Investigation of treatment volume versus circulating blood volume during Rheocarna treatment.

INTRODUCTION: Rheocarna's therapeutic effect is associated with fibrinogen (Fib) and low-density lipoprotein cholesterol (LDL-C) adsorptive removal. This study aimed to retrospectively investigate the association between treatment volume (TV) and circulating blood volume (CBV) and the Fib removal rate (Fib-RR) and LDL-C-RR. METHODS: CBV and TV/CBV, cut-off value (CO value), and area under the receiver operating characteristic (ROC) curve (AUC) were calculated. The Fib-RR and LDL-C-RR at the midterm and end of treatment were compared. The groups were further categorized into three groups with TV/CBV lower than or higher than the CO value at the midterm and end (midterm/end; Group L: lower than/lower than CO; Group L/H: lower than/higher than CO; Group H: higher than/higher than CO), and the Fib-RR and LDL-RR of each group at the midterm and end were compared. RESULTS: ROC analysis revealed a TV of 1.480 times the BV as CO value, which showed a maximum Youden index predicting a Fib-RR of 20% (AUC: 0.828). Among the three groups, Group L and Group L/H demonstrated significantly higher Fib-RR and LDL-C-RR at the end of the study than in the midterm, while Group H exhibited no difference. CONCLUSION: The results reveal that a treatment volume of 1.5 times the circulating blood volume is a sufficient solute removal capacity in the Rheocarna-enabled cases.

Evaluation of the treatment volume and removal rate of Rheocarna: A novel adsorption-type blood purification device for patients with chronic limb-threatening ischemia.

INTRODUCTION: Chronic limb-threatening ischemia (CLTI) is a clinical syndrome defined by peripheral arterial disease (PAD) combined with rest pain, gangrene, or leg ulceration for longer than two weeks resulting in lower extremity amputation. In recent years, low-density lipoprotein apheresis (LDL-A) has been implemented for PAD treatment. However, it has not been possible to ensure insurance coverage for patients with lower LDL levels than 140 mg/dL under cholesterol-lowering drugs. Rheocarna is a novel adsorption-type blood purification device for the treatment of CLTI by adsorbing LDL and fibrinogen (Fib) that is not constrained by hypercholesterolemia and is not amenable to or nonresponsive to revascularization surgery. The only requirements for use are that the blood flow rate increases up to 200 mL/min gradually. METHODS: To evaluate the applicability of this treatment procedure, we compared the removal rates of Fib and LDL following Rheocarna therapy using various blood treatment volumes (6, 10.5, and 19.5 L). RESULTS: Fib and LDL removal rates were about 20% and 15%-25% per treatment, with no significant differences between treatment volumes. Following treatment with Rheocarna, blood pressure tends to decrease at first, which later increases, and the higher the treatment volume, the longer the time of low blood pressure tended to be. CONCLUSION: Although no significant difference was found in the removal rate of Fib and LDL in response to increase volume to 6 L or beyond in this study, the 6 L volume is considered effective enough for the removal of Fib and LDL.

Low-Density Lipoprotein Adsorption by Centrifugal Plasma Separation Can Shorten Treatment Time.

Low-density lipoprotein (LDL) apheresis is effective for nephrotic syndrome in drug-resistant focal segmental glomerulosclerosis (FSGS). Dextran sulfate adsorption of LDL (DSAL) is widely used for this purpose. The Liposorber LA-15 system performs DSAL by membrane plasma separation (mDSAL) using an MA-03 plasma purification device. However, sufficient blood flow (Qb) frequently cannot be obtained from a peripheral vein with mDSAL. The recommended plasma filtration flow rate (Qf) when using the OP-05W membrane plasma separator is no more than 1/3 of Qb, giving plasma removal efficiency (PRE) of about 30%. In contrast, the centrifugal blood component separator Spectra Optia has PRE of 87-92.5% because centrifugal separation enables effective separation of plasma components even at low Qb. Here, we present the case of a man in his 40s with FSGS, for whom we began treatment with mDSAL with the intention of completing a 12-session cycle, but extended treatment times were required due to low Qb. Therefore, we switched to DSAL by centrifugation (cDSAL) using the Liposorber LA-40 system from the 6th session onward. Treatment time decreased from 190 min for the fifth session using mDSAL to 140 min for the sixth session using cDSAL. Mean treatment time also decreased from 155 ± 9 min for mDSAL (5 sessions) to 119 ± 20 min for cDSAL (7 sessions). Moreover, the LDL removal rate at a processed plasma volume was similar for both modalities. In conclusion, cDSAL can enable efficient plasma separation even with low Qb, with a comparable LDL removal rate and shorter treatment time relative to mDSAL.

