Thyroid-stimulating hormone restores bone volume, microarchitecture, and strength in aged ovariectomized rats.

We show the systemic administration of low levels of TSH increases bone volume and improves bone microarchitecture and strength in aged OVX rats. TSH's actions are mediated by its inhibitory effects on RANKL-induced osteoclast formation and bone resorption coupled with stimulatory effects on osteoblast differentiation and bone formation, suggesting TSH directly affects bone remodeling in vivo. INTRODUCTION: Thyroid-stimulating hormone (TSH) receptor haploinsufficient mice with normal circulating thyroid hormone levels have reduced bone mass, suggesting that TSH directly affects bone remodeling. We examined whether systemic TSH administration restored bone volume in aged ovariectomized (OVX) rats and influenced osteoclast formation and osteoblast differentiation in vitro. MATERIALS AND METHODS: Sprague-Dawley rats were OVX at 6 months, and TSH therapy was started immediately after surgery (prevention mode; n = 80) or 7 mo later (restoration mode; n = 152). Hind limbs and lumbar spine BMD was measured at 2- or 4-wk intervals in vivo and ex vivo on termination at 8-16 wk. Long bones were subjected to microCT, histomorphometric, and biomechanical analyses. The direct effect of TSH was examined in osteoclast and osteoblast progenitor cultures and established rat osteosarcoma-derived osteoblastic cells. Data were analyzed by ANOVA Dunnett test. RESULTS: In the prevention mode, low doses (0.1 and 0.3 microg) of native rat TSH prevented the progressive bone loss, and importantly, did not increase serum triiodothyroxine (T3) and thyroxine (T4) levels in aged OVX rats. In restoration mode, animals receiving 0.1 and 0.3 microg TSH had increased BMD (10-11%), trabecular bone volume (100-130%), trabecular number (25-40%), trabecular thickness (45-60%), cortical thickness (5-16%), mineral apposition and bone formation rate (200-300%), and enhanced mechanical strength of the femur (51-60%) compared with control OVX rats. In vitro studies suggest that TSH's action is mediated by its inhibitory effects on RANKL-induced osteoclast formation, as shown in hematopoietic stem cells cultivated from TSH-treated OVX rats. TSH also stimulates osteoblast differentiation, as shown by effects on alkaline phosphatase activity, osteocalcin expression, and mineralization rate. CONCLUSIONS: These results show for the first time that systemically administered TSH prevents bone loss and restores bone mass in aged OVX rats through both antiresorptive and anabolic effects on bone remodeling.     

Controversies in tuberculosis

Tuberculous infection among children continues to be a significant cause of morbidity. The symptom complex are so variable among children that the final diagnosis often rests on the laboratory tests. Proper interpretation of the tests, specially tuberculin test and radiographic studies, are necessary for establishing correct diagnosis. The usefulness of tuberculin test in both unimmunized and BCG vaccinated children is highlighted. BCG accelerated response as a test should be reserved for identifying serious form of pulmonary disease or CNS tuberculosis when the tuberculin test is negative. Radiographic assessment may be sensitive in some instances but not always specific and hence needs cautious interpretation. Tuberculosis among BCG vaccinated children though not uncommon, needs proper documentation. Current trends in the management of tuberculosis including CNS forms are briefly outlined.     

Phase-sensitive cardiac tagging--REALTAG.

Fully inverting spins, instead of merely saturating them, provides superior contrast for tagging procedures. The resulting improvement in tag contrast-to-noise ratio (CNR) yields higher-precision tag detection. Also, thinner slices and hence reduced tag separations can be employed, providing displacement and strain measurements with better spatial resolution. Alternatively, the improved tag contrast can be used to obtain cine images covering a greater portion of the cardiac cycle. The use of standard magnitude reconstruction for images of these inversion tags causes rectification of the negative-valued signals from the tags, confounding the image interpretation. Therefore, a phase-sensitive reconstruction scheme of the inverted tags must be employed. Here we demonstrate the implementation of inverted tags with phase-sensitive reconstruction in a ramped-flip-angle, steady-state free precession (SSFP) sequence.     

Cardiac injuries--a clinical and autopsy profile

One hundred two patients sustaining cardiac injuries over a 4-year period were analysed to highlight the natural history of the cardiac injuries. There were 45 blunt, 36 stab, and 21 gunshot injuries. The injury involved the ventricle in 85, atrium in seven, pulmonary artery in five cases, and resulted in crush injury to the heart in the remaining five cases. Thirty-three patients (32.3%) died on the scene and 58 (56.9%) died during the transportation. Only 11 patients (10.8%) reached the hospital alive, and ten of these patients survived following thoracotomy and repair of the cardiac injury. The factors influencing the natural course of cardiac injury were analysed: 2.2% of patients with blunt cardiac trauma reached the hospital alive compared to 19.4% with stab and 14.3% with gunshot injuries; ventricular injuries had a greater prehospital mortality compared to atrial or pulmonary artery injuries; 11.3% of patients sustaining injury to right ventricle reached the hospital alive compared to 3% of those with left ventricular injuries. These data emphasize the need for rapid transport, immediate recognition, and aggressive surgical management, to make a favourable impact on the natural history of cardiac injuries.     

