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Resveratrol, a natural polyphenolic phytoalexin, is a dietary supplement that improves the outcomes of metabolic, cardiovascular, and other age-related diseases due to its diverse pharmacological activities. Although there have been several preclinical and clinical investigations of resveratrol, the contributions of gut phase-II metabolism and enterohepatic circulation to the oral bioavailability and pharmacokinetics of resveratrol remain unclear. Furthermore, a physiologically-based pharmacokinetic (PBPK) model that accurately describes and predicts the systemic exposure profiles of resveratrol in clinical settings has not been developed. Experimental data were acquired from several perspectives, including in vitro protein binding and blood distribution, in vitro tissue S9 metabolism, in situ intestinal perfusion, and in vivo pharmacokinetics and excretion studies. Using these datasets, an in-house whole-body PBPK model incorporating route-dependent phase-II (glucuronidation and sulfation) gut metabolism and enterohepatic circulation processes was constructed and optimized for chemical-specific parameters. The developed PBPK model aligned with the observed systemic exposure profiles of resveratrol in single and multiple dosing regimens with an acceptable accuracy of 0.538-0.999-fold errors. Furthermore, the model simulations elucidated the substantial contribution of gut first-pass metabolism to the oral bioavailability of resveratrol and suggested differential effects of enterohepatic circulation on the systemic exposure of resveratrol between rats and humans. After partial modification and verification, our proposed PBPK model would be valuable to optimize dosage regimens and predict food-drug interactions with resveratrol-based natural products in various clinical scenarios.

Entrectinib (Rozlytrek®) is an oral antineoplastic agent approved by the U.S. Food and Drug Administration in 2019 for the treatment of c-ros oncogene 1 (ROS1)-positive non-small cell lung cancer and neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumors. Although there have been a few studies on the pharmacokinetics of entrectinib, the relative contributions of several kinetic factors determining the oral bioavailability and systemic exposure of entrectinib are still worthy of investigation. Experimental data on the intestinal absorption and disposition of entrectinib in rats were acquired from studies on in vitro protein binding/tissue S9 metabolism, in situ intestinal perfusion, and in vivo dose-escalation/hepatic extraction. Using these datasets, an in-house whole-body physiologically based pharmacokinetic (PBPK) model incorporating the QGut model concepts and segregated blood flow in the gut was constructed and optimized with respect to drug-specific parameters. The established rat PBPK model was further extrapolated to humans through relevant physiological scale-up and parameter optimization processes. The optimized rat and human PBPK models adequately captured the impact of route-dependent gut metabolism on the systemic exposure to entrectinib and closely mirrored various preclinical and clinical observations. Our proposed PBPK model could be useful in optimizing dosage regimens and predicting drug interaction potential in various clinical conditions, after partial modification and validation.

Nanoparticles (NPs) have distinct pharmacokinetic (PK) properties and can potentially improve the absorption, distribution, metabolism, and elimination (ADME) of small-molecule drugs loaded therein. Owing to the unwanted toxicities of anticancer agents in healthy organs and tissues, their precise delivery to the tumor is an essential requirement. There have been numerous advancements in the development of nanomedicines for cancer therapy. Physiologically based PK (PBPK) models serve as excellent tools for describing and predicting the ADME properties and the efficacy and toxicity of drugs, in combination with pharmacodynamic (PD) models. The recent preliminary application of these modeling approaches to NPs demonstrated their potential benefits in research and development processes relevant to the ADME and pharmacodynamics of NPs and nanomedicines. Here, we comprehensively review the pharmacokinetics of NPs, the developed PBPK models for anticancer NPs, and the developed PD model for anticancer agents.

Febuxostat (FEB) is a selective xanthine oxidase (XO) inhibitor approved for chronic management of hyperuricemia (HU) in patients with gout. Non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DIC) are the first choice for the prevention and treatment of gouty inflammation and flare. In this study, a sensitive and simple bioanalytical method using HPLC coupled with a fluorescence detector (HPLC-FL) was developed for the simultaneous determination of FEB and DIC. The linearity (1–1500 ng mL−1 for FEB and 5–1500 ng mL−1 for DIC), precision, accuracy, recovery, matrix effect, and stability of the newly developed method were validated as per the US Food and Drug Administration (FDA) guidelines. Next, the in vivo and in vitro metabolic interactions between FEB and DIC were comprehensively examined. The in vivo pharmacokinetics of FEB were found to be significantly altered by the co-administration of DIC in rats. Further, the in vitro microsomal metabolism study revealed that the altered pharmacokinetics of FEB could be attributed primarily to the competitive inhibition of FEB metabolism by DIC. To our knowledge, this is the first systematic study showing the in vivo pharmacokinetic interaction of FEB with DIC following intravenous and oral administration in rats and the associated metabolic inhibition mechanism together with a new HPLC-FL method to simultaneously determine FEB and DIC in biological matrices.