Adjustment by hematocrit level in calculation of removal rate in therapeutic apheresis.

Plasma volume (PV) variation during therapeutic apheresis (TA) (such as plasma exchange [PE] and selective PE using albumin solution as replacement solution or immunoadsorption plasmapheresis) has been considered to be unignorable. It changes the concentration of the target molecule and might impact its removal rate (RR.) This study aimed to evaluate the effects of PV variation on the calculation of the RR of fibrinogen and immunoglobulin by categorizing the hematocrit (Ht) change during TA into two patterns, that is, increased group and decreased group. In all modalities of TA, the Ht level frequently changed during apheresis sessions. In calculating RR, RR calculated with Ht adjustment was significantly higher than that calculated without adjustment in the increased group and significantly lower than it in the decreased group. Therefore, RR might have been underestimated in the increased group and overestimated in the decreased group when RR was calculated without Ht adjustment. Ht adjustment is suggested to be crucial in calculating RR in TA.

Removal Characteristics of Immunoadsorption with the Tryptophan-Immobilized Column Using Conventional and Selective Plasma Separators in the Treatment of Myasthenia Gravis.

Autoimmune neurological diseases are often treated by immunoadsorption using a conventional plasma separator and tryptophan-immobilized column (IA). However, there is only one case report on treatment with immunoadsorption using a selective plasma separator and tryptophan-immobilized column (SeIA) in clinical practice. This study aimed to investigate the removal characteristics of antibodies against acetylcholine receptors (AChRAb), immunoglobulin G, fibrinogen, and factor XIII (FXIII) in IA and SeIA in four patients with myasthenia gravis. A total of 19 sessions of immunoadsorption were performed (five sessions of IA and 14 sessions of SeIA) when the processed plasma volume was 2 L. The corresponding reductions were 52.5% ± 6.2% for AChRAb, 58.8% ± 4.2% for fibrinogen, and 36.9% ± 5.5% for FXIII after one session of IA. The corresponding reductions were 45.2% ± 9.9% for AChRAb, 3.5% ± 6.9% for fibrinogen, and -4.6% ± 11.1% for FXIII after one session of SeIA. The removal rates for AChRAb, fibrinogen, and FXIII in IA were significantly higher than those in SeIA. IA could effectively remove AChRAb, and SeIA could retain fibrinogen and FXIII. IA can be combined with SeIA, resulting in both IgG autoantibodies removal by IA and retention of coagulation factors by SeIA.

Removal Dynamics of Autoantibodies, Immunoglobulins, and Coagulation Factors by Selective Plasma Exchange on Three Consecutive Days.

Selective plasma exchange has been shown to be effective in various diseases, but no studies have assessed the benefits of daily treatment. We aimed to investigate the removal dynamics of immunoglobulins, fibrinogen, and factor XIII on three consecutive days in three patients. For mean processed plasma volumes of 1.06 × plasma volume, reductions of 79.6%, 49.3%, and 8.6% were seen for immunoglobulins G, A, and M, respectively. The reductions for fibrinogen and factor XIII were 18.4% and 13.0%, respectively. Removal dynamics were similar for immunoglobulin G-related autoantibodies and immunoglobulin G when using daily selective plasma exchange. Moreover, daily use effectively removed the immunoglobulin G while retaining the coagulation factors. When disease-specific autoantibodies are limited to immunoglobulin G, daily selective plasma exchange may be a useful and safe method of intensive induction treatment for plasmapheresis. However, further study is required in larger cohorts to confirm these findings.

Selective plasma exchange.

