Post-marketing surveillance of zinc acetate dihydrate for hypozincemia in Japan.

Zinc is an essential microelement, and its deficit causes various diseases and symptoms. In adults, especially in elderly individuals, zinc shortage can cause symptoms such as taste disorder, dermatitis, and susceptibility to infection. In children, zinc deficiency can lead to growth retardation. In 2017, the indication for zinc acetate dihydrate (NOBELZIN®) was expanded from Wilson's disease to include hypozincemia, leading to wider use of zinc acetate dihydrate. At five years after this broadening of use, we conducted a post-marketing study (PMS) to investigate the utilization, safety, and effectiveness of zinc acetate dihydrate. Over 52 weeks, the overall incidence of adverse drug reactions (ADRs) was 9.4% (87/928). The most common ADR was copper deficiency (2.4%), followed by nausea (1.4%). Among 928 patients, 19 (2%) developed serious ADRs. Of the patients with copper deficiency, 92% were >65 years of age, and all had comorbidities at baseline. Physicians evaluated the effectiveness of zinc acetate dihydrate using three categories: "effective", "not effective", and "indeterminate". The overall efficacy rate was 83.0%. The average serum zinc levels were elevated from 50-60 µg/dL to >90 µg/dL within 12 weeks, and were maintained up to 52 weeks after administration. Among the symptomatic sub-categories, the efficacy rate was highest in pressure ulcer (96.2%; 25/26), followed by in stomatitis (87.5%; 42/48), and taste disorder (87.4%; 181/207). Among pediatric patients with developmental symptoms, an efficacy rate of 66% was achieved. In conclusion, zinc acetate dihydrate has been safely used, and has produced beneficial effects on various diseases and symptoms.

Factors influencing wound healing of critical ischaemic foot after bypass surgery: is the angiosome important in selecting bypass target artery?

OBJECTIVES: The aim of the study is to determine factors affecting ischaemic wound healing and role of the angiosome concept in bypass surgery. DESIGN: Single-centre, retrospective clinical study. MATERIALS AND METHODS: A total of 249 consecutive critical ischaemic limbs with tissue loss in 228 patients who underwent distal bypasses from 2003 to 2009 were reviewed. A total of 81% of patients were diabetic, and 49% of patients had dialysis-dependent renal disease (end-stage renal disease, ESRD). Distal targets of bypasses were the crural artery (57%) and the pedal artery (43%). RESULTS: The complete healing of ischaemic wounds was achieved in 211 limbs (84.7%). ESRD (odds ratio (OR) 0.127, p < 0.001), diabetes (OR 0.216, p = 0.030), Rutherford category 6 (R6) with heel ulcer/gangrene (OR 0.134, p < 0.001), R6 except heel (OR 0.336, p = 0.025) and low albuminaemia (OR 0.387, p = 0.049) were negative predictors of wound healing. Regarding the angiosome, the healing rate in the indirect revascularisation (IR) group was slower than in the direct revascularisation (DR) group, especially in patients with ESRD (p < 0.001). However, the healing rates of the DR and IR groups were similar after minimising background differences with propensity score methods (p = 0.185). CONCLUSIONS: In the field of bypass surgery, the angiosome concept seems unimportant, at least in non-ESRD cases. The location and extent of ischaemic wounds as well as co-morbidities may be more relevant than the angiosome in terms of wound healing.

Osteoinduction of porous Ti implants with a channel structure fabricated by selective laser melting.

Many studies have shown that certain biomaterials with specific porous structures can induce bone formation in non-osseous sites without the need for osteoinductive biomolecules, however, the mechanisms responsible for this phenomenon (intrinsic osteoinduction of biomaterials) remain unclear. In particular, to our knowledge the type of pore structure suitable for osteoinduction has not been reported in detail. In the present study we investigated the effects of interconnective pore size on osteoinductivity and the bone formation processes during osteoinduction. Selective laser melting was employed to fabricate porous Ti implants (diameter 3.3mm, length 15 mm) with a channel structure comprising four longitudinal square channels, representing pores, of different diagonal widths, 500, 600, 900, and 1200 µm (termed p500, p600, p900, and p1200, respectively). These were then subjected to chemical and heat treatments to induce bioactivity. Significant osteoinduction was observed in p500 and p600, with the highest observed osteoinduction occurring at 5mm from the end of the implants. A distance of 5mm probably provides a favorable balance between blood circulation and fluid movement. Thus, the simple architecture of the implants allowed effective investigation of the influence of the interconnective pore size on osteoinduction, as well as the relationship between bone quantity and its location for different pore sizes.

