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Biomedical subjects

P Westermark

Publications and source records attributed to P Westermark.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cutaneous malignant melanoma in Swedish children and teenagers 1973-1992: a clinico-pathological study of 130 cases.

To assess whether there has been a change in histological features and prognostic factors of primary cutaneous malignant melanoma (CMM) in young individuals in Sweden, an unselected, population-based study was undertaken; 177 cases of primary CMM in persons below 20 years of age were reported to the Swedish National Cancer Registry between 1973 and 1992. In 87% of the cases, original tumor tissue was available for histo-pathological review. The original diagnosis was verified in 88% (n = 126) of these cases. All tumors had histological features similar to adult CMM; 17% had an associated precursor lesion. Superficial spreading melanoma (SSM) was the most common sub-type, constituting 20/36 cases in the first decade and 59/90 in the second. Corresponding figures for nodular melanoma (NM) were 11/36 and 23/90. Only 5 melanomas in situ were diagnosed. In girls, the mean thickness of SSM decreased from 1.5 to 0.6 mm (p < 0.001). Overall mortality was 10%, 22% in the group with CMM diagnosed 0-15 years of age and 8% in individuals 15-19 years. Fatal CMM cases diagnosed below 15 years of age (n = 4) were NM > 1.6 mm thick and in subjects 15-19 years (n = 9) 44% of fatal tumors were NM with a mean thickness of 2.2 mm. Breslow index was the single most important prognostic factor. However, when known prognostic factors were adjusted for in a Cox regression analysis, young age remained an independent risk factor, with a relative death rate of 0.21 for individuals aged 15-19 compared with children < 15 years of age.

Adolescent↗
PubMed1999

Differences in amyloid deposition in islets of transgenic mice expressing human islet amyloid polypeptide versus human islets implanted into nude mice.

Islet amyloid polypeptide (IAPP)-derived amyloid is frequently deposited in the islets of Langerhans in patients with chronic non-insulin-dependent diabetes mellitus (NIDDM). When human islets were implanted under the renal capsule in nude mice, amyloid occurred in 73% of the grafts within 2 weeks. In this study, we compare the deposition of amyloid in islets from a transgenic mouse strain expressing human IAPP (hIAPP) and in normal human islets after implantation in nude mice. The implantations were performed as follows: (1) nondiabetic recipients were given islets from transgenic mice alone, (2) human islets were implanted in the upper pole of the kidney and islets from transgenic mice were implanted in the lower pole of the kidney, (3) grafts containing a mixture of human and transgenic islets were implanted, and (4) transgenic islets and islets from nontransgenic littermates were implanted in therapeutic numbers into recipients made diabetic by a single injection of alloxan prior to implantation. The implants were removed after various periods from 4 days to 8 weeks. The implants were either fixed in Formalin, stained for amyloid, and viewed in polarized light, or processed for immunoelectron microscopy and studied after immunolabeling with specific antibodies against IAPP. We found that the course of amyloid deposition differed significantly between human islets and hIAPP-expressing mouse islets. In human islets, amyloid was mainly deposited intracellularly and only small amounts of amyloid were found extracellularly. In contrast, in islets from transgenic mice, amyloid was exclusively deposited extracellularly and deposition in this site was preceded by an aggregation of immunoreactive material along the basement membrane. These findings point to separate mechanisms for amyloid formation in these two models.

Amyloid↗
PubMed1999

The use of subcutaneous fat tissue for amyloid typing by enzyme-linked immunosorbent assay.

The amyloidoses are biochemically heterogeneous diseases with pathophysiologic deposits of various proteins. The clinical course, prognosis, and therapy are different for each type of amyloidosis and, therefore, a type-specific diagnosis is demanded as early as possible. We describe a method for typing the most common systemic amyloidoses of AL, AA, and transthyretin types by enzyme-linked immunosorbent assay (ELISA), using abdominal wall subcutaneous fat biopsy specimens. The method was tested on 21 abdominal fat biopsy specimens that were sent to the laboratory. Of these, 15 contained amyloid that was successfully characterized in 14 cases. One specimen contained amyloid that did not react with any antisera used. The 6 specimens without amyloid gave no reaction in ELISA. The described ELISA method is reliable and easy to perform, and the tissue sample needed is obtained by minor surgery.