Selective plasma exchange (SePE) is a new modality of simple plasma exchange that uses a selective membrane plasma separator Evacure EC-4A10 (EC-4A) (Kawasumi Laboratories Inc., Tokyo, Japan). EC-4A has a relatively small pore size of 0.03µm, which is around one-tenth that of conventional plasma separators. The sieving coefficients of albumin, immunoglobulin G (IgG), factor XIII (FXIII), and fibrinogen using EC-4A have been shown to be 0.73, 0.5, 0.17, and 0, respectively. Therefore, one session of SePE can remove approximately 50% of IgG regardless of the IgG subclasses while retaining coagulation factors, such as FXIII and fibrinogen. SePE may lower the risk of bleeding when compared with other plasmapheresis modalities. SePE cannot remove large molecular substances, including IgM. When only IgG is targeted by plasmapheresis, SePE is a useful and safe option. When various immunoglobulins are targeted by plasmapheresis, PE can be combined with SePE, which results in both the unspecific removal of pathogens by PE and the retention of coagulation factors by SePE. Careful selection of the modality is important, and when necessary, appropriate plasmapheresis modalities should be combined on the basis of the characteristics and removal kinetics of the pathogenic substances.

Selective Plasma Exchange for the Removal of Pemphigus Autoantibodies, Fibrinogen, and Factor XIII in Pemphigus Vulgaris.

Pemphigus vulgaris is a serious autoimmune skin disorder associated with desmoglein 1 and 3. Selective plasma exchange (SePE) for pemphigus vulgaris remains unknown. We investigated the removal characteristics of pemphigus autoantibodies, immunoglobulins, and fibrinogen in three cases. When the mean processed volume for SePE was 1.2 plasma volumes, the mean percent reduction was 50.7% for desmoglein 1, 48.9% for desmoglein 3, 50.3% for IgG, 29.8% for IgA, 1.9% for IgM, and 17.6% for fibrinogen. In one case, the percent reduction after four sessions of SePE within eight days was 87.0% for desmoglein 1, 85.1% for desmoglein 3, 76.6% for IgG, 53.5% for IgA, 7.9% for IgM, 41.6% for fibrinogen, and 31.4% for factor XIII. SePE can effectively remove pemphigus autoantibodies and retain coagulation factors, e.g. factor XIII and fibrinogen. In severe cases, SePE can be useful and safe for induction therapy.

Fibrinogen Reduction During Selective Plasma Exchange due to Membrane Fouling.

Fibrinogen is substantially reduced by most plasmapheresis modalities but retained in selective plasma exchange using Evacure EC-4A10 (EC-4A). Although EC-4A's fibrinogen sieving coefficient is 0, a session of selective plasma exchange reduced fibrinogen by approximately 19%. Here, we investigated sieving coefficient in five patients. When the mean processed plasma volume was 1.15 × plasma volume, the mean reduction of fibrinogen during selective plasma exchange was approximately 15%. Fibrinogen sieving coefficient was 0 when the processed plasma volume was 1.0 L, increasing to 0.07 when the processed plasma volume was 3.0 L, with a mean of 0.03 during selective plasma exchange. When fibrinogen sieving coefficient was 0, selective plasma exchange reduced fibrinogen by approximately 10%. Scanning electron microscopy images revealed internal fouling of EC-4A's hollow fiber membrane by substances such as fibrinogen fibrils. Thus, fibrinogen reduction by selective plasma exchange may be predominantly caused by membrane fouling rather than filtration.

Influence of proton pump inhibitors and histamine H2 receptor antagonists on serum phosphorus level control by calcium carbonate in patients undergoing hemodialysis: a retrospective medical chart review.

BACKGROUND: Hyperphosphatemia is one of the common complications in patients undergoing hemodialysis. Although calcium carbonate (CaC) is often used to control serum inorganic phosphorus level in dialysis patients, co-administration of gastric acid reducers (ARs) may interfere with the phosphate binding effect of CaC. We performed a retrospective medical chart review to study whether ARs attenuate the hypophosphatemic effect of CaC in patients undergoing hemodialysis. METHODS: One hundred and eight chronic hemodialysis patients receiving either CaC alone or CaC concomitant with one of the ARs (proton pump inhibitors and histamine H2-receptor antagonists) were retrieved from the medical charts in Juntendo University Nerima Hospital. The patients were subdivided according to the interval between hemodialysis sessions (interdialysis interval of 48 or 72 h). A multivariate analysis was performed to identify clinical covariates associated with the variability of serum inorganic phosphorus levels. The study protocol was approved by the Institutional Review Board before the study was begun. RESULTS: Among patients on hemodialysis with a 72-h interdialysis interval, the magnitude of increase in serum inorganic phosphorus concentration in patients receiving CaC and AR was significantly greater than in those receiving CaC alone. While a similar trend was observed among patients with a 48-h interdialysis interval, the difference did not reach a significant level. A multivariate regression analysis revealed that concomitant administration of ARs with CaC and a longer interdialysis interval (72 h) were significantly and independently associated with the magnitude of increase in serum phosphorus concentration between dialysis sessions. No significant differences in albumin-corrected serum calcium concentrations and incidence of pathological fractures were observed between patients receiving CaC alone and those receiving CaC with ARs. CONCLUSIONS: Concomitant use of ARs with CaC may attenuate the hypophosphatemic effect of CaC in patients undergoing chronic hemodialysis. When hemodialysis patients require prescription of ARs for the prevention of upper gastrointestinal mucosal diseases (such as peptic ulcer), it may be prudent to choose a phosphate binder other than CaC.

