Safety Prediction of Infants Born to Mothers with Crohn's Disease Treated with Biological Agents in the Late Gestation Period.

OBJECTIVES: Knowledge gaps exist in the use of biologics for pregnant patients with Crohn's disease (CD), especially the usage of ustekinumab (UST) and infliximab (IFX) infusion during the late gestation period. In this case series, we investigated perinatal and neonatal outcomes and pharmacokinetics of these biologics in pregnant CD patients. METHODS: Pregnant CD patients under treatment with IFX or UST during January 2017 to December 2019 were monitored. Growth and development of their babies were followed up to six months. Drug concentrations were measured in maternal peripheral and cord blood at delivery and infants' blood at six months of age. RESULTS: Four cases were kept IFX treatment until late gestation (median last dose: 31.2 weeks). One case received UST until 23 weeks of gestation. All cases were in clinical remission but moderately undernourished. Babies were delivered by cesarean section at full term without any complications or congenital abnormalities. No growth or developmental defects and no susceptibility to infections were observed by six months. However, two babies whose mothers received IFX after 30 weeks of gestation were detected IFX in their blood at six months of age (0.94 and 0.24 pg/ml). Concentrations of UST in maternal and cord blood were 267.7 and 756.5 ng/ml, respectively. UST was not detected in the infant at six months of age. CONCLUSIONS: Administration of UST or IFX to pregnant patients with CD is safe, particularly IFX to be given in the late gestation period. Understanding of the pharmacokinetics of biologics in maternal-infant interactions may improve the management of pregnant CD patients.

Association of orthostatic blood pressure with the symptoms of orthostatic hypotension and cognitive impairment in patients with multiple system atrophy.

The degree and frequency of orthostatic hypotension (OH) are high in patients with multiple system atrophy (MSA); however, the association of orthostatic blood pressure (BP) with the symptoms of OH and cognitive impairment in these patients remains unclear. The aim of this study was to clarify whether absolute BP and/or changes in BP during standing are related to OH symptoms and cognitive impairment in patients with MSA. Thirty-two patients with MSA were examined using the head-up tilt and cognitive function tests. OH symptoms were evaluated using a patient-reported scale. The results were compared with those for 15 age- and sex-matched healthy controls. Seventeen of the 32 (53.1%) patients had OH, with eight of them exhibiting OH symptoms, which were related to the absolute BP value at 60° tilt. However, OH symptoms were not related to the degree of decrease in BP during the tilt test, and they were frequently observed in patients with a mean BP of <80 mmHg at 60° tilt (sensitivity, 67%; specificity, 91%). Cognitive dysfunction assessed by the Mini-Mental State Examination (MMSE; ≤ 26) was also associated with a low mean BP at 60° tilt (odds ratio, 1.32; 95% confidence interval, 1.04-1.67; p = 0.02). The upright BP value is associated with OH symptoms and the MMSE score in patients with MSA. Thus, careful observation of OH symptoms can enable early management of BP and the detection of cognitive impairment in these patients.

Relationship between cardiac parasympathetic dysfunction and the anteroposterior diameter of the medulla oblongata in multiple system atrophy.

PURPOSE: Neurodegeneration of the nucleus ambiguus and the dorsal vagal motor nucleus has been implicated in cardiac parasympathetic dysfunction in multiple system atrophy (MSA). The nucleus ambiguus and the dorsal vagal motor nucleus, which are located in the medulla oblongata (MO), control the autonomic-specifically, the parasympathetic-functions of the body. The aim of our study was to investigate the relationship between cardiac parasympathetic dysfunction and the anteroposterior diameter of the MO in MSA by quantitatively analyzing magnetic resonance imaging (MRI) outcome measures. METHODS: We retrospectively assessed 40 consecutive patients with probable MSA and 25 age- and sex-matched controls. The anteroposterior diameter of the MO at two locations (MO diameter-A and -B) and the diameters of the midbrain and pons were measured by conventional MRI. A cardiac parasympathetic function score (CP-score) and cardiac sympathetic function score (CS-score) were generated by calculating the z-scores of multiple autonomic function tests. The relationship between the scores and the measured diameters of the brainstem was also investigated. RESULTS: The CP-score and CS-score were significantly lower in the patients with MSA than in the controls (CP-score: 0.61 ± 0.75 vs. - 0.38 ± 0.52, p < 0.001; CS-score: 0.91 ± 1.06 vs. - 0.57 ± 1.07, p < 0.001). Also, in the patients with MSA, the CP-score was significantly correlated with MO diameter-A (r = 0.40, p = 0.010), and the CS-score was significantly correlated with the diameter of the midbrain (r = 0.33, p = 0.038). CONCLUSION: The anteroposterior diameter of the MO is a potential imaging marker of parasympathetic dysfunction in MSA.

