Worldwide Network for Blood and Marrow Transplantation (WBMT) recommendations for establishing a hematopoietic stem cell transplantation program in countries with limited resources (Part II): Clinical, technical and socio-economic considerations.

The development of hematopoietic stem cell transplantation (HSCT) programs can face significant challenges in most developing countries because such endeavors must compete with other government health care priorities, including the delivery of basic services. While this is may be a limiting factor, these countries should prioritize development of the needed expertise to offer state of the art treatments including transplantation, by providing financial, technological, legal, ethical and other needed support. This would prove beneficial in providing successful programs customized to the needs of their population, and potentially provide long-term cost-savings by circumventing the need for their citizens to seek care abroad. Costs of establishing HSCT program and the costs of the HSCT procedure itself can be substantial barriers in developing countries. Additionally, socioeconomic factors intrinsic to specific countries can influence access to HSCT, patient eligibility for HSCT and timely utilization of HSCT center capabilities. This report describes recommendations from the Worldwide Network for Blood and Marrow Transplantation (WBMT) for establishing HSCT programs with a specific focus on developing countries, and identifies challenges and opportunities for providing this specialized procedure in the resource constrained setting.

First report of pediatric hematopoietic stem cell transplantation activities in the eastern mediterranean region from 1984 to 2011: on behalf of the pediatric cancer working committee of the eastern mediterranean blood and marrow transplantation group.

To describe the hematopoietic stem cell transplantation (HSCT) activities for children in the Eastern Mediterranean (EM) region, data on transplants performed for children less than 18 years of age between 1984 and 2011 in eight EM countries (Egypt, Iran, Jordan, Lebanon, Oman, Pakistan, Saudi Arabia and Tunisia) were collected. A total of 5187 transplants were performed, of which 4513 (87%) were allogeneic and 674 (13%) were autologous. Overall, the indications for transplantation were malignant diseases in 1736 (38.5%) and non-malignant in 2777 (61.5%) patients. A myeloablative conditioning regimen was used in 88% of the allografts. Bone marrow (BM) was the most frequent source of stem cells (56.2%), although an increasing use of PBSC was observed in the last decade. The stem cell source of autologous HSCT has shifted over time from BM to PBSC, and 80.9% of autologous HSCTs were from PBSCs. The donors for allogeneic transplants were matched-related in 94.5% of the cases, and unrelated transplants, mainly cord blood (99%) in 239 (5.5%) cases. This is the first report to describe the pediatric HSCT activities in EM countries. Non-malignant disorders are the main indication for allogeneic transplantation. Frequency of alternate donor transplantation is low.

Clinical and molecular findings of chronic granulomatous disease in Oman: family studies.

Chronic granulomatous disease (CGD), a rare inherited disorder of the innate immune system, results from mutations in any one of the five genes encoding the subunits of the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase enzyme, and is characterized by recurrent life-threatening bacterial and fungal infections. Molecular analysis of 14 Omani CGD patients from 10 families, diagnosed to have CGD on clinical (recurrent infections) and biochemical grounds (positive for both the nitroblue tetrazolium (NBT) test and the dihydrorhodamine (DHR-1,2,3 assay), revealed that only one patient had X-linked CGD, with a large deletion involving both the gp91-phox gene (CYBB) and the McLeod gene (XK). The remaining 13 patients were all homozygotes from a previously described c.579G>A (p.Trp193X) mutation in the NCF1 gene on chromosome 7, responsible for autosomal recessive CGD (AR-CGD). Although X-linked CGD is the most common type of CGD disorder in most population groups, AR-CGD is the most prevalent type in Oman.

Biomechanical comparison of three fixation techniques used for four-corner arthrodesis.

Clinical results following four-corner arthrodesis vary and suggest that nonunion may be related to certain fixation techniques. The purpose of our study was to examine the displacement between the lunate and capitate following a simulated four-corner arthrodesis with the hypothesis that three types of fixation (Kirschner wires, dorsal circular plate, and a locked dorsal circular plate) would allow different amounts of displacement during simulated wrist flexion and extension. Cadaver wrists with simulated four-corner arthrodeses were loaded cyclically either to implant failure or until the lunocapitate displacement exceeded 1 mm. The locked dorsal circular plate group was significantly more stable than the dorsal circular plate and K-wire groups (p = 0.018 and p = 0.006). While these locked dorsal circular plates appear to be very stable our results are limited only to the biomechanical behavior of these fixation techniques within a cadaver model.

Acquired pericentric inversion of chromosome 9 in acute myeloid leukemia.

