Exercise and diabetes.

Diet and exercise form the foundation of a healthy lifestyle. These are especially important for people living with diabetes mellitus, as they are the most practical non-pharmacological means by which patients may significantly improve their blood glucose levels. Exercise increases insulin sensitivity (both short and long term), lowers blood sugar levels, reduces body fat and improves cardiovascular (CV) function. Because of this, exercise offers enormous benefit to patients with diabetes. Blood glucose levels can significantly drop during and after physical activities, due to the increased utilisation of glucose as a fuel during exercise and the up-regulation of glucose transport into working muscles. Therefore, patients (especially those with type 1 diabetes) must account for the effects of exercise and adjust their medications and nutrition accordingly. Improvements in real-time continuous glucose monitoring and optimisation of basal insulin dosing may offer significant benefit to preventing hypoglycaemia in patients with type 1 diabetes who regularly exercise. Diverse exercise programmes and devices can also assist patients in monitoring their activities as well as motivating them to achieve their exercise goals. For patients with type 1 diabetes, questions such as how much, how long, how strenuous and what kind of exercise must be addressed in order for healthcare professionals to offer maximum benefit to their patients. Additionally, since patients with type 2 diabetes often have other significant co-morbidities such as obesity and CV disease, care providers must evaluate each patient's risk factors before designing an exercise programme. Several publications in the last year have addressed these issues and may serve as a valuable resource to provide safe and effective recommendations to patients and their healthcare providers. To be included in the Exercise and Diabetes chapter for the 2010 YEARBOOK, we reviewed leading peer-reviewed manuscripts that were published in the period July 2009 to June 2010. PubMed was used in the initial screening of articles.

Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors.

BACKGROUND: Normal hematopoietic development depends on the activity of the Ikaros transcription factor, which contains distinct zinc-finger domains that mediate DNA binding and protein dimerization. Mice homozygous for a transgene encoding a dominant-negative version of Ikaros that lacks the DNA-binding domain but not the dimerization domain have a more severe phenotype than Ikaros null mice. This observation suggests the presence of factor(s) that can dimerize with Ikaros and partially complement its function. One previously identified factor, Aiolos, probably serves this role in the lymphoid system; a related factor involved in hematopoietic progenitors remains unknown, however. RESULTS: Here, we describe the cloning of an Ikaros-related gene, Helios. Analysis of the primary sequences of Helios, Ikaros and Aiolos revealed that the DNA-binding, transcriptional activation and dimerization domains are functionally conserved. Helios activated transcription from Ikaros DNA-binding sites and could dimerize with itself, Ikaros or Aiolos. Expression of Helios was detected in the earliest hematopoietic sites of the embryo, in hematopoietic stem cells in the adult and was subsequently restricted to a subset of cells in the T cell lineage. Helios co-localized with Ikaros and Aiolos proteins in macromolecular nuclear structures and formed stable complexes in vivo with the dominant-negative version of Ikaros. CONCLUSIONS: Distinct but overlapping expression patterns of members of the Ikaros gene family during hematopoiesis might result in the formation of different multimeric complexes that have specific roles in lineage progression. The preferential expression of Helios in the earliest stages of hematopoiesis suggests that this gene functions predominantly in early progenitors.

Effect of clinical history on diagnostic accuracy in the cytologic interpretation of bronchial brush specimens.

There has been little study of the effect of clinical history on pathologic diagnostic accuracy. Five pathologists retrospectively examined 97 bronchial brush specimens with and without clinical historic information. Forty-nine patients had a biopsy-proven malignant lesion, and 48 had a benign lesion. Diagnostic accuracy with and without history for each pathologist was determined with likelihood ratios and receiver operating characteristic curves. The overall diagnostic accuracy with and without history was 0.84 and 0.76, respectively. The average negative predictive value of a benign diagnosis decreased from 89.2% (with history) to 74.0% (without history). Overall, the cytopathologists were more reluctant to make a definitive malignant diagnosis without history compared with history. The average positive predictive value of a malignant diagnosis with and without history was almost identical. The absence of history leads to lower diagnostic accuracy in the cytologic interpretation of bronchial brush specimens partly because pathologists underdiagnose malignant lesions.