Bioactive Ti metal analogous to human cancellous bone: Fabrication by selective laser melting and chemical treatments.

Selective laser melting (SLM) is a useful technique for preparing three-dimensional porous bodies with complicated internal structures directly from titanium (Ti) powders without any intermediate processing steps, with the products being expected to be useful as a bone substitute. In this study the necessary SLM processing conditions to obtain a dense product, such as the laser power, scanning speed, and hatching pattern, were investigated using a Ti powder of less than 45 µm particle size. The results show that a fully dense plate thinner than 1.8 mm was obtained when the laser power to scanning speed ratio was greater than 0.5 and the hatch spacing was less than the laser diameter, with a 30 µm thick powder layer. Porous Ti metals with structures analogous to human cancellous bone were fabricated and the compressive strength measured. The compressive strength was in the range 35-120 MPa when the porosity was in the range 75-55%. Porous Ti metals fabricated by SLM were heat-treated at 1300 °C for 1h in an argon gas atmosphere to smooth the surface. Such prepared specimens were subjected to NaOH, HCl, and heat treatment to provide bioactivity. Field emission scanning electron micrographs showed that fine networks of titanium oxide were formed over the whole surface of the porous body. These treated porous bodies formed bone-like apatite on their surfaces in a simulated body fluid within 3 days. In vivo studies showed that new bone penetrated into the pores and directly bonded to the walls within 12 weeks after implantation into the femur of Japanese white rabbits. The percentage bone affinity indices of the chemical- and heat-treated porous bodies were significantly higher than that of untreated implants.

Bone bonding bioactivity of Ti metal and Ti-Zr-Nb-Ta alloys with Ca ions incorporated on their surfaces by simple chemical and heat treatments.

Ti15Zr4Nb4Ta and Ti29Nb13Ta4.6Zr, which do not contain the potentially cytotoxic elements V and Al, represent a new generation of alloys with improved corrosion resistance, mechanical properties, and cytocompatibility. Recently it has become possible for the apatite forming ability of these alloys to be ascertained by treatment with alkali, CaCl2, heat, and water (ACaHW). In order to confirm the actual in vivo bioactivity of commercially pure titanium (cp-Ti) and these alloys after subjecting them to ACaHW treatment at different temperatures, the bone bonding strength of implants made from these materials was evaluated. The failure load between implant and bone was measured for treated and untreated plates at 4, 8, 16, and 26 weeks after implantation in rabbit tibia. The untreated implants showed almost no bonding, whereas all treated implants showed successful bonding by 4 weeks, and the failure load subsequently increased with time. This suggests that a simple and economical ACaHW treatment could successfully be used to impart bone bonding bioactivity to Ti metal and Ti-Zr-Nb-Ta alloys in vivo. In particular, implants heat treated at 700 °C exhibited significantly greater bone bonding strength, as well as augmented in vitro apatite formation, in comparison with those treated at 600 °C. Thus, with this improved bioactive treatment process these advantageous Ti-Zr-Nb-Ta alloys can serve as useful candidates for orthopedic devices.

Bioengineered titanium surfaces affect the gene-expression and phenotypic response of osteoprogenitor cells derived from mouse calvarial bones.

