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The pattern of haemoglobin production changes at the embryonic, fetal and postnatal stages of human development, reflecting the expression of different globin genes in both the α-like and β-like gene clusters1,2. Recent studies have identified alterations in the state of DNA methylation3and sensitivity to nuclease digestion4associated with developmental expression of the globin genes in red blood cell precursors, but the mechanism initiating these changes remains unknown. Despite the screening of large numbers of blood samples from newborn infants5,6, no mutants have been found which affect the timing of these changes (with one possible exception involving a chromosomal translocation7), thus necessitating alternative approaches to analysing the cellular basis for the timing of haemoglobin switching. Although many mechanisms are possible, the initiation of the switch from fetal to adult haemoglobin could be regulated essentially either by a developmental clock inherent to haematopoietic stem cells or by an inductive enrivonment8,9, and in an attempt to distinguish between these possibilities, we have transplanted sheep fetal haematopoietic tissue into adult animals. Although previous experiments of this type produced conflicting results10–12, the accumulated results presented here demonstrate that the pattern of haemoglobin production after transplantation is determined largely by the gestational age of the fetal donor cells.

1. The conversion of cytosine arabinoside into its active metabolite cytosine arabinoside triphosphate, and catabolism by deamination to uracil arabinoside, was measured in intact marrow myeloblasts from patients with acute myeloid leukaemia. The ratio of uracil arabinoside/cytosine arabinoside triphosphate ranged from 0.32 to 19.11. 2. The effect of tetrahydrouridine, an inhibitor of cytosine arabinoside deamination, on cytosine arabinoside triphosphate production was studied. The greatest increase of cytosine arabinoside triphosphate production caused by addition of tetrahydrouridine was 27%. 3. The increase in cytosine arabinoside triphosphate production was not related to the ratio of uracil arabinoside/cytosine arabinoside triphosphate or to the deaminase activity per 106 cells. It was proportional to the percentage change of cytosine arabinoside in the incubation medium. 4. The sensitivity of DNA synthesis to inhibition by cytosine arabinoside was measured in myeloblasts from 11 patients. Addition of tetrahydrouridine did not increase the sensitivity of the marrow to cytosine arabinoside. 5. Cytosine arabinoside deamination is unlikely to be an important mechanism of resistance in myeloblasts in vivo, although it may produce apparent resistance in vitro.

6 out of 7 patients with severe neutropenia associated with the use of amodiaquine for malaria prophylaxis amodiaquine (400 mg weekly) plus proguanil (200 mg daily); 1 of these patients had also taken co-trimoxazole and another had taken sulphaguanidine. The 7th patient had taken amodiaquine alone, but at a higher dose. A retrospective analysis suggests that the frequency of severe neutropenia complicating amodiaquine taken prophylactically may be as high as 1 in 2000.

SummaryChronic graft‐versus‐host‐disease (GVHD) is a major complication of bone marrow transplantation. Until recently, little effective therapy has been available. We report a case of chronic cutaneous GVHD successfully treated with penicillamine.

A beta is a 39-43-amino acid peptide that accumulates as extracellular aggregates in Alzheimer's disease-afflicted brain tissue. Contact between these aggregates and neurons is potentially pathogenic, although little is known about the cellular transduction mechanisms. We have investigated the impact of A beta aggregates on the neuronal control of protein tyrosine phosphorylation, which underlies signal transduction for multiple families of growth factor and adhesion receptors. Added to cultures of rat and human nerve cell lines, A beta aggregates evoked a non-desensitizing increase (1.3-3.6-fold) in tyrosine phosphorylation in a band at 118 kDa. The 118-kDa protein was determined by immunoprecipitation to be pp125FAK, not previously documented in cells of neuronal lineage. Immunoblots with anti-focal adhesion kinase (FAK) showed that A beta aggregates had no effect on FAK protein levels. The increase in FAK tyrosine phosphorylation occurred at doses of A beta aggregates that evoked lactate dehydrogenase release; evoked tyrosine phosphorylation preceded the first detectable lactate dehydrogenase release by 4 h. Like degeneration, the FAK response was dependent on A beta aggregation and neuronal differentiation. Since tyrosine phosphorylation of FAK is essential to its activity as a transduction component of integrin-, peptide-, and lysophosphatidic acid-mediated signaling, the data establish a link between A beta aggregates and signal transduction pathways implicated in diverse cell functions including neurite outgrowth, control of the cell cycle, and apoptosis.

Humoral hypercalcemia of malignancy is a common paraneoplastic syndrome which is characterized by hypercalcemia resulting from secretion by tumors of a circulating bone-resorbing factor. Evidence suggests that in many instances this factor is an adenylate cyclase-stimulating protein which shares features with, but is distinct from, parathyroid hormone (PTH). The current report describes the purification to homogeneity from a humoral hypercalcemia of malignancy-associated tumor of a novel, basic, highly potent PTH-like adenylate cyclase-stimulating protein. This factor differs from previously described PTH-like factors with respect to size, amino acid composition, and specific activity.