Mutant selection in the self-incompatible plant radish (Raphanus sativus L. var. sativus) using two-step TILLING.

Radish (Raphanus sativus L. var. sativus), a widely cultivated root vegetable crop, possesses a large sink organ (the root), implying that photosynthetic activity in radish can be enhanced by altering both the source and sink capacity of the plant. However, since radish is a self-incompatible plant, improved mutation-breeding strategies are needed for this crop. TILLING (Targeting Induced Local Lesions IN Genomes) is a powerful method used for reverse genetics. In this study, we developed a new TILLING strategy involving a two-step mutant selection process for mutagenized radish plants: the first selection is performed to identify a BC1M1 line, that is, progenies of M1 plants crossed with wild-type, and the second step is performed to identify BC1M1 individuals with mutations. We focused on Rubisco as a target, since Rubisco is the most abundant plant protein and a key photosynthetic enzyme. We found that the radish genome contains six RBCS genes and one pseudogene encoding small Rubisco subunits. We screened 955 EMS-induced BC1M1 lines using our newly developed TILLING strategy and obtained six mutant lines for the six RsRBCS genes, encoding proteins with four different types of amino acid substitutions. Finally, we selected a homozygous mutant and subjected it to physiological measurements.

Cardiac parasympathetic dysfunction in the early phase of Parkinson's disease.

Cardiac parasympathetic function is strongly affected by aging. Although sympathetic dysfunction has been well documented in Parkinson's disease (PD), cardiac parasympathetic dysfunction has not been well studied. The objective of this study was to clarify the development of cardiac parasympathetic dysfunction in the early phase of PD and to explore the age-corrected correlation between cardiac parasympathetic dysfunction and cardiac sympathetic dysfunction. We reviewed 25 healthy controls and 56 patients with idiopathic PD of Hoehn and Yahr stages I-III. We evaluated cardiac parasympathetic function using the Valsalva ratio, the baroreflex sensitivity (BRS) and the coefficient of variation of RR intervals in the resting state (resting-CVRR) and during deep breathing (DB-CVRR). In addition, we measured cardiac 123I-metaiodobenzylguanidine (MIBG) uptake to investigate the relationship between cardiac sympathetic and parasympathetic dysfunction in PD. Compared with healthy controls, patients with PD showed significantly decreased cardiac parasympathetic parameters (resting-CVRR 2.8 ± 1.3 vs. 1.7 ± 0.6%, p < 0.001; DB-CVRR 5.8 ± 2.3 vs. 3.8 ± 1.7%, p < 0.001; Valsalva ratio 1.52 ± 0.26 vs. 1.34 ± 0.17, p < 0.01; BRS 10.6 ± 9.5 vs. 5.0 ± 5.4 ms/mmHg, p < 0.01). In particular, resting-CVRR and DB-CVRR were significantly decreased in the early phase of PD. In age-corrected analyses, none of the parasympathetic indices correlated with the delayed cardiac 123I-MIBG uptake. These observations indicate that cardiac parasympathetic dysfunction occurs in the early phase of PD, but not necessarily in parallel with cardiac sympathetic dysfunction.

Lower body mass index is associated with orthostatic hypotension in Parkinson's disease.

INTRODUCTION: Lower body mass index (BMI) is associated with orthostatic hypotension (OH) in the general population, especially in the elderly; however, no studies have addressed this issue in Parkinson's disease (PD). METHODS: We investigated the results of the head-up tilt test and BMI of patients with PD, and evaluated whether BMI is related to orthostatic systolic blood pressure (SBP) change during the head-up tilt test. PD patients were divided into male and female groups, and further divided into middle-aged (age<65years) and elderly (age≥65years) subgroups in each sex. RESULTS: OH was observed in 13 of 64 male and 12 of 75 female patients with PD. BMI was lower in patients with OH than in those without, in both men and women. In the elderly group, a significant correlation between BMI and orthostatic SBP change was found (men, r=0.47, p=0.006; women, r=0.43, p=0.005), and a BMI below mean-0.5 standard deviation increased OH odds (men: BMI<20.5; odds ratio, 6.79; 95% CI, 1.06-43.36; women: BMI<18.5; odds ratio, 5.11; 95% CI, 1.05-24.96). CONCLUSION: Lower BMI is a predisposing factor of OH in elderly patients with PD.

