2'3'-Dideoxycytidine-induced thymic lymphoma correlates with species-specific suppression of a subpopulation of primitive hematopoietic progenitor cells in mouse but not rat or human bone marrow.

The nucleoside analogue, 2',3'-dideoxycytidine (ddC), is a potent inhibitor of HIV replication, and AIDS patients receiving ddC experience clinical improvement without significant hematologic toxicity. Repeated ddC administration (1,000 mg/kg per day) for 13 wk produces an increased incidence of thymic lymphoma in B6C3F1 mice. Previous studies reveal a common link between chemically induced and genetically associated models of mouse thymic lymphoma that involves a defect in a subpopulation of primitive hematopoietic progenitor cells. This defect is characterized by suppression of a subpopulation of IL-3-responsive cells and ablation of stem cell factor synergy with GM-CSF. The present study was undertaken to ascertain whether ddC produces the same pattern of bone marrow toxicity in mice, and whether this effect is observed in rat and human bone marrow. ddC exposure in vivo and in vitro produced a select suppression of murine CFU identical to that previously described for other models of mouse thymic lymphoma. In contrast, this selective CFU suppression was not observed in rat and human bone marrow or in CD34+ cells. These studies suggest that the mouse may not be a good predictive model for ddC hematotoxicity in humans and that susceptibility to the development of thymic lymphoma may be unique to the mouse.     

Effect of bombesin, dermorphin and salmon calcitonin on gastric acid secretion in rats

A comparison of the effect of bombesin, dermorphin and salmon calcitonin on gastric acid secretion was assayed in rats two hours after their intracerebroventricular or subcutaneous administration. All three peptides significantly reduced gastric acid output after central administration. The order of potency was: bombesin greater than salmon calcitonin greater than dermorphin. After subcutaneous injection salmon calcitonin was very potent in reducing gastric acid output, while dermorphin was active only at high doses; bombesin had a very weak effect on the same parameter. Time-course studies demonstrated that the effect of these peptides reached a peak 1-2 h after their central administration, followed by a slow recovery toward control values. Salmon calcitonin, however, has a very prolonged action on the gastric parameters studied. These data indicate that bombesin and dermorphin might act centrally to modulate gastric acid secretion in the rat, while the very potent intracerebroventricular and subcutaneous action of salmon calcitonin suggests a different mechanism of action.     

Emphysema in the renal allograft

Two diabetic patients in whom emphysematous pyelonephritis developed after renal transplantation are described. Clinical recognition of this unusual and serious infection is masked by the effects of immunosuppression. Abdominal radiographic, ultrasound, and computed tomography findings are discussed. The clinical presentation includes urinary tract infection, sepsis, and acute tubular malfunction of the allograft in insulin-dependent diabetics.     

Kinetics of fibrous sheath formation in the rat spermatid

The morphogenesis of the fibrous sheath in the rat spermatid has been studied by electron microscopy and by EM radioautogaphy following injection of ³H-proline. The appearance of the developing fibrous sheath from the distal to proximal end of the principal piece has been examined in spermatids in each of the 19 steps of spermiogenesis. The precise timing of the various steps of its formation has been established and related to radioautographic observations on the synthesis and incorporation of proteins into the developing fibrous sheath. The longitudinal columns form slowly over a period of 15 days, appearing first at the distal end of the principal piece in step 2 and gradually extending in a proximal direction, ending at the level of the annulus in step 17. Throughout this 15-day period, proline-containing proteins are synthesized and incorporated into the growing columns. All of the ribs, on the other hand, arise from anlagen which are assembled along the length of the principal piece during a much shorter (4.5-day) period between steps 11 and 15 of spermiogenesis. New rib anlagen seemingly originate from bundles of proteinaceous filamentous material which are synthesized in the cytoplasm of step 11–15 spermatids and become aligned along the plasma membrane of the principal piece, starting at the distal end. These observations suggest that the two components of the fibrous sheath are assembled by means of two independent mechanisms that proceed asynchronously except during an overlap period of 2.5 days between steps 12 and 14.     