Ertugliflozin (ERTU) is a novel, potent, and highly selective sodium glucose cotransporter 2 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. We describe a novel bioanalytical method using high-performance liquid chromatography (HPLC) coupled with fluorescence detection for quantitative determination of ERTU in rat plasma. Acetonitrile-based protein precipitation method was used for sample preparation, and chromatographic separation was performed on a Kinetex® C18 column with an isocratic mobile phase comprising acetonitrile and 10 mM potassium phosphate buffer (pH 6.0). The eluent was monitored by a fluorescence detector at an optimized excitation/emission wavelength pair of 277/320 nm. The method was validated to demonstrate the selectivity, linearity (ranging from 4 to 2000 ng/mL), precision, accuracy, recovery, matrix effect, and stability in line with the current FDA guidelines. The newly developed method was successfully applied to investigate the pharmacokinetic interactions of ERTU with mefenamic acid (MEF) and ketoconazole (KET). The findings of the present study revealed that the pharmacokinetics of ERTU may be altered by concurrent administration of MEF and KET in rats. To our knowledge, the present study is the first to develop a validated bioanalytical method for quantification of ERTU using HPLC coupled with fluorescence detection and to assess the drug interaction potential of ERTU with non-steroidal anti-inflammatory (MEF) and azole antifungal (KET) drugs.

Diabetes mellitus (diabetes) is a group of chronic metabolic diseases characterized by high blood sugar levels over a prolonged period, eventually leading to damage of multiple body systems. To date, drug-based therapies have not provided ideal clinical outcomes for effective and safe management of diabetes and its complications. Over the past decade, the use of complementary and alternative medicines (e.g., medicinal herbs and dietary supplements) for the management of chronic diseases such as diabetes has greatly increased around the world. However, herbal medicinal products are complex mixtures of various bioactive constituents that can modulate drug-metabolizing enzymes, particularly cytochrome P450 (CYP), and interact with prescription drugs through pharmacokinetic mechanisms. Thus, a summary on the effects of antidiabetic herbs and phytochemicals on the pharmacokinetics of antidiabetic drugs may prove relevant for optimizing antidiabetic therapy. The aim of this article is to provide an updated review of the pharmacokinetic characteristics of antidiabetic herbs and phytochemicals and their interactions with conventional antidiabetic drugs. Since herb-drug interactions may lead to substantial pharmacodynamic and/or pharmacokinetic consequences, further research in relevant fields of diabetes and herbal medicine is needed to continuously improve our knowledge of potential risks and benefits associated with these interactions.

Repaglinide (RPG), a rapid-acting meglitinide analog, is an oral hypoglycemic agent for patients with type 2 diabetes mellitus. Quercetin (QCT) is a well-known antioxidant and antidiabetic flavonoid that has been used as an important ingredient in many functional foods and complementary medicines. This study aimed to comprehensively investigate the effects of QCT on the metabolism of RPG and its underlying mechanisms. The mean (range) IC50 of QCT on the microsomal metabolism of RPG was estimated to be 16.7 (13.0–18.6) μM in the rat liver microsome (RLM) and 3.0 (1.53–5.44) μM in the human liver microsome (HLM). The type of inhibition exhibited by QCT on RPG metabolism was determined to be a mixed inhibition with a Ki of 72.0 μM in RLM and 24.2 μM in HLM as obtained through relevant graphical and enzyme inhibition model-based analyses. Furthermore, the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of RPG administered intravenously and orally in rats were significantly increased by 1.83- and 1.88-fold, respectively, after concurrent administration with QCT. As the protein binding and blood distribution of RPG were observed to be unaltered by QCT, it is plausible that the hepatic first-pass and systemic metabolism of RPG could have been inhibited by QCT, resulting in the increased systemic exposure (AUC and Cmax) of RPG. These results suggest that there is a possibility that clinically significant pharmacokinetic interactions between QCT and RPG could occur, depending on the extent and duration of QCT intake from foods and dietary supplements.