The passing of the tuning fork as an instrument of precision in measurements of auditory acuity has been brought about by the recent advances in electrical equipment, particularly in the development of the telephone receiver. With an oscillating electric current and a reliable control of this current in the telephone receiver, accuracy and flexibility not to be secured with the tuning forks have been made possible.Methods for testing the acuity of hearing for diagnostic purposes have developed along two rather widely diverging paths. From one group of examiners we hear the statement that hearing values for a few tones only are necessary. Opposed to these is another group, who insist that values for the tones of the entire audible range are essential for differential diagnosis. The factors determining the method in each individual case are the training and experience of the examiner, the ease of application of the

Audiometer curves, fields of hearing, audiograms and other types of charts illustrating in empirical or absolute values the power of hearing, are being discussed more and more frequently in the current journals. Interest in these records is by no means confined to the physiologist and psychologist who are interested in the solution of the problem of "how we hear," but physicists and engineers, railroads, the air service and other types of corporations are forced by necessity to take cognizance of such measurements in making adjustments for their special services. However, the greatest interest in these records and the keenest scrutiny of their context is undoubtedly being shown by otologists. In France, England, Italy and Germany we note that the members of this profession are becoming more interested, not only from the point of view of determining the effects of operative procedure or treatment, but more especially from that of diagnosis.

The consideration of this subject necessitates answers to two questions: 1. Is it generally recognized that hearing losses result from certain industrial hazards? 2. Can anything be done and is anything being done to prevent them?The first of these must be answered in a qualified negative. Some hazards to hearing are recognized and preventive measures, either direct or indirect, are being taken to eliminate them. Other hazards, because of the peculiar type of hearing loss which they cause, are not being recognized and no concerted action toward conservation has been taken.Recently an employer was asked what his reaction would be if some one asked permission to test the hearing of his employees. He replied that he preferred to let sleeping dogs lie. A locomotive engineer was asked if he would invite some members of his union to come to the laboratory for hearing tests. No charge was to

The causes of the variations in auditory acuity that are seen in the results of routine audiometric tests of hospital patients with "normal" hearing have been studied from the point of view of age1 as well as from that of the effects of certain systemic conditions.2 The purpose of the present study is to analyze the differences shown in the results secured by tests of males and females and of white and colored patients.The records analyzed are, as in the previous studies, secured from tests of patients in the medical and surgical departments of the Johns Hopkins Hospital. All tests were made with the same 1A Western Electric audiometer. The testing was done in the wards or in a small room set apart for that purpose. Neither was ideal for testing hearing, as neither was free from the disturbing effects of accessory noises, but the two

In an earlier paper1 is presented a statistical study of the records secured by testing the auditory acuity of 353 patients from the medical and surgical departments of the Johns Hopkins Hospital. The results of the study indicate that if the averages of the thresholds are computed, there is a distinct loss of acuity in each successive decade for tones above 512 double vibrations, but the averages of the thresholds for tones of lower pitch are fairly constant for all patients regardless of age. The statement was made that "it is hoped that the information thus secured will make possible the statistical analysis of the auditory defects associated with cerebral arteriosclerosis, hypertension, hypotension, syphilis, nephritis, disturbances of the ductless glands, the various diseases of the blood, lesions of the central nervous system and other conditions."In this paper the age variations in auditory acuity in a group of 468

For several years an attempt has been made at the Otological Laboratory of the Johns Hopkins University to correlate losses in hearing and defects shown histologically in the conductive and perceptive mechanisms of the organ of hearing. In carrying out this program, about 4,000 records of hearing tests have been secured, and serial sections of several hundred temporal bones have been made.The staff of the medical and surgical departments of the Johns Hopkins Hospital and of the medical department of the Bay View division of the City Hospital have cooperated in permitting an examination of the auditory and vestibular function on their patients and securing permission for necropsy. A large percentage of the patients tested recover and leave the hospitals, but the results of the hearing tests and the hospital histories are available for study along other lines.Accurate and complete hearing tests are necessary if

A randomized crossover study of prophylactic immunoglobulin (IgG) therapy was performed in patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin's lymphoma (NHL). Twelve patients with hypogammaglobulinemia or a history of recurrent infections received infusions of IgG or placebo intravenously (IV) every 3 weeks for 1 year. They were then switched to the alternative preparation for another year. The number of serious bacterial infections was significantly less (P = .001; Mainland's cross-over method) in the months in which patients received IgG. Serious bacterial infections showed a trend to be associated with an IgG level less than 6.4 g/L (P = .046; Fisher's exact test).

In a group of haemodialysis patients who were iron loaded secondary to parenteral iron administration a slight but significant increase in red cell size was noted when compared to a normal population. This macrocytosis was not related to serum B12 or folate levels, or to the reticulocyte count. On stopping iron therapy both mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) values declined significantly as did serum ferritin and iron levels. Bone marrow smears were of normal or increased cellularity. When iron therapy was discontinued there was a steady fall in serum ferritin levels without a drop in haemoglobin values suggesting that the excess iron was available for haemopolesis. These findings suggest that the increase in red cell size in this group of patients may have been induced directly by iron overload.