Plant-plant interactions mediate the plastic and genotypic response of Plantago asiatica to CO2: an experiment with plant populations from naturally high CO2 areas.

BACKGROUND AND AIMS: The rising atmospheric CO2 concentration ([CO2]) is a ubiquitous selective force that may strongly impact species distribution and vegetation functioning. Plant-plant interactions could mediate the trajectory of vegetation responses to elevated [CO2], because some plants may benefit more from [CO2] elevation than others. The relative contribution of plastic (within the plant's lifetime) and genotypic (over several generations) responses to elevated [CO2] on plant performance was investigated and how these patterns are modified by plant-plant interactions was analysed. METHODS: Plantago asiatica seeds originating from natural CO2 springs and from ambient [CO2] sites were grown in mono stands of each one of the two origins as well as mixtures of both origins. In total, 1944 plants were grown in [CO2]-controlled walk-in climate rooms, under a [CO2] of 270, 450 and 750 ppm. A model was used for upscaling from leaf to whole-plant photosynthesis and for quantifying the influence of plastic and genotypic responses. KEY RESULTS: It was shown that changes in canopy photosynthesis, specific leaf area (SLA) and stomatal conductance in response to changes in growth [CO2] were mainly determined by plastic and not by genotypic responses. We further found that plants originating from high [CO2] habitats performed better in terms of whole-plant photosynthesis, biomass and leaf area, than those from ambient [CO2] habitats at elevated [CO2] only when both genotypes competed. Similarly, plants from ambient [CO2] habitats performed better at low [CO2], also only when both genotypes competed. No difference in performance was found in mono stands. CONCLUSION: The results indicate that natural selection under increasing [CO2] will be mainly driven by competitive interactions. This supports the notion that plant-plant interactions have an important influence on future vegetation functioning and species distribution. Furthermore, plant performance was mainly driven by plastic and not by genotypic responses to changes in atmospheric [CO2].

Combination therapy with renin-angiotensin-aldosterone system inhibitor telmisartan and serine protease inhibitor camostat mesilate provides further renoprotection in a rat chronic kidney disease model.

We previously reported that camostat mesilate (CM) had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE), a renin-angiotensin-aldosterone system (RAS) inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day) and/or TE (10 mg/kg/day) on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors.

[A case of dural arteriovenous fistula at the craniocervical junction, which spinal MRI findings reveals increased intensity signal in Th3-medullary cone].

A 60-year-old woman had transient weakness of the legs and urinary retention for six weeks. She presented with a gait disorder and was admitted to the hospital. She showed symptoms of paraplegia, tingling in the lower extremities, dysuria. She underwent an MRI, and T2-weighted images showed an enlargement of the thoracolumbar spinal cord and high intensity signal from Th3 to the medullary cone, and a contrast-enhanced T1-weighted image showed abnormal vessels anterior to the spine cord. Cervical and spinal angiography documented a dural arteriovenous fistula at the craniocervical junction that was fed by the right vertebral artery and the right ascending pharyngeal arteries and drained into the perimedullary veins. Surgical therapy improved her symptoms and MRI images. Craniocervical junction DAVF with thoracic-medullary cones lesion is rare.

The serine protease inhibitor camostat mesilate attenuates the progression of chronic kidney disease through its antioxidant effects.

