Serum interleukin-3 levels following autologous or allogeneic bone marrow transplantation: effects of T-cell depletion, blood stem cell infusion, and hematopoietic growth factor treatment

Engraftment of marrow following autologous or allogeneic bone marrow transplantation (BMT) may be influenced by quantity and function of stem cells. T lymphocytes, supporting microenvironmental cells, and hematopoietic growth factors (HGF). To elucidate the physiologic role of interleukin-3 (IL-3) in the engraftment process, serum IL-3 levels were measured in over 400 samples from 77 transplant recipients before and for up to 3 weeks following transplantation using a novel enzyme- linked immunoabsorbent assay (ELISA) with a sensitivity of > or = 78 pg/mL. Thirty-seven patients received two to three log T-cell-depleted allografts. In the remaining 40 patients (18 autologous marrow, 12 allogeneic marrow, and 10 autologous peripheral blood [PB] stem cell), T cells were not depleted (non-TCD) from the grafts. A burst of IL-3 (peak levels, 1,500 to 6,000 pg/mL) was detected in the immediate posttransplant period between day 0 and day 14 in all non-TCD recipients and in 21 of 37 (57%) of TCD recipients. A strong inverse relationship between IL-3 levels and absolute neutrophil count (ANC) was observed in both non-TCD recipients (r = -.796) and in TCD recipients (r = -.897). However, both peak IL-3 levels and mean IL-3 levels from day 0 through 14 were significantly lower in TCD recipients compared with either autologous or unmodified allogeneic marrow recipients (P < .01). The lowest peak or mean day 0 through 14 IL-3 levels were observed in matched related recipients undergoing the most aggressive (2.5 to 3.0 log) T-cell-depleted BMT. Autografted patients receiving blood stem cell transplants alone or posttransplant granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) also had significantly lower peak IL- 3 levels (P < .01). In patients receiving TCD grafts, administration of antithymocyte globulin (ATG) posttransplant significantly increased peak IL-3 levels compared with patients not treated with ATG (P < .04). This study shows that endogenous release of IL-3 is strongly associated with myeloid engraftment and inversely related to ANC. Removal of T lymphocytes from donor marrow or acceleration of engraftment by use of stem cells or growth factors appears to blunt the endogenous release of IL-3 whereas use of ATG posttransplant increases IL-3 release.     

Kernicterus in an adult who is heterozygous for Crigler-Najjar syndrome and homozygous for Gilbert-type genetic defect

Gilbert syndrome is a common genetic disorder associated with mild unconjugated hyperbilirubinemia and no clinical illness. In contrast, Crigler-Najjar syndrome types I and II are rare genetic disorders associated with severe unconjugated hyperbilirubinemia and a life-long risk of kernicterus. Patients with Gilbert syndrome have low levels of a normal form of uridinediphosphoglucuronate glucuronosyltransferase because of a defect in the promoter region of both alleles, whereas patients with Crigler-Najjar syndrome are homozygous for a defect that yields an abnormal form of the enzyme that has limited or no activity. This case report describes a young adult with Crigler-Najjar syndrome type II in whom kernicterus developed after a laparoscopic cholecystectomy. The development of kernicterus was the result of a largely preventable series of events that lead to an increase in the free fraction of his serum bilirubin. Analysis of his genetic defect showed that he was homozygous for the mutation associated with Gilbert syndrome and heterozygous for a second mutation in the open reading frame of one allele of the bilirubin uridinediphosphoglucuronate glucuronosyltransferase gene. The combined defect leads to severe hyperbilirubinemia and shows how seemingly benign genetic defects, when combined, can cause serious clinical disease. (Gastroenterology 1997 Jun;112(6):2099-103)     