Abdomen↗
PubMed1999

Islet amyloid polypeptide and insulin relationship in a longitudinal study of the genetically obese (ob/ob) mouse.

Obese mice (Umeå ob/ob) and their lean litter-mates were investigated from 7 to 52 weeks of age with respect to the plasma concentration of islet amyloid polypeptide (IAPP) and insulin. Plasma levels of IAPP were highly elevated in the ob/ob mice and remained unchanged until age 33 weeks, after which a sudden significant increase occurred at age 40 weeks. The plasma concentration of insulin gradually increased from start to end and reached extremely high levels. In the lean mice, there were no age-related differences in plasma levels of IAPP and insulin, being of the same magnitude as in normal NMRI mice. The plasma IAPP/insulin molar ratio was similar in lean and obese mice until age 14 weeks. At 21 weeks, the ratio in the ob/ob mice had decreased dramatically and remained markedly (sixfold) lower than in the lean mice until the end of the study. The IAPP concentration in the pancreata of 21-week-old ob/ob mice was 25-fold higher than that in the lean mice. Immunohistochemically, a majority of the ob/ob mice displayed enlarged and more numerous pancreatic islets, compared with the lean mice, and the IAPP- and insulin-labeling intensity was equal for all animals. At the electron-microscopic level, there was an increase in the number of IAPP- and insulin-immunoreactive gold particles per whole granule area as well as per core granule area. We conclude that the dramatically increased IAPP levels in severely hyperinsulinemic ob/ob mice may be of importance for the development of insulin resistance. Further, the disproportionate secretion of IAPP and insulin in the adult obese mouse might indicate a disturbed negative feedback effect of IAPP on insulin secretory mechanisms, resulting in very high plasma insulin levels.

Aging↗
PubMed1999

What is the role of giant cells in AL-amyloidosis?

AL-amyloidosis is one of the most common amyloidoses and can be found in a localized and a systemic form. The precursor protein is an immunoglobulin light chain which as AL-protein in both localized and systemic AL-amyloidosis shows the same pattern of fragmentation and changes of primary structure. In this work it is shown that that there is a difference between localized and systemic amyloidosis in respect to accompanying giant cells which constantly are found associated with amyloid deposits in localized AL-amyloidosis. In addition, giant cells were found together with amyloid deposits in lymph nodes of some cases of systemic AL-amyloidosis. Based on these findings and electron microscopic studies, it is discussed whether the giant cells actively participate in amyloid fibril formation by uptake and modification of the precursor protein or the giant cells are part of a foreign body reaction. Included in this work are two new cases of localized lung (lambda I) and ureteric (kappa I) AL-amyloidosis.

Amino Acid Sequence↗
PubMed1998

Fragments of the constant region of immunoglobulin light chains are constituents of AL-amyloid proteins.

Immunoglobulin light chains are the precursor proteins of AL-amyloidosis. In the fibril formation process properties of the variable part of the immunoglobulin light chains are believed to be of major importance. In this work it is shown that fragments of the constant part of the immunoglobulin light chain are a constituent of the AL-amyloid proteins of kappa type. A specific antiserum has identified these fragments in gel filtration fractions where the absorbance approached the base line after the main retarded peak. The fragments are small and have been overlooked previously in the purification process. The significance of the constant part in AL-proteins is unclear, but adds new aspects to the discussion of pre- or post-fibrillogenic cleavage of the immunoglobulin light chains.

Amino Acid Sequence↗
PubMed1998

Increased insulin secretion and glucose tolerance in mice lacking islet amyloid polypeptide (amylin).