BACKGROUND/AIMS: We have so far demonstrated the renoprotective effect of camostat mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidant effect. However, precise mechanisms were not fully clarified. Therefore, we now examined the renoprotective and antioxidant mechanisms of CM by using the adenine-induced chronic kidney disease (CKD) rat model. METHODS: In protocol 1, we analyzed the effect of CM on CKD. Rats were fed on a 0.75% adenine diet for 3 weeks to induce CKD followed by the experimental period with vehicle, CM, or hydralazine (HYD) treatment for 5 weeks. In protocol 2, we examined the safety of CM and HYD on the normal rats. In addition, we explored free radical scavenging activities of CM and its metabolites in vitro using electron paramagnetic resonance (EPR) spectroscopy. RESULTS: CM, but not HYD, significantly reduced the serum creatinine levels, although both treatments showed similar reduction in the blood pressure. CM decreased mRNA expression and protein levels of fibrotic markers, the severity of renal fibrosis, the accumulation of oxidative stress, and the expression of NADPH oxidase components in the kidney. In the protocol 2, there were no statistically significant differences in general parameters except for the systolic blood pressure in HYD group. EPR study revealed that CM and its metabolites have potent hydroxyl radical scavenging activities in vitro. CONCLUSION: Our findings indicate that CM significantly ameliorates the progression of CKD partly through its antioxidant effect independently from its blood pressure-lowering effect. Our results suggest the possibility that CM could be a new therapeutic agent that could arrest the progression of CKD.

Product identification of non-reducing polyketide synthases with C-terminus methyltransferase domain from Talaromyces stipitatus using Aspergillus oryzae heterologous expression.

Talaromyces stipitatus ATCC 10500 possesses 17 non-reducing polyketide synthase (NR-PKS) genes. During the course of our functional analysis of PKS genes with a C-terminus methyltransferase domain from T. stipitatus, we expressed tspks2, tspks3 and tspks4 genes in the heterologous host Aspergillus oryzae, respectively. Although the tspks4 transformant gave no apparent product in HPLC analysis, a novel azaphilone pentaketide (3) was identified along with two known related products from the tspks2 transformant. Of four hexaketide products from the tspks3 transformant, two new compounds were identified to be 2-acetyl-7-methyl-3,6,8-trihydroxynaphthalene (4) and its derivative fused with α-methyl-α,ß-unsaturated γ-lactone (7).

Open-label study to evaluate the pharmacodynamics, clinical efficacy, and safety of meropenem for adult bacterial meningitis in Japan.

The aim of this study was to assess the efficacy, safety, and concentration of meropenem in cerebrospinal fluid when meropenem (2 g every 8 h) was administered to Japanese adult patients with bacterial meningitis. Five Japanese patients (mean age 60.6 years [range 35-71]) were enrolled. Infection with Streptococcus pneumoniae (three patients), Streptococcus salivarius (one patient), and Staphylococcus aureus (one patient) was confirmed by cerebrospinal fluid culture. Meropenem (2 g every 8 h) was administered to all five patients. Treatment duration ranged from 14 to 28 days (mean 22.6 days). All the patients were successfully treated. The concentration of meropenem in cerebrospinal fluid ranged from 0.27 to 6.40 µg/ml up to 8.47 h and was over 1 µg/ml 3 h after starting meropenem infusion. In each patient, the present study confirmed for the first time that the concentration of meropenem in cerebrospinal fluid exceeded the minimal inhibitory concentration for these pathogens. Eleven clinical and laboratory adverse events considered to be related to meropenem were observed in all patients, but no serious adverse event and no discontinuance of treatment due to adverse events occurred. Thus meropenem appeared to be a well-tolerated and effective agent for Japanese adult patients with bacterial meningitis. 2 g every 8 h of meropenem was delivered to CSF and its concentration was exceed in MICs for the detected pathogens.

The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling.

The effects of high-fat diet (HFD) and postprandial endotoxemia on the development of type 2 diabetes are not fully understood. Here we show that the serine protease prostasin (PRSS8) regulates hepatic insulin sensitivity by modulating Toll-like receptor 4 (TLR4)-mediated signalling. HFD triggers the suppression of PRSS8 expression by inducing endoplasmic reticulum (ER) stress and increases the TLR4 level in the liver. PRSS8 releases the ectodomain of TLR4 by cleaving it, which results in a reduction in the full-length form and reduces the activation of TLR4. Liver-specific PRSS8 knockout (LKO) mice develop insulin resistance associated with the increase in hepatic TLR4. Restoration of PRSS8 expression in livers of HFD, LKO and db/db mice decreases the TLR4 level and ameliorates insulin resistance. These results identify a novel physiological role for PRSS8 in the liver and provide new insight into the development of diabetes resulting from HFD or metabolic endotoxemia.

The antifibrotic effect of a serine protease inhibitor in the kidney.

