The study of heterogeneity and natural history--the importance of this type of research with chondrodystrophies as an example.
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Biomedical subjects
Publications and source records attributed to J G Hall.
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The Blom-Singer prosthesis was used on 18 male patients. 61% of these acquired fluent speech, 11% spoke partially and 28% were not able to use the prosthesis at all. Complications included dysphagia and difficulties with the function of the prosthesis. In some cases surgical revision or removal of the prosthesis was necessary. Older patients and those living in poor social conditions should not be selected for this procedure as their cooperation and motivation often seem to fail.
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Two glucosephosphate isomerase (GPI; D-glucose-6-phosphate ketolisomerase; EC 5.3.1.9) alleloenzymes from the blue mussel, Mytilus edulis, were purified to homogeneity. The steady-state kinetic properties of GPI1.00 and GPI.96, which exhibit latitudinal clines in frequency along the Atlantic coast of North America, were determined in both the glycolytic and the gluconeogenic reaction directions at physiological temperatures and pH levels. The two alleloenzymes are catalytically similar at low temperatures (5-10 degrees C), while GPI1.00 diverges to become more efficient at higher physiological temperatures (15-25 degrees C). This pattern of differentiation is consistent with the latitudinal distributions of the alleloenzymes and is due to the greater temperature sensitivities of GP1.00 Vmax/Km values; the Vmax values of the two alleloenzymes are virtually the same over the physiological range of temperatures. The observed pattern of catalytic differentiation is similar to that seen for interspecific GPI variants.
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A group of fetuses with a perinatally lethal variety of osteogenesis imperfecta (O.I. type II) is characterized by short limbs, and clinical and roentgenological evidence of severe osseous fragility and defective ossification. Forty-eight cases were reviewed and can be subdivided into 3 groups on the basis of small but probably significant differences in clinical and radiographic findings. Group A (38 cases): short, broad, "crumpled" long bones, angulation of tibiae and continuously beaded ribs. Group B (6 cases): short, broad, crumpled femora, angulation of tibiae but normal ribs or ribs with incomplete beading. Group C (4 cases): long, thin, inadequately modelled, rectangular long bones with multiple fractures and thin beaded ribs. Consistency of findings within sibships suggests the groups reflect genetic heterogeneity. An increased frequency of parental consanguinity, sib occurrence with normal parents, and normal mean paternal age at birth, suggest that most cases of O.I. type II represent autosomal recessive traits. Some previously reported cases and the biochemical findings in one case suggest still further genetic heterogeneity.
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We review six families in which recurrence of achondroplasia, inexplicable through autosomal dominant inheritance, has occurred. The clinical and radiographic characteristics of affected individuals in these families are identical to those usually seen in achondroplasia. Family histories and parental characteristics likewise seemed not to set this group apart from others with achondroplasia. While various mechanisms for these occurrences of achondroplasia in family members related through unaffected relatives can be postulated, the hypothesis that these recurrences were simply the result of two independent chance events cannot, at least for the moment, be excluded.
Small lymphocytes from the efferent lymph of the caudal mediastinal lymph node (CMLN), the regional node of the lower respiratory tract, were labelled in vitro either with 51Cr, or with the fluorochrome rhodamine isothiocyanate. The labelled lymphocytes were washed and returned to the sheep by intravenous (i.v.) injection; their later appearance in the lymph from the CMLN was monitored, as was their appearance in lymph from either a peripheral somatic lymph node (PSLN) or the intestinal lymph duct. It was found that the labelled lymphocytes entered the lymph from the CMLN and PSLNs with equal facility but were significantly less able to enter the intestinal lymph. Similarly, the large lymphocytes (immunoblasts) which were released into the lymph after antigenic stimulation of the CMLN, and which were labelled in vitro with [125I]Udr, showed little tendency to enter the gut after i.v. injection and became distributed throughout the body in the same way as immunoblasts efferent from the PSLN, i.e. they went principally to the lungs, and spleen.
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Thirteen infants with achondroplasia and sudden unexpected death or unexplained apnea were discovered through nonsystematic retrospective case collection. Most were initially thought to have died from sudden infant death syndrome. However, historical and pathologic findings suggest that many of these infants had apnea and sudden unexpected death secondary to acute or chronic compression of the lower brainstem or cervical spinal cord. Infants with achondroplasia evidently are at considerably increased risk for such deaths between 1 month and 1 year of age. Appropriate intervention, given these previously unrecognized risks, may include cervical restraint, polysomnographic evaluation, and apnea monitoring.
The trismus pseudocamptodactyly syndrome is a relatively rare condition with autosomal dominant inheritance, characterized by decreased ability to open the mouth (trismus), interphalangeal flexion deformity with wrist extension (pseudocamptodactyly), various foot deformities, and slightly less than normal stature. Five affected individuals from one family are reviewed and the orthopaedic aspects are described. The presence of trismus is emphasized for the orthopaedic surgeon, as it may lead to anaesthetic complications during the treatment of the musculoskeletal problems.
