[Internal medicine in the last 40 years]. / De interne geneeskunde in de laatste 40 jaar.

Internal medicine in the last 40 years has known many eminent teachers at universities, such as Hijmans van den Bergh, Van Buchem, Borst, Mulder, Lindeboom, De Langen, Hulst, Jordan, Formijne, Major, Snapper, Groen and Querido, and others outside universities such as Stuyt, Van Hees, Eindhoven, Pannekoek, Schalm, Bruins Slot, Heeres, Stolte and Pompen. The main scientific platform on which the bequeathors assembled in the first few decades after World War II was the Algemene Ziektekundige Vereniging ('General Medical Association'), which met in Utrecht. Important medical steps forward in that period were the virtually complete eradication of tuberculosis in the Netherlands, the developing of vaccines against smallpox and polio, but also against the various types of virus hepatitis, and the progress in intensive care, transplantation and molecular biology. The Nederlandsche Internisten Vereeniging ('Dutch Association of Internists') has had its own scientific journal since 1958. Essentials in modern internal medicine are appropriate care and demonstrated usefulness of a treatment (evidence-based medicine); standards, values and ethics are core issues, as are quality control and cost control. Change is also in progress in the doctor-patient relationship, as manifested in the Wet Geneeskundige Behandelingsovereenkomst ('Medical Treatment Accord Act').

An inherited restriction in the idiotypic variability as a possible explanation of a genetic predisposition for a monoclonal component.

Genetic factors have been proposed to play a role in the aetiology of a monoclonal proliferation of B lymphocytes. As an additional genetic factor we postulate that a restriction in the idiotypic variability of an individual contributes to a genetic predisposition to monoclonal gammopathy. To support our hypothesis, we have examined three families with multiple occurrence of M-components for sharing of idiotypic antigenicity between the related M-components and between the M-components and the sera of unaffected relatives. Idiotypic antisera against five isolated M-components were raised in guinea-pigs and used in a radiobinding inhibition assay. In none of the three families was idiotypic cross-reactivity observed between the familial M-components. However, in a family with three members with an M-component, sera of first-degree relatives showed a higher inhibitory capacity than sera of non-related individuals when an idiotypic antiserum, raised against the M-component of proposita, was employed. Within this particular family the observed restriction in the idiotypic variability could have contributed to the multiple occurrence of M-components.

Immune complexes in peripheral blood polymorphonuclear leucocytes of patients with Raynaud's phenomenon.

Phagocytosed immune complexes in polymorphonuclear (PMN) leucocytes of sixty-nine patients with Raynaud's phenomenon were studied by scoring the cells for IgG and complement inclusions. The results were compared with the degree of vasospasm, as measured by photoelectric plethysmography of the fingers after cooling. Median IgG and complement scores of PMN cells were significantly elevated in patients with Raynaud's phenomenon when compared with those of the control group (P less than 0.01). Patients with a positive (n = 35) or a strongly positive (n = 11) plethysmographic test showed significantly higher median IgG and complement scores than those with a negative plethysmorgraphic test (n = 23). They also showed elevated IgG and complement scores in a greater proportion (89 and 100%, respectively, vs 48%).Thus, a positive relationship was shown to exist between the degree of vasospasm and the levels of phagocytosed immune complexes in circulating PMN leucocytes. In secondary Raynaud's phenomenon high levels of phagocytosed immune complexes were found. In primary Raynaud's, patients with some clinical or laboratory signs of an auto-immune disease (n = 12), who were classified as "suspected secondary", had higher IgG and complement scores than those without such signs (n = 37). This suggests that the test for immune complex detection may distinguish patients with connective tissue disease-associated Raynaud's phenomenon from those with truly primary Raynaud's, in an early stage of the disease. The clinical and patho-physiological implications of these findings with regard to the Raynaud phenomenon are discussed.

Immunoglobulins in families of myeloma patients.