Interstitial fibrosis is a final common pathway for the progression of chronic kidney diseases. Activated fibroblasts have an extremely important role in the progression of renal fibrosis, and transforming growth factor (TGF)-ß1 is a major activator of fibroblasts. Since previous reports have indicated that serine protease inhibitors have a potential to inhibit TGF-ß1 signaling in vitro, we hypothesized that a synthetic serine protease inhibitor, camostat mesilate (CM), could slow the progression of renal fibrosis. TGF-ß1 markedly increased the phosphorylation of TGF-ß type I receptor, ERK 1/2, and Smad2/3 and the levels of profibrotic markers, such as α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and plasminogen activator inhibitor-1, in renal fibroblasts (NRK-49F cells), and they were all significantly reduced by CM. In protocol 1, 8-wk-old male Sprague-Dawley rats were subjected to unilateral ureteral obstruction (UUO) and were concurrently treated with a slow-release pellet of CM or vehicle for 14 days. Protocol 2 was similar to protocol 1 except that CM was administered 7 days after UUO. CM substantially improved renal fibrosis as determined by sirius red staining, collagen expression, and hydroxyproline levels. The phosphorylation of ERK1/2 and Smad2/3 and the levels of α-SMA, CTGF, promatrix metalloproteinase-2, and matrix metalloproteinase-2 were substantially increased by UUO, and they were all significantly attenuated by CM. These antifibrotic effects of CM were also observed in protocol 2. Our present results suggest the possibility that CM might represent a new class of therapeutic drugs for the treatment of renal fibrosis through the suppression of TGF-ß1 signaling.

In vivo contribution of serine proteases to the proteolytic activation of γENaC in aldosterone-infused rats.

Aldosterone plays an important role in the regulation of blood pressure by modulating the activity of the epithelial sodium channel (ENaC) that consists of α-, ß-, and γ-subunits. Aldosterone induces a molecular weight shift of γENaC from 85 to 70 kDa that is necessary for the channel activation. In vitro experiments demonstrated that a dual cleavage mechanism is responsible for this shift. It has been postulated that furin executes the primary cleavage in the Golgi and that the second cleavage is provided by other serine proteases such as prostasin or plasmin at the plasma membrane. However, the in vivo contribution of serine proteases to this cleavage remains unclear. To address this issue, we administered the synthetic serine protease inhibitor camostat mesilate (CM) to aldosterone-infused rats. CM decreased the abundance of the 70-kDa form of ENaC and led to a new 75-kDa form with a concomitant increase in the urinary Na-to-K ratio. Because CM inhibits the protease activity of serine proteases such as prostasin and plasmin, but not furin, our findings strongly indicate that CM inhibited the second cleavage of γENaC and subsequently suppressed ENaC activity. The results of our current studies also suggest the possibility that the synthetic serine protease inhibitor CM might represent a new strategy for the treatment of salt-sensitive hypertension in humans.

Effect of a serine protease inhibitor on the progression of chronic renal failure.

The number of the chronic renal failure (CRF) patients is increasing explosively. Hypertension, proteinuria, inflammation, fibrosis, and oxidative stress are intertwined in a complicated manner that leads to the progression of CRF. However, the therapeutic strategies to delay its progression are limited. Since serine proteases are involved in many processes that contribute to these risk factors, we investigated the effects of a synthetic serine protease inhibitor, camostat mesilate (CM), on the progression of CRF in 5/6 nephrectomized (Nx) rats. Eighteen male Sprague-Dawley rats were divided into three groups: a sham-operated group (n = 6), a vehicle-treated Nx group (n = 6), and a CM-treated Nx group (n = 6). Following the 9-wk study period, both proteinuria and serum creatinine levels were substantially increased in the vehicle-treated Nx group, and treatment with CM significantly reduced proteinuria and serum creatinine levels. The levels of podocyte-associated proteins in glomeruli, such as nephrin and synaptopodin, were markedly decreased by 5/6 nephrectomy, and this was significantly ameliorated by CM. CM also suppressed the levels of inflammatory and fibrotic marker mRNAs including transforming growth factor-ß1, TNF-α, collagen types I, III, and IV, and reduced glomerulosclerosis, glomerular hypertrophy, and interstitial fibrosis in histological studies. Furthermore, CM decreased the expression of NADPH oxidase component mRNAs, as well as reactive oxygen species generation and advanced oxidative protein product levels. Our present results strongly suggest the possibility that CM could be a useful therapeutic agent against the progression of CRF.