Mechanisms of cell signaling by nitric oxide and peroxynitrite: from mitochondria to MAP kinases

Many of the biological and pathological effects of nitric oxide (NO) are mediated through cell signaling pathways that are initiated by NO reacting with metalloproteins. More recently, it has been recognized that the reaction of NO with free radicals such as superoxide and the lipid peroxyl radical also has the potential to modulate redox signaling. Although it is clear that NO can exert both cytotoxic and cytoprotective actions, the focus of this overview are those reactions that could lead to protection of the cell against oxidative stress in the vasculature. This will include the induction of antioxidant defenses such as glutathione, activation of mitogen-activated protein kinases in response to blood flow, and modulation of mitochondrial function and its impact on apoptosis. Models are presented that show the increased synthesis of glutathione in response to shear stress and inhibition of cytochrome c release from mitochondria. It appears that in the vasculature NO-dependent signaling pathways are of three types: (i) those involving NO itself, leading to modulation of mitochondrial respiration and soluble guanylate cyclase; (ii) those that involve S-nitrosation, including inhibition of caspases; and (iii) autocrine signaling that involves the intracellular formation of peroxynitrite and the activation of the mitogen-activated protein kinases. Taken together, NO plays a major role in the modulation of redox cell signaling through a number of distinct pathways in a cellular setting.     

Comparison of nasal pressure transducer and thermistor for detection of respiratory events during polysomnography in children

STUDY OBJECTIVES: The results of small studies have suggested that a nasal-cannula pressure transducer has a higher sensitivity than a thermistor in detecting hypopneas and diagnosing sleep-disordered breathing in both adults and children. We compared a thermistor alone, and in conjunction with a pressure transducer, for detection of sleep-disordered breathing in children during in-home polysomnography. DESIGN: Retrospective analysis of a subsample of a prospective cohort study. SETTING: Students attending elementary school in the Tucson Unified School District. PARTICIPANTS: A subsample of the Tucson Children's Assessment of Sleep Apnea study population. MEASUREMENTS AND RESULTS: Polysomnographic recordings of 40 children (24 girls and 16 boys, mean age 9.2 +/- 1.7 years; range 6-11 years) were analyzed to compare the detection of sleep-disordered breathing events by 2 different methods of measuring airflow: thermistor alone and thermistor with nasal-cannula pressure transducer (transducer) used simultaneously. The transducer detected all the respiratory events detected by the thermistor, but the thermistor detected only 84% of the transducer-defined events. Consequently, the transducer-derived mean respiratory disturbance index was higher than that detected by the thermistor (7.0 +/- 3.8 vs 5.9 +/- 3.4, P < .001). The bias error between transducer respiratory disturbance index and thermistor respiratory disturbance index on a Bland-Altman plot was 1.08 (95% confidence interval, 0.8 - 1.4). There was good agreement between the thermistor and the transducer for making the diagnosis of sleep apnea using a cutoff of a respiratory disturbance index greater than 5 (kappa = 0.69). The quality of the tracings with the transducer was comparable to that of the thermistor, but the transducer dislodged more frequently. CONCLUSION: The use of a nasal transducer in conjunction with a thermistor was more sensitive than the thermistor alone in detecting sleep-disordered breathing in children during unattended polysomnography.     

Conformation of O6-alkylguanosines: molecular mechanism of mutagenesis

The O⁶-alkylation of guanine residues in DNA treated with alkylatingagents induce mutations due to mis-pairing resulting from thedeprotonation of N1. In addition to the deprotonation of N1,the conformation of the O⁶-alkyl group with respect to N7 ofguanine is very important. Here, we present X-ray crystallographicevidence that shows that the methyl group in O⁶-methylguanosinehas a preference for the distal conformation, blocking the Watson-Cricksites. This distal conformation persists in the solid statefor several analogs of O⁶-alkylguanosine also. This preferredconformation agrees with the result that poly(O⁶-methyl GMP)does not form any stable complex with poly(U). However, themispairing of O⁶-methylguanine with thymine and the resultantGA transition is known from in vitro studies. The above twoopposite results strongly indicate that the conformation ofthe O⁶-alkyl group and the base pairing properties of O⁶-alkylguanineat the monomer and polymer levels must be different from thesituation when the modified base is embedded with a small frequencyin a duplex. It is interesting to note that the sterical blockingof the Watson-Crick site at the monomer level and the alteredbase pairing properties when present as occasional bases ina duplex emerge as a common property for several mutagenic baseslike O⁶-alkylguanmes, O⁴ -methyluracil and N⁴-hydroxycytosine.