Transforming growth factor beta selectively inhibits normal and leukemic human bone marrow cell growth in vitro

The effects of transforming growth factor beta 1 or beta 2 (TGF-beta 1 or -beta 2) on the in vitro proliferation and differentiation of normal and malignant human hematopoietic cells were studied. Both forms of TGF- beta suppressed both the normal cellular proliferation and colony formation induced by recombinant human interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF). In the presence of GM-CSF or IL-3, optimal concentrations of TGF-beta (400 pmol/L) inhibited colony formation by erythroid (BFU-E), multipotential (CFU-GEMM), and granulocyte-macrophage (CFU-GM) progenitor cells by 90% to 100%, whereas granulocyte or monocyte cluster formation was not inhibited. In contrast, neither form of TGF-beta had any effect on G- CSF-induced hematopoiesis. The suppressive action appeared to be mediated directly by TGF-beta since antiproliferative responses were also observed in accessory cell-depleted bone marrow cells. In contrast to normal bone marrow cells, both GM- and G-CSF-induced proliferation of cells from patients with chronic myelogenous leukemia were suppressed in a dose-dependent manner by TGF-beta. Differential effects of TGF-beta on the proliferation of established leukemic lines were also observed since most cell lines of myelomonocytic nature studied were strongly inhibited where erythroid cell lines were either insensitive or poorly inhibited by TGF-beta. These results suggest that TGF-beta is an important modulator of human hematopoiesis that selectively regulates the growth of less mature hematopoietic cell populations with a high proliferative capacity as opposed to more differentiated cells, which are not affected by TGF-beta.     

Systematic review and stratified meta-analysis of the efficacy of carnosine in animal models of ischemic stroke

Carnosine is a naturally occurring pleotropic dipeptide which influences multiple deleterious mechanisms that are activated during stroke. Numerous published studies have reported that carnosine has robust efficacy in ischemic stroke models. To further evaluate these data, we have conducted a systematic review and meta-analysis of published studies. We included publications describing in vivo models of ischemic stroke where the neuroprotective efficacy of carnosine was being evaluated through the reporting of infarct volume and/or neurological score as outcomes. Overall efficacy was evaluated using weighted mean difference random effects meta-analysis. We also evaluated for study quality and publication bias. We identified eight publications that met our inclusion criteria describing a total of 29 comparisons and 454 animals. Overall methodological quality of studies was moderate (median = 4/9). Carnosine reduced infarct volume by 29.4% (95% confidence interval (CI), 24.0% to 34.9%; 29 comparisons). A clear dose-response effect was observed, and efficacy was reduced when carnosine was administered more than 6 h after ischemia. Our findings suggest that carnosine administered before or after the onset of ischemia exhibits robust efficacy in experimental ischemic stroke. However, the methodological quality of some of the studies was low and testing occurred only in healthy young male animals.     

Reinduction therapy in 297 children with acute lymphoblastic leukemia in first bone marrow relapse: a Pediatric Oncology Group Study

Many children with acute lymphoblastic leukemia (ALL) develop a marrow relapse during or shortly following initial continuation chemotherapy. Achievement of a second complete remission is the initial step in a successful retreatment effort. Reinduction results using two or three drugs have been unsatisfactory, and previous reports of four-drug reinduction programs have included relatively small numbers of patients. Pediatric Oncology Group protocol 8303 was designed for patients with ALL in first marrow relapse during or within 6 months after cessation of chemotherapy. The results of reinduction therapy in 297 study patients are described here. Four-drug reinduction therapy consisted of daily oral prednisone, weekly vincristine and daunorubicin, and asparaginase three times weekly for 4 weeks (PVDA). CNS retreatment consisted of two doses of triple intrathecal chemotherapy. Of the 297 patients receiving reinduction, 245, or 82%, entered second complete remission, six died of infection or progressive disease, and 46 others still had M2 or M3 bone marrow status. Forty of these latter patients received four doses (during a 2-week period) of teniposide and cytarabine, after which 13 (32%) achieved complete remission status. Thus, the overall second complete remission rate with PVDA with or without teniposide/cytarabine was 258 of 297, or 87%. The treatment program was generally well tolerated. Among the numerous factors analyzed by using logistic regression, only female sex (P = .035), the presence of blasts on the blood smear at the time of relapse (P = .0002), and a length of initial complete remission less than 12 months (P = .021) were independent predictors of failure to enter second remission. We conclude that the intensive reinduction program described here is a highly effective first step in the delivery of salvage therapy to patients with ALL in first marrow relapse. The current challenge is to develop improved continuation treatment for these children.     