Alpelisib, a novel phosphatidylinositol 3-kinase inhibitor, is an oral anticancer agent approved for the treatment of advanced or metastatic breast cancer. In this study, a sensitive bioanalytical method using high-performance liquid chromatography combined with a fluorescence detector (HPLC-FLD) was developed for the determination of alpelisib in rat plasma. This newly developed method was validated in terms of linearity (1–1,000 ng/mL), precision, accuracy, recovery, matrix effect, and stability according to the US Food and Drug Administration guideline and these parameters were within the acceptable limits. Alpelisib tended to be stable in plasma, urine, simulated intestinal fluid, and buffer with pH > 4.0 for 24 h, but in the pH 1.2 buffer and simulated gastric fluid for up to 4 h only. A study involving intravenous administration of alpelisib in rats showed that the dose-normalized area under the plasma concentration versus time curve (AUC) of alpelisib changed significantly as the dose increased from 1 to 10 mg/kg. Similarly, an oral rat study indicated that the dose-normalized AUC and the fraction of dose that remained in the gastrointestinal (GI) tract changed significantly as the dose increased from 0.5 to 10 mg/kg. These nonlinear (dose-dependent) pharmacokinetics of intravenous and oral alpelisib could be attributed to the saturation of ubiquitous metabolism among most tissues and/or GI absorption processes. To the best of our knowledge, this is the first study to investigate the in vivo nonlinear pharmacokinetics of alpelisib and its possible mechanisms, together with a new HPLC-FLD method to determine alpelisib in biological matrices.

A bending sensor was fabricated with ionic polymer-metal composite (IPMC) and its characteristics as a sensor was studied. The IPMC senor, made by stacking a few Nafion films and water-proofed by Parylene coating, was robust and stable enough to be operated over 5 h in the air. Through the experiments examining the relation between the sensor signal and the deformation of the sensor, the output voltage of the sensor appeared to be linearly proportional to the curvature of the sensor. The proportional relation was maintained in the more realistic conditions like when the sensor is surface-mounted on the static and dynamic fingerjoint. The sensor signal was not affected by the sensor size change in length, width and thickness within the range we tested. Through the reliability tests the IPMC sensor was characterized to be inferior to mechanical sensors in accuracy and precision, and superior in sensitivity and resolution.

Dutasteride (DUT) is a selective, potent, competitive, and irreversible inhibitor of both type-1 and type-2 5&alpha, reductase (5AR) commonly used in the treatment of benign prostatic hyperplasia and androgenetic alopecia. In the present study, we developed a simple and sensitive high-performance liquid chromatography with fluorescence detection (HPLC-FL) method for simultaneous determination of DUT and its major active metabolite, 6&beta, hydroxydutasteride (H-DUT). Next, the pharmacokinetic interactions of DUT with ketoconazole (KET), a potent CYP3A inhibitor, were comprehensively investigated. In vivo rat intravenous and oral studies revealed that the pharmacokinetics of DUT and H-DUT were significantly altered by the co-administration of KET. Furthermore, the in vitro microsomal metabolism, blood distribution, and protein-binding studies suggest that the altered pharmacokinetics of DUT could be attributed primarily to the inhibition of the DUT metabolism by KET. To the best of our knowledge, this is the first study to show the drug interaction potential of DUT with azole antifungal drugs including KET, together with a newly developed HPLC-FL method for the simultaneous quantification of DUT and H-DUT.

Mistletoes, hemiparasites, contain many components with various biological activities and have been used in cosmetics industry. Loranthacease (1,000 species) and Viscaceae (550 species) have the most dominant species in mistletoes (nearly 1,600 species). It can be expected that the biological activities vary from species to species; therefore, we have tested