This study investigated the in vitro effects of bioactive titanium surfaces on osteoblast differentiation. Three titanium substrates were tested: a commercially pure titanium (Cp Ti), an alkali- and heat-treated titanium (AH Ti), and an apatite-formed titanium (Ap Ti) generated by soaking AH Ti in a simulated body fluid. Chemical evaluation of the surface reactivity was analysed at nanometre scale by X-ray photoelectron spectroscopy (XPS), and at micrometre scale by energy dispersive X-ray microanalysis (EDX). It showed that the estimated proportion of the surface covered by adsorbed serum proteins differed between the three substrates and confirmed the bioactivity of AH Ti, illustrated by surface calcium and phosphate deposition when immersed in biological fluids. Mouse calvaria osteoblasts were cultured on the substrates for 15 days with no sign of cytotoxicity. Enzyme immunoassay and Real-Time RT-PCR were used to follow osteoblast differentiation through the production of osteocalcin (OC) and expression of several bone markers. At day 15, a significant up-regulation of Runx2, Osx, Dlx5, ALP, BSP, OC and DMP1 mRNA levels associated with an increase of OC production were observed on AH Ti and Ap Ti when compared to Cp Ti. These results suggest that bioengineered titanium has a great potential for dental applications in enhancing osseointegration.

Preparation of bioactive titania films on titanium metal via anodic oxidation.

OBJECTIVES: To research the crystal structure and surface morphology of anodic films on titanium metal in different electrolytes under various electrochemical conditions and investigate the effect of the crystal structure of the oxide films on apatite-forming ability in simulated body fluid (SBF). METHODS: Titanium oxide films were prepared using an anodic oxidation method on the surface of titanium metal in four different electrolytes: sulfuric acid, acetic acid, phosphoric acid and sodium sulfate solutions with different voltages for 1 min at room temperature. RESULTS: Anodic films that consisted of rutile and/or anatase phases with porous structures were formed on titanium metal after anodizing in H(2)SO(4) and Na(2)SO(4) electrolytes, while amorphous titania films were produced after anodizing in CH(3)COOH and H(3)PO(4) electrolytes. Titanium metal with the anatase and/or rutile crystal structure films showed excellent apatite-forming ability and produced a compact apatite layer covering all the surface of titanium after soaking in SBF for 7d, but titanium metal with amorphous titania layers was not able to induce apatite formation. SIGNIFICANCE: The resultant apatite layer formed on titanium metal in SBF could enhance the bonding strength between living tissue and the implant. Anodic oxidation is believed to be an effective method for preparing bioactive titanium metal as an artificial bone substitute even under load-bearing conditions.

Growth of a bonelike apatite on chitosan microparticles after a calcium silicate treatment.

Bioactive chitosan microparticles can be prepared successfully by treating them with a calcium silicate solution and then subsequently soaking them in simulated body fluid (SBF). Such a combination enables the development of bioactive microparticles that can be used for several applications in the medical field, including injectable biomaterial systems and tissue engineering carrier systems. Chitosan microparticles, 0.6microm in average size, were soaked either for 12h in fresh calcium silicate solution (condition I) or for 1h in calcium silicate solution that had been aged for 24h before use (condition II). Afterwards, they were dried in air at 60 degrees C for 24h. The samples were then soaked in SBF for 1, 3 and 7 days. After the condition I calcium silicate treatment and the subsequent soaking in SBF, the microparticles formed a dense apatite layer after only 7 days of immersion, which is believed to be due to the formation of silanol (Si-OH) groups effective for apatite formation. For condition II, the microparticles successfully formed an apatite layer on their surfaces in SBF within only 1 day of immersion.

Functionalization of different polymers with sulfonic groups as a way to coat them with a biomimetic apatite layer.

