Putative living entities called nanobacteria (NB) are unusual for their small sizes (50–500 nm), pleomorphic nature, and accumulation of hydroxyapatite (HAP), and have been implicated in numerous diseases involving extraskeletal calcification. By adding precipitating ions to cell culture medium containing serum, mineral nanoparticles are generated that are morphologically and chemically identical to the so-called NB. These nanoparticles are shown here to be formed of amorphous mineral complexes containing calcium as well as other ions like carbonate, which then rapidly acquire phosphate, forming HAP. The main constituent proteins of serum-derived NB are albumin, fetuin-A, and apolipoprotein A1, but their involvement appears circumstantial since so-called NB from different body fluids harbor other proteins. Accordingly, by passage through various culture media, the protein composition of these particles can be modulated. Immunoblotting experiments reveal that antibodies deemed specific for NB react in fact with either albumin, fetuin-A, or both, indicating that previous studies using these reagents may have detected these serum proteins from the same as well as different species, with human tissue nanoparticles presumably absorbing bovine serum antigens from the culture medium. Both fetal bovine serum and human serum, used earlier by other investigators as sources of NB, paradoxically inhibit the formation of these entities, and this inhibition is trypsin-sensitive, indicating a role for proteins in this inhibitory process. Fetuin-A, and to a lesser degree albumin, inhibit nanoparticle formation, an inhibition that is overcome with time, ending with formation of the so-called NB. Together, these data demonstrate that NB are most likely formed by calcium or apatite crystallization inhibitors that are somehow overwhelmed by excess calcium or calcium phosphate found in culture medium or in body fluids, thereby becoming seeds for calcification. The structures described earlier as NB may thus represent remnants and by-products of physiological mechanisms used for calcium homeostasis, a concept which explains the vast body of NB literature as well as explains the true origin of NB as lifeless protein-mineralo entities with questionable role in pathogenesis.

Concerns over global energy supply have spurred intensive research on energy storage technologies to enable electric vehicles and an electric grid that can utilize renewable energy sources such as wind and solar. [1][2][3][4][5][6][7][8][9][10][11] Recently, several emerging aqueous energy storage technologies have been demonstrated that feature low cost, high rate capability, and durability. The potential for use in large-scale grid application has revived focus on these systems. [12][13][14][15][16][17] Here, we demonstrate ultrafast rate capability ( > 100C current rates) and superior high-rate cycling stability ( > 1500 cycles) in aqueous NaTi 2 (PO 4 ) 3 /Na 0.44 MnO 2 (NTP/NMO) cells, an electrochemical couple which has the highest specifi c and volumetric energy amongst reported aqueous Na-ion systems to date.Aqueous rechargeable Li-ion batteries previously garnered interest as a possible substitute for conventional aqueous rechargeable systems such as Pb-acid and NiMH. These were fi rst proposed and demonstrated by the Dahn group using VO 2 /LiMn 2 O 4 electrodes and LiNO 3 aqueous solution as the electrolyte. [18][19][20] Additional electrode couples were later studied, most of which exhibited limited cycle life. [21][22][23] However, the Xia group was able to raise the cycling stability of a LiTi 2 (PO 4 ) 3 /LiFePO 4 aqueous rechargeable Li-ion batteries to a commercially acceptable level. [ 15 ] Of equal or greater interest, due to the high natural abundance and low cost of Na, are aqueous rechargeable Na-ion batteries. A variety of Na intercalation electrode compounds have been identifi ed. [ 6 ] The fi rst working demonstration of an aqueous Na-ion full cell was presented by Okada using a NMO cathode and NTP anode. [ 24 ] However, only two low rate cycles were shown for these cells. The reported properties of NMO and NTP suggest that this electrochemical couple may be capable of stable and high rate electrochemical performance. [ 16 , 25 ] In the present work, we fi rst show that without modifi cation, the low electronic conductivity of the NTP anode causes it to be rate-limiting. Secondly, upon optimizing the synthesis of NTPcarbon composite anodes to remove the electronic conductivity limitation, ultrafast rate capability and superior high-rate cycling stability are obtained. Finally, careful measurement of the NTP crystallite size in the modifi ed and unmodifi ed electrodes allow a lower limit for the Na diffusivity in NTP to be established.NMO was synthesized by solid-state reaction as described in the Experimental Section. The crystal structure derived from Reitveld refi nement, and an SEM image of the as-prepared powder are shown in Figure 1 . The structure of the as-prepared compound was refi ned using the atomic coordinates of isostructural Na 4 Mn 4 Ti 5 O 18 ( Pbam space group). The orthorhombic lattice cell parameters thus obtained are a = 9.09355(26) Å, b = 26.4628(5) Å and c = 2.82683(12) Å with wRp = 3.72%, in good agreement with literature. [26][27][28][29][30][31] The inset in Figur...

