Herbert T. Abelson

Osteosarcoma: Fifteen Years Later

IN 1974, companion papers in the Journal discussed the improved disease-free survival among patients with osteosarcoma who had received adjuvant chemotherapy after surgery for the primary tumor. On...

Changes in RNA in relation to growth of the fibroblast. III. Posttranscriptional regulation of mRNA formation in resting and growing cells

The proportion of hnRNA processed into cytoplasmic mRNA in resting and growing 3T3 and 3T6 cells has been investigated by measuring the efficiency of transfer of nuclear poly(A) to the cytoplasm. When nuclear poly(A) is either labeled continuously with precursor or pulse labeled and then chased with cordycepin, growing cells transfer approximately twice as much of the poly(A) from the nucleus to the cytoplasm as do resting cells. When cells undergo a serum-induced transition from the resting to growing state, the efficiency of poly(A) transfer is increased to that characteristic of growing cells by 3 hr after the addition of the serum. On the other hand, the proportion of hnRNA which is polyadenylated and the total nuclear poly(A) content are the same in resting and growing cells. It appears that the principal means by which the cell regulates its poly(A)+ mRNA content in the growing and resting states is by regulating the efficiency which nuclear poly(A)+ RNA is converted to cytoplasmic mRNA.

Methotrexate-induced renal impairment: clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine.

Four separate groups of patients have been studied: (1) The effect of high-dose methotrexate (MTX) administration on glomerular filtration rate was determined by pre- and posttreatment inulin and creatinine clearances in nine patients. Measurements were made prior to and 24-40 hr after drug administration. Inulin and creatinine clearances both decreased a mean of 43%. No signs of systemic toxicity occurred. (2) Three other patients given high-dose courses of MTX developed MTX toxicity. Their creatinine clearance decreased an average of 61%. (3) In a separate group of five patients undergoing weekly MTX treatment, comparison of serum MTX pharmacokinetics with and without alkalinization of the urine demonstrated no significant difference in peak serum MTX levels or serum MTX decay. (4) Eight additional patients with severe renal dysfunction secondary to MTX were treated with increased doses of leucovorin and a continuous infusion of thymidine (8 g/m2/day) once renal failure was recognized. When high-dose leucovorin and thymidine were begun 48-72 hr after the MTX infusion, severe toxicity in the form of leukopenia, thrombocytopenia, diffuse mucositis, stomatitis, or skin rash was averted. We concluded the following: (1) high-dose MTX causes a subclinical decrease in glomerular filtration rate with each administration, even in nontoxic courses; (2) alkalinization of the urine with sodium bicarbonate does not alter plasma MTX decay, while volume expansion (hydration) is maintained constant; and (3) rigorous monitoring of serum creatinine and serum MTX levels 24-48 hr after MTX administration allows for the institution of rescue measures, including leucovorin and thymidine, which will abort the systemic toxicity that accompanies MTX-induced renal failure.

Osteogenic sarcoma: alterations in the pattern of pulmonary metastases with adjuvant chemotherapy.

The number and time to appearance of pulmonary metastases were evaluated in 15 patients with osteogenic sarcoma receiving adjuvant chemotherapy with high-dose methotrexate and doxorubicin (adjuvant group). The results were compared to 33 age- and sex-matched controls (control group). The adjuvant group demonstrated a reduction in the number and a delay in the appearance of the metastases. The median time to development of metastases was 17 mo in the adjuvant group and 7 mo in the control group, and the median number of metastases was 2 and 12, respectively.

Nuclear pores: the pore-annulus relationship in thin section

In situ determinations of the spatial relationship between the nuclear pore and its annulus were made in ultrathin sections of African green monkey kidney and mouse 3T3 tissue culture cells, embedded as monolayers. A variety of fixation procedures, enzyme digestions, serial sections, and rotational analysis of selected images were used to analyze the structure of the pore complex. The results indicated that the annulus of each pore consists of at least two types of subunits; that it extends both into the cytoplasm and into the nucleoplasm and fits within the margins of the pore at the level of the nuclear envelope. The pore complex is hourglass-shaped since the diameter of the cytoplasmic and nuclear extensions are greater than the nuclear pore. The octagonal nature of the nuclear pore itself was confirmed. In addition, the predominant number of subannular components was also found to be eight. These observations are discussed in the light of the findings of earlier investigators and serve to clarify the structural complexity of the pore complex. On the basis of our results, which have been confirmed by three-dimensional reconstruction of the pore-annulus relationship from serial sections, we suggest that the nuclear pore complex be included among the classical cellular organelles.

Creating effective leadership for improving patient safety.

Leadership has emerged as a key theme in the rapidly growing movement to improve patient safety. Leading an organization that is committed to providing safer care requires overcoming the common traps in thinking about error, such as blaming individuals, ignoring the underlying systems factors, and blaming the bureaucracy of the organization. Leaders must address the system issues that are at work within their organizations to allow individual and organizational learning to occur.

Resolution of breath-holding spells with treatment of concomitant anemia.

We describe two children who had breath-holding spells that were accelerating in frequency and severity and in one case had recrudesced. Both patients had signs, symptoms, and laboratory findings of severe anemia. With correction of anemia the breath-holding spells promptly and completely resolved in each case. We conclude that in some patients anemia may be a factor contributing to breath-holding spells and that correction of concomitant anemia may produce amelioration or remission of the spells.

Identification of dihydrofolate reductase in rabbit brain

Abstract After partial purification, rabbit brain extracts were assayed for dihydrofolate reductase by spectrophometric, radiochemical and methotrexate binding assays. By these assays, the specific activity of rabbit brain dihydrofolate reductase was about 15 per cent that of liver. Both rabbit liver and brain dihydrofolate reductase activities were abolished by methotrexate and had comparable K m (3 μM), pH maxima (4.8), and cofactor requirements (NADPH). In vivo , a small percentage of [ 3 H]folic acid was reduced to [ 3 H]methyltetrahydrofolate when injected into the left lateral ventricle. Thus, both in vitro and in vivo , the central nervous system has the ability to reduce oxidized folates.

Messenger RNA formation: Resistance to inhibition by 3′-deoxycytidine

Abstract Cordycepin (3′-deoxyadenosine) has been previously shown to inhibit nucleolar RNA synthesis and mRNA production. 3′-Deoxycytidine shares with cordycepin the ability to inhibit nucleolar RNA synthesis, but it does not affect the appearance of mRNA. Neither compound affects heterogeneous nuclear RNA (HnRNA). The results are interpreted to mean that cordycepin inhibits proper poly(A) metabolism.

Bilateral renal hypoplasia with oligonephronia

This is the first case report in the English literature of bilateral renal hypoplasia with oligonephronia. Shortly after birth the patient had vomiting, polydipsia, polyuria, hyposthenuria, salt wasting, azotemia, and subsequently renal osteodystrophy and growth retardation. She had demonstrably deficient renal ammonia production. The kidneys were small; the glomeruli were few in number, larger than normal, and had no evidence of inflammatory disease or preceding glomerular destruction. The tubules were dilated. Peritubular, periglomerular, and interstitial fibrosis were widespread. No other congential anomalies were found. The identical twin of the patient had no evidence of renal disease. Although this disease closely resembles nephronophthisis, it may be distinguished from it by careful consideration of clinical and morphologic features.