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2.
J Infect Chemother ; 29(11): 1075-1080, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37451619

ABSTRACT

Klebsiella pneumoniae (Kpn) is one of the most common gram-negative bacilli causing lung, urinary tract, and biliary tract infections. However, as a distinct entity from classic Kpn, hypervirulent Kpn causing liver abscess, endophthalmitis, and lung abscess with poor prognoses has been reported mainly in East and Southeast Asia since the mid-1980s. Although the definition of hypervirulent Kpn is unclear, the hypermucoviscosity of Kpn is considered an important feature of hypervirulence. We present a case of emphysematous pyelonephritis accompanied by septic shock and acute kidney injury caused by hypermucoviscous Kpn infection that was successfully treated by intensive treatment. A 70-year-old woman with type 2 diabetes mellitus was diagnosed with emphysematous pyelonephritis, and string test-positive Kpn was detected in blood and urine cultures and percutaneous catheter drainage fluid from the renal pelvis. The patient was treated with intensive therapies including antibiotics, ventilator management, and continuous hemodiafiltration (CHDF) using AN69ST, which can absorb cytokines. During the course of treatment, the infection was complicated by pyogenic spondylitis, which was cured by antimicrobial therapy, and the patient was transferred to another hospital for rehabilitation on day 119 after admission. Hypermucoviscous Kpn infection often has a severe course, and it is important to initiate multidisciplinary treatment at an early stage, including rifampicin, which is expected to inhibit the viscosity of hypermucoviscous Kpn. In the current case, immediate CHDF using AN69ST was also considered a life-saving treatment because it improved both volume overload and neutrophil-activated hypercytokinemia.


Subject(s)
Diabetes Complications , Diabetes Mellitus, Type 2 , Hemodiafiltration , Klebsiella Infections , Liver Abscess , Pyelonephritis , Female , Humans , Aged , Klebsiella pneumoniae , Diabetes Mellitus, Type 2/complications , Pyelonephritis/complications , Diabetes Complications/complications , Klebsiella Infections/complications , Klebsiella Infections/drug therapy
3.
Diagnostics (Basel) ; 12(2)2022 Jan 28.
Article in English | MEDLINE | ID: mdl-35204430

ABSTRACT

Certain biomarkers predict death due to acute respiratory distress syndrome in COVID-19 patients. We retrospectively analyzed biomarkers associated with time to mechanical ventilation for respiratory failure due to COVID-19 (time-to-mechanical ventilation) in 135 consecutive patients in our hospital. We analyzed biomarkers that were elevated immediately (at admission) and later (3 days after admission) using Cox proportional hazards regression analysis. Independent biomarkers of time-to-mechanical ventilation were high C-reactive protein (CRP), interleukin (IL)-6, and Krebs von den Lungen-6 (KL-6) concentrations at admission and elevated CRP, high-mobility group box-1 protein (HMGB-1), and d-dimer levels and low platelets 3 days after admission. Receiver operating characteristic analysis for detecting the association between independent biomarkers associated with time-to-event in multivariate analyses and the start of mechanical ventilation revealed that these biomarkers had area under the curve values higher than 0.700. The present study suggests that CRP was the only biomarker associated with time-to-mechanical ventilation both at admission and 3 days after admission. Moreover, IL-6 (an inflammatory cytokine), HMGB-1 (a late inflammatory mediator), and KL-6 (reflecting injury and/or remodeling of type II pneumocytes) were associated with outcomes in COVID-19 as reported previously. In conclusion, increased CRP, IL-6, KL-6, HMGB-1, and d-dimer levels and decreased platelet counts were associated with the start of mechanical ventilation due to COVID-19.

4.
Mod Rheumatol Case Rep ; 4(2): 248-252, 2020 07.
Article in English | MEDLINE | ID: mdl-33086997

ABSTRACT

A 52-year-old woman was diagnosed as having anti-centromere antibody (ACA)-positive primary Sjögren syndrome (pSS). Eight years later, she visited our hospital because she had developed dyspnoea. She was diagnosed as having pulmonary arterial hypertension (PAH) with pulmonary veno-occlusive disease on the basis of the results of right heart catheterisation, a severe decrease in diffusing capacity of the lung for carbon monoxide (DLCO, 17%) and desaturation (69%) after a 6-minute walk test. She was also diagnosed as having limited cutaneous systemic sclerosis (lcSSc) because she had developed finger sclerosis. The six-minute walk distance had improved by 54 m 3 months after commencing treatment with tadalafil. Clinicians should be alert to the possibility of patients with ACA-positive SS developing lcSSc and PAH during their clinical course.