Jumper's knee is characterized by consistent changes at MR imaging, US, and histopathologic examination and is appropriately described as patellar tendinosis.

Type 1 diabetes (T1D) animal models such as the nonobese diabetic (NOD) mouse have improved our understanding of disease pathophysiology, but many candidate therapeutics identified therein have failed to prevent/cure human disease. We have performed a comprehensive evaluation of disease-modifying agents tested in the NOD mouse based on treatment timing, duration, study length, and efficacy. Interestingly, some popular tenets regarding NOD interventions were not confirmed: all treatments do not prevent disease, treatment dose and timing strongly influence efficacy, and several therapies have successfully treated overtly diabetic mice. The analysis provides a unique perspective on NOD interventions and suggests that the response of this model to therapeutic interventions can be a useful predictor of the human response as long as careful consideration is given to treatment dose, timing, and protocols; more thorough investigation of these parameters should improve clinical translation.

Calcium and apatite granulations are demonstrated here to form in both human and fetal bovine serum in response to the simple addition of either calcium or phosphate, or a combination of both. These granulations are shown to represent precipitating complexes of protein and hydroxyapatite (HAP) that display marked pleomorphism, appearing as round, laminated particles, spindles, and films. These same complexes can be found in normal untreated serum, albeit at much lower amounts, and appear to result from the progressive binding of serum proteins with apatite until reaching saturation, upon which the mineralo-protein complexes precipitate. Chemically and morphologically, these complexes are virtually identical to the so-called nanobacteria (NB) implicated in numerous diseases and considered unusual for their small size, pleomorphism, and the presence of HAP. Like NB, serum granulations can seed particles upon transfer to serum-free medium, and their main protein constituents include albumin, complement components 3 and 4A, fetuin-A, and apolipoproteins A1 and B100, as well as other calcium and apatite binding proteins found in the serum. However, these serum mineralo-protein complexes are formed from the direct chemical binding of inorganic and organic phases, bypassing the need for any biological processes, including the long cultivation in cell culture conditions deemed necessary for the demonstration of NB. Thus, these serum granulations may result from physiologically inherent processes that become amplified with calcium phosphate loading or when subjected to culturing in medium. They may be viewed as simple mineralo-protein complexes formed from the deployment of calcification-inhibitory pathways used by the body to cope with excess calcium phosphate so as to prevent unwarranted calcification. Rather than representing novel pathophysiological mechanisms or exotic lifeforms, these results indicate that the entities described earlier as NB most likely originate from calcium and apatite binding factors in the serum, presumably calcification inhibitors, that upon saturation, form seeds for HAP deposition and growth. These calcium granulations are similar to those found in organisms throughout nature and may represent the products of more general calcium regulation pathways involved in the control of calcium storage, retrieval, tissue deposition, and disposal.