Chloramphenicol-induced bone marrow injury: possible role of bacterial metabolites of chloramphenicol

To explore the potential role of some bacterial metabolites of chloramphenicol (CAP) in CAP-induced hematotoxicity, we examined their cytotoxic effects on bone marrow cells in vitro using a number of cytotoxicity parameters. Among the metabolites tested, dehydro-CAP (DHCAP) and p-nitrophenyl-2-amino-3 hydroxypropanone-HCI (NPAP) were more toxic than CAP. DHCAP was at least as toxic as nitroso-CAP. At concentrations of less than or equal to 10(-4) mol/L, DHCAP caused total irreversible inhibition of myeloid colony (CFU-GM) growth and 80% inhibition of DNA synthesis in human bone marrow. Incubation of human bone marrow cells with 10(-4) mol/L nitroso-CAP or DHCAP for 24 hours resulted in 75% and 65% cell death respectively. Although DHCAP was 10- to 20-fold more cytotoxic than CAP, it was only one third as effective in inhibiting mitochondrial protein synthesis, indicating that DHCAP exerts its toxic effect by alternate mechanisms. The cytotoxicity of DHCAP and its relative stability, compared to the unstable nitroso CAP, suggest that this bacterial metabolite of CAP, and possibly others, may play a significant role in CAP-induced hematotoxicity.     

Effectiveness of intensified rotational combination chemotherapy for late hematologic relapse of childhood acute lymphoblastic leukemia

Relapsed acute lymphoblastic leukemia (ALL) usually carries a dire prognosis. We evaluated the effectiveness and long-term complications of intensive rotational combination chemotherapy for late hematologic relapse (median, 16 months after elective cessation of therapy) among 34 children and young adults (ages 4 to 23 years). Concurrent central nervous system (CNS) relapse was present in 3 cases and testicular relapse in 4. Secondary therapy comprised an intensive five-drug reinduction (6 weeks) followed by continuation treatment with four drug pairs, rotated weekly in 4-week cycles over 120 weeks. Intrathecal chemotherapy (methotrexate, hydrocortisone, cytarabine) was given three times during reinduction and every 8 weeks during continuation. Treatment was electively discontinued at week 120 in the absence of detectable disease. Thirty-three patients (97%) attained a second complete remission. At a median follow-up of 9.3 years (range, 4.5 to 11.4), estimates of 5-year second event-free and overall survival (+/- SE) are 65% +/- 8% and 79% +/- 7%, respectively. Eleven patients had a second relapse (9 marrow, 2 testicular) and one developed secondary myeloid leukemia. There have been no CNS relapses or deaths in remission. Treatment was well-tolerated and was given largely on an outpatient basis. Late effects are primarily endocrinologic; one child had a second malignant solid tumor (presumed related to initial radiation therapy) that was treated successfully. Intensive treatment with alternating non-cross-resistant drug pairs for late hematologic relapses of ALL is effective and well-tolerated, and produces results similar to those achieved in patients with newly diagnosed ALL. Event- free survival compares favorably with reports of other relapse regimens, including those incorporating bone marrow transplantation.     