Direct versus indirect tests of memory for source: judgments of modality.

We studied the relation between performance on direct versus indirect tests of memory for modality. Subjects read or heard words in a mixed list and then were tested by visual perceptual identification (the indirect test) and direct report of items as read, heard, or new. There was a dependent relation between perceptual identification performance and modality judgments, in accord with the hypothesis that subjects base their judgments of modality on relative perceptual fluency. In Experiment 2, we attempted to change the degree of dependence by providing subjects with an alternative basis for modality judgments. Subjects given a mnemonic to encode modality exhibited less dependence between perceptual identification performance and modality judgments than did subjects who encoded modality incidentally. The relation between direct and indirect tests of memory for source characteristics depends on the basis used for each.

Utility of fine-needle aspiration biopsy in solid renal masses.

Renal fine-needle aspiration biopsy (FNAB) is used in several clinical scenarios: in patients with classic radiographic lesions; in non-operable patients with presumed high stage disease; and in patients with radiographic problematic lesions. Although overall, FNAB is a sensitive test, its role in the latter two populations has not been clearly established. To investigate the utility of FNAB in these patients, we retrospectively evaluated 43 renal FNABs in regards to diagnostic accuracy and clinical outcome. FNAB diagnoses were: malignant (36), suspicious (6), and insufficient (1). Our results indicate: 1) renal FNAB is accurate in patients with high stage lesions; 2) FNAB is less accurate in patients with radiographic problematic lesions; 3) the FNAB diagnosis of malignant increases the post-FNAB probability of malignancy, whereas the diagnosis of suspicious decreases the probability; and 4) there is excellent correlation for nuclear grade. We conclude that renal FNAB is useful in evaluating renal masses.

Fine-needle aspiration cytology of pancreatoblastoma.

Pancreatoblastoma is a rare pancreatic neoplasm seen most commonly in the pediatric age group. We report on the aspiration cytology and immunohistochemical findings of a pancreatoblastoma in a 16-yr-old male.

The influence of retrieval processes in verbal overshadowing.

Recent studies of eyewitness memory have observed deleterious effects of producing a verbal description on later identification accuracy of a previously viewed face, an effect termed verbal overshadowing (Schooler & Engstler-Schooler, 1990). The present research investigated whether the phenomenon of verbal overshadowing may be constrained by variation in participants' initial retrieval processes, such that verbalization of a previously viewed stimulus could produce either positive or negative influences on subsequent attempts at recollection. To assess the validity of this hypothesis, we manipulated participants' response criterion during the verbal description task. As predicted, variation in response criterion significantly influenced not only the quality of the description generated but also accuracy on a subsequent identification task. This retrieval-based effect was found to persist despite either a postdescription delay (Experiment 1) or source-monitoring instructions at the time of the identification task (Experiment 2). We conclude that retrieval-based processes exert a powerful influence over the accuracy of verbalization and subsequent identification of a target face.

Transcriptional activation of lck by retrovirus promoter insertion between two lymphoid-specific promoters.

p56lck, a member of the src family of cytoplasmic tyrosine protein kinases, is expressed primarily in lymphoid cells. Previous RNase protection data demonstrated the existence of at least two lck mRNAs (type I and type II) with different 5' untranslated regions in most T cells. These have been found here to arise from two separate promoters. S1 nuclease analysis and primer extension were used to locate the site of initiation of type I lck mRNA. The nucleotide sequence of the region upstream of this start site contains no classical promoter motifs. A cDNA clone of type II lck mRNA was isolated. The promoter of this mRNA must be more than 10 kilobases upstream of the type I promoter region. In two murine thymoma cell lines, LSTRA and Thy19, lck is expressed at elevated levels as a result of Moloney murine leukemia virus retrovirus promoter insertion. p56lck is encoded in these cells by a hybrid virus-lck mRNA containing the 5' untranslated region of Moloney virus mRNA. The structures and the sites of integration of the proviruses upstream of lck in these cells were examined by molecular cloning and Southern analysis. A truncated and rearranged provirus, flanked by 554 nucleotides (nt) of duplicated cellular sequences, was found 962 nt upstream of the start site for type I lck mRNA in LSTRA cells. What appears to be a Moloney mink cytopathic focus-forming provirus was found between 584 to 794 nt upstream of the start site for type I lck mRNA in Thy19 cells. Thus in both tumor cell lines, viral DNA is present between the promoters for type I and type II lck mRNAs. Comparison of the sequences of the 5' ends of the lck and c-src genes suggests that divergence of these two genes involved exon shuffling and that a homolog of the neuronal c-src(+) exon is not present in lck.