Modulation of polymorphonuclear leukocyte function by cetiedil

Cetiedil citrate monohydrate inhibits sickling of red cells and aggregation of platelets. We assessed its ability to attenuate polymorphonuclear leukocyte (PMN) function. PMN aggregation in response to 2 X 10(-7) M formyl-met-leu-phe (FMLP) was inhibited in a dose- dependent fashion by cetiedil concentrations ranging from 60 to 250 microM. Additionally, 125 microM cetiedil inhibited PMN aggregation in response to 2 X 10(-7) M FMLP, 20 ng/ml phorbol myristate acetate (PMA), and 1 X 10(-6) M A23187 by 69% +/- 18%, 72% +/- 20%, and 65% +/- 4%, respectively. Inhibition of FMLP-induced aggregation was provided by only 5 min of incubation of the drug with the cells and was partially reversible. Cell viability was unaffected by exposure of PMN to the drug. Correspondingly, 125 microM cetiedil prevented the translocation of calcium from the PMN membrane as assessed by chlorotetracycline fluorescence. Paralleling the effect of the drug on PMN aggregation, 125 microM cetiedil inhibited release of superoxide by 55% and decreased the number of available 3H-FMLP receptors. However, its effect on release of the primary granule constituent, myeloperoxidase, was minimal (4.5% inhibition), while the effect on release of the specific granule product, lactoferrin (27% inhibition), was modest. These studies indicate that cetiedil affects PMN aggregation and superoxide release to a much greater extent than PMN degranulation. Thus, cetiedil may have potential uses in modulating inflammatory response in vivo.     

Ultrasound-guided, vacuum-assisted excision in the diagnosis and treatment of clinically benign breast lesions

INTRODUCTION

Ultrasound-guided, vacuum-assisted biopsy has a definitive role in the diagnosis of breast lesions. Its role in the treatment of benign breast lesions like fibroadenomas has not been established.

PATIENTS AND METHODS

This is a retrospective review of patients undergoing ultrasound-guided, vacuum-assisted biopsy for clinically benign breast lesions. The procedures were performed in all cases by two consultant radiologists with special interest in breast radiology between February 2002 and January 2004. Patients were followed up in the clinic 6 weeks after the procedure.

RESULTS

Seventy-six patients had ultrasound-guided, vacuum-assisted excision of clinically benign breast lesions during this 2-year period. Mean age of the patients was 31 years. Altogether, 86 procedures were performed. Six patients with larger lesions (> 2 cm) had two procedures on separate sitting and 4 patients had separate lesions excised on a later date. Fifty-six patients were identified to have fibroadenomas and had complete excisions as evidenced on scan. Three out of nine patients identified with equivocal disease on fine needle aspiration cytology (FNAC) were found to have cancer following ultrasound-guided, vacuum-assisted excision. One patient who was diagnosed with cancer on FNAC, proved to be fibroadenoma on final histopathology. Four patients developed haematomas following ultrasound-guided, vacuum-assisted excision and all were managed conservatively.

CONCLUSIONS

Our study shows that ultrasound-guided, vacuum-assisted excision can play an efficient role in the diagnosis of benign breast lesions and is a safe and successful alternative in treatment of fibroadenomas.     

Worsening of symptoms is associated with lower physical activity levels in individuals with multiple sclerosis

The present study examined the relationship between the worsening of symptoms across a 3-5-year period of time and self-reported physical activity in a sample of 51 individuals with multiple sclerosis (MS). Of the 51 participants, 35 reported a worsening of symptoms over the 3-5-year period of time. The worsening of symptoms was associated with significantly and moderately lower levels of self-reported physical activity independent of depression and EDSS scores and MS-disease course (P=0.04). This study provides novel evidence that a worsening of symptoms is associated with lower levels of physical activity in individuals with MS.     

Calcium phosphate ceramics as bone graft substitutes in filling bone tumor defects

Background:

Synthetic bio-inert materials are currently used as an alternative to autogenous bone graft. Calcium hydroxyapatite (HA) and Beta tri-calcium phosphate (β-TCP), which belong to the calcium phosphate ceramics group, are biocompatible and osteo-conductive. The purpose of this study is to analyse the use of HA and β-TCP in their ceramic forms as a bone graft substitute in filling bone voids after curettage of benign bone tumors.