Persistence of circulating blasts after 1 week of multiagent chemotherapy confers a poor prognosis in childhood acute lymphoblastic leukemia

Early response to therapy, typically assessed by bone marrow status, is predictive of outcome in childhood acute lymphoblastic leukemia (ALL). Less is known about the significance of early clearance of blast cells in peripheral blood. We reviewed medical records of all patients with ALL enrolled on St Jude Total Therapy Study XI (February 1984 to September 1988) to determine the presence of blast cells in peripheral blood at diagnosis and after 1 week of intensive induction therapy. Of the 358 patients, 59 lacked evidence of circulating blast cells at diagnosis, and data were unavailable for 2 patients. The prognostic significance of persistent circulating blast cells in the remaining 297 patients was assessed in a multivariate analysis that included known adverse prognostic factors. Persistent circulating leukemic blasts were present at day 8 in 41 patients (14%). Compared with the "blast- negative" group, these patients had a significantly higher frequency of several adverse clinical features (leukocyte count > 50 x 10(9)/L, mediastinal mass, central nervous system leukemia, T-cell phenotype, lack of CD10 expression, and L2 morphology) and a significantly poorer 5-year event-free survival (34% +/- 8% [SE] v 77% +/- 3%, P < .01). By multivariate analysis, blast cell persistence at week 1 was the most significant adverse feature in the overall cohort (relative risk, 2.9; 95% confidence interval, 1.8 to 4.8) and in an analysis limited to B- lineage cases (relative risk, 3.6; 95% confidence interval, 1.9 to 7.1). Patients identified by this simple, noninvasive measure may benefit from early modification of therapy.     

The potential of neural stem cells to repair stroke-induced brain damage

Acute injuries to CNS such as stroke induce neural progenitor proliferation in adult brain which might be an endogenous attempt to self-repair. This process is known to be altered by several exogenous and endogenous modulators including growth factors that could help to reinforce the post-stroke neurogenesis. Increasing the neurogenesis may be a future therapeutic option to decrease the cognitive and behavioral deficits following stroke. In addition, transplantation of various types of stem cells into the injured brain is currently thought to be an exciting option to replace the neurons lost in the post-ischemic brain. These include immortalized stem cell lines, neural progenitors prepared from embryonic and adult animals and mesenchymal stem cells. Using exogenous stem cells in addition to modulating endogenous neurogenesis, we may be able to repair the injured brain after a devastating stroke. This article reviewed the current literature of these two issues.     

Combined use of Amplified Fragment Length Polymorphism and IS<Emphasis Type="Italic">6110</Emphasis> -RFLP in fingerprinting clinical isolates of <Emphasis Type="Italic">Mycobacterium tuberculosis</Emphasis> from Kerala,South India

Background  

DNA fingerprinting by IS6110-RFLP has shown a high incidence of Mycobacterium tuberculosis isolates having no and low copies of the insertion sequence in Kerala, South India. Amplified Fragment Length Polymorphism (AFLP) would scan the entire genome rather than a few repetitive elements, we thought that this technique would help us in differentiating the large reservoir of isolates from an endemic region. Here we evaluate the ability of Amplified Fragment Length Polymorphism (AFLP) to type clinical isolates.     

Results of definitive radiotherapy in T1 and T2 glottic carcinoma: Institute of Rotary Cancer Hospital experience

Early glottic carcinomas (T₁ and T₂) constitute only 2% of all laryngeal cancers in our data. Seventy patients were seen between 1985 and 1992. All patients were treated by cobalt-60 small field radiotherapy using a beam directed shell. The total dose delivered was 60–65 Gy in 31 patients and 66–70 Gy in 39 patients. The follow-up period ranged from 5 to 126 months, with a mean follow up of 37 months overall and 55 months in the surgical salvage group. Radiation therapy controlled disease in 71% (50 of 70) of patients overall; 75% with T₁ and 67% with T₂ lesions. Total laryngectomy as salvage surgery was performed in 70% (14 of 20) of patients whose disease recurred. Ultimate control including surgical salvage occurred in 64 (91%) of 70 patients in the present study. The actuarial 5 year survival was 83 and 80% in T₁ and T₂ tumours, respectively (statistically insignificant). This report supports the policy of definitive irradiation, reserving surgical salvage for radiation failures in early laryngeal cancers.