The Effect of Human Cord Blood on SJL/J Mice after Chemoablation and Irradiation and its Possible Clinical Significance

There is evidence from the existing published literature that human umbilical cord blood, when used for purposes of bone marrow transplantation, does not necessarily have to be HLA matched in order to be efficacious. These reports include experimental observations on the ability of human umbilical cord blood to rescue lethally irradiated mice and clinical observations from China wherein HLA mismatched umbilical cord blood has been engrafted successfully in children with malignant disease.

The study reported herein describes an experimental immunocompetent murine model to determine if human umbilical cord blood can be used to improve survival after chemoablation and irradiation. The animals received chemoablation followed by irradiation, and irradiation alone. The presence of human DNA in these mice following injection of human umbilical cord blood cells was determined, and the immunological status of the animals was evaluated. Animals receiving human umbilical cord blood cells after chemoablation and irradiation had a better mean survival at day 50 than animals receiving syngeneic marrow. Human DNA could be found in various organs, particularly the lung, spleen and liver of the mice for the first 30 days. Thereafter, human DNA became more difficult to detect but trace amounts of human DNA could be found up to one year later. The results of mixed lymphocyte reactions and phenotype analyses for murine T cell markers performed after injection of HUCB cells both indicated endogenous repopulation, and relatively intact immune systems in these mice.

Since human umbilical cord blood allowed mice to survive the lethal effects of chemoablation plus irradiation, or irradiation alone, with reconstitution of the animals' own, relatively intact, immune systems, it would appear that HLA mismatched human umbilical cord blood could potentially be used as an adjuvant treatment for patients with advanced malignancies or other diseases for which hematopoietic reconstitution is indicated.     

Can genes influencing muscle function affect the therapeutic response to enzyme replacement therapy (ERT) in late-onset Type II Glycogenosis?

The purpose of this study is to analyze the role of genes known to influence muscle performances on the outcome after enzyme replacement treatment (ERT) in type II Glycogenosis (GSDII). We analyzed 16 patients receiving ERT for ≥two years. We assessed the changes in muscle strength by hand-held dynamometry, muscle mass by quantitative MRI, and resistance to exercise by the 6-minute walking test. Exercise gene assessment included angiotensin converting enzyme insertion/deletion polymorphism (ACE), alpha-actinin3 R577X polymorphism (ACTN3), and peroxisome proliferator activated receptor alpha G/C polymorphism (PPARα). Independent of disease severity, one third of patients had a poor response to ERT, which was found to be associated with ACE DD genotype. The ACTN3 null polymorphism appeared to exert a positive effect on treatment efficacy, while PPARα did not seem to exert any influence at all. We conclude that poor treatment outcome in ACE DD genotypes is in line with previous observation of a worse disease course in this subpopulation, and suggests the need for a more careful follow-up and individualized treatment approaches for these patients. Exercise genes may provide a new opportunity for studying the outcome after treatment and the muscle regeneration abilities in other models of genetic myopathies.     

Q-angle, Pelvic width, and Intercondylar notch width as predictors of knee injuries in women soccer players in South Africa

Objective

To investigate the association between the three anatomical factors of Q-angle (QA), pelvic width (PW) and Intercondylar notch width (INW) and knee injuries among the U-23 female soccer players of South Africa

Methods

The study is a case-control prospective study design. Twenty four U-23 women soccer players of the South African team were purposively chosen to participate in this study. Participants were divided into two groups: group1 (Case) was those with knee injuries, while those without injuries were in group-2 (Control). PW and INW were measured after X-rays of the hip were taken while the QA was measured manually with the goniomenter. Association between anatomical factors and knee injuries were tested with ANOVA.

Results

Q-angle ranged from 14° to 18° for both injured and non injured groups. PW was between 24 –29 cm for both injured and non injured groups. INW was between 1.3mm and 2.8mm for the right and between 1.4mm and 2.5mm for the left notch for the injured group, while INW for the right and left of the non injured group were between 1.7mm to 2.1mm and 1.8mm to 2.1mm, respectively No significant association between knee injuries and each of the anatomical factors was found QA (p= 0.74), PW (p=0.34), INW (right and left respectively) (p=0.142 & p=0.089).

Conclusion

The three anatomical factors of QA, PW and INW could not be used to predict knee injuries amongst the U-23 female players in South Africa.     

Differential effects of fluoxetine and venlafaxine on memory recognition: possible mechanisms of action

Serotonin-specific reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) are antidepressant drugs commonly used to treat a wide spectrum of mood disorders (Wong and Licinio, 2001). Although they have been clinically used for more than 50 years, the molecular and cellular basis for the action of SSRIs and SNRIs is not clear. Considering that the changes in gene expression involved in the action of antidepressant drugs on memory have not been identified, in this study we investigated the impact of chronic treatment with a SSRI (fluoxetine) and a SNRI (venlafaxine) on the mRNA expression of genes related to memory cascade in the mouse hippocampus, namely, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), nitric oxide synthase 1 (NOS1), neurotrophic tyrosine kinase receptor type 2 (TrKB), mitogen-activated protein kinases (MAPK/ERK) and serotonin transporter (SERT). Animals treated with fluoxetine 10 mg/Kg/day for 28 days showed a significant decrease in the percentage of time spent in the novel object recognition test (p≤0.005) and induced MAPK1/ERK2 down-regulation (p=0.005). Our results suggest that the effect on cognition could probably be explained by fluoxetine interference in the MAPK/ERK memory pathway. In contrast, chronic treatment with venlafaxine did not reduce MAPK1/ERK2 expression, suggesting that MAPK1/ERK2 down-regulation is not a common effect of all antidepressant drugs. Further studies are needed to examine the effect of chronic fluoxetine treatment on the ERK-CREB system, and to determine whether there is a causal relationship between the disruption of the ERK-CREB system and the effect of this antidepressant on memory performance.     