Gross nitrogen retranslocation within a canopy of Quercus serrata saplings.

Nitrogen (N) retranslocation within tree canopies has been intensively studied and assumed to function as a one-way process (e.g., from older to newer leaves). However, recent studies have found that both N output and input occur in individual leaves, suggesting that 'gross' N retranslocation exists behind 'net' N retranslocation. In the present study, the amount and direction of gross N retranslocation within a canopy of deciduous oak Quercus serrata Thunb. ex. Murray saplings were investigated. Labeling was conducted with leaves of Q. serrata saplings cultivated under conditions of low-N (LN) or high-N (HN) fertility. Subsequently, N movement within the canopy was traced. Leaves at two different positions in the canopy (top and lateral) were labeled to determine the direction of gross N retranslocation. To detect seasonal differences, the leaf-labeling experiment was conducted twice during the early and late phases of the growing season. In addition, to compare the quantitative importance of gross N retranslocation and root N uptake, the latter was determined by labeling Q. serrata roots. The N-labeling experiment revealed gross N retranslocation among leaves, i.e., from top to lateral, lateral to top and lateral to lateral positions. Gross N retranslocation was quantitatively more important than root uptake, especially for plants cultivated at LN fertility. Season also affected the amount of gross N retranslocation, and these effects differed between LN and HN fertilities. These findings suggest that N allocation within a canopy is controlled dynamically by both gross N output and input. The mechanisms controlling gross N output and input likely function as key determinants of N allocation within a tree canopy.

Foliage nitrogen turnover: differences among nitrogen absorbed at different times by Quercus serrata saplings.

BACKGROUND AND AIMS: Nitrogen turnover within plants has been intensively studied to better understand nitrogen use strategies. However, differences among the nitrogen absorbed at different times are not completely understood and the fate of nitrogen absorbed during winter is largely uncharacterized. In the present study, nitrogen absorbed at different times of the year (growing season, winter and previous growing season) was traced, and the within-leaf nitrogen turnover of a temperate deciduous oak Quercus serrata was investigated. METHODS: The contributions of nitrogen absorbed at the three different times to leaf construction, translocation during the growing season, and the leaf-level resorption efficiency during leaf senescence were compared using (15)N. KEY RESULTS: Winter- and previous growing season-absorbed nitrogen significantly contributed to leaf construction, although the contribution was smaller than that of growing season-absorbed nitrogen. On the other hand, the leaf-level resorption efficiency of winter- and previous growing season-absorbed nitrogen was higher than that of growing season-absorbed nitrogen, suggesting that older nitrogen is better retained in leaves than recently absorbed nitrogen. CONCLUSIONS: The results demonstrate that nitrogen turnover in leaves varies with nitrogen absorption times. These findings are important for understanding plant nitrogen use strategies and nitrogen cycles in forest ecosystems.

Drug discontinuation after treatment with minimum maintenance dose of an antithyroid drug in Graves' disease: a retrospective study on effects of treatment duration with minimum maintenance dose on lasting remission.

According to the guideline issued by the Japan Thyroid Association in 2006 for treatment of Graves' disease, discontinuing antithyroid drug (ATD) therapy is recommended when serum free thyroxine (FT4) and thyroid stimulating hormone (TSH) concentrations have been maintained within the reference range for a certain period after treatment with one ATD tablet every other day (minimum maintenance dose therapy, MMDT). In this retrospective study, the relationship between MMDT duration and remission rate was investigated. The participants were 107 consecutive patients with Graves' disease whose ATD therapy was stopped according to the guideline. Serum FT4, TSH, and TSH receptor antibody (TRAb) levels were measured when ATD was discontinued and every 3 months thereafter. The percentage of patients in remission was 86.9% at 6 months, 73.8% at 1 year, and 68.2% at 2 years after ATD discontinuation. The remission rate increased with MMDT duration, being significantly higher in patients with MMDT durations of 19 months or more than those with MMDT durations of 6 months or less. In patients with MMDT durations of 6 months or less, the remission rate was significantly lower in TRAb-positive patients than in TRAb-negative patients at the time of withdrawal of ATD; however, this was not observed in patients with MMDT durations of 7 months or more. These findings suggest that in patients who discontinue ATD after a certain MMDT duration, the remission rate increases as the MMDT duration increases, and ATD should not be discontinued in TRAb-positive patients with MMDT durations of 6 months or less.