Subject(s)
Antibodies, Antinuclear/immunology , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/etiology , Scleroderma, Limited/diagnosis , Scleroderma, Limited/etiology , Sjogren's Syndrome/complications , Sjogren's Syndrome/immunology , Autoantibodies/immunology , Autoimmunity , Biomarkers , Disease Susceptibility , Female , Humans , Middle Aged , Severity of Illness Index , Sjogren's Syndrome/diagnosis , Sjogren's Syndrome/drug therapy
5.
Bioorg Med Chem ; 28(5): 115307, 2020 03 01.
Article in English | MEDLINE | ID: mdl-32007387

ABSTRACT

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a key role in maintaining cellular metabolism. AMP or adenosine diphosphate (ADP) levels rise during metabolic stress, such as during nutrient starvation, hypoxia and muscle contraction, and bind to AMPK to induce activity. Recently, activation of AMPK has been considered an attractive therapeutic strategy in the field of human oncology. Structural optimization of lead compound 2, a new type of AMPK activator with potent AMPK activation activity and attractive selective growth inhibition against human cancer cells, improved aqueous solubility, metabolic stability and animal pharmacokinetics (PK) and culminated in the identification of (5-{1-[(6-methoxypyridin-3-yl)methyl]piperidin-4-yl}-1H-benzimidazol-2-yl)(4-{[4-(trifluoromethyl)phenyl]methyl}piperazin-1-yl)methanone ditosylate, ASP4132 (28). Studies on ASP4132 had advanced to clinical trials for the treatment of cancer.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Antineoplastic Agents/pharmacology , Drug Development , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Mice , Mice, Nude , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
6.
Bioorg Med Chem ; 25(21): 6024-6038, 2017 11 01.
Article in English | MEDLINE | ID: mdl-28988626

ABSTRACT

Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted structural optimization of the glycine amide derivative 1, which we previously reported as a novel VAP-1 inhibitor, to improve stability in dog and monkey plasma, and aqueous solubility. By chemical modification of the right part in the glycine amide derivative, we identified the carbamimidoylcarbamate derivative 20c, which showed stability in dog and monkey plasma while maintaining VAP-1 inhibitory activity. We also found that conversion of the pyrimidine ring in 20c into saturated rings was effective for improving aqueous solubility. This led to the identification of 28a and 35 as moderate VAP-1 inhibitors with excellent aqueous solubility. Further optimization led to the identification of 2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate (40b), which showed similar human VAP-1 inhibitory activity to 1 with improved aqueous solubility. 40b showed more potent ex vivo efficacy than 1, with rat plasma VAP-1 inhibitory activity of 92% at 1h after oral administration at 0.3mg/kg. In our pharmacokinetic study, 40b showed good oral bioavailability in rats, dogs, and monkeys, which may be due to its improved stability in dog and monkey plasma.


Subject(s)
Amine Oxidase (Copper-Containing)/antagonists & inhibitors , Carbamates/pharmacology , Cell Adhesion Molecules/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Administration, Oral , Amine Oxidase (Copper-Containing)/blood , Amine Oxidase (Copper-Containing)/metabolism , Animals , Carbamates/administration & dosage , Carbamates/chemistry , Cell Adhesion Molecules/blood , Cell Adhesion Molecules/metabolism , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Injections, Intravenous , Macaca fascicularis , Male , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
7.
Bioorg Med Chem ; 22(24): 6899-907, 2014 Dec 15.
Article in English | MEDLINE | ID: mdl-25456079

ABSTRACT

N-type calcium channels represent a promising target for the treatment of neuropathic pain. The selective N-type calcium channel blocker ziconotide ameliorates severe chronic pain but has a narrow therapeutic window and requires intrathecal administration. We identified tetrahydroisoquinoline derivative 1a as a novel potent N-type calcium channel blocker. However, this compound also exhibited potent inhibitory activity against hERG channels. Structural optimizations led to identification of (1S)-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-{[(1-hydroxycyclohexyl)methyl]amino}ethanone ((S)-1h), which exhibited high selectivity for hERG channels while retaining potency for N-type calcium channel inhibition. (S)-1h went on to demonstrate in vivo efficacy as an orally available N-type calcium channel blocker in a rat spinal nerve ligation model of neuropathic pain.