Covalent coupling of sulfonic group (-SO 3H) was attempted on different polymers to evaluate efficacy of this functional group in inducing nucleation of apatite in body environment, and thereupon to design a simple biomimetic process for preparing bonelike apatite-polymer composites. Substrates of polyethylene terephthalate (PET), polycaprolactam (Nylon 6), high molecular weight polyethylene (HMWPE) and ethylene-vinyl alcohol co-polymer (EVOH) were subjected to sulfonation by being soaked in sulfuric acid (H2SO4) or chlorosulfonic acid (ClSO 3H) with different concentrations. In order to incorporate calcium ions, the sulfonated substrates were soaked in saturated solution of calcium hydroxide (Ca(OH)2). The treated substrates were soaked in a simulated body fluid (SBF). Fourier transformed infrared spectroscopy, thin-film X-ray diffraction, and scanning electron microscopy showed that the sulfonation and subsequent Ca(OH)2 treatments allowed formation of -SO3H groups binding Ca2+ ions on the surface of HMWPE and EVOH, but not on PET and Nylon 6. The HMWPE and EVOH could thus form bonelike apatite layer on their surfaces in SBF within 7 d. These results indicate that the -SO3H groups are effective for inducing apatite nucleation, and thereby that surface sulfonation of polymers are effective pre-treatment method for preparing biomimetic apatite on their surfaces.

Surface modification of organic polymers with bioactive titanium oxide without the aid of a silane-coupling agent.

Polyethylene (PE), polyethylene terephthalate (PET), ethylene-vinyl alcohol copolymer (EVOH), and poly(epsilon-caprolactam) (Nylon 6) were successfully modified with a thin crystalline titanium oxide layer on their surfaces by a simple dipping into a titanium alkoxide solution and a subsequent soak in hot HCl solution, without the aid of a silane-coupling agent. The surface modified polymers formed a bone-like apatite layer in a simulated body fluid (SBF) within a period of 2 days. PE, PET, and Nylon 6 formed an apatite layer faster and had a higher adhesive strength to the apatite. Three-dimensional fabrics with open spaces in various sizes containing such surface modified polymer fibers are expected to be useful as bone substitutes, since they may be able to form apatite on their constituent fibers in the living body, and thus, integrate with living bone.

Alkaline treatments to render starch-based biodegradable polymers self-mineralizable.

The present research aims to develop a new route for surface functionalization of biodegradable polymers. The method is based on a wet chemistry modification, resulting in etching and/or hydrolysis in order to increase the amount of polar groups, such as hydroxyl (--OH) and carboxylic (--COOH) groups on the surface of the polymer. The polymer used as substrate was a corn starch-ethylene vinyl alcohol biodegradable blend (SEVA-C). For that purpose it was used in two different types of activation: (a) calcium hydroxide solution [Ca(OH)(2)] and (b) sodium hydroxide solution (NaOH). These treatments lead to the formation carboxylic acid-rich SEVA-C surfaces. Then, the samples were soaked in simulated body fluid (SBF) for different time periods of time until 7 days. After 1 day in SBF, the surface of SEVA-C was fully covered with spherulite particles. As the soaking time increased, the particles increased and coalesced, leading to the formation of a dense and uniform layer. Furthermore, thin-film X-ray diffraction confirms that the layer formed on the surface of the polymer was an apatite-like layer. These results suggest that this rather simple treatment is a good method for surface functionalization and subsequent mineral nucleation and growth on biodegradable polymeric surfaces to be used for bone-related applications.

Bone-bonding ability of a hydroxyapatite coated zirconia-alumina nanocomposite with a microporous surface.

Using a combination of hydroxyapatite (HA) coating and microporous surface treatment, bone-bonding ability was given to composites of ceria-stabilized tetragonal zirconia and alumina (CZA), which possesses excellent mechanical and wear properties and phase stability. Four types of CZA plates (2 x 10 x 15 mm3) were prepared for this study, which were CZA with a polished surface (group 1), a microporous surface prepared by hydrofluoric acid and heat treatment (group 2), a microporous surface with a submicron HA coating prepared by alternately soaking the plate from group 2 in aqueous CaCl2/HCl and Na2HPO4 solutions (group 3), and a microporous surface with a 4-microm HA coating prepared by the biomimetic method, where the plates from group 3 were soaked in simulated body fluid (group 4). Plates were implanted into rabbit tibia, and after 4, 8, and 16 weeks, tensile testing and histological examination of the bone-implant interface were conducted. At 4 weeks, group 4 had superior bone-bonding ability compared with other implants, which was maintained at the later postimplantation times. This HA-coated CZA with a microporous surface has the possibility of clinical use as a bearing material in cementless joint prostheses or as a load-bearing bone substitute.