Gamma (immune) interferon production by leukocytes from a patient with a TG cell proliferative disease

We report a patient with a disease characterized by proliferation of T cells with Fc receptors for IgG (TG). However, unlike lymphoid cells from normal individuals or from patients with other lymphoid malignancies, the patient's lymphocytes spontaneously produced gamma interferon (IFN-gamma) in vitro. The peripheral lymphocytes consisted of 95% TG cells, which exhibited the morphological characteristics of T- cell chronic lymphocytic leukemia (CLL) and were normal on cytochemical and chromosome analysis. The majority of TG cells were OKT3+, OKT8+, and OKT4-, 3A1-. These cells failed to express suppressor cell activity and displayed depressed levels of natural killer activity, but mediated antibody-dependent cell-mediated cytotoxicity. The spontaneous production of IFN-gamma by human peripheral lymphoid cells as demonstrated in this study may serve as a probe for studying the relationship between IFN-gamma and the proliferation of human T-cell subsets.     

Cross-talk between RhoGTPases and stress activated kinases for matrix metalloproteinase-9 induction in response to keratinocytes injury

Cell migration and extracellular matrix remodeling are two essential processes of wound healing, regulated by extracellular metalloproteinases such as matrix metalloproteinase-2 (Gelatinase A) and matrix metalloproteinase-9 (Gelatinase B). Expression of matrix metalloproteinase-9 is deregulated in numerous wound healing pathologies. To date the mechanisms regulating matrix metalloproteinase-9 during normal wound healing are poorly documented. Using both primary cultures of normal human keratinocytes and a wounding device especially designed to dissect the molecular events during the healing process in vitro, we show that matrix metalloproteinase-9 is stimulated by injury in normal human keratinocytes. This upregulation results from the mechanical stress created by injury and not from a soluble factor, secreted by wounded normal human keratinocytes. We also demonstrate that the Rho family of small GTPases, p38[MAPK] and JNK together play a key part in the signaling pathways controlling the stimulation of matrix metalloproteinase-9 in wounded cells. We provide lines of evidence indicating that in wounded keratinocytes, upregulation of matrix metalloproteinase-9 depends on two distinct pathways. The first involves Rac1 and/or Cdc42 that control the activation of p38[MAPK]. The second depends on RhoA activation that is required for stimulation of JNK.     

IL-10 production in a CD5+ B cell lymphoma arising in a CD4 monoclonal antibody-treated SJL mouse.

A majority of SJL mice develop spontaneous reticulum cell sarcomas (RCS) at about 1 year of age which can be transplanted into young SJL recipients. Previous studies have shown that RCS tumors are of B cell lineage, and that the development of these lymphomas and their subsequent growth depends upon host-derived T helper cell factors. In vivo treatment of SJL mice with anti-CD4 monoclonal antibody (mAb) prevents the development of the characteristic B lymphomas. Most of the mAb-treated animals were tumor free and had a significantly prolonged life span. However, one such CD4 mAb-treated mouse developed a transplantable IgM+ CD5+ B cell lymphoma (designated NJ101), which has not previously been described in SJL/J mice. NJ101 is clonal on the basis of a discrete non-germ line Ig heavy chain gene rearrangement by Southern blot analysis. Unlike the sIg- CD5- transplantable RCS-X cell line, the IgM+ CD5+ NJ101 lymphoma cells will grow in immuno-compromised hosts, such as irradiated recipients or in recipients treated with CD4 mAb in vivo. The RCS (B cell) lymphoma requires CD4+ T cells for progressive growth, whereas the growth of the CD5+ B lymphoma cells is enhanced by the removal of such cells. Thus, CD5+ B cell clonal development may be aided by the removal of regulatory T cells and/or the malignant CD5+ B cells may produce their own growth factors in an autocrine manner. Examination of IL-10 message by quantitative polymerase chain reaction techniques indicate that the CD5+ B lymphoma cells produce increased levels of IL-10 relative to normal LN cells or purified RCS lymphoma cells. These results suggest that two different types of B cell tumors, both of which can develop in SJL mice, have different growth requirements. Furthermore, treatment to prevent the occurrence of the characteristic RCS malignancy of SJL mice may lead to the development of another form of B cell neoplasia.     

Metaphyseal bone loss in revision knee arthroplasty

The etiology of bone loss encountered during revision total knee arthroplasty (TKA) is often multifactorial and can include stress shielding, osteolysis, osteonecrosis, infection, mechanical loss due to a grossly loose implant, and iatrogenic loss at the time of implant resection. Selection of the reconstructive technique(s) to manage bone deficiency is determined by the location and magnitude of bone loss, ligament integrity, surgeon experience, and patient factors including the potential for additional revision, functional demand, and comorbidities. Smaller, contained defects are reliably managed with bone graft, cement augmented with screw fixation, or modular augments. Large metaphyseal defects require more extensive reconstruction such as impaction bone grafting with or without mesh augmentation, prosthetic augmentation, use of bulk structural allografts, or use of metaphyseal cones or sleeves. While each technique has advantages and disadvantages, the most optimal method for reconstruction of large metaphyseal bone defects during revision TKA is not clearly established.