Materials and Methods:

Twenty-four patients in the age range of 3.5-55 years (mean 14.3 years) having benign bone tumors with bone defects were filled with bone graft substitute following curettage. In 20 patients bone defects were filled with block/granules of HA ceramic and in four with β-TCP. Fibular strut graft was packed with HA in four patients. The patients were followed up for an average of 18 months (range 12-36 months).

Results:

The functional status of the patients at follow-up was evaluated and compared with preoperative functional status. Early incorporation of graft substitutes became evident radiologically between 6 and 10 weeks (Stage I). Complete incorporation (Stage III) was observed in an average of nine months (6-18 months). Clinical healing was observed before radiological healing. The average time taken to return to preoperative function was 14 weeks. There was no recurrence of lesion or growth retardation.

Conclusion:

Calcium hydroxyapatite and β-TCP are excellent bone graft substitutes for autogenous bone graft in filling voids after curettage of benign bone tumors.     

Radiotheranostics in oncology: Making precision medicine possible

A quintessential setting for precision medicine, theranostics refers to a rapidly evolving field of medicine in which disease is diagnosed followed by treatment of disease-positive patients using tools for the therapy identical or similar to those used for the diagnosis. Against the backdrop of only-treat-when-visualized, the goal is a high therapeutic index with efficacy markedly surpassing toxicity. Oncology leads the way in theranostics innovation, where the approach has become possible with the identification of unique proteins and other factors selectively expressed in cancer versus healthy tissue, advances in imaging technology able to report these tissue factors, and major understanding of targeting chemicals and nanodevices together with methods to attach labels or warheads for imaging and therapy. Radiotheranostics—using radiopharmaceuticals—is becoming routine in patients with prostate cancer and neuroendocrine tumors who express the proteins PSMA (prostate-specific membrane antigen) and SSTR2 (somatostatin receptor 2), respectively, on their cancer. The palpable excitement in the field stems from the finding that a proportion of patients with large metastatic burden show complete and partial responses, and this outcome is catalyzing the search for more radiotheranostics approaches. Not every patient will benefit from radiotheranostics; but, for those who cross the target-detected line, the likelihood of response is very high.     

Relationship between global cognitive decline and depressive symptoms in multiple sclerosis

Cognitive impairment and depressed mood are common symptoms in multiple sclerosis (MS), which significantly impact patients' role functioning and quality of life. Cross-sectional studies indicate a modest association between cognitive impairment and depressive symptoms in MS. Longitudinal studies show inconsistent results but provide some data indicating a relationship between increasing global cognitive decline and increasing depressive symptoms over time. Establishing whether such a relationship exists represents an important first step in understanding the temporal nature of that relationship along with any treatment implications. The current study investigated this relationship by using the adjusted difference between a demographic estimate of premorbid intellectual functioning (Barona) and a performance measure of current intellectual functioning (Shipley Institute of Living) to capture long-term global cognitive decline in MS patients. Degree of global cognitive decline was then related to a self-report measure of mood, evaluative, and vegetative depression symptoms (Chicago Multiscale Depression Inventory). Global cognitive decline accounted for 5% of the variance in mood-evaluative symptoms but none of the variance in vegetative symptoms. When groups experiencing moderate, mild, and no global cognitive decline were compared on depression symptom subscales, MS patients experiencing moderate cognitive decline reported significantly higher mood and evaluative, but not vegetative, depressive symptoms than MS patients with stable cognitive functioning.     

Temporal lenses for attosecond and femtosecond electron pulses

Here, we describe the “temporal lens” concept that can be used for the focus and magnification of ultrashort electron packets in the time domain. The temporal lenses are created by appropriately synthesizing optical pulses that interact with electrons through the ponderomotive force. With such an arrangement, a temporal lens equation with a form identical to that of conventional light optics is derived. The analog of ray diagrams, but for electrons, are constructed to help the visualization of the process of compressing electron packets. It is shown that such temporal lenses not only compensate for electron pulse broadening due to velocity dispersion but also allow compression of the packets to durations much shorter than their initial widths. With these capabilities, ultrafast electron diffraction and microscopy can be extended to new domains,and, just as importantly, electron pulses can be delivered directly on an ultrafast techniques target specimen.