Human otoliths, primarily formed from salts of calcium and carbonate, are different from bones of the skeleton, which are composed of calcium phosphate. The echinoderms, which share the earliest common ancestor with us, began to protect the body by making an endoskeleton out of calcium and carbon dioxide dissolved in the sea. In subsequent vertebrates, aerobic respiration supported strong muscle activity, but an occasional shortage of oxygen led to low pH due to the accumulation of lactate produced by anaerobic respiration, increasing the risk of melting bones composed of calcium carbonate. So, all vertebrates used calcium phosphate to increase bone strength, having a stronger ionic bonding than calcium carbonate. But otoliths, which are in the inner ear and thereby not connected to muscles, still use calcium carbonate. Benign paroxysmal positional vertigo (BPPV) is a disorder in which otoliths detached from the utricle enter the semicircular canals and cause a sense of rotation. Otoliths, the calcium carbonate ear bones retaining a long evolutionary history, can be easily broken at low pH. During sleep, shallow breathing produces mild respiratory acidosis and low pH in the blood. Since otoliths are corroded at low pH during nighttime, BPPV occurs frequently in the morning. In addition, diabetes mellitus or gout often decreases pH in the blood and increases the occurrence of BPPV.

Reflection loss at the water-castor oil interface as a function of temperature was measured in a direction normal to the interface using a 200-kHz acoustic signal. The acoustic impedance of water increases with temperature, whereas that of castor oil decreases. The measured reflection losses varied from 30 to 65 dB, and a sharp rising peak in reflection loss was observed at the temperature at which the acoustic impedance of water became equal to that of castor oil. This temperature is called the temperature of intromission in this paper. These measurements were compared with the model predictions based on a Rayleigh-reflection model using the measured sound speeds of both fluids. The sound speeds in water and castor oil as functions of temperature are the input parameters of the Rayleigh-reflection model, and were measured directly using an arrival time difference method in the temperature range of 5 to 30 &deg, C. The comparison results imply that temperature is an important factor affecting the reflection at the interface separating the two fluids.

Silybin (SBN) is a major active constituent of silymarin, a mixture of flavonoids found in fruits and seeds of milk thistle. The aim of this study was to describe a simple bioanalytical method for quantifying SBN in rat plasma. A simple protein deproteinization procedure with acetonitrile (ACN) was employed for plasma sample preparation. A reversed column and gradient elution of a mobile phase (mixture of phosphate buffer (pH 5.0) and ACN) were used for chromatographic separation. The selectivity, linearity (50–5000 ng/mL), precision, accuracy, recovery, matrix effect, and stability for this method were validated as per the current Food and Drug Administration (FDA) guidelines. Our method for SBN was applied to a comparative pharmacokinetic study on four different commercial silymarin products. This in vivo rat study demonstrated that product #4 significantly enhanced the relative oral bioavailability of SBN, as compared to product #1–3. Therefore, the bioanalytical method proposed herein could serve as a promising alternative for preclinical pharmacokinetic studies on silymarin products and, by extension, clinical use after partial modification and validation.

This study was conducted in order to develop a finger exoskeleton system using ionic polymer metal composites (IPMCs) as the actuator and sensor in a hybrid structure. To use the IPMC as an actuator producing large force, a first order transfer function was obtained using results from a block force for DC excitation that applied to two IPMCs of 20mm-width, 50mm-length, and 2.4mm thickness together. After which the validation of 200gf control with anti-windup PI controller was confirmed. A 5mm-width, 50mm-length, 0.6mm-thickness of IPMC was also modeled as a sensor for tip displacement. As a result, the IPMC sensor could been utilized as a trigger role for the actuator. Finally, an IPMC sensor and actuator were installed on the joint of a single DOF exoskeleton in the hybrid structure, and test for the control of 40gf of block force and predefined sequence of motion was performed.

Measurements of mid-frequency bottom backscattering strength were made on May 30, 2017, as part of the Korea Reverberation Experiment (KOREX-17) in a shallow water region located at the south coast of Korea. The acoustic data were transmitted and received as functions of frequency (4, 6, and 8 kHz) and pulse length (2 and 4 ms) using semi-monostatic sonar system composed of omni-directional acoustic source and receiver, which was deployed from the R/V Mirae. The bottom backscattering strength were extracted from intensity-averaged reverberation level for 30 individual pings. The water depth measured by an echo sounder was about 35 m and bottom was approximately flat, having a slope less than 1° over the experimental area. The surficial sediment was estimated to be silty sediment, having a mean grain size of 6 phi from grain size analysis. In this talk, the measurement results of bottom backscattering strengths will be presented as a function of grazing angle and compared to the predictions obtained by Lambert’s law and APL-UW scattering model. [Work supported by Agency for Defense Development, Korea(UD160006DD).]