The serum immunoglobulin levels of 200 first-degree relatives and 23 spouses of 32 patients with myelomatosis were compared with those of age- and sex-matched control persons. First-degree relatives of myeloma patients appeared to have higher serum levels of IgG (P less than 0.05), IgA (P less than 0.05), and IgM (P less than 0.01) than their age- and sex-matched controls. The spouses as a group did not differ from their controls in this respect. No statistically significant difference in the incidence of M-components among family members (0.6%) and spouses (4.3%) was found compared with the incidence in the general population (0.9%). Myelomatosis as such appeared to be more frequent than in the general population (P less than 0.05).

Immune response in asymptomatic paraproteinemia. I. Primary and secondary antibody response to Helix pomatia hemocyanin.

In a group of 20 patients with asymptomatic paraproteinemia, as judged after at least 3 years of follow-up, the primary and secondary antibody response to Helix pomatia hemocyanin (HPH) was defective as compared with the response in controls. The class of antibody was assessed by mercaptoethanol (ME) treatment of serum. A lowered response was found not only in the total but also in the ME-resistant (mainly 7S, IgG) antibody titer. Low anti-HPH antibody titers were preferentially found in the patients with high serum paraprotein levels, whereas in half of the patients with low serum paraprotein levels a completely normal antibody response was found. No differences in the total or 7S anti-HPH antibody response were found between patients with IgG, IgM, or IgA paraproteinemia. The polyclonal serum Ig levels were not predictive for the measured anti-HPH response. The anamnestic diphtheria and tetanus antibody response was not different from that of controls.

Soft-tissue uptake of 99mTc-diphosphonate and 99mTc-pyrophosphate in amyloidosis.

This study describes the results of scintigraphy with 99mTc-labeled methylene-diphosphonate (99mTc-MDP) and pyrophosphate (99mTc-PYP) as a noninvasive test for the distribution of organ involvement in five different types of amyloidosis. Scintigraphy with 99mTc-labeled phosphates appeared to be a sensitive noninvasive screening test for the extent and the distribution of organ involvement in systemic AA and systemic AL amyloidosis as well as in local bronchial amyloid, local dermal amyloid, and familial amyloidotic polyneuropathy. Echocardiography, however, was more sensitive for demonstrating cardiac involvement in systemic amyloidosis than 99mTc-MDP or 99mTc-PYP scintigraphy. 99mTc-MDP images showed a better contrast than 99mTc-PYP images, although there was no difference in the extent or the intensity of soft-tissue uptake.

Class- and subclass-specific antibody response to hemocyanin in nonmalignant paraproteinemia.

IgM, IgG, and IgA class-specific, as well as IgG subclass-specific antibody titers against the primary immunogen HPH were measured with ELISA in 19 patients with nonmalignant paraproteinemia (eight with IgG1, two with IgG2, two with IgG4, four with IgM, and three with IgA) and in a simultaneously studied age- and sex-matched control group. After primary immunization only IgM and IgA anti-HPH titers were significantly lower in the patient group. Four patients with relatively high IgG or IgA serum paraprotein levels did not produce antibodies in some Ig classes or IgG subclasses, whereas all other patients and all controls developed antibody titers in all classes and IgG subclasses. Low or absent antibody titers did not occur preferentially in the Ig (sub)classes to which the paraproteins belonged. After secondary immunization the patients could not increase or maintain their antibody titers as well as the controls, and this was most clear in the IgM and IgA antibody class. A direct correlation between polyclonal serum IgM levels and IgM anti-HPH titers was present in the patients. Such a correlation was absent for IgA in the patients and for all classes in the controls. It is concluded that humoral immunosuppression as measured with a newly encountered antigen in patients with nonmalignant paraproteinemia is most clearly expressed in the IgM and IgA antibody class and that the paraprotein (sub)class is not preferentially involved.

Classification of amyloidosis: immunohistochemistry versus the potassium permanganate method in differentiating AA from AL amyloidosis.

