all 17 who progressed, and was independent of nephrotic status. In both membrano-proliferative disease (98 patients) and membranous glomerulopathy (59 patients) 20-year survival was 20 to 30 per cent. Epithelial cell proliferation (85 patients) had the worst prognosis, and survival after 12 years was negligible. In these last three groups decay in survival was almost linear against time and independent of nephrotic status. In focal proliferative disease 20-year survival in nephrotics (31 patients) was only 30 per cent, contrasting with non-nephrotics (23 patients) with 80 per cent survival. Of 105 patients presenting with proteinuria without symptoms, in 30 the proteinuria was postural and biopsies were not done. The other 75 showed a range of histological changes and prognosis similar to the group with symptoms.

Actuarial Analysis↗
PubMed1985

The role of urea in albumin dimerisation in nephrotic urines.

Albumin dimerisation in nephrotic urine frozen to -20 degrees C occurs at low ionic strength in the presence of quite low concentrations of urea (greater than 0.2 mol/l). Urea will also dimerize normal serum albumin under these conditions. The appearance of dimer in patients with a nephrotic syndrome treated with steroids is significantly correlated (p less than 0.001) with an increase in urinary urea concentration.

Albuminuria↗
PubMed1984

Whole body cellular and collagen nitrogen in healthy and wasted man.

The classical literature shows that wasting of body protein takes place mainly from the cellular compartment leaving high proportions of extracellular collagen. Whole body nitrogen ( WBN ) is proportional to whole body protein (cellular + extracellular) while whole body potassium ( WBK ) is almost entirely intracellular. WBK might be an adequate index of cellular wasting. WBN was measured by neutron activation and WBK by counting 40K in 29 healthy males and 131 male and female patients with wide ranges of body composition. Our wasted patients with Crohn's disease or ulcerative colitis, had higher WBN / WBK ratios than matched healthy controls and the difference between the two groups was in the cellular ratio (23.6 mol of N/mol of K, 0.33 g of N/mmol of K, 3 mmol of K/g of N). A multiple regression model for all the subjects represented cellular nitrogen by a term in WBK and extracellular nitrogen by simple anthropometric measurements. The partial regression coefficient of WBN on WBK was 22.6 +/- 1.1 (SE) mol of N/mol of K; this was also similar to the cellular ratio. Our results were compatible with extracellular protein (mainly collagen, which is 35% of normal whole body protein) remaining resistant to wasting even when severe loss of cellular protein occurs. The high ratios of WBN / WBK in wasted patients can be explained by this disproportionate wasting of cellular substances and they do not imply alterations in the cellular N/K ratio. We suggested that the stable ratio of WBK to cellular protein makes it an effective index of cellular wasting. The resistance of collagen to wasting and the preponderance of extracellular mass in the fat-free mass of wasted subjects, make WBN and fat-free mass unreliable guides to the extent of wasting.

Activation Analysis↗
PubMed1984

Proteinuria--the future?

Classification of proteinurias, based on physiopathology, was first comprehensively achieved about 1966 [Hardwicke 1970]. This classification, sometimes with minor modifications, has now received widespread acceptance, and the current status of proteinuria has been recently reviewed [Pesce and Furst 1979]. In this short talk I will not attempt to review again the whole field, but will rather try to highlight a few outstanding areas where inconsistencies remain, and where new advances are likely to be made in the next few years. In doing so I hope that I may convince you that the study of proteinuria is by no means exhausted, but is likely to remain a rich field of clinical research for some years to come.

Antigens↗
PubMed1984

IgG subclass composition of monomeric and polymeric IgG in the serum of patients with nephrotic syndrome.

The serum levels of immunoglobulins G, A and M and of the four subclasses of IgG have been measured in 54 patients with the nephrotic syndrome; 27 had minimal change disease (MCD), 9 membranous glomerulopathy (MGN), 5 focal glomerulosclerosis (FGS), 5 proliferative glomerulonephritis (PGN) and 8 miscellaneous forms of nephrotic syndrome (Table 1). Low levels of IgG and A, previously described in MCD, were found in all histological diagnoses; only about half the cases of MCD showed a high IgM. Measurement of the subclasses IgG 1-4 showed all to be depressed. Proportionately, however, the IgG2 was most affected (8.8% total IgG, cf 18.3% controls). Urinary protein loss, either total or IgG, only partially correlated with IgG suppression, while IgG2 in the urine usually comprised an even lower proportion of total IgG than in serum. The polyethylene glycol (PEG) 6,000 precipitate from serum at 4% concentration was also examined for IgG and subclasses in MCD (27 cases), MGN (9 cases) and PGN (3 cases). Raised levels above those of 14 normal controls were found in nearly all cases of MCD, even in remission, but in no cases of MGN. In MCD no IgG4 was found in any of the precipitates, while IgG2 was proportionately raised (22% of total) in the precipitate as compared with whole serum (8.8%). Serial studies on 9 adults (3 MCD, 3 MGN, 1 FGS, 1 PGN, 1 IgA nephropathy) showed only that the low levels of IgG and subclasses were associated with relapses and reverted toward normal in remission.

Adolescent↗
PubMed1980

Conditions for albumin dimerisation in hephrotic urines. Dependence on an ultrafilterable factor.

At--14 degrees C the albumin in the urine of some patients with a nephrotic syndrome polymerises into dimer and higher polymers. This occurs at low ionic strengths within 1-3 days and in the pH range 5-10. For polymerisation both an altered albumin molecule and a low molecular weight ultrafilterable fraction in the urine are necessary. The appearance of both is probably related to steroid therapy. The ultrafiltrate fraction has molecular mass < 700, and is not peptide, amino acid, fatty acid or highly charged ion.

Albumins↗
PubMed1977

Studies on acid eluates from kidneys of sheep with glomerulonephritis mediated by antibody to glomerular basement membrane.

Kidneys from six sheep having glomerulonephritis mediated by antibody to glomerular basement membrane (GBM) were extracted at acid pH. Each preparation was characterised using immunological techniques and the eluates contained between 3.6 and 13% anti-GBM antibody of IgG class. It appears that this low antibody content is due to the presence of contaminants, mainly serum proteins.

Acids↗
PubMed1977

Polymeric albumin in the urine of patients with nephrotic syndrome.

Dimer and polymer albumin was detected in the urine of a proportion of pantients with a nephrotic syndrome. Most of it was present as S-S bonded dimer and polymer; co-polymers, however, with IgG and alpha (1) anti-trypsin could be demonstrated. It is suggested that albumin polymerizes after it has passed the glomerular membrane. Albumin dimer was associated mainly with minimal change disease and early membranous glomerulopathy in patients, who in general responded well to therapy.

Albumins↗
PubMed1977

Asymmetric depression in the serum level of IgG subclasses in patients with nephrotic syndrome.

Thirty-three nephrotic patients were studied for IgG-subclass levels in matched pairs of serum and urinary specimens. Levels in the serum were compared with those found in the sera of non-nephrotic control children and normal adults. Results have shown an asymmetric depression in the serum level of certain IgG subclasses in some patients with minimal-change nephrotic syndrome, focal glomerulosclerosis, and proliferative glomerulonephritis, indicating that the urinary loss of IgG alone cannot account for the low blood levels of this immunoglobulin class in these conditions.

Adolescent↗