Visceral injury induces referred pain, autonomic concomitants, skeletal muscle spasm, and hyperalgesia of segmental pattern on the specific area of somatic tissue. Therefore, since visceral referred pain does not mean only a feeling which is considered as misperception of brain but accompanies accessory phenomena, referred phenomenon can be more reasonable expression. Visceral referred phenomenon has segmental pattern and is shown on the segmental constituents related to viscus and further spreads to multi-segments through central sensitization if visceral injury become severe and chronic. Segmental pattern observed in our body is not a feature developing only in human. Segmentation of animals is a general concept in body organization from Annelida to Vertebrata. The evolutionary advent of segmentation made possible development of much greater complexity in structure and function. Segmentation increased efficiency of movements, and further made fine neural control of movements possible. It is definite that segmentation of body bestows obvious advantages to an animal. If abnormality in a segment develops, to lessen energy expenditure of an organism consisting of multi-segments, the organism sacrifices the abnormal segment for the whole segments via defunctionalization. Defunctionalization of abnormal segment is just segmental phenomenon. Functional unit of grouped segments called as tagma in Arthropoda or its equivalent in Vertebrata could also show this phenomenon if abnormality develops in tagma or its equivalent. Visceral referred pain, referred pain originating from musculoskeletal structure, complex regional pain syndrome I and II are representatives of segmental or tagmatic phenomena.

Because heart originates from primitive endocardial tube (ventral aorta) embryologically, coronary arteries that supply this tube can be thought as "cardiac vasa vasorum" like arterial vasa vasorum that supply peripheral arteries. Coronary arteries have vasodilative reaction to noradrenaline, different from the most arteries that show vasoconstriction. This phenomenon is similar to vasa vasorum that are insensitive to noradrenaline and has its own vasoregulation. Coronary arteries can supply blood from epicardium, myocardium to endocardium under normal physiological conditions. But heart having a significant myocardial hypertrophy can be susceptible to subendocardial ischemia because the metabolic demands of hypertrophic myocardium cannot be met by a parallel increase of coronary myocardial capillaries. This peculiar characteristic of coronary arteries is similar to vasa vasorum that give rise to ischemic necrosis of media of the host vessel under chronic hypertension. Inherency of coronary arteries is the same endarteries as vasa vasorum. Coronary arteries have many smooth muscle fibers than elastic fibers in media, which protect them to collapse during systole to some extent. This feature also is similar to vasa vasorum. The above similarities support the hypothesis that coronary arteries are a kind of vasa vasorum.

Referred pain from visceral organs tends to be expressed on the specific area of body surface, called as Head's zone. Although it is well known that sympathetic referred pains of viscera appear on the body trunk, the fact that parasympathetic referred pains exist and are expressed on the head, sacrum and posterior thigh is not appreciated properly. Functional gastrointestinal diseases accompany frequently headache, and cyclic vomiting and recurrent abdominal pains in childhood progress to migraine later. Such clinical observations on relationship between headache and viscera suggest that longstanding disease processes of viscera could induce central sensitization of trigeminocervical nuclear complex, and express "parasympathetic referred pain" on the head, like sympathetic referred pain on the body trunk, that is headache.

Muscular referred pain, that is, pain perceived in a somatic area other than the site of the noxious stimulation, takes place on a specific place to each muscle in constant and predictable pattern. The central hyperexcitability theory focused on spinal cord, the most proper theory at present, can explain well the segmental pattern of referred pain showing delayed onset. But it is hard to explain the non segmental pattern of referred pain areas of superficial-seated or limb girdle and limb muscles. Referred pain areas of limb girdle and limb muscles appear on the skin above a belt of synergistic muscles beyond the segmental areas. In the case of forearm and calf muscles, referred pain shows up on the palm and sole, the point of force application to the outer object. This finding reflects biomechanical relationship between muscle and its referred pain area. From the phylogenetic perspective, aquatic vertebrated animals (e.g. fish) use myoseptum surrounding myomere, connected to skin to keep tensile strength with it for effective swimming. Likewise, in terrestrial vertebrated animals, there are skin parts weakly interconnected with muscles, though the tensile property of nearly all the skin devolutes except the points of action with the outside. These points are dynamic maximal skin tension areas connected with muscles through superficial fascia, in other words, referred pain areas. Referred pain of deep-seated or truncal muscles appears on the trunk segmentally via spinal cord (the central hyperexcitability theory), but superficial-seated or limb girdle and limb muscles elicit referred pain on dynamic maximal skin tension area through connective tissue (the "connective tissue" theory).