Islet amyloid polypeptide (IAPP or amylin) is costored and cosecreted with insulin and may regulate insulin secretion and blood glucose handling. However, the role and importance of endogenous IAPP in the regulation of insulin release and glucose homeostasis have been controversial. Here we report on the generation and phenotypic analysis of IAPP-deficient mice. These mice have normal, or near to normal, basal levels of circulating insulin and glucose. However, following glucose administration, IAPP-deficient males presented increased insulin responses paralleled with a more rapid blood glucose elimination compared to wild-type controls. Blood glucose elimination was also found to be enhanced in IAPP-deficient females, but the insulin response in this gender did not differ from controls. In a transgenic rescue experiment, using an insulin-promoter human-IAPP fusion gene, insulin responses and blood glucose elimination were reversed in IAPP-deficient males, whereas the female phenotype appeared unaffected. Our results provide the first firm evidence of a physiological role for endogenous IAPP and indicate that IAPP, apparently in a gender-dependent manner, limits the degree of glucose-induced insulin secretion and the rate of blood glucose elimination.

Amyloid↗
PubMed1998

Extended analysis of AL-amyloid protein from abdominal wall subcutaneous fat biopsy: kappa IV immunoglobulin light chain.

In AL-amyloidosis the cause of amyloid fibril formation in beta-pleated sheets from the precursor protein immunoglobulin light chain is not established, but studies of AL-proteins indicate that amino acid substitutions are important in the pathogenesis. Amyloid material was extracted from a subcutaneous fat tissue biopsy and submitted to extended protein separation, typing and amino acid sequence analyses. The AL-protein belonged to the rare immunoglobulin light chain kappa, subtype kappa IV and contained unique amino acid substitutions, mostly in the highly preserved framework regions. The study shows that subcutaneous fat biopsies are useful sources of amyloid material for biochemical studies.

Abdomen↗
PubMed1998

Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils.

Amyloid protein A (AA) amyloidosis is a consequence of some long-standing inflammatory conditions, and subsequently, an N-terminal fragment of the acute phase protein serum AA forms beta-sheet fibrils that are deposited in different tissues. It is unknown why only some individuals develop AA amyloidosis. In the mouse model, AA amyloidosis develops after approximately 25 days of inflammatory challenge. This lag phase can be shortened dramatically by administration of a small amount of amyloid extract containing an as yet undefined amyloid-enhancing factor. In the present study, we show that preformed amyloid-like fibrils made from short synthetic peptides corresponding to parts of several different amyloid fibril proteins exert amyloidogenic enhancing activity when given i.v. to mice at the induction of inflammation. We followed i.v. administered, radiolabeled, heterologous, synthetic fibrils to the lung and to the perifollicular area in the spleen and found that new AA-amyloid fibrils developed on these preformed fibrils. Our findings thus show that preformed, synthetic, amyloid-like fibrils have an in vivo nidus activity and that amyloid-enhancing activity may occur, at least in part, through this mechanism. Our findings also show that fibrils of a heterologous chemical nature exert amyloid-enhancing activity.

Amino Acid Sequence↗
PubMed1998

Extensive intimal apolipoprotein A1-derived amyloid deposits in a patient with an apolipoprotein A1 mutation.

In the aortic intima amyloid deposits are often associated with atherosclerotic plaques. In a recent study of one patient with aortic intimal amyloid the major fibril protein was an N-terminal fragment of apolipoprotein A1 (apoA1) consisting of 69 amino acid residues. In the present study, we have screened the apoA1 gene for mutations in autopsy cases with aortic intimal amyloid immunohistochemically positive for apoA1, using single stranded conformational polymorphism (SSCP) analysis and DNA sequencing. All cases except one had a normal apoA1 gene sequence. One case of exceptionally severe atherosclerosis combined with extensive intimal amyloid deposits showed an apoA1 deletion corresponding to Lys 107. Thus, wild type apoA1 is amyloidogenic but our findings suggest that the expression of a mutant apoA1-form may be associated with enhanced amyloidogenicity.

Amyloid↗
PubMed1998

Constant region of a kappa III immunoglobulin light chain as a major AL-amyloid protein.

AL-amyloidoses are generally described as a group of disorders in which N-terminal fragments of monoclonal immunoglobulin light chains are transferred into amyloid fibrils. We have, by amino acid sequence analyses and immunological methods, characterized the Bence-Jones protein and the corresponding AL protein as a kappa III immunoglobulin light chain from material of a patient with systemic AL-amyloidosis presenting as a local inguinal tumour. The two proteins showed some unique features. The major part of the AL amyloid fibril protein consisted of C-terminal fragments of the Bence-Jones protein. Furthermore, both the Bence-Jones protein and the AL protein were glycosylated, with possibly a glycosylation in the constant part of the light chain.