Application of the Etest to the antimicrobial susceptibility testing of Mycobacterium marinum clinical isolates.

Mycobacterium marinum, a well-recognized cutaneous pathogen, is usually treated by chemotherapy without available standardized in vitro susceptibility testing information. In this study, we have attempted to apply the stable-gradient method (Etest; AB Biodisk, Solna, Sweden) to susceptibility testing of M. marinum in order to assess the activities of eight antimicrobial agents against 60 recent clinical strains of M. marinum collected from 10 geographic sites within the United States. Two plated media (5% sheep blood Mueller-Hinton agar and Middlebrook 7H11 agar) were compared, and 7H11 agar was found to be superior in supporting the growth of all strains. Four reference strains of M. marinum were tested on five occasions with eight drugs (160 tests) in order to evaluate Etest reproducibility. Results were observed to be within 1 log2 dilution of the all-test median MIC for 97.5% of the Etests. Our MIC results for the 60 strains clearly demonstrate the best in vitro potency against M. marinum isolates to be as follows (rank order): trimethoprim-sulfamethoxazole (MIC at which 90% of the isolates are inhibited [MIC90], 0.25 and 4.25 microg/ml, respectively) = ethambutol > clarithromycin (MIC90, 1 microg/ml) > minocycline = doycycline (MIC90, 4 microg/ml) > amikacin (MIC90, 8 microg/ml). Rifampin was only marginally active against the M. marinum strains tested (MIC90, at the National Committee for Clinical Laboratory Standards) breakpoint of 1 microg/ml), and ciprofloxacin was not active (MIC90, 8 microg/ml). These data should enhance the empiric drug selection for contemporary M. marinum infections and also provide evidence that the Etest can be utilized to guide chemotherapy with alternative agents.

Bipotential primitive-definitive hematopoietic progenitors in the vertebrate embryo.

Two regions of the vertebrate embryo, the blood islands and the dorsal lateral plate (DLP), participate in early hematopoietic development. In Xenopus, primitive erythrocytes are derived solely from the ventral blood islands (VBI), while definitive hematopoietic cells such as lymphocytes are derived from both VBI and DLP. We have utilized a transplantation technique to demonstrate in vivo that all hematopoietic cells (embryonic, fetal, or adult) originate from ventral mesoderm. Reciprocal grafts between VBI and DLP demonstrated that both regions are bipotential with respect to primitive and definitive hematopoiesis. Commitment of the VBI to primitive erythropoiesis and restriction of the DLP to definitive hematopoiesis occurs during neurula stages. Thus, hematopoietic development involves the induction of the blood program on the ventral axis of the embryo followed by environmentally regulated specification to the primitive or definitive lineages.

Outcome of transfusion of K:11 erythrocytes in a patient with anti-K11 antibody.

BACKGROUND AND OBJECTIVES: The clinical significance of anti-K11 in red cell transfusion therapy is unknown. We report the outcome of transfusion of K:11 erythrocytes into a patient with a known anti-K11 antibody. MATERIALS AND METHODS: The patient was monitored clinically following transfusion of 11 units of K:11 erythrocytes. A red cell survival study with K:11 erythrocytes and a monocyte monolayer assay (MMA) were performed. RESULTS: No adverse clinical outcome was detected. The red cell survival study showed normal survival of K:11 erythrocytes, and the MMA showed no increase in reactive monocytes. CONCLUSION: These findings suggest that K:11 red cells can safely be transfused to individuals with anti-K11 antibody.

SCL specifies hematopoietic mesoderm in Xenopus embryos.