[Evaluation of imaging before lung volume reduction surgery for pulmonary emphysema; fused image of multi-detector row computed tomography and scintigram].

Lung volume reduction surgery (LVRS) is performed as surgical therapy for severe pulmonary emphysema. In assessing diagnostic imaging indications, emphysematous change is the strongest in the thoracic computed tomography (CT), while the accumulation decrease is most remarkable in ventilation scintigram and lung perfusion scintigram. Preoperative evaluation of imaging using multidetector-row CT (MDCT) and scintigram were performed, and the multiplanar reconstruction (MPR) image of the MD CT and the single photon emission CT (SPECT) image of the scintigram were fused by the workstation. It was possible to evaluate the excision and the range of LVRS easily by looking at the fused image, and it was useful in deciding on the surgical approach. It is believed that accurate, comprehensible imaging information contributed to an improvement in the surgical outcome of LVRS.

[Imaging aid for thoracoscopic thymectomy; thymic vein visualization].

The spread and progress of thoracoscopic surgery has been remarkable. There are many important organs and blood vessels in the mediastinal space, thus, as inadvertent injury invites serious consequences, it is necessary to understand the anatomical position of existing structures. When enucleating the thymoma under a thoracoscope, one of the blood vessels to be careful about is the thymic vein. Therefore, we examined whether the thymic vein could be confirmed using a multidetector-row computed tomography (MD CT). We believed we could understand the anatomical position of the thymic vein by analyzing the high resolution slice data provided in MD CT using a work station. The diameter of the thymic is from a little less than 1 mm to 3 mm, and there were individual variations in position and the number of the vein. The thymic vein flowed into the left brachiocephalic vein in many cases. In some cases, the thymic vein flowed into the right internal thoracic vein or superior vena cava. It appears that visualization of the thymic vein could provide useful data when performing thoracoscopic thymectomy.

[Selection of the bronchial tube for one-lung anesthesia by multidetector-row computed tomography (MD CT) evaluation].

One-lung anesthesia is a method of anesthesia performed by inserting the tip of a bronchial tube into either the right main bronchus or the left main bronchus. The right bronchial tube is a special structure. Since the distance of the carina to the right upper lobe bronchus is short, a side hole is made to prevent blockading of the right upper lobe bronchus, and the cuff is attached aslant to it. When inserting a bronchial tube into the right main bronchus, care is required to prevent the occurrence of atelectasis though a gap in the bronchial tube. We evaluated the structure of a trachea and a bronchus using the multidetector-row computed tomography (MD CT), and tried to select the right bronchial tube most suitable for each structure. There are individual differences in the structure of a trachea and a bronchus. By creating a 3-dimensional image of a trachea and a bronchus, the structure could be easily grasped, and therefore selection of the most appropriate bronchial tube according to the structure was possible.

Bioactive bone cements containing nano-sized titania particles for use as bone substitutes.

Three types of bioactive polymethylmethacrylate (PMMA)-based bone cement containing nano-sized titania (TiO2) particles were prepared, and their mechanical properties and osteoconductivity are evaluated. The three types of bioactive bone cement were T50c, ST50c, and ST60c, which contained 50 wt% TiO2, and 50 and 60 wt% silanized TiO2, respectively. Commercially available PMMA cement (PMMAc) was used as a control. The cements were inserted into rat tibiae and allowed to solidify in situ. After 6 and 12 weeks, tibiae were removed for evaluation of osteoconductivity using scanning electron microscopy (SEM), contact microradiography (CMR), and Giemsa surface staining. SEM revealed that ST60c and ST50c were directly apposed to bone while T50c and PMMAc were not. The osteoconduction of ST60c was significantly better than that of the other cements at each time interval, and the osteoconduction of T50c was no better than that of PMMAc. The compressive strength of ST60c was equivalent to that of PMMAc. These results show that ST60c is a promising material for use as a bone substitute.