Pericentric inversion of chromosome 9 involving the qh region is relatively common as a constitutional genetic aberration without any apparent phenotypic consequences. However, it has not been established as an acquired abnormality in cancer. Among the three patients reported so far in the literature with acquired inv(9), only one had acute myeloid leukemia (AML). Here we describe an unique case where both chromosomes 9 presented with an acquired pericentric inversion with breakpoints at 9p13 and 9q12 respectively, in a AML patient with aberrant CD7 and CD9 positivity. Additionally, one der(9) also showed short arm deletion at 9p21 to the centromeric region and including the p16 gene. The constitutional karyotype was normal. This is probably the first report describing an acquired inv(9) involving both chromosomes 9 in AML. The possible significance of this inversion is discussed.

Special issues related to hematopoietic SCT in the Eastern Mediterranean region and the first regional activity report.

Although several centers are now performing allogeneic hematopoietic SCT (HSCT) in the Eastern Mediterranean (EM) region, the availability is still limited. Special issues including compatible donor availability and potential for alternative donor programs are discussed. In comparison to Europe and North America, differences in patterns of diseases and pre-HSCT general status, particularly for patients with BM failure, are described. Other differences including high sero-positivity for CMV, hepatitis B and C infection, and specific observations about GVHD and its relation to genetically homogeneous communities are also discussed. We report that a total of 17 HSCT programs (performing five or more HSCTs annually) exist in 9 countries of the EM region. Only six programs are currently reporting to European Group for Blood and Marrow Transplantation or Center for International Blood and Marrow Transplantation Research. A total of 7617 HSCTs have been performed by these programs including 5701 allogeneic HSCTs. The area has low-HSCT team density (1.56 teams per 10 million inhabitants vs 14.43 in Europe) and very low-HSCT team distribution (0.27 teams per 10 000 sq km area vs <1-6 teams in Europe). Gross national income per capita had no clear association with low-HSCT activity. Much improvement in infrastructure and formation of an EM regional HSCT registry are needed.

Hematopoietic stem cell transplantation in Oman.

Hematopoietic SCT (HSCT) is an integral part of the management of patients with hematologic disorders. The Sultanate of Oman, with a population of 2.3 million, has an HSCT program based in the Sultan Qaboos University (SQU) hospital. Initiated in 1995, this two-bed unit continues to be the only program in the country. Between June 1995 and August 2006, a total of 128 patients underwent HSCT in this center, averaging about 10-12 transplants per year. The median age of these patients was 11 years (2 months to 45 years). Hematologic malignancies (49%) and inherited disorders (42%) constituted the major transplant indications, whereas BM failure accounted for the remaining. The majority of transplants carried out so far have been HLA-matched sibling-donor allogeneic HSCTs. Among the inherited disorders, homozygous beta-thalassemia and primary immunodeficiency are important transplant indications in this center. The approximate cost of an uncomplicated transplant in this center is US$50,000. The success of this program has now led to the initiation of a new and larger HSCT complex to provide the opportunity for more patients to benefit from this treatment modality within the country.

Randomized trial of two different conditioning regimens for bone marrow transplantation in thalassemia--the role of busulfan pharmacokinetics in determining outcome.

In total, 94 patients with homozygous beta thalassemia were randomized to two different conditioning regimens: busulfan 600 mg/m2 + cyclophosphamide 200 mg/kg or busulfan 16 mg/kg + cyclophosphamide 200 mg/kg and antilymphocyte globulin (47 in each group), for bone marrow transplantation, to see whether increased myeloablation or increased immunosuppression would reduce rejection. Busulfan pharmacokinetics in determining outcome was evaluated. There was no significant difference in engraftment, graft-versus-host disease, rejection, and overall and disease-free survival in the two groups. Systemic exposure to busulfan was significantly higher in the 600 mg/m2 group, but in both groups there was a wide interindividual variation in the busulfan kinetics. Six patients rejected the graft, two in the busulfan 600 mg group and four in busulfan 16 mg group (P = 0.677 CI -0.17, 0.07), but in five patients (pharmacokinetic data not available in one patient) who rejected the graft busulfan first dose trough level (C(min)-1) was below 150 ng/ml while it was above this level in the 66 of 68 patients with successful engraftment (P < or = 0.001). This randomized trial shows that rejection is influenced by busulfan levels and suggests that monitoring of busulfan levels and dose adjustment based on first-dose kinetics may reduce the risk of rejection.

Heterozygous methylene tetrahydrofolate reductase mutation with mild hyperhomocysteinemia associated with deep vein thrombosis.

Hyperhomocysteinemia is known to be associated with arterial occlusive vascular disease and venous thrombosis. Here, we report a young ethnic Omani patient with recurrent venous thrombosis who was found to be heterozygous for 677C-T mutation in the methyltetrahydrofolate reductase (MTHFR) enzyme. Moderate hyperhomocystenemia was also observed, in the presence of normal red cell folate and serum B12 levels. No other documented marker of hereditary thrombophilia could be demonstrated in this patient, in spite of extensive investigation on multiple occasions.