Although the occurrence of dendritic, macrophage-like cells in the peripheral lymph of sheep, pigs, rabbits, and man is well documented, the exact nature of these cells has become controversial. Generally, such cells tend not to adhere firmly to glass or exhibit phagocytosis in in vitro systems. However, when immunized sheep were given a subcutaneous injection of specific antigen (horseradish peroxidase), most of the macrophage-like cells in the lymph from the injection site could be shown by transmission electron microscopy to have engulfed the immune complexes that had been formed in the subcuticulum.
Inbred rats were given sub-lethal doses of irradiation so that they were unable to make antibodies unless they were reconstituted with syngeneic lymphoid cells. The ability of the reconstituted rats to make antibodies of the IgA class was measured in terms of the titres of specific antibodies that appeared in their bile. After syngeneic spleen cells, together with antigen, were injected into the spleens of irradiated rats, the titres of specific antibodies that appeared in the bile were low. After the same dose of spleen cells and antigen had been injected into the GALT of irradiated rats, the titres of biliary antibodies were substantial. These results, together with those of appropriate control experiments, suggest that radio-resistant influences in the microenvironment of the GALT may be important in inducing lymphoid cells to produce antibodies of the IgA class in response to local antigen.
Rat X rat hybridomas secreting antibodies with tumour specificity have been prepared using cells from the mesenteric nodes of rats bearing syngeneic sarcomata in their Peyer's patches. The antibodies obtained, which embraced all of the major immunoglobulin classes, varied in cellular reactivity from the individually tumour specific to cross-reactive with both normal and tumour cells. Several IgA producing hybridomas were prepared using this protocol but IgG secretors were obtained more frequently and they accounted for about half of the specific hybridomas. Specific IgG producers were found to predominate also when hybridomas were prepared from the mesenteric nodes of a rat immunized by injection of horseradish peroxidase into the Peyer's patches. Comparison of these data with our earlier results using spleen cells taken from rats that were either hyperimmunized with, or were bearing the same tumours in the leg, show that mesenteric nodes draining a tumour growing in the Peyer's patches are a much better source specific IgG producing B cells.
Peripheral intestinal lymph afferent to the mesenteric nodes has been collected from rats bearing syngeneic sarcomata in their Peyer's patches and the B cells used to produce rat X rat hybridomas. Analysis of the hybridoma supernatants by radioimmunoassay for the presence of immunoglobulins, showed that hybridomas secreting IgA predominated. Eleven out of the 15 hybridomas selected for antibody binding to cells of the immunising tumour secreted IgA antibodies, and six of these were tumour specific. Efferent mesenteric lymph (i.e. normal thoracic duct lymph), on the other hand, was found to be a poor source of B cells for hybridoma production and no specific IgA secreting hybridomas were obtained. The high yield of IgA secreting hybridomas obtained shows that peripheral intestinal lymph is a better source of IgA committed B cells than are the mesenteric nodes or thoracic duct lymph. We conclude that the IgA producing cells in the latter tissues are too far along the differentiation pathway to plasma cells to undergo successful somatic cell fusion.
When 5 mg doses of beryllium hydroxide, Be(OH)2, were injected intravenously (i.v.) into rats, much of the injected material was retained in the lungs. When the injection of Be(OH)2 was accompanied by particulate antigens such as killed B. abortus organisms or SRBC, immune responses took place in the intra-thoracic lymph nodes (ITLN) so that antibodies of the IgA class were generated and endowed the bile with significant agglutinating activity. This did not happen when the antigens were injected without the beryllium adjuvant. Similarly, a soluble antigen, bovine serum albumin (BSA) only gave rise to significant amounts of biliary and serum antibodies after i.v. injection if Be(OH)2 was used too. The highest titres occurred when the antigen followed the adjuvant after an interval of a few seconds but substantial titres still resulted if the injection of antigen was delayed for 24 hr. The amounts of biliary antibodies generated by the parenteral injection of antigen and adjuvant were comparable to those that occurred after the same materials were injected directly into the GALT. The adjuvant action of Be(OH)2 was able to induce in athymic (nude) rats the production of measurable amounts of both biliary and serum antibodies to SRBC.
Beryllium was injected subcutaneously (s.c.) into sheep in the form of a suspension of insoluble Be(OH)2 in isologous lymph plasma. Even in the absence of added antigen, doses of 50-150 mg induced rapid and vigorous proliferative responses in the regional lymph nodes so that large numbers of immunoblasts appeared in the efferent lymph within 4 days. Dendritic macrophages and dead white cells, which are excluded normally from efferent lymph, also appeared in significant numbers. When horseradish peroxidase was added to the injections of Be(OH)2, specific, high-affinity antibody appeared in the immunoblasts. This did not happen when the antigen was injected on its own or in combination with conventional, alum adjuvant. By the incorporation of radioactive 7Be in the injected material, it was shown that most of the Be(OH)2 remained at the site of injection and relatively little reached the node. In spite of this the cellular composition of peripheral lymph draining directly from the sites of injection showed no significant changes, and it was concluded that a 'depot' effect was unlikely to account for the heightened immune responses. These observations on the effects of beryllium are consistent with the view that its adjuvant action results from damage to intra-nodal macrophages, and that factors released from such cells caused intense immunoblastic proliferation.