Subject(s)
Calcium Channel Blockers/chemistry , Calcium Channels, N-Type/metabolism , Ether-A-Go-Go Potassium Channels/metabolism , Tetrahydroisoquinolines/chemistry , Animals , Calcium Channel Blockers/metabolism , Calcium Channel Blockers/therapeutic use , Calcium Channels, N-Type/chemistry , Cell Line, Tumor , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Drug Evaluation, Preclinical , Ether-A-Go-Go Potassium Channels/chemistry , Humans , Male , Neuralgia/drug therapy , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tetrahydroisoquinolines/metabolism , Tetrahydroisoquinolines/therapeutic use
8.
Bioorg Med Chem ; 22(21): 6026-38, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-25281269

ABSTRACT

A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT(2B) and 5-HT(7) receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4',5'-dihydro-3'H-spiro[fluorene-9,2'-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT(2B) (Ki = 5.1 nM) and 5-HT(7) (K(i) = 1.7 nM) receptors with high selectivity over 5-HT(2A), 5-HT(2C), α(1), D(2) and M(1) receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials.


Subject(s)
Receptor, Serotonin, 5-HT2B/metabolism , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Animals , CHO Cells , Cricetulus , Guinea Pigs , HEK293 Cells , Humans , Molecular Docking Simulation , Serotonin 5-HT2 Receptor Antagonists/chemical synthesis , Serotonin 5-HT2 Receptor Antagonists/chemistry , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Serotonin Antagonists/chemical synthesis
9.
Bioorg Med Chem ; 22(15): 4323-37, 2014 Aug 01.
Article in English | MEDLINE | ID: mdl-24916029

ABSTRACT

We previously reported that the novel dual 5-HT2B and 5-HT7 receptor antagonist N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (4) exerted a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs. To develop a synthetic strategy, we performed docking studies of lead compound 4 bound to 5-HT2B and 5-HT7 receptors, and observed that the carbonyl guanidine group forms a tight interaction network with an active center Asp (D135:5-HT2B, D162:5-HT7), Tyr (Y370:5-HT2B, Y374:5-HT7) and aromatic residue (W131:5-HT2B, F158:5-HT7). Based on molecular modeling results, we optimized the substituents at the 5- to 8-position and 9-position of the fluorene ring and identified N-(diaminomethylene)-9-hydroxy-9-methyl-9H-fluorene-2-carboxamide (24a) exhibits potent affinity for 5-HT2B (Ki=4.3 nM) and 5-HT7 receptor (Ki=4.3 nM) with high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 24a reversed the hypothermic effect of 5-carboxamidotryptamine (5-CT) in mice and also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered at 30 mg/kg. Compound 24a is therefore a promising candidate for a novel class of anti-migraine agent without any adverse effects.


Subject(s)
Guanidine/analogs & derivatives , Receptor, Serotonin, 5-HT2B/chemistry , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemical synthesis , Administration, Oral , Animals , Binding Sites , Body Temperature/drug effects , CHO Cells , Cricetinae , Cricetulus , Guanidine/chemical synthesis , Guanidine/pharmacokinetics , Guinea Pigs , HEK293 Cells , Humans , Hypothermia, Induced , Male , Mice , Molecular Docking Simulation , Protein Binding , Protein Structure, Tertiary , Receptor, Serotonin, 5-HT2B/genetics , Receptor, Serotonin, 5-HT2B/metabolism , Receptors, Serotonin/genetics , Receptors, Serotonin/metabolism , Serotonin/analogs & derivatives , Serotonin/pharmacology , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacokinetics , Structure-Activity Relationship
10.
Bioorg Med Chem ; 21(24): 7841-52, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-24189186

ABSTRACT

To identify potent dual 5-HT2B and 5-HT7 receptor antagonists, we synthesized a series of novel carbonyl guanidine derivatives and examined their structure-activity relationships. Among these compounds, N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (10) had a good in vitro profile, that is, potent affinity for human 5-HT2B and 5-HT7 receptor subtypes (Ki=1.8 nM and Ki=17.6 nM, respectively) and high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 10 also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered.