Removal Dynamics of Immunoglobulin and Fibrinogen by Conventional Plasma Exchange, Selective Plasma Exchange, and a Combination of the Two.

While plasma exchange (PE) can eliminate plasma proteins, including all immunoglobulin (Ig) and coagulation factors, selective plasma exchange (SePE) can retain fibrinogen (Fbg). Here, we investigated the removal dynamics of Ig and Fbg in 53 patients with immunological disorders by PE, SePE, and a combination of the two. When the mean processed plasma volume (PPV) was 0.9 plasma volume (PV), the mean percent reductions of Ig and Fbg by PE were both approximately 62%-65%. When the mean PPV was 1.1 PV, the mean percent reductions by SePE were 53.1% for IgG, 30.1% for IgA, 3.6% for IgM, and 19.0% for Fbg, respectively. In the three plasmapheresis sessions performed on alternate days, we classified treatments into three categories: PE group (PE-PE-PE, N = 2), SePE group (SePE-SePE-SePE, N = 14), and PE/SePE group (PE-SePE-SePE, N = 4). The mean percent reductions of IgG, IgA, IgM, and Fbg were 82.0%, 80.4%, 87.3%, and 80.9%, respectively, for the PE group; 76.4%, 57.7%, 43.3%, and 35.9%, respectively, for the PE/SePE group; and 75.4%, 50.6%, 3.2%, and 29.3%, respectively, for the SePE group. Plasmapheresis modalities can be combined according to clinical conditions, for instance, to achieve both the unspecific removal of pathogens by PE and retention of coagulation factors, such as Fbg, by SePE.

Removal Characteristics of Immunoadsorption With the Immusorba TR-350 Column Using Conventional and Selective Plasma Separators.

In Japan, immunoadsorption (IA) is performed using a conventional plasma separator and Immusorba TR-350 column (TR-350) for the treatment of neurological immune diseases. By this method, TR-350 has the limited maximal capacity of the immunoglobulin G (IgG) adsorption, and fibrinogen (Fbg) is reduced remarkably. Evacure EC-4A10 (EC-4A) is a selective plasma separator and the sieving coefficients of IgG and Fbg using EC-4A were 0.5 and 0, respectively. Here, we investigated the removal characteristics of IgG and Fbg in IA by TR-350 using two different plasma membrane separators: conventional plasma separator (PE-IA) and EC-4A (EC-IA). In vitro filtration using plasma effluent was performed with a closed circuit. When the processed volume was 3 L, estimated removal amounts by PE-IA were 3172 mg for IgG and 3329 mg for Fbg, respectively. When the processed volume was 3 L, estimated removal amounts by EC-IA were 4946 mg and 1916 mg, respectively. EC-IA can be considered useful for the removal of IgG, including auto-antibodies, while retaining Fbg, thereby allowing even daily use.

SLAP repair with arthroscopic decompression of spinoglenoid cyst.