Objectives-Jumper's knee causes significant morbidity in athletes of all standards. However, there are few reference data on the clinical course of this condition in a large number of patients, and the aim of this study was to rectify this. Methods-A retrospective study of the course of jumper's knee in 100 athletes who presented to a sports medicine clinic over a nine year period was carried out. Subjects completed a questionnaire designed to collect details of sport participation, symptoms, and time out of sport. Ultrasonographic results were recorded from the radiologists' reports. Histopathological results were obtained for patients who had surgery. Results-Forty eight subjects recalled that symptoms of jumper's knee began before the age of 20 years. Symptoms prevented 33 from participating in sport for more than six months, and 18 of these were sidelined for more than 12 months. Forty nine of the subjects had two or more separate episodes ofsymptoms. Ultrasonography showed a characteristic hypoechoic region at the junction of the inferior pole of the patella and the deep surface of the patellar tendon. Histopathological examination showed separation and disruption of collagen fibres on polarisation light microscopy and an increase in mucoid ground substance consistent with damage of tendon collagen without inflammation.Conclusions-Jumper's knee has the potential to be a debilitating condition for a sports person. About 33% of athletes presenting to a sports medicine clinic with jumper's knee were unable to return to sport for more than six months. (BrJ Sports Med 1997;31:332-336)

Serum-derived granulations and purported nanobacteria (NB) are pleomorphic apatite structures shown to resemble calcium granules widely distributed in nature. They appear to be assembled through a dual inhibitory-seeding mechanism involving proteinaceous factors, as determined by protease (trypsin and chymotrypsin) and heat inactivation studies. When inoculated into cell culture medium, the purified proteins fetuin-A and albumin fail to induce mineralization, but they will readily combine with exogenously added calcium and phosphate, even in submillimolar amounts, to form complexes that will undergo morphological transitions from nanoparticles to spindles, films, and aggregates. As a mineralization inhibitor, fetuin-A is much more potent than albumin, and it will only seed particles at higher mineral-to-protein concentrations. Both proteins display a bell-shaped, dose-dependent relationship, indicative of the same dual inhibitory-seeding mechanism seen with whole serum. As ascertained by both seeding experiments and gel electrophoresis, fetuin-A is not only more dominant but it appears to compete avidly for nanoparticle binding at the expense of albumin. The nanoparticles formed in the presence of fetuin-A are smaller than their albumin counterparts, and they have a greater tendency to display a multi-layered ring morphology. In comparison, the particles seeded by albumin appear mostly incomplete, with single walls. Chemically, spectroscopically, and morphologically, the protein-mineral particles resemble closely serum granules and NB. These particles are thus seen to undergo an amorphous to crystalline transformation, the kinetics and completeness of which depend on the protein-to-mineral ratios, with low ratios favoring faster conversion to crystals. Our results point to a dual inhibitory-seeding, de-repression model for the assembly of particles in supersaturated solutions like serum. The presence of proteins and other inhibitory factors tend to block apatite nuclei formation or to stabilize the nascent nuclei as amorphous or semi-crystalline spherical nanoparticles, until the same inhibitory influences are overwhelmed or de-repressed, whereby the apatite nuclei grow in size to coalesce into crystalline spindles and films—a mechanism that may explain not only the formation of calcium granules in nature but also normal or ectopic calcification in the body.

We report the findings of an independent review of 230 consecutive Birmingham hip resurfacings (BHRs) in 213 patients (230 hips) at a mean follow-up of 10.4 years (9.6 to 11.7). A total of 11 hips underwent revision; six patients (six hips) died from unrelated causes; and 13 patients (16 hips) were lost to follow-up. The survival rate for the whole cohort was 94.5% (95% confidence interval (CI) 90.1 to 96.9). The survival rate in women was 89.1% (95% CI 79.2 to 94.4) and in men was 97.5% (95% CI 92.4 to 99.2). Women were 1.4 times more likely to suffer failure than men. For each millimetre increase in component size there was a 19% lower chance of a failure. The mean Oxford hip score was 45.0 (median 47.0, 28 to 48); mean University of California, Los Angeles activity score was 7.4 (median 8.0, 3 to 9); mean patient satisfaction score was 1.4 (median 1.0, 0 to 9). A total of eight hips had lysis in the femoral neck and two hips had acetabular lysis. One hip had progressive radiological changes around the peg of the femoral component. There was no evidence of progressive neck narrowing between five and ten years. Our results confirm that BHR provides good functional outcome and durability for men, at a mean follow-up of ten years. We are now reluctant to undertake hip resurfacing in women with this implant.