Sources of axonal calcium loading during in vitro ischemia of rat dorsal roots

A detailed understanding of injury mechanisms in peripheral nerve fibers will help guide successful design of therapies for peripheral neuropathies. This study was therefore undertaken to examine the ionic mechanisms of Ca2+ overload in peripheral myelinated fibers subjected to chemical inhibition of energy metabolism. Myelinated axons from rat dorsal roots were co-loaded with Ca2+-sensitive (Oregon Green BAPTA-1) and Ca2+-insensitive (Alexa Fluor 594) dextran-conjugated fluorophores and imaged using confocal laser scanning microscopy. Axoplasmic regions were clearly outlined by the Ca2+-insensitive dye, from which axonal Ca2+-dependent fluorescence changes (FCa.ax) were measured. Block of Na+-K+ ATPase (ouabain), opening of Na+ channels (veratridine), and inhibiting energy metabolism (iodoacetate + NaN3) caused a rapid rise in FCa.ax to 96% above control after 30 min. Chemical ischemia (iodoacetate + NaN3) caused a more gradual increase in FCa.ax (54%), which was almost completely dependent on bath Ca2+, indicating that most of the Ca2+ accumulation occurred via influx across the axolemma. Na+ channel block (tetrodotoxin) reduced ischemic FCa.ax rise (14%); however, inhibition of L-type Ca2+ channels (nimodipine) had no effect (60%). In contrast, Na+-Ca2+ exchange inhibition (KB-R7943) significantly reduced ischemic FCa.ax rise (18%). Together our results indicate that the bulk of Ca2+ overload in injured peripheral myelinated axons occurs via reverse Na+-Ca2+ exchange, driven by axonal Na+ accumulation through voltage-gated tetrodotoxin-sensitive Na+ channels. This mechanism may represent a viable therapeutic target for peripheral neuropathies.     

School-based intervention acutely improves insulin sensitivity and decreases inflammatory markers and body fatness in junior high school students

CONTEXT: Risk factors for type 2 diabetes mellitus (T2DM) include obesity, family history, dyslipidemia, a proinflammatory state, impaired insulin secretory capacity, and insulin resistance. OBJECTIVE: The aim of this study was to examine the effects of a 3- to 4-month school-based intervention consisting of health, nutrition, and exercise classes plus an aerobic exercise program on diabetes risk. DESIGN: This study was a randomized before/after controlled trial. METHODS: Seventy-three eighth-grade students in a predominantly Hispanic New York City public school were divided into a control group (studied twice without receiving the intervention) and an experimental group (studied before and after the intervention). OUTCOME MEASURES: We measured body fatness (bioelectrical impedance), insulin sensitivity, beta-cell function (insulin release in response to an iv glucose load corrected for insulin sensitivity), lipid profiles, and circulating concentrations of IL-6, C-reactive protein, adiponectin, and TNF-alpha. RESULTS: Participation in the intervention was associated with significant reductions in body fatness, insulin resistance, and circulating concentrations of C-reactive protein and IL-6, irrespective of somatotype on enrollment. CONCLUSION: Short-term school-based health, nutrition, and exercise intervention is beneficial to all students and affects multiple diabetes risk factors.     

Anaplastic thyroid carcinoma: clinical outcome of 30 consecutive patients referred to a single institution in the past 5 years

OBJECTIVE: Treatment options for anaplastic thyroid carcinoma (ATC), which is one of the most lethal human malignant tumors, include surgery, chemotherapy and radiotherapy usually combined in a multimodal approach, to improve survival and avoid death from local invasion. However, there is no standard protocol for ATC treatment and the optimal sequence within multimodal therapy is debated. We retrospectively report the clinical outcome of 30 ATC patients referred consecutively to the Oncological Endocrinology Unit of San Giovanni Battista Hospital (Turin, Italy) between 2000 and 2005. DESIGN: Patients were treated by one of the following approaches: i) surgery followed by adjuvant-combined chemoradiotherapy; ii) neo-adjuvant chemoradiotherapy followed by surgery and adjuvant chemotherapy; or iii) chemotherapy alone. The surgical procedures were classified as 'maximal debulking' or 'palliative resection'. Maximal debulking entailed total or near-total thyroidectomy and complete resection of all gross tumor or minimal residual disease adherent to vital structures, independently of the presence or absence of distant metastases. In palliative resections, macroscopic residual disease was left in the neck. Survival of patients stratified by treatment was assessed. RESULTS: Analysis of multivariate hazard ratios showed that maximal debulking followed by adjuvant chemoradiotherapy was the only treatment that modified survival of ATC patients (hazard ratio= 0.23, 95% CI: 0.07-0.79), even if factors determining poor prognosis or increased surgical risk were present. CONCLUSIONS: Despite the overall grim outcome of ATC, these results justify an attempt at maximal debulking surgery, followed by adjuvant chemoradiotherapy, possibly in all ATC patients.     