Evidence for direct action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on thymic epithelium

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) acts on selected targets within the immune system to produce a characteristic profile of pathologic responses typified by thymic atrophy, suppressed cellular immunity, and inhibition of antibody production to T-lymphocyte-dependent antigens. Studies in inbred mice differing in sensitivity to TCDD indicate that TCDD-induced thymic atrophy is mediated by a receptor protein (designated the Ah receptor). To study the cellular and molecular basis for TCDD-induced thymic atrophy, primary cultures of thymic epithelial (TE) cells were established from C57BL/6 mice, a strain sensitive to TCDD. Treatment of TE monolayers with TCDD (0.1 to 10 nM) resulted in the altered maturation of cocultured syngeneic thymocytes as judged by suppression (40% of control at 10 nM TCDD) of TE-dependent responsiveness of thymocytes to the mitogens concanavalin A and phytohemagglutinin. TE-conditioned medium enhanced the mitogen responsiveness of thymocytes three- to four-fold; however, the enhanced mitogen response mediated by the TE-conditioned medium was not suppressed in thymocytes incubated in medium collected from TCDD-treated cultures or in TE-conditioned medium to which TCDD (10 nM) had been added directly. The suppression of TE-dependent maturation of thymocytes was concentration dependent (EC50 approximately 1 nM) and stereospecific, suggesting involvement of the Ah receptor. The Ah receptor in cytosol fractions from cultured TE cells was measured directly and was found to be present at a concentration 3 and 3.5 times greater than that measured in whole thymus and thymocytes, respectively. The results of this study indicate that TCDD can act directly on epithelial target cells in the thymus: one consequence of this action appears to be the altered thymus-dependent maturation of T-lymphocyte precursors, mediated through direct cell-cell contact between thymocytes and TE cells.     

The call from the newborn screening laboratory: frustration in the afternoon

Newborn screening programs in the United States are evolving in concert with technologic advances in analytic chemistry and medicine. Many more disorders are being identified on dried filter paper blood spots without fundamentally altering the basic principles first put forward in the 1960s. Some disorders have been added without researchers knowing if there is a true benefit to early diagnosis and treatment; some disorders currently being detected will merit little or no follow-up in the future. The general principles underlying newborn screening are discussed, as are the individual disorders screened in most programs. The expanding and evolving impact of tandem mass spectrometry on newborn screening is also explored.     

Clinical presentation of 13 patients with subtelomeric rearrangements and a review of the literature

To re-examine the potential clinical indications for subtelomeric FISH testing and to provide additional cases to the growing literature on subtelomeric abnormalities and their genotype-phenotype correlations, we present a single center case series of 13 patients with chromosomal abnormalities detected by subtelomeric FISH testing over a 21 month period. The most common abnormality involved chromosome 1p (23%). Partial monosomy was present in 69% of the patients, complex rearrangements in 23%, and partial trisomy in 8%. The mean time from first normal karyotype to positive subtelomeric FISH result was 3.8 years (n = 11, median 3.5 years, range: 6 months-10 years). One patient had an abnormal high resolution karyotype recognized retrospectively, and two other patients had abnormal karyotypes that were fully deciphered only after subtelomeric FISH analysis. Eighty five percent of cases occurred de novo. The subtelomeric FISH results were useful for adjusting the recurrence risks and helping to focus medical screening and monitoring. The results impacted family planning and satisfied families in search of a diagnosis. Our findings support the use of subtelomeric FISH analysis as a second tier test in patients suspected of having a chromosomal abnormality with a normal karyotype. Potential benefits of subtelomeric FISH testing include faster time to diagnosis, better informed patient prognosis, and more accurate genetic counseling.     

Delaying the onset of type 2 diabetes mellitus in patients with prediabetes

The frequency of type 2 diabetes mellitus is increasing at an alarming rate. Prediabetes, also referred to as impaired glucose tolerance (IGT) and/or impaired fasting glucose, is a major risk factor for development of type 2 diabetes mellitus. In addition, IGT has been associated with an increased risk of cardiovascular disease and mortality. Several studies have measured the effects of various interventions in patients with IGT on the development of type 2 diabetes mellitus. Intensive lifestyle modifications through alterations in diet and improvement in exercise have delayed the development of type 2 diabetes mellitus by 58% in patients with IGT. Therapy with metformin, troglitazone, or acarbose also has reduced the progression of IGT to diabetes mellitus by 31%, 49% and 25%, respectively. The mechanisms by which lifestyle interventions and drugs reduce the progression may be through alterations in insulin sensitivity. The American Diabetes Association recommends screening for prediabetes in patients who are 45 years or older and those with a body mass index of 25 kg/m2 or greater who have additional diabetes mellitus risk factors. Pharmacists can promote awareness, counsel patients on intervention strategies to delay the onset of diabetes mellitus, and screen high-risk patients.