Aged↗
PubMed1998

Increased release of IAPP in response to long-term high fat intake in mice.

In the present study, mice were fed high-fat diet or standard animal chow during 6 months. Animals fed high-fat diet showed a 4.5-fold increase in the fasting plasma IAPP levels compared to animals fed standard chow. No significant change in plasma insulin levels occurred between the groups. These differences in hormone response result in a change of the molar ratio between IAPP and insulin in the group fed high-fat diet. An increased IAPP to insulin molar ratio might be important in the pathogenesis of islet amyloid in man.

Amyloid↗
PubMed1998

Increasing incidence of cutaneous malignant melanoma in children and adolescents 12-19 years of age in Sweden 1973-92.

One-hundred-and-seventy-seven cases of cutaneous malignant melanoma were reported to the Swedish National Cancer Registry in subjects below the age of 20 during the period 1973-92. One-hundred-and-fifty-four (87%) were re-examined histologically, and the original diagnosis of primary cutaneous malignant melanoma was verified in 88%. The age-specific mean annual incidence rate increased to 0.5/100,000 in 1983-92 from 0.2/100,000 in 1973-82. Cutaneous malignant melanoma remained extremely rare in children below the age of 12, where only two cases were found. In subjects aged 12-19, the incidence doubled to 93 cases in the second 10-year period compared to 41 in the first. In boys, most of the melanomas occurred on the trunk, and, in girls, on the legs. Sixty-three percent of the melanomas were of the superficial spreading type, which also was the most rapidly increasing type of melanoma. These results emphasize the importance of surveillance and intensified preventive measures in protecting children and adolescents from the harmful effects of excessive exposure to the sun.

Adolescent↗
PubMed1998

Quantitative immunohistochemical analysis of islet amyloid polypeptide (IAPP) in normal, impaired glucose tolerant, and diabetic cats.

Islet amyloid polypeptide (IAPP, "amylin") has been proposed as having important roles in the pathogenesis of type 2 diabetes mellitus via its biological activity and by forming islet amyloid. The domestic cat develops a type of diabetes that closely resembles type 2 diabetes in humans, including the frequent formation of islet amyloid deposits in the impaired glucose tolerant (IGT) and diabetic state. With the aid of computerized image analysis and immunohistochemistry, we examined the IAPP and insulin content in pancreatic islets of normal, IGT and diabetic cats. IAPP immunoreactivity in beta cells from IGT cats was significantly stronger (p < 0.01) as compared with cells from normal cats, while the insulin labelling strength was unchanged. Overtly diabetic cats were usually almost devoid of beta cells. As in humans, cellular IAPP but not IAPP in islet amyloid deposits was labelled by the newly developed monoclonal antibody to IAPP 4A5, thus providing further evidence that IAPP is modified by a yet unknown mechanism during the amyloidogenic process. The study provides evidence that an increased beta cell storage of IAPP independent of insulin may be an important factor in the early phase of the development of islet amyloid in this form of diabetes.

Amyloid↗
PubMed1997

Renal elimination of islet amyloid polypeptide.

Six healthy volunteers showed significantly higher plasma islet amyloid polypeptide levels following an oral glucose tolerance test compared to fasting levels. The urine IAPP concentration before and after the OGTT was comparable to that in plasma. Reverse phase HPLC and radioimmunoassay analysis of urine samples revealed a single IAPP-immunoreactive peak. Before hemodialysis, the plasma levels of IAPP and C-peptide, but not of insulin, were significantly elevated in eight fasting patients with chronic renal failure, compared to eight healthy matched control subjects. After hemodialysis, there was a tendency for decreased IAPP levels compared to before dialysis. In summary, elevated levels of plasma IAPP were found in patients with chronic renal failure and the peptide is eliminated by hemodialysis. Furthermore, immunoreactive IAPP is normally present in the urine. These results suggest that IAPP is, at least in part, renally eliminated from the plasma by excretion (glomerular filtration and/or tubular secretion.

Adult↗