Subject(s)
Guanidine/analogs & derivatives , Guanidine/pharmacology , Receptor, Serotonin, 5-HT2B/metabolism , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Dose-Response Relationship, Drug , Guanidine/chemistry , Humans , Molecular Structure , Serotonin Antagonists/chemical synthesis , Structure-Activity Relationship
11.
J Colloid Interface Sci ; 297(2): 672-7, 2006 May 15.
Article in English | MEDLINE | ID: mdl-16313919

ABSTRACT

Calcination of a cerium-S-phenylene-O-holmium-O-phenylene-S hybrid copolymer under a vacuum gave cerium oxide-carbon cluster-holmium oxide composite material. The material calcined at 600 degrees C loaded with Pt particles could decompose water to H2 and O2 with a H2/O2 ratio of 2 under visible light irradiation. ESR spectral examinations of the calcined materials revealed the possibility of a two-step electron transfer in the process of CeO2 --> carbon cluster --> Ho2O3 --> Pt with an oxidation site at CeO2 particles and a reduction site at Pt particles.

12.
Int Heart J ; 46(5): 933-8, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16272786

ABSTRACT

A 62-year-old woman was struck by lightning while on a mountain and fortunately did not suffer burns or unconsciousness. She stayed at a mountain lodge overnight and was taken to our hospital by helicopter the next day. Upon admission, electrocardiography showed ST segment elevation indicating acute lateral myocardial infarction, and echocardiography showed takotsubo-shaped hypokinesis of the left ventricle indicating an apical aneurysm. Her serum escaped enzyme levels were increased, as is typical in cases of myocardial infarction, however, she did not complain of cardiac symptoms. Coronary arteriography performed 4 days after admission showed a normal coronary artery while left ventriculography showed apical akinesia. An echocardiogram obtained 2 days later showed resolution of the LV wall motion abnormality. This is the first reported case of takotsubo cardiomyopathy caused by lightning. Takotsubo-shaped hypokinesis is not described as a complication of lightning-induced cardiac injury and its pathogenesis remains controversial.


Subject(s)
Cardiomyopathies/etiology , Heart Injuries/etiology , Hypokinesia/etiology , Lightning Injuries/complications , Aspirin/administration & dosage , Cardiomyopathies/drug therapy , Drug Therapy, Combination , Female , Heart Ventricles/pathology , Humans , Isosorbide Dinitrate/administration & dosage , Isosorbide Dinitrate/analogs & derivatives , Middle Aged , Mountaineering
13.
Chem Pharm Bull (Tokyo) ; 53(8): 1043-7, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16079546

ABSTRACT

In the setting of heart failure and myocardial ischemia-reperfusion, the sodium-calcium exchanger (NCX) can lead to calcium overload, which is responsible for contractile dysfunction and arrhythmia. NCX is an attractive target for treatment in heart failure and myocardial ischemia-reperfusion. We have designed and synthesized a series of benzyloxyphenyl derivatives based on compound 3. These derivatives have been evaluated for their inhibitory activity against both the reverse and forward modes of NCX. We have discovered a novel potent and selective reverse NCX inhibitor (12) with an IC50 value of 0.085 microM against reverse NCX.


Subject(s)
Acetamides/chemistry , Pyridines/chemistry , Sodium-Calcium Exchanger/antagonists & inhibitors , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom Bombardment
14.
Bioorg Med Chem ; 13(12): 4022-36, 2005 Jun 02.
Article in English | MEDLINE | ID: mdl-15911315

ABSTRACT

Ca(2+) overload in myocardial cells is responsible for arrhythmia. Sodium-calcium exchanger (NCX) inhibitors are more effective than sodium-hydrogen exchanger (NHE) inhibitors with regard to modulation of Ca(2+) overload, because NCX inhibitors can directly inhibit the influx of Ca(2+) into cells. NCX is an attractive target for the treatment of heart failure and ischemia-reperfusion. We have designed and synthesized a series of N-(2-aminopyridin-4-ylmethyl)nicotinamide derivatives, based on compound 5. We have discovered a novel NCX inhibitor (23 h) with an IC(50) value of 0.12 microM against reverse NCX. The inhibitory activities of our NCX inhibitors against cytochrome P450 were also evaluated. The effects on heart failure and the pharmacokinetic profile of compound 23 h are discussed.


Subject(s)
Calcium Channel Blockers/chemical synthesis , Niacinamide/analogs & derivatives , Sodium-Calcium Exchanger/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Calcium/metabolism , Calcium Channel Blockers/pharmacology , Cytochrome P-450 Enzyme System/drug effects , Disease Models, Animal , Heart Failure/drug therapy , Humans , Inhibitory Concentration 50 , Male , Myocardial Reperfusion Injury/drug therapy , Niacinamide/chemical synthesis , Niacinamide/pharmacology , Pharmacokinetics , Rats , Rats, Inbred Strains , Structure-Activity Relationship
15.
Chem Pharm Bull (Tokyo) ; 53(4): 448-50, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15802851

ABSTRACT

A practical and cost-effective procedure has been developed for the synthesis of 7-methyl-2-naphthalenecarbonitrile, the precursor of the anticoagulant agents YM-60828 or YM-96765. This new route generates the key intermediate in only two steps from readily available 3-cyanopropionaldehyde dimethyl acetal and m-tolualdehyde, without requiring chromatographic purification. The synthesis involves condensation of the cyano derivative with the aldehyde and subsequent cyclodehydration.