Targeted gene disruption experiments in the mouse have demonstrated an absolute requirement for several transcription factors for the development of hematopoietic progenitors during embryogenesis. Disruption of the basic helix-loop-helix gene SCL (stem cell leukemia) causes a block early in the hematopoietic program with defects in all hematopoietic lineages. To understand how SCL participates in the organogenesis of blood, we have isolated cDNAs encoding Xenopus SCL and characterized the function of SCL during embryogenesis. We demonstrate that SCL is expressed in ventral mesoderm early in embryogenesis. SCL expression is induced by BMP-4, and a dominant negative BMP-4 receptor inhibits SCL expression in the ventral region of the embryo. Expression of SCL in either bFGF-treated animal pole explants or dorsal marginal zone explants leads to the expression of globin protein. Furthermore, over-expression of SCL does not alter normal dorsal-ventral patterning in the embryo, indicating that SCL acts to specify mesoderm to a hematopoietic fate after inductive and patterning events have occurred. We propose that SCL is both necessary and sufficient to specify hematopoietic mesoderm, and that it has a similar role in specifying hematopoietic cell fate as MyoD has in specifying muscle cell fate.

BMP-4-responsive regulation of dorsal-ventral patterning by the homeobox protein Mix.1.

In an expression screen for factors that pattern or induce ventral mesoderm, we isolated a complementary DNA encoding Mix.1, a paired class homeobox gene with no previously known function. Injection of Mix.1 messenger RNA results in extensive blood formation in the whole embryo and transforms dorsal mesoderm to a ventral fate. Mix.1 expression is induced by bone morphogenetic protein-4 (BMP-4), and a dominant inhibitory mutant of Mix.1 can restore a dorsal axis in embryos ventralized by ectopic BMP-4 expression. Mix.1 can form heterodimers with the dorsalizing gene siamois, which encodes a homeodomain protein that is structurally similar to Mix.1. Furthermore, Mix.1 blocks the duplicated axis induced by ectopic siamois expression. Our findings indicate that Mix.1 participates in a BMP-4 signalling pathway to pattern ventral mesoderm, and suggest a model whereby dimerization of homeodomain proteins regulates dorsal-ventral patterning.

Expandable endoprosthesis reconstruction in skeletally immature patients with tumors.

Between September 1984 and January 1996, 32 expandable endoprostheses were used for limb reconstruction after resection of malignant bone tumors in patients who were skeletally immature. The 20 boys and 12 girls ranged in age from 3 to 15 years (mean, 9.7 years). One patient had a Stage IIA tumor, 22 patients had Stage IIB tumors, and seven patients had Stage III tumors according to the classification of the Musculoskeletal Tumor Society. There also were two patients with parosteal osteosarcomas. The histologic diagnosis was osteosarcoma in 23 patients and Ewing's sarcoma in nine. All patients except the patients with parosteal osteosarcoma received standard neoadjuvant therapy. Twenty-two Lewis Expandable Adjustable Prostheses, four modular Wright Medical prostheses, four modular Howmedica prostheses, and two Techmedica expandable prostheses were used. Thirteen patients died, two have no evidence of disease, and 17 are continuously disease free. Sixteen of 32 patients (50%) have not had an expansion procedure because of early death in 10 and early amputation in three. Three patients are waiting to undergo an expansion procedure. Sixteen of the 32 patients (50%) have undergone 32 expansion procedures, to a maximum of 9 cm, without any infection. To maintain range of motion before the expansion procedure, a complete resection of the pseudocapsule was done routinely. Fourteen of the 32 patients did not have complications. Eighteen of the 32 patients had 27 complications. All Lewis Expandable Adjustable Prosthesis endoprostheses and the two nonmodular Techmedica prostheses were associated with a large amount of titanium debris. The children's functional results were similar to the results reported for adults with an average Musculoskeletal Tumor Society rating of good to excellent at the knee, fair to good at the hip, and fair about the shoulder. Rehabilitation of the knee in very young patients (5-8 years) remains problematic and careful selection of patient and family is necessary. The Lewis Expandable Adjustable Prosthesis probably should be reserved for very young patients (5-8 years) and modular systems should be used for large preadolescent and adolescent children.