erm(B)-carrying elements in tetracycline-resistant pneumococci and correspondence between Tn1545 and Tn6003

This study investigated the genetic organization of erm(B)-carrying transposons of Streptococcus pneumoniae and their distribution in tetracycline-resistant clinical isolates. By comparatively analyzing reference pneumococci carrying erm(B)/tet(M) transposon Tn1545, Tn6003, Tn6002, or Tn3872, we demonstrated a substantial correspondence between Tn1545 and Tn6003, which have the same resistance gene combination [tet(M) (tetracycline), erm(B) (erythromycin), and aphA-3 (kanamycin)]; share the macrolide-aminoglycoside-streptothricin element, containing a second erm(B); and only differ by a ca. 1.2-kb insertion (containing a putative IS1239 insertion sequence) detected in Tn1545 from S. pneumoniae reference strain BM4200. These results enabled elucidation of the structure of Tn1545, the first erm(B)-carrying transposon described in S. pneumoniae. A collection of 83 erythromycin- and tetracycline-resistant clinical pneumococci, representative of recent Italian isolates carrying erm(B) as the sole erythromycin resistance gene, was used to investigate the distribution of the different transposons. All 83 organisms were positive for tet(M) and bore an erm(B)/tet(M) transposon that could be characterized by using a specific set of primer pairs; Tn3872 was detected in 18 isolates, Tn6002 in 59 isolates, and Tn6003 in 6 (the sole kanamycin-resistant) isolates. The genetic organization of transposon Tn1545, with its specific insertion, was not detected in any of the isolates tested. The erm(B)-carrying elements of tetracycline-resistant pneumococci substantially corresponded to those [bearing a silent tet(M) gene] recently detected in tetracycline-susceptible pneumococci. Overall, in erm(B)-positive pneumococci, Tn6003 was the least common erm(B)-carrying Tn916-related element and Tn6002 the most common.     

Osteogenesis imperfecta: diagnosis and treatment

Osteogenesis imperfecta is a heritable disorder characterized by extremely fragile bones, blue sclerae, dentinogenesis imperfecta, hearing loss, and scoliosis. In 1979, Sillence classified the condition into four types based on genetic and clinical criteria. Three more classifications have subsequently been added. Diagnosis of osteogenesis imperfecta may be done prenatally (in severe cases), clinically, radiographically, or via biochemical or genetic examination. Medical treatment consists of bisphosphonate use, even in patients younger than age 2 years. Surgical treatment consists of internal splinting of long bones. Research is currently being done on the use of smart intramedullary rods (ie, composed of nitinol shape-memory alloy) for correction of bone deformity and on the use of bone marrow transplantation to increase osteoblast density, thereby reducing fracture frequency.     

Medication-related osteonecrosis of the jaw: A disease of significant importance for older patients

Background

Medication-related osteonecrosis of the jaw (MRONJ) is clinically defined as a non-healing jawbone ulcerative-necrotic lesion appearing after dental therapy or minor trauma in patients treated previously with anti-resorptive, anti-angiogenic or immunomodulators. Older patients with osteoporosis and cancer receive these pharmacological agents regularly. As these patients are long-term survivors, efficient treatment is of paramount importance for their quality of life.

Methods

Literature searches via PubMed were conducted to identify relevant MRONJ studies. Basic information on MRONJ classification, clinical features, and pathosphysiology is presented herein as well as various clinical studies dealing with MRONJ in patients with osteoporosis and cancer. Lastly, we discuss current managment of patients and new trends in treatment of MRONJ.

Results

Although close follow-up and local hygiene have been advocated by some authors, severe forms of MRONJ are not responsive to conservative therapy. At present, there is no “gold standard” therapy for this condition. However, as the physiopathological basis of MRONJ is represented by the anti-angiogenic action of various pharmacological agents, new methods to increase and promote local angiogenesis and vascularization have recently been successfully tested in vitro, limited preclinical studies, and in a pilot clinical study.

Conclusions

It appears that the best method implies application on the lesion of endothelial progenitor cells as well as pro-angiogenic factors such as Vascular Endothelial Growth Factor (VEGF) and other related molecules. More recently, scaffolds in which these factors have been incorporated have shown positive results in limited trials. However, these studies must be replicated to include a large number of cases before any official therapeutic protocol is adopted.