INTRODUCTION: A spinoglenoid cyst with suprascapular nerve disorders is highly associated with superior labrum anterior posterior (SLAP) lesion. Conservative or surgical treatment is applied to relieve pain and neurological symptoms. The purpose of this study was to evaluate clinical outcomes of patients treated by arthroscopic surgery for SLAP lesion with a spinoglenoid cyst. METHODS: The subjects of this study were six patients with SLAP lesion with a spinoglenoid cyst who underwent arthroscopic surgery. There was one female and five males with a mean age of 48.5 years. SLAP lesion was found in all the patients at arthroscopy. A small tear of the rotator cuff was found in the two patients. The SLAP lesion was repaired using suture anchors, and the rotator cuff tears were repaired by suture-bridge fixation. The spinoglenoid cyst was decompressed through the torn labrum in three patients, and through the released superior to posterior portion of the capsule in the other three patients. RESULTS: All patients showed excellent improvement in pain and muscle strength at the final follow-up examination. The mean Constant score was improved from 60.5 points preoperatively to 97.2 points postoperatively. The mean visual analog scale (VAS) score decreased from 4.5 on the day of the surgery to 2.5 within one week postoperatively. Postoperative MRI showed disappearance or reduction of the spinoglenoid cyst in four and two patients, respectively. There were no complications from the surgical intervention and in the postoperative period. DISCUSSION: The patients treated by decompression through the released capsule obtained pain relief at an early period after the surgery. Arthroscopic treatment for a spinoglenoid cyst can provide a satisfactory clinical outcome. Arthroscopic decompression of a spinoglenoid cyst through the released capsule is recommended for a safe and reliable procedure for patients with suprascapular nerve disorders.

Removal Characteristics of Immunoglobulin G Subclasses by Conventional Plasma Exchange and Selective Plasma Exchange.

Selective plasma exchange (SePE) using a selective membrane separator is a modified method of simple plasma exchange (PE). Immunoglobulin G (IgG) subclass distribution is one of the important immunological characteristics of IgG. However, there is little information regarding the removal characteristics of IgG subclasses by SePE and conventional PE. Here, we investigated the removal ratio of IgG subclasses by PE and SePE in seven patients with immunological disorders. When the mean processed volume was 0.88 plasma volume (PV) (corresponding to 2.12 L), the mean percent reductions by PE were as follows: IgG, 63.2%; IgG1, 64.5%; IgG2, 64.0%; IgG3, 61.4%; and IgG4, 69.5%. When the mean processed volume was 1.18 PV (corresponding to 2.98 L), the mean percent reductions by SePE were as follows: IgG, 51.6%; IgG1, 55.3%; IgG2, 52.0%; IgG3, 53.7%; and IgG4, 64.6%. In both PE and SePE, using albumin solution as the supplementary fluid, IgG was effectively eliminated regardless of IgG subclasses.

Stress fracture of the radial styloid process in a judo player: a case report.

Stress fractures of the upper limbs are uncommon, and are most often reported as individual cases or small series. In particularly, stress fractures around the wrist are even less common. A stress fracture of the radial styloid process in a judo player was surgically treated, and a favorable treatment outcome was obtained. A 16-year-old adolescent boy experienced pain in the right wrist, with no apparent trigger, while playing judo. Stress fracture of the radial styloid process was diagnosed with plain radiographs and was treated conservatively with cast immobilization. Although bone union was achieved, the fracture recurred after he resumed paying judo. Thus, surgical treatment was performed. The procedure was resection of the distal bone fragment. He resumed practicing 2 months postoperatively and returned to judo matches after 1 more month. As of 1 year after distal bone fragment resection, he was able to participate in judo without pain, limited range of motion, or instability of the wrist.

The outcome of hemiarthroplasty for proximal humeral fractures is dependent on the status of the rotator cuff.

PURPOSE: The purpose of this study was to evaluate clinical and radiological outcomes of hemiarthroplasty for proximal humerus fractures. METHODS: Thirty-five patients (33 women and two men), average age at the time of surgery of 75.1 (range, 64-92) years, who underwent hemiarthroplasty for proximal humerus fracture or fracture-dislocation of the shoulder were enrolled in this study. The Constant score was used for clinical evaluation of outcomes, and X-rays were performed after a minimum follow-up period of 12 months postoperatively. Parameters for radiological evaluation were as follows: value of acromiohumeral interval (AHI), humeral offset, medial and lateral projection, and the existence of subacromial spur, a radiolucent zone around humeral stem and an osteolytic change of the greater tuberosity. RESULTS: The average follow-up after surgery was 45.8 (range, 13-114) months. The average postoperative Constant score was 76.2 (range, 53-96) points. The mean values of AHI and humeral offset were 8.4 and 28.3 mm, respectively. A subacromial spur was observed in ten patients, and an osteolytic change of the greater tuberosity in seven patients. There was a significant correlation between Constant score and values of AHI or humeral offset. The Constant score in patients with a subacromial spur or radiolucent zone around humeral stem was markedly lower than that in patients without them. CONCLUSIONS: The clinical outcome of hemiarthroplasty was influenced by factors reflecting function and conditions of the rotator cuff. Anatomical reconstruction and bone union of the tuberosities need to ensure clinical success in hemiarthroplasty.

