Autologous bone marrow transplantation using marrow incubated with Asta Z 7557 in adult acute leukemia

The sensitivity of human myeloblastic leukemic (CFU-L) and normal hemopoietic stem cells (CFU-GM and BFU-e) to Asta Z 7557 (INN Mafosfamide) was studied with regard to autologous bone marrow transplantation (ABMT) with cleansed marrow for consolidation therapy in adult patients with acute leukemia (AL) in remission. Establishment of the dose-response curves for CFU-GM (n = 37), BFUe (n = 11), and myeloblastic CFU-L (n = 9) demonstrated a wide range of sensitivity from patient to patient for all three progenitors. Whereas CFU-L, CFU- GM, and BFU-e grown in semisolid cultures disclosed similar sensitivities to Asta Z 7557, long-term culture (LTC) studies (n = 41) indicated a higher resistance of early progenitors. In an effort to achieve a maximum tumor cell kill and yet spare a sufficient amount of normal stem cells to ensure consistent engraftment, we defined the optimal dose for marrow cleansing as the dose sparing 5% CFU-GM (LD95). This dose was established from a preincubation test (PIT) realized on a 10-mL marrow aspirate taken 15 days before marrow collection in each individual patient. Twenty-four adult patients while in remission of AL (20 in complete remission, four in partial remission) were consolidated by cyclophosphamide 60 mg/kg X 2 and total body irradiation at 10 Gy followed by ABMT with marrow cleansed by Asta Z 7557 according to the specification described above. Patients were divided in two groups: group 1, unfavorable prognosis (11 patients); group 2, standard prognosis [13 patients in first complete remission (CR)]. All patients engrafted on leukocytes (median day for recovery to 10(9)/L: day 30), patients with ALL recovered faster than patients with ANL (median day 19 v 34). Similarly, recovery of platelets to 50.10(9)/L occurred sooner in patients with ALL (median day 67, range day 23 through 90) whereas three patients with acute nonlymphoblastic leukemia (ANLL) in group 2 had to be supported with platelet transfusions for more than one year. In group 1, six patients had recurrent tumor within six months; three patients died from toxicity with no evidence of tumor. Two patients are still disease-free with a short follow-up (nine and ten months). In group 2, two patients died from toxicity with no evidence of leukemia three and 16 months post-ABMT. One patient with a M5 ANLL and one patient with ALL relapsed at six and 15 months, respectively. Nine patients have remained in CR or are disease-free with a median follow-up of 22 months.(ABSTRACT TRUNCATED AT 400 WORDS)     

The changing role of the primary school teacher in Swaziland in the context of HIV/AIDS: teacher as caretaker and economic provider

Swaziland has the world''s highest HIV prevalence with 26% of adults aged 15–49 years living with HIV. There are approximately 17,000 Swazi children aged 0 to 14 years living with HIV. This qualitative study explored the experiences of Swazi teachers supporting learners living with or affected by HIV/AIDS, with a specific focus on the extent to which teachers are aware of the “Rights of the Child” in their teaching and approaches. Important themes emerged from thematic analysis including the following: teachers provided more than education to learners living with and affected by HIV, including material goods and additional time, in some cases at the expense of other learners. In the era of HIV/AIDS, the teacher has become the emotional caretaker and economic provider in addition to the predictable role of educator in Swaziland. Education curricula in HIV-burdened countries need to modify training programmes and support services available to teachers to accommodate the complex role that teachers play in caring for learners living with and affected by HIV.     

Phonological and orthographic cueing therapy: A case of generalised improvement

Background: Phonological and orthographic cues can both be effective in the treatment of anomia, and are often used clinically. However, studies using phonological and orthographical cues in aphasia therapy have tended to be equivocal about their benefits, and most demonstrate improvements limited to treated items. Few previous studies investigate change in conversation or in people's own views of their aphasia.

Aims: The aim of the study was to investigate the effect of a weekly delivered therapy, using combined phonological and orthographic cues, on word retrieval, connected speech, conversation, and on the participant's own views of his aphasia.

Methods & Procedures: A person with anomia (TE) is presented as a detailed single-case study. Two baselines, 8 weeks apart, were followed by two 8-week phases of therapy, delivered weekly in a clinical setting. The first phase involved the use of combined phonological and orthographic cues to aid retrieval of a targeted set of words. The second phase encouraged the use of targeted words in connected speech and conversation. TE was reassessed after each phase of therapy and again 2 months later, after a period of no therapy. The study involved controls for improvement due to regular contact but without intervention (the baseline phase) and investigated generalisation to untreated items (treated and untreated sets were used, balanced for performance prior to therapy). Finally non-specific effects of therapy were determined by testing throughout the study on a set of language control tasks (predicted to be unaffected by the therapy).