Allogeneic bone marrow transplantation in the developing world: experience from a center in India.

We describe our experience of setting up an allogeneic BMT program at the Christian Medical College Hospital, Vellore over a period of 13 years, from October 1986 to December 1999. Two hundred and twenty-one transplants were performed during this period in 214 patients, with seven patients undergoing second transplants. Indication for BMT were thalassemia major - 106 (48%), CML - 30, AML - 35, ALL - 10, SAA - 22, MDS - six and six for other miscellaneous disorders. The mean age of this patient cohort was 15.6 years (range 2-52). Graft-versus-host disease of grades III and IV was seen in 36 patients (17%) and this was the primary cause of death in 20 patients (9.2%). All patients and donors were CMV IgG positive. Sepsis was the primary cause of death in 16 patients (7.4%), 10 bacterial, four fungal and two viral. One hundred and ten of this series of patients are alive and disease free (50%) with a median follow-up of 24 months (range 2-116). These results are comparable to those achieved for patients with similar disease status in transplant units in the Western world and cost a mean of US$15 000.

Nerve injuries of the elbow, wrist, and hand in athletes.

Upper extremity compression neuropathies are fairly rare in athletes. Initially, most can be managed conservatively. These conditions can follow direct contusion of the tissues that overlay these peripheral nerves or can result from vigorous, repetitive, athletic activity leading to tissue swelling and ischemia with nerve compression symptoms. A complete history and physical examination, including a neurologic examination, should be paramount when treating athletes with upper extremity injuries. Early diagnosis and treatment with conservative measures such as splinting, rest, activity modification, and medications can afford the athlete an earlier return to sports. Surgery can be employed when conservative treatment fails and a specific diagnosis has been ascertained.

Glutathione S-transferase activity influences busulfan pharmacokinetics in patients with beta thalassemia major undergoing bone marrow transplantation.

Busulfan, at a dose of 16 mg/kg, is widely used in combination with cyclophosphamide as a conditioning regimen for patients undergoing bone marrow transplantation. Wide interindividual variation in busulfan kinetics and rapid clearance of the drug have been reported, especially in children. Some of the factors contributing to interpatient variability have been identified. They include circadian rhythms, age, disease, drug interaction, changes in hepatic function, and busulfan bioavailability. In this study, we demonstrate that hepatic glutathione S-transferase (GST) activity correlates negatively with busulfan maximum and minimum concentrations (Pearson's correlation r = -0.74 and -0.77, respectively) and positively with busulfan clearance (Pearson's correlation r = 0.728) in children with thalassemia major in the age range of 2 to 15 years. We also found that plasma alpha GST levels were 5 to 10 times higher in patients with thalassemia than in normal controls and age-matched leukemic patients, either reflecting extensive liver damage, elevated expression of the enzyme, or both in thalassemic patients. Plasma alpha GST concentrations showed a similar correlation with busulfan kinetic parameters to that observed for hepatic GST. The status of hepatic GST activity accounts, at least in part, for the observed interindividual variation in busulfan kinetics, while the observed association with plasma alpha GST is difficult to explain at present.

Focus on primary care: periodontal disease: implications for women's health.

A definite relationship is emerging between periodontal infections and systemic conditions. The objective of this review is to address this relationship as it pertains to cardiovascular disease and diabetes mellitus. Furthermore, because recent reports link the presence of periodontal disease to preterm delivery, the possible relationship between the development and progression of periodontal disease and certain hormonal states in women such as puberty, oral contraceptive use, menopause, and pregnancy will also be discussed. Although the current literature suggests a strong association between periodontal disease and a number of the discussed systemic conditions, causality can only be established with prospective studies. Intervention studies are needed to address how treatment effects the incidence and/or severity of periodontal disease-related systemic illness.

A pilot study of HTLV-I infection in high-risk individuals & their family members from India.

BACKGROUND & OBJECTIVES: Human T lymphotropic virus-I (HTLV-I) has been associated with adult T cell lymphoma/leukemia (ATLL). There are Indian studies on HTLV-I infection among people with sexually transmitted infection, but no large study has been conducted on individuals with haematological malignancies. In this group of individuals, serology is known to under-diagnose HTLV-I infection. This study was carried out to identify serologically and where possible with molecular techniques, HTLV-I infection in individuals with haematological malignancies. To understand the modes of transmission, family members of individuals with proven HTLV-I infection were also studied. Individuals with sexually transmitted infection (STI), blood donors and pregnant women were also studied. METHODS: Particle agglutination test was used to detect antibody to HTLV-I. HTLV genome was amplified by polymerase chain reaction (PCR) and detected with probes by digoxiginin (Dig) ELISA. RESULTS: There was no serological evidence of HTLV-I infection among the healthy blood donors and pregnant women studied. High prevalence of anti-HTLV-I antibody was identified in the patients with haematological malignancies (8 of 86 patients, 9.3%) and a lower prevalence in individuals with STI (8 of 670 individuals, 1.2%). In the STI group, all 8 individuals seroreactive to HTLV-I were coinfected with human immunodeficiency virus (HIV). In the group with haematological malignancies, three of 22 (13.6%) patients with leukemia, 3 of 11 (27.3%) with cutaneous T-cell lymphoma (CTCL) and 2 of 53 (3.8%) with lymphoma were reactive for anti-HTLV-I antibody. In this group, PCR identified all the seroreactive individuals tested. There were also seronegative infected individuals who were only identified by PCR. There was also a large number of seronegative family members who were only positive by PCR. INTERPRETATION & CONCLUSION: The study revealed a strong disease association of HTLV-I with haematological malignancies and evidence for both horizontal and vertical transmission of the infection in the Indian population. HTLV-I infection appears to be common among family members of individuals with HTLV-I associated haematological malignancies.

Interaction between gravitropism and phototropism in sporangiophores of Phycomyces blakesleeanus.

The interaction between gravitropism and phototropism was analyzed for sporangiophores of Phycomyces blakesleeanus. Fluence rate-response curves for phototropism were generated under three different conditions: (a) for stationary sporangiophores, which reached photogravitropic equilibrium; (b) for sporangiophores, which were clinostated head-over during phototropic stimulation; and (c) for sporangiophores, which were subjected to centrifugal accelerations of 2.3g to 8.4g. For blue light (454 nm), clinostating caused an increase of the slope of the fluence rate-response curves and an increase of the maximal bending angles at saturating fluence rates. The absolute threshold remained, however, practically unaffected. In contrast to the results obtained with blue light, no increase of the slope of the fluence rate-response curves was obtained with near-ultraviolet light at 369 nm. Bilateral irradiation with near-ultraviolet or blue light enhanced gravitropism, whereas symmetric gravitropic stimulation caused a partial suppression of phototropism. Gravitropism and phototropism appear to be tightly linked by a tonic feedback loop that allows the respective transduction chains a mutual influence over each other. The use of tropism mutants allowed conclusions to be drawn about the tonic feedback loop with the gravitropic and phototropic transduction chains. The results from clinostating mutants that lack octahedral crystals (implicated as statoliths) showed that these crystals are not involved in the tonic feedback loop. At elevated centrifugal accelerations, the fluence-rate-response curves for photogravitropic equilibrium were displaced to higher fluence rates and the slope decreased. The results indicate that light transduction possesses a logarithmic transducer, whereas gravi-transduction uses a linear one.

Thyrotropin regulation of cyclic adenosine monophosphate production in human coronary artery smooth muscle cells.

Thyroid disease has been associated with the occurrence of pathophysiologic changes in the vasculature that may result in part from altered serum thyroid hormone and serum lipid levels. Thyrotropin (TSH) levels are also altered in thyroid disease, but a direct effect of TSH on vascular smooth muscle has not previously been considered. In the present study, human coronary artery smooth muscle cells (CASMC) were induced into two morphologically distinct forms by culturing in either (1) growth factor supplemented, 0.5% serum medium (SmGM-3) or (2) basal medium (SmBM) plus 10% fetal bovine serum (FBS). Intracellular cyclic adenosine monophosphate (cAMP) accumulation was determined by radioimmunoassay after exposure to increasing doses of bovine TSH. Cells grown in SmBM/10% FBS for 3 days exhibited a dose-dependent increase in intracellular cAMP that reached a level 10 times higher than baseline at the highest dose examined (100 mIU/mL). In contrast, cells grown in SmGM-3 medium exhibited no change in intracellular cAMP on exposure to increasing TSII. Low serum (0.5% FBS) reduced the ability of TSH to stimulate cAMP above the control value in CASMC. Pretreatment of CASMC with either transforming growth factor-beta1 (TGF-beta1) or tumor necrosis factor-alpha (TNF-alpha) lowered basal levels of cAMP production, but did not inhibit the ability of TSH to stimulate cAMP production. Human, but not rat aortic smooth muscle cells in culture also responded to TSH with a significant increase in cAMP. The results of this study suggest that TSH may exert direct effects on vascular smooth muscle mediated by adenylate cyclase activation that could conceivably affect the progression of vascular disease associated with thyroid dysfunction.

Diagnostic imaging and arthroscopy for wrist pain.

Chronic wrist pain may be evaluated by physical examination, imaging, and arthroscopy. Arthroscopy provides an attractive diagnostic and therapeutic modality in selected patients. Currently the correlation between arthroscopic findings and symptomatic pathology is not clear, because arthroscopy often identifies asymptomatic pathology. Nevertheless, the ability to diagnose and treat intra-articular pathology simultaneously provides a substantial advantage over radiographic analysis.