Subject(s)
Anticoagulants/chemical synthesis , Naphthalenes/chemical synthesis , Nitriles/chemical synthesis , Benzaldehydes , Chromatography, Thin Layer , Heterocyclic Compounds/chemical synthesis , Magnetic Resonance Spectroscopy , Piperidines/chemical synthesis , Spectrophotometry, Ultraviolet
16.
Bioorg Med Chem ; 13(3): 725-34, 2005 Feb 01.
Article in English | MEDLINE | ID: mdl-15653340

ABSTRACT

In the context of heart failure and myocardial ischemia reperfusion, the activity of the sodium-calcium exchanger can lead to calcium overload, which in turn can lead to contractile dysfunction and arrhythmia. Therefore, NCX is an attractive target for treatment of heart failure and myocardial ischemia reperfusion. We have designed and synthesized a series of benzyloxyphenyl derivatives as potential NCX inhibitors, based on compound 4. These derivatives have been evaluated for their inhibitory activity against both the reverse and forward modes of NCX, and two novel potent NCX inhibitors (7i, 10a) were discovered. Compound 7i was evaluated for its efficacy on ouabain-induced tonotropy and arrhythmia in a heart-failure model.


Subject(s)
Benzyl Compounds/chemistry , Benzyl Compounds/chemical synthesis , Cardiac Output, Low/drug therapy , Myocardial Ischemia/drug therapy , Sodium-Calcium Exchanger/chemistry , Sodium-Calcium Exchanger/pharmacology , Benzyl Compounds/pharmacology , Humans , Magnetic Resonance Spectroscopy , Sodium-Calcium Exchanger/chemical synthesis , Spectrometry, Mass, Fast Atom Bombardment , Structure-Activity Relationship
17.
Bioorg Med Chem ; 12(19): 5039-56, 2004 Oct 01.
Article in English | MEDLINE | ID: mdl-15351388

ABSTRACT

The sodium-calcium exchanger (NCX) is known as the transporter that controls the concentration of Ca(2+) in cardiac myocytes. In the setting of heart failure and myocardial ischemia-reperfusion, NCX underlies an arrhythmogenic transient inward current responsible for delayed after--depolarizations and nonreentrant initiation of ventricular tachycardia. NCX is an attractive target for treatment in heart failure and myocardial ischemia-reperfusion. We have designed and synthesized a series of phenoxypyridine derivatives, based on compound 3. These derivatives have been evaluated for their inhibitory activity against both the reverse and forward mode of NCX in CCL39 cells. We have discovered several novel potent NCX inhibitors (39q, 48k), which have a high selectivity for reverse NCX inhibitory activity.


Subject(s)
Pyridines/chemical synthesis , Pyridines/pharmacology , Sodium-Calcium Exchanger/antagonists & inhibitors , Animals , Calcium/metabolism , Cell Line , Cricetinae , Fibroblasts/cytology , Fibroblasts/drug effects , Inhibitory Concentration 50 , Necrosis/chemically induced , Structure-Activity Relationship
18.
Intern Med ; 42(3): 268-72, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12705793

ABSTRACT

A young man with repetitive deep venous thrombosis of the legs and the inferior vena cava, and his family were eventually diagnosed by means of molecular genetic analysis as having both hereditary protein C and protein S deficiency. There have been a few reports of families with combined protein C and protein S deficiency and only one report of such a family characterized at the DNA level. This was the first reported family in Japan with combined deficiency of protein C and protein S accompanied by segregation of gene lesions.


Subject(s)
Protein C Deficiency/complications , Protein C Deficiency/genetics , Protein S Deficiency/complications , Protein S Deficiency/genetics , Thromboembolism/complications , Thromboembolism/genetics , Venous Thrombosis/complications , Venous Thrombosis/genetics , Adult , Chromosome Segregation , DNA Mutational Analysis , Genotype , Humans , Male , Point Mutation , Recurrence
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