Predicting the development of gastric cancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective endoscopic cohort study.

BACKGROUND AND AIMS: Helicobacter pylori infection and gastric atrophy are both risk factors for gastric cancer. We aimed to elucidate the natural history of gastric cancer development according to H pylori infection and gastric atrophy status. SUBJECTS AND METHODS: A total of 9293 participants in a mass health appraisal programme were candidates for inclusion in the present prospective cohort study: 6983 subjects revisited the follow up programme. Subjects were classified into four groups according to serological status at initial endoscopy. Group A (n = 3324) had "normal" pepsinogen and were negative for H pylori antibody; group B (n = 2134) had "normal" pepsinogen and were positive for H pylori antibody; group C (n = 1082) had "atrophic" pepsinogen and were positive for H pylori antibody; and group D (n = 443) had "atrophic" pepsinogen and were negative for H pylori antibody. Incidence of gastric cancer was determined by annual endoscopic examination. RESULTS: Mean duration of follow up was 4.7 years and the average number of endoscopic examinations was 5.1. The annual incidence of gastric cancer was 0.04% (95% confidence interval (CI) 0.02-0.09), 0.06% (0.03-0.13), 0.35% (0.23-0.57), and 0.60% (0.34-1.05) in groups A, B, C, and D, respectively. Hazard ratios compared with group A were 1.1 (95% CI 0.4-3.4), 6.0 (2.4-14.5), and 8.2 (3.2-21.5) in groups B, C, and D, respectively. Age, sex, and "group" significantly served as independent valuables by multivariate analysis. CONCLUSIONS: The combination of serum pepsinogen and anti-H pylori antibody provides a good predictive marker for the development of gastric cancer.

Localization of ubiquitin carboxyl-terminal hydrolase-L1 in cynomolgus monkey placentas.

Ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) is a restrictedly expressed enzyme in neural and reproductive tissues, and it is considered to have a significant role in reproduction. In the present study, we investigated the localization of UCH-L1 in placenta of cynomolgus monkeys (Macaca fascicularis). UCH-L1 protein was detected in cytotrophoblasts of chorionic plate and villi, and decidual cells of decidua basalis in cynomolgus monkey placenta, and the amount of UCH-L1 protein in whole placenta increased as pregnancy progressed. These results supported that UCH-L1 is necessary for placental and fetal development in primate placenta. This is the first report to demonstrate the presence of UCH-L1 in primate placenta, and the cynomolgus monkey may be a useful model for the study of the functions of the ubiquitin-proteasome system in human pregnancy.

Metallic materials stimulating bone formation.

Metallic materials implanted into bone defects are generally encapsulated by a fibrous tissue. Some metallic materials such as titanium and tantalum, however, have been revealed to bond to the living bone without forming the fibrous tissue, when they were subjected to NaOH solution and heat treatments. Thus treated metals form bone tissue around them even in muscle, when they take a porous form. This kind of osteoconductive and osteoinductive properties are attributed to sodium titanate or tantalate layer on their surfaces formed by the NaOH and heat treatments. These layers induce the deposition of bonelike apatite on the surface of the metals in the living body. This kind of bioactive metals are useful as bone substitutes even highly loaded portions, such as hip joint, spine and tooth root.

Apatite-forming ability of alginate fibers treated with calcium hydroxide solution.

Calcium alginate fibers were prepared by extruding an aqueous sodium alginate solution into an aqueous calcium chloride solution. The fibers were treated with a saturated aqueous calcium hydroxide solution for various periods and their apatite-forming ability was examined in a simulated body fluid (SBF). The calcium alginate fibers were treated with the aqueous calcium hydroxide solution for periods longer than five days formed apatite on their surfaces in SBF, and their apatite-forming ability improved with increasing calcium hydroxide treatment time. The amount of calcium ions released from the fibers also increased with increasing calcium hydroxide treatment time, resulting in acceleration of nucleation and growth of apatite on the fiber surfaces. The resultant apatite-alginate fiber composite is expected to be useful as a flexible bioactive bone-repairing material.