As systemic AA and Al amyloidosis differ considerably with regard to prognosis and therapeutic approach, it is of importance to make an accurate histochemical classification with regard to the amyloid protein involved. In the present study the results of the potassium permanganate (KMnO4) method, an indirect histochemical procedure based on differences in cross-beta-potential of different amyloid fibril proteins, were compared with the results of an immunohistochemical method utilizing anti-AA and anti-AP antibodies. Renal biopsy sections of patients with systemic amyloidosis related to inflammatory conditions, systemic amyloidosis associated with plasma cell dyscrasia, idiopathic systemic amyloidosis, and nonamyloidotic controls were studied. Positive reaction of anti-AA was observed on all KMnO4-sensitive amyloid deposits, whereas the KMnO4-resistant amyloid deposits remained unstained, provided that highly purified anti-AA antiserum was used. Anti-AP produced not only comparable staining of both KMnO4-sensitive and -resistant amyloid deposits, but also of glomerular basement membranes and elastin layers of blood vessels in amyloid and control biopsies. The intensity of anti-AP reactivity was comparable with the reaction of anti-AA on KMnO4-sensitive amyloid deposits. The present results confirm the specificity of the KMnO4 method, which is a simple method available to every laboratory, in differentiating between AA and AL amyloidosis. Furthermore, the results indicate that, at least in renal biopsy specimens, anti-AP may serve as a general marker for AA and AL amyloid deposition; this finding is in contrast to the results of a recently published report.

A biclonal origin of two monoclonal proteins, IgG3(kappa) and IgA1(lambda), from a single patient.

The cellulose acetate electrophoretic pattern of the serum from patient Sik disclosed two distinct peaks, representing two monoclonal proteins. On immunoelectrophoresis the two M-components were found to differ in heavy chain class as well as in light chain type, IgG3(kappa) and IgA1(lambda). Serum immunoglobulin levels remained relatively constant over a period of 7 years and no clinical symptoms of a malignant deterioration occurred. It was found that the isolated M-components did not share idiotypic antigenicity. Bone marrow cells synthesizing the monoclonal proteins were identified by means of the immunofluorescent technique using isotypic as well as idiotypic antisera. Two distinct monoclonal cell populations were observed, containing either the IgG3(kappa) or the IgA1(lambda) monoclonal protein. The alpha 1-chain belonged to the VHIII subgroup, whereas the gamma 3-chain was found to be blocked. Subsequent sequence determination showed the gamma 3-chain to belong to the VHIII subgroup. It was concluded that the two M-components in the serum of patient Sik resulted from two independent neoplastic transformations.

Nephroptosis and hypertension.

The degree of renal mobility was measured in patients with and without hypertension to evaluate a suggested causal relation between nephroptosis and hypertension. In contrast to men, women often showed pronounced renal mobility and the degree of renal mobility correlated positively with the blood-pressure. Fibromuscular dysplasia of the renal artery was always accompanied by a considerable degree of renal mobility on the side involved. The results of this study indicate that in women there may be an association between abnormal renal mobility and the development of high blood-pressure.

High immune responsiveness in a family with multiple paraproteinaemia and autoimmune thyroid disease.

Immune responsiveness was investigated in a family comprising 12 first- and second-degree relatives, one of whom had kappa-myelomatosis, one IgA-lambda paraproteinaemia, two Graves' disease and a further two thyroid antibodies without disease. Relatives by marriage served as controls. Parameters of immune capacity studied were the humoral and cellular immune response to haemocyanin of Helix pomatia (HPH), dinitrochlorobenzene (DNCB) skin reactivity and in vitro lymphocyte proliferation capacity to phytohaemagglutinin (PHA). Mean antibody titres to HPH were higher in the family than in the control group in all main Ig classes and IgG subclasses after primary and secondary immunization, and the difference was statistically significant for IgG, IgG2 and IgG4 titres. This could not have been predicted from the (normal) serum Ig levels in this family. In vitro lymphocyte proliferation capacity to HPH after primary and secondary immunization was also significantly increased. DNCB skin reactivity also tended to be high in the family, whereas PHA-induced lymphocyte proliferation was normal. These findings support the idea that myelomatosis clusters in families with immune dysregulation.