Removal kinetics of antibodies against glutamic acid decarboxylase by various plasmapheresis modalities in the treatment of neurological disorders.

Plasmapheresis is one of the acute treatment modalities for neurological disorders associated with antibodies against glutamic acid decarboxylase (anti-GAD). However, there is little information about the removal kinetics of anti-GAD by various plasmapheresis modalities. Here, we investigated the removal rate of anti-GAD and fibrinogen (Fib) by immunoadsorption (IA), plasma exchange using a conventional plasma separator (OP-PE), and plasma exchange using a high cut-off selective membrane plasma separator (EC-PE) in two cases of anti-GAD-associated neurological diseases. In case 1, IA and OP-PE were used, and the percent reductions were as follows: anti-GAD: 38.2% and 69.1% and Fib: 67.7% and 68.2%, respectively. In case 2, OP-PE and EC-PE were used, and the percent reductions were as follows: anti-GAD: 65.8% and 48.5% and Fib: 68.5% and 19.8%, respectively. OP-PE could remove anti-GAD more efficiently than IA. Further, EC-PE could maintain coagulation factors such as Fib better than IA and OP-PE. It is important to select the appropriate plasmapheresis modality on the basis of the removal kinetics.

Solute removal capacity of high cut-off membrane plasma separators.

In vitro blood filtration was performed by a closed circuit using high cut-off membrane plasma separators, EVACURE EC-2A10 (EC-2A) and EVACURE EC-4A10 (EC-4A). Samples were obtained from sampling sites before the plasma separator, after each plasma separator, and from the ultrafiltrate of each separator. The sieving coefficient (S.C.) of total protein (TP), albumin (Alb), IgG, interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), fibrinogen (Fib), antithrombin III (AT-III), and coagulation factor XIII (FXIII) were calculated. The S.C. of each solute using EC-2A and EC-A4 were as follows; TP: 0.25 and 0.56, Alb: 0.32 and 0.73, IgG: 0.16 and 0.50, IL-6:0.73 and 0.95, IL-8:0.85 and 0.82, TNF-α: 1.07 and 0.99, Fib: 0 and 0, FXIII: 0.07 and 0.17, respectively. When compared with the conventional type of membrane plasma separators, EVACURE could efficiently remove cytokines while retaining coagulation factors such as fibrinogen. Moreover, EC-2A prevented protein loss, whereas EC-4A could remove approximately 50% of IgG.

Effects of kojic acid on thyroidal functions in rats by single-dose administration and in cultured rat thyroid cells (FRTL-5 cells).

The effects of kojic acid (KA) on thyroidal function were studied by single-dose administration in rats and in cultured rat thyroid cells (FRTL-5 cells). In rats receiving a single dose of 1,000 mg/kg KA orally, the 125I uptake from blood into the thyroid gland was significantly lower than that of the control group from 30 min to 24 hr after administration. The 125I organification activity of the KA groups was significantly lower than control from 30 min to 6 hr after administration. However, the 125I organification activity at 24 hr or 48 hr after administration recovered enough to be nearly comparable with the control group. In the study in FRTL-5 cells, KA inhibited iodine organification dose-dependently, but did not inhibit iodine uptake. These results suggest that the observed lower iodine uptake activity in the single-dose administration study in rats was due to the inhibition of iodine organification caused by the oral administration of KA, consequently decreasing iodine in the entire thyroid gland. Although serum T4 showed a tendency to decrease from 2 hr to 48 hr after administration of KA, serum TSH did not show any evident change associated with KA in the single-dose administration study in rats. Based on these results, it is presumed that a massive dose or long administration period might be needed to decrease serum T4 and increase serum TSH. From these results, it is presumed that KA affected thyroidal function when given at a massive dose or in a long administration period by inhibiting iodine organification in the thyroid.