Some asymmetry of body parts (thumbs, cubital crease levels, popliteal crease levels, toes, breasts, gonads and facial structures) is commonly observed. And there is also neurobehavioral asymmetry such as handedness and language lateralization. Since right-handedness is closely associated with left-hemisphere dominance for language, it is known that handedness can be linked with language lateralization. But because cultural and social pressures influence handedness, handedness is able to shift. If so, handedness can't always reflect language lateralization. We can also detect another asymmetry in protracted tongue which is thought to be inherently unchangeable. Some midline deviation of fully protracted tongue is observed in every person. Protractor of the tongue, genioglossus muscle, is solely innervated by contralateral corticobulbar fibers from the inferior part of precentral gyrus. This part is closely related with language expressive area. Therefore, the midline deviation of tongue observed when it is fully protracted could be more related with language lateralization than handedness changeable to external pressures.

General somatic afferents of facial nerve innervate skin of the concha, the posterior external ear canal and a small area behind the ear. But pain around the ear that precedes or develops at the same time as Bell's palsy frequently is beyond the territory of sensory innervations of facial nerve. Cranial nerves are richly innervated by their own nerves called nervi nervorum that have nociceptive function. So, stimulation of nervi nervorum dominating facial nerve trunk can be transmitted to trigeminocervical nuclear complex and make referred pain on the craniofacial region segmentally. The reason why referred pain of facial nerve origin develops around the ear is that facial nerve and its ensheathing connective tissue are derivatives of second branchial arch which is homologous to the somites of body.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and genetically heterogeneous disorder characterized by immune dysregulation with a defect in apoptosis triggering and in natural killer and cytotoxic T lymphocyte cellular cytotoxicity. It occurs mostly in infancy and early childhood, and without treatment, is invariably fatal with a median survival of less than 2 months after diagnosis. Only early hematopoietic stem cell transplantation (HSCT) has been shown to cure the disease. The molecular genetic defect causing FHL has been intensively investigated for recent years and classification of FHL according to the genetic abnormality has been tried. It has been noted that some mutations appear to be more frequent in patients from a certain geographical region, but there is no data available for the genetic background of Korean FHL patients. The aim of this study was to identify causative gene(s) and mutation(s) by mutation analyses of three known HLH causative genes, namely PRF1, UNC13D, and STX11 in Korean FHL patients. We also analyzed whether there were genotype-phenotype correlations among these genetic subtypes, and intended to provide critical information for the decision making for timely and most appropriate treatment of FHL patients. Fifteen patients with suspected FHL were recruited from the Korean National Registry of HLH between January 2007 and March 2008. By using genomic DNA samples extracted from peripheral blood leukocytes, direct sequencing was performed in all the exons and their flanking intronic sequences of the PRF1 gene, UNC13D gene, and STX11 gene by genetic analyzer. The correlation between clinical features and genetic subtypes was investigated. Of the 15 HLH patients, 8 mutations of UNC13D gene were found in 5 patients, and 5 of the 8 mutations were novel (Q98X, IVS24+1G>A, IVS21-2A>G, IVS30+5G>A, c.1693delG). Neither PRF1 nor STX11 mutation was identified. IVS9-1G>C, one of the previously reported UNC13D mutations, was found in 3 patients. The clinical features of the patients with UNC13D mutation were associated with earlier age of disease onset (median: 2 months, versus 21 months), more frequent involvement of central nervous system (60% versus 20%), and poorer treatment response (complete response rate 20% versus 70%) than those of FHL patients without UNC13D mutation. This study is the first report to indicate UNC13D mutations as a molecular genetic cause in Korean patients with FHL by direct gene sequencing. The novel UNC13D mutations found in Korean FHL patients implicate the possible presence of an ethnical difference in the genetic background of FHL development. Further study with a larger number of FHL patients would be needed to identify other potential causative genes and mutations and to clarify the genotype-phenotype correlation for each mutation. Moreover, earlier detection of UNC13D mutation on the basis of this study in a suspected FHL patient would provide important information for the decision making for timely HSCT.