The Effect of Vitamin K2 Supplementation on PIVKA-II Levels in Patients with Severe Motor and Intellectual Disabilities Undergoing Long-Term Tube Feeding.

Nutritional support is essential for patients with severe motor and intellectual disabilities (SMID) to ensure the smooth provision of medical care. These patients often require long-term tube feeding with enteral formulas, potentially leading to deficiencies in vitamins and trace elements. Additionally, frequent antibiotic use for infections often disrupts gut microbiota, inhibiting vitamin K2 production by intestinal bacteria. We assessed the serum protein induced by vitamin K absence or antagonists-II (PIVKA-II) and undercarboxylated osteocalcin (ucOC) levels to assess the vitamin K status in 20 patients with SMID (median age: 44.1 years, 11 men and 9 women) undergoing long-term tube feeding for durations ranging from 3 to 31 years. Thirteen (65%) and nine (45%) patients had elevated PIVKA-II (<40 mAU/mL) and serum ucOC levels (reference value < 4.50 ng/mL), respectively. Dietary vitamin K1 intake did not differ between patients with and without elevated PIVKA-II levels. Vitamin K2 supplementation for 3 months decreased serum PIVKA-II levels near those within the reference range. Approximately half of the patients with SMID on tube feeding had subclinical vitamin K deficiency. Further studies are needed to ascertain if long-term vitamin K2 supplementation effectively prevents vitamin K deficiency-induced hypercoagulation, osteoporosis, and vascular calcification in patients with SMID.

Clostridium butyricum affects nutrition and immunology by modulating gut microbiota.

The gut microbiota has nutritional and protective functions. In patients with end-stage renal disease, changes in the gut microbiota disrupt their protective functions. Probiotics help maintain normal bowel function. However, their role in patients with end-stage renal disease is controversial. We investigated whether Clostridium butyricum affects the nutrition and immune function of patients with end-stage renal disease undergoing maintenance dialysis between 2014 and 2015; thirty-seven patients were included. The patients were divided into two groups: one in which C. butyricum was administered and one in which it was not. One tablet of the probiotics, which contained 20 mg of C. butyricum, was administered orally three times daily for 2 years in the C. butyricum group. The 16S rRNA genes were sequenced from stool samples of 14 (37.8%) patients in the C. butyricum group and 23 (62.2%) patients in the control group. The differences in the gut microbiota of the two groups were analyzed. The α-diversity index indicated that the C. butyricum group had significantly more operational taxonomic units and higher albumin and transferrin levels than the control group. The effector to target cell ratio was significantly higher in the C. butyricum group. In addition, interleukin-6 levels were significantly lower in the C. butyricum group, and inflammation was less severe in this group. The patients undergoing maintenance dialysis with C. butyricum had abundant gut microbiota. They also had a good nutritional status, low systemic inflammation, and a good immunological status.

Isolated neutropenia caused by copper deficiency due to jejunal feeding and excessive zinc intake: A case report.

BACKGROUND: Percutaneous endoscopic gastrostomy with jejunal extension (PEG-J) is often used to treat patients with neