Prognosis of chronic low back pain: design of an inception cohort study

Background

Although clinical guidelines generally portray chronic low back pain as a condition with a poor prognosis this portrayal is based on studies of potentially unrepresentative survival cohorts. The aim of this study is to describe the prognosis of an inception cohort of people with chronic low back pain presenting for primary care.

Methods/Design

The study will be an inception cohort study with one year follow-up. Participants are drawn from a cohort of consecutive patients presenting with acute low back pain (less than 2 weeks duration) to primary care clinics in Sydney, Australia. Those patients who continue to experience pain at three months, and are therefore classified as having chronic back pain, are invited to participate in the current study. The cohort will be followed up by telephone at baseline, 9 months and 12 months after being diagnosed with chronic low back pain. Recovery from low back pain will be measured by sampling three different outcomes: pain intensity, interference with function due to pain, and work status. Life tables will be generated to determine the one year prognosis of chronic low back pain. Prognostic factors will be assessed using Cox regression.

Discussion

This study will determine the prognosis of chronic non-specific low back pain in a representative cohort of patients sourced from primary care. The results of this study will improve understanding of chronic low back pain, allowing clinicians to provide more accurate prognostic information to their patients.     

Allele Specificity of Gamma Interferon Responses to the Carboxyl-Terminal Region of Plasmodium falciparum Merozoite Surface Protein 1 by Kenyan Adults with Naturally Acquired Immunity to Malaria

Cross-sectional seroepidemiological studies of populations naturally exposed to Plasmodium falciparum suggest an association between protection from malaria and circulating antibodies to the carboxyl terminus of merozoite surface protein 1 (MSP1). Questions remain regarding the significance of cell-mediated immunity to MSP1 in conferring protection and inducing immunologic memory. Vaccine constructs have been based on the 42-kDa recombinant MSP1 protein (MSP1₄₂), which includes the 19-kDa (MSP1₁₉) and 33-kDa (MSP1₃₃) fragments containing the major B- and T-cell epitopes, respectively. To evaluate T-cell responses to the MSP1₃₃ fragment, two libraries of overlapping 18-mer peptides from the 3D7 and FVO MSP1₃₃ regions were used to screen a cohort of asymptomatic Kenyan adults. Gamma interferon (IFN-γ) measured by enzyme-linked immunospot assay (ELISPOT) at multiple time points assessed the magnitude and stability of these responses. The percentage of individuals with IFN-γ responses to single MSP1₃₃ peptides ranged from nil to 24%, were clustered among a subset of peptides, and were not consistently recalled over time. In comparison to peptide responses, IFN-γ ELISPOT responses to recombinant MSP1₄₂ were more prevalent, more frequently elicited by the 3D7 as opposed to the FVO allele, and more stable over time. The prevailing MSP1₃₃ genotype infection was 3D7, with few mixed infections and no sole FVO infections. This study demonstrates that immunity against MSP1₃₃ after cumulative natural infections consists of low-magnitude and difficult-to-detect IFN-γ responses. Although immunity against MSP1 alone will not confer protection against malaria, demonstrating a relative and sustained increase in T-cell immunity to MSP1 after vaccination would be a reasonable measurement of vaccine responsiveness.Infection with Plasmodium spp., the protozoan parasites responsible for malaria, results in an estimated 350 to 500 million infections per year with an ensuing 1 to 2 million deaths, the majority of which are caused by Plasmodium falciparum (45). Adults who have maintained lifelong residence in areas where malaria transmission is stable and of high intensity gradually develop naturally acquired immunity, an age-related phenomenon marked by a reduced frequency and severity of clinical malaria and high-density blood stage parasitemia relative to that of infants and children. Maintaining naturally acquired immunity is thought to require continuing exposure to malaria blood stage antigens mediated through asymptomatic low-density blood stage infection. A malaria vaccine that would accelerate the development of naturally acquired immunity during infancy and childhood has been a high priority for many years. The recent success of vector interventions, such as insecticide-treated bed nets, in decreasing transmission of P. falciparum in sub-Saharan Africa suggests that a blood stage vaccine would also be desirable in order to maintain the strength and duration of naturally acquired immunity among adults (17).Merozoite surface protein 1 (MSP1) is one of several candidates that have been considered for a blood stage vaccine. The primary ∼195-kDa MSP1 protein is expressed during schizogony and is processed initially to form a 42-kDa carboxyl-terminal fragment (MSP1₄₂) that remains attached to the merozoite surface. A second proteolytic cleavage results in the shedding of a 33-kDa fragment (MSP1₃₃) with formation of a 19-kDa carboxyl-terminal fragment (MSP1₁₉) anchored to the merozoite surface during invasion of the red blood cell (RBC) (4, 5). The 19-kDa fragment of MSP1 contains the major B-cell epitopes (18), the recognition of which is enhanced by T-helper epitopes in the 33-kDa fragment (1). Antibodies to MSP1₁₉ that interfere with RBC invasion by merozoites are one of several possible mechanisms by which naturally acquired immunity and experimental MSP1 vaccines may mediate protection against blood stage infection (27, 34). Studies of primates and mice immunized with MSP1 and more limited observations of residents of areas in which P. falciparum is endemic who have naturally acquired immunity and malaria-naïve human volunteers vaccinated with MSP1₄₂ suggest that T-cell responses to MSP1 are driven primarily by epitopes within the shed MSP1₃₃ fragment and that gamma interferon (IFN-γ) is important for optimal protective immunity (20, 23, 44, 46).A challenge to developing malaria vaccines that enhance protective immunity against blood stage parasitemia has been antigenic polymorphism that arises through selection by the human immune response; i.e., inclusion of several blood stage alleles might be required in order to mitigate selection of alleles not included in the vaccine. The P. falciparum msp1 gene has been divided into 17 blocks based on conserved, semiconserved, and variant DNA sequences (30). The C-terminal MSP1₄₂ protein is encoded by blocks 15 to 17; MSP1₃₃ is encoded by block 15 and 16. MSP1₄₂ alleles expressed by most clinical isolates and laboratory cultures of P. falciparum exist as either the MAD20 (3D7) or FVO (K1 or Wellcome) allele of MSP1₁₉ and MSP1₃₃ (although genetic recombination between the two [and other] alleles encoded by block 17 and block 15 to 16 also occurs). Whereas most studies from sub-Saharan Africa and other areas where malaria is endemic have characterized msp1 block 17 haplotypes and cross-reactivity of IgG antibodies to the corresponding MSP1₁₉ polypeptides (14, 43), block 15 to 16 polymorphisms underlying the variation in MSP1₃₃ and its impact on naturally acquired T-cell immunity are less well understood. The objectives of the current study were to evaluate MSP1₃₃ polymorphism in an area of western Kenya in which malaria is holoendemic and the corresponding allele specificity of IFN-γ responses by adults with naturally acquired immunity to malaria.     

Low prevalence of Plasmodium falciparum infection among asymptomatic individuals in a highland area of Kenya

In areas of highly seasonal Plasmodium falciparum transmission, the presence of a large reservoir of persistently infected but asymptomatic individuals in the dry season leads to predictable increases in the incidence of clinical malaria in the rainy season. Highland areas, by contrast, are prone to unpredictable epidemics of malaria. To determine the importance of persistent asymptomatic infection in highland areas, we assessed asymptomatic individuals in the highland area of Kipsamoite, Kenya for the presence of P. falciparum blood-stage infection by microscopy and PCR. Five sample collections were performed during rainy and dry seasons over a 31-month period. The final collection was obtained at the start of a rainy season epidemic. Asymptomatic parasitemia was infrequent, ranging from 1.3 to 8.1% by microscopy and 5.9 to 14.5% by PCR testing. Microscopy had low sensitivity (22.2-54.8%) but excellent specificity (95.4-100%) in comparison to PCR testing. Frequency of asymptomatic parasitemia did not differ by age. Gametocyte prevalence was <1% in all periods, except at the start of the epidemic, when it increased to 5.3%. In this epidemic-prone highland area, inter-epidemic periods are characterized by low frequencies of asymptomatically infected individuals. Increases in gametocyte prevalence may be an early indicator of impending outbreaks.     

Frequencies of sickle cell trait and glucose-6-phosphate dehydrogenase deficiency differ in highland and nearby lowland malaria-endemic areas of Kenya

Sickle cell genotype prevalence was 26% in a malaria-holoendemic lowland area compared with 3% in a highland area of Kenya. The prevalence of glucose-6-phosphate dehydrogenase deficiency was 7% and 1% in holoendemic lowland and highland areas, respectively. Lack of protective polymorphisms may contribute to morbidity and mortality during outbreaks of malaria in the highlands.     

Evidence for engraftment of donor-type multipotent CD34+ cells in a patient with selective T-lymphocyte reconstitution after bone marrow transplantation for B-SCID

Severe combined immunodeficiencies (SCID), a heterogeneous group of disorders of infancy, are fatal without treatment directed at immunologic reconstitution. Allogeneic bone marrow transplantation (BMT), which is such a treatment presents some unique features in SCID, especially when T-lymphocyte-depleted HLA haploidentical allografts are used. Donor-type T lymphopoiesis, less often B lymphopoiesis, develops, whereas myelopoiesis remains the recipient-type. Little is known about the engrafting cells in this peculiar lymphohematopoietic chimerism and the pathophysiology of the frequent failure of B-lymphocyte reconstitution. To address these issues, we purified CD34+ BM cells from a patient with selective T-lymphocyte reconstitution after HLA haploidentical BMT for B-SCID. Phenotypic analysis of CD34+ cells was performed by flow cytometry, and functional studies of donor- and recipient-type CD34+ cells were performed in vitro. Donor-type CD34+ cells, constituting approximately 2% of the CD34+ cells, were detected; both CD34+ HLA-DR- cells and CD34+ cells coexpressing B-(CD10 and CD19) and T-(CD2 and CD7) lymphocyte-associated cell surface molecules. Donor- type CD34+ cells coexpressing myeloid-associated molecules (CD13, CD14, CD15, and CD33) were undetectable. However, donor-type CD34+ myeloid progenitors could be shown in functional assays. Recipient-type CD34+ cells coexpressing B- and T-lymphocyte- as well as myeloid-associated molecules were detected, but recipient-type CD34+ cells could not be driven into T-lymphocyte differentiation in vitro. These findings provide evidence for engraftment of multipotent stem cells in our patient with B-SCID. Furthermore, the failure of B-lymphocyte reconstitution cannot be explained by lack of donor-type B-lymphocyte progenitors. Donor-type B lymphopoiesis and myelopoiesis are prevented by an unidentified mechanism.     

Spectrum of Haemoglobinopathies in a Tertiary Care Hospital of Armed Forces

Background

Thalassaemia and other structural haemoglobinopathies are the major genetic disorders prevalent in certain parts of the world including India. This study presents the pattern of haemoglobinopathies amongst the referred patients of anaemia in a two-year period.

Methods

A total of 1032 patients were studied during a two-year period for anaemia investigation. Haematological indices, sickling test and haemoglobin electrophoresis with quantification of the bands was done in all cases.

Result

Out of 1032 cases, 774 (75%) were normal and 258 (25%) cases had abnormal haemoglobin pattern. Of the 258 abnormal cases, 136 (53%) were males and 122 (47%) were females. Of all cases of anaemia 370 (36%) were microcytic hypochromic, 237 (23%) macrocytic, 151 (15%) were dimorphic and the rest (26%) had normocytic normochromic picture. 82% of microcytic hypochromic anaemias had reduced serum iron and elevated total iron binding capacity (TIBC), whereas 85% had decreased serum ferritin levels. Spectrum of haemoglobinopathies prevalent were β-Thalassemia trait (17%), followed by sickle cell trait (2.3%). Other haemoglobinopathies in descending order of frequency were sickle cell disease (1.7%), Hb D trait (1%), Hb E trait (0.8%), sickle cell – β thalassemia, Hb E disease, E – β thalassemia (0.6% each) and thalassemia major (0.4%).

Conclusion

This study provides a comprehensive database on the spectrum of haemoglobinopathies in the Armed Forces. It is suggested that detection of HbA₂ should be carried out in all the high-risk groups with anaemia.Key Words: Haemoglobinopathies, Anaemia, Thalassemia     

Stability of interferon-gamma and interleukin-10 responses to Plasmodium falciparum liver stage antigen-1 and thrombospondin-related adhesive protein in residents of a malaria holoendemic area

The stability of anti-malarial immunity will influence the interpretation of immunologic endpoints during malaria vaccine trials conducted in endemic areas. Therefore, we evaluated cytokine responses to Plasmodium falciparum liver stage antigen-1 (LSA-1) and thrombospondin-related adhesive protein (TRAP) by Kenyans from a holoendemic area at a 9-month interval. The proportion of adults with interferon-gamma (IFN-gamma) responses to 9-mer LSA-1 peptides was similar at both time-points, whereas responses from children decreased (P < 0.05). Response to the longer, 23-mer LSA-1 peptide was variable, decreasing in adults and children over time (P < 0.02 and P < 0.001, respectively). The proportion of children with IFN-gamma responses to either antigen at the second time-point was significantly lower than that of adults, yet more adults responded to 9-mer TRAP peptides (P < 0.02). In contrast, the proportion of interleukin-10 responses to LSA-1 and TRAP was similar at both time-points for both age groups. Most noteworthy was that even when the repeat cross-sectional frequency of cytokine responses was the same, these responses were not generated by the same individuals. This suggests that cytokine responses to LSA-1 and TRAP are transient under natural exposure conditions.