Outcome & Results: TE demonstrated significant and enduring improvements in picture naming, which had generalised to untreated items. Significant improvements were also demonstrated in the broader measures of connected speech, aspects of conversation, and his own views of his aphasia, while performance on control tasks remained fairly stable. There was a significant relationship between changes in word finding and changes in TE's views of his communication activity across the course of the study, with a pattern of stability over baseline and change with intervention, particularly the first phase of therapy, i.e., using cues.

Conclusions: These findings demonstrate that a combined phonological and orthographic cueing therapy targeting word retrieval can have lasting benefits, not just on targeted items but also on untreated words, connected speech, and the views of the person with aphasia. Furthermore, such improvements can be achieved within a prevalent service delivery model.     

Marrow purging in autologous bone marrow transplantation for T-lineage acute lymphoblastic leukemia: efficacy of ex vivo treatment with immunotoxins and 4-hydroperoxycyclophosphamide against fresh leukemic marrow progenitor cells

A lymphoblast progenitor cell assay was used to evaluate the antileukemic efficacy of marrow-purging protocols that employed intact ricin immunotoxins (IT) and 4-hydroperoxycyclophosphamide (4-HC) against clonogenic primary T-lineage marrow blasts freshly obtained from 12 T-lineage acute lymphoblastic leukemia (ALL) patients. Residual T-lineage blast colonies were observed after treatment with 1 micrograms/mL T101 (anti-CD5)-Ricin (R) + G3.7 (anti-CD7)-R in eight of 12 cases and after 100 micrograms/mL 4-HC in six of nine cases. By comparison, a combination of IT and 4-HC proved very effective against T-lineage leukemic progenitor cells, and no residual blast colonies were observed in any of the eight cases studied. We conclude that future trials should consider combined treatment protocols such as IT + 4-HC for more effective purging of autologous marrow grafts.     

From the Cover: The role of older children and adults in wild poliovirus transmission

As polio eradication inches closer, the absence of poliovirus circulation in most of the world and imperfect vaccination coverage are resulting in immunity gaps and polio outbreaks affecting adults. Furthermore, imperfect, waning intestinal immunity among older children and adults permits reinfection and poliovirus shedding, prompting calls to extend the age range of vaccination campaigns even in the absence of cases in these age groups. The success of such a strategy depends on the contribution to poliovirus transmission by older ages, which has not previously been estimated. We fit a mathematical model of poliovirus transmission to time series data from two large outbreaks that affected adults (Tajikistan 2010, Republic of Congo 2010) using maximum-likelihood estimation based on iterated particle-filtering methods. In Tajikistan, the contribution of unvaccinated older children and adults to transmission was minimal despite a significant number of cases in these age groups [reproduction number, R = 0.46 (95% confidence interval, 0.42–0.52) for >5-y-olds compared to 2.18 (2.06–2.45) for 0- to 5-y-olds]. In contrast, in the Republic of Congo, the contribution of older children and adults was significant [R = 1.85 (1.83–4.00)], perhaps reflecting sanitary and socioeconomic variables favoring efficient virus transmission. In neither setting was there evidence for a significant role of imperfect intestinal immunity in the transmission of poliovirus. Bringing the immunization response to the Tajikistan outbreak forward by 2 wk would have prevented an additional 130 cases (21%), highlighting the importance of early outbreak detection and response.The Global Polio Eradication Initiative (GPEI) has achieved >99% reduction in the global annual incidence of poliomyelitis since the program began in 1988, and in 2012, just three countries were yet to interrupt wild poliovirus transmission—Afghanistan, Pakistan, and Nigeria—and 223 poliomyelitis cases were reported, the lowest in history (1). However, the absence of wild poliovirus transmission from most of the world, together with long-standing suboptimal vaccination coverage, has created cohorts of susceptible children and adults. As a result, an increased number of polio outbreaks affecting older children and adults have occurred in countries previously free of wild poliovirus (2–6). These outbreaks have significantly raised the cost of the GPEI and are a major challenge to achieving the goal of stopping all transmission by end-2014.It has also become clear that intestinal immunity to poliovirus wanes over time, allowing individuals vaccinated with oral poliovirus vaccine (OPV) to become reinfected and shed poliovirus (7). Therefore, older children and adults could theoretically contribute to wild poliovirus transmission without developing poliomyelitis. The World Health Organization (WHO) has recommended vaccination of older age groups as a standard for outbreak response (8). In addition, the recent GPEI strategic plan proposes expanding the age range of mass vaccination campaigns that currently target 0- to 4-y-old children in endemic countries as a potential measure to accelerate eradication, even though poliomyelitis is rarely reported at older ages (9, 10).Poliovirus shedding may not necessarily result in secondary infections, which depends on where the virus is deposited, routes of transmission, contact rates, and population immunity. Older children and adults are considered more hygienic than younger children, and these behavioral factors may limit onward transmission of shed poliovirus (11). Furthermore, the quantity and duration of virus shedding following reinfection of OPV-vaccinated individuals is reduced compared with naïve individuals (7). Where cases of poliomyelitis among older children and adults are rare, consideration of mass vaccination of this age group therefore requires an understanding of their contribution to transmission. This is challenging, however, because traditional methods such as contact tracing are not possible for wild poliovirus, which causes poliomyelitis in only 1 in ∼200 primary infections (12).In 2010, a large outbreak of imported wild poliovirus type 1 of Indian origin in Tajikistan resulted in 518 cases of poliomyelitis (Fig. 1 A and B) (2). Although this outbreak was associated with poliomyelitis among older children and adults, the initial response with serotype 1 monovalent OPV (mOPV1) targeted children 0–5 y of age, permitting a direct assessment of the contribution of these children and older age groups to transmission. We examined the transmission dynamics during this epidemic and the impact of vaccination by fitting an age-structured mathematical model of transmission using maximum likelihood with a particle-filtering algorithm (13, 14). As a comparison, we also examined the transmission dynamics during a large type 1 poliovirus outbreak in the Republic of Congo that commenced in late 2010 (442 cases of poliomyelitis) (Fig. 2 A and B) following introduction of virus from Angola (3, 15), as this lower income country, with a poorer level of sanitation, is likely to have had a different transmission pattern.Open in a separate windowFig. 1.The 2010 poliomyelitis outbreak in Tajikistan. (A) Geographic distribution of poliomyelitis cases plotted by district and colored according to their age group. The total population size for each district is indicated by the shading. Within a district, dots are randomly placed. (B) The age distribution of reported poliomyelitis cases by week of onset of paralysis. (C) Number of cases of poliomyelitis by week of onset of paralysis by age group (bars) with the median (blue line) and interquartile range (blue shading) of simulations under the best-fit transmission model, conditional on a major epidemic. The median (orange line) and interquartile range (orange shading) for simulations in the absence of a vaccination response are also shown. (D) Predicted number of cases prevented by the age-targeted vaccination response and under alternative scenarios (bars, median; error bars, interquartile range).Open in a separate windowFig. 2.The 2010–2011 poliomyelitis outbreak in the Republic of Congo. (A) Geographic distribution of poliomyelitis cases plotted by district and colored according to their age group. The total population size for each district is indicated by the shading. Within a district, dots are randomly placed. (B) The age distribution of reported poliomyelitis cases by week of onset of paralysis. (C) Number of cases of poliomyelitis by week of onset of paralysis for each age group (bars) with the median (blue line) and interquartile range (blue shading) of simulations under the best-fit transmission model, conditional on a major epidemic. The expected outbreak dynamics in the absence of a response are not shown (compare with Fig. 1) because of uncertainty in the estimated vaccine efficacy.     

IS CARDIOVASCULAR DISEASE A RISK FACTOR IN THE DEVELOPMENT OF AXONAL POLYNEUROPATHY?

Objectives: To determine if cardiovascular disease may be a risk factor in the development of chronic idiopathic axonal polyneuropathy (CIAP). Methods: In this incidence case-control study, the prevalence of cardiovascular disease and risk factors in 97 patients with CIAP (mean age 67.5 (SD 7.9) years) and the prevalence of neuropathic features in 97 patients with peripheral arterial disease (PAD) (mean age 67.1 (SD 7.3) years) were investigated. The results were compared with those for 96 age and sex matched controls without diagnosed PAD or polyneuropathy (mean age 67.5 (SD 9.1) years). In a randomly chosen subgroup of 23. patients with CIAP, 42 patients with PAD, and 48 controls, an electrodiagnostic investigation was performed. Results: Patients with CIAP more often had manifest cardiovascular disease and cardiovascular risk factors than controls (stroke 18% v 6% of patients, odds ratio (OR) 3.2 (95% confidence interval (0) 1.8 to 5.9); heart disease 29% v 15%, OR 2.4 (95% Cl 1.2 to 4.9); family history of cardiovascular disease 42% v 21%, OR 2.8 (95% Cl (1.5 to 5.2); hypertension 56% v 39%, OR 2.0 (95% Cl 1.1 to I I 3.6); hypercholesterolaemia 46% v 21%, OR 3.3 (95% Cl 1.5 to 7.3); current smoking 38% v 23%, OR 2.1 (95% Cl I. I to 3.9)). The prevalence of cardiovascular disease and cardiovascular risk factors was lower than in patients with PAD. Patients with PAD more often had polyneuropathy than controls (15% v 5%, OR 3.3 (95% Cl 1.1 to 10.0)). There was a trend towards lower nerve conduction velocities and lower amplitudes on electrodiagnostic investigation compared with controls. Conclusion: This study shows that cardiovascular disease and CIAP often coexist, and therefore cardiovascular disease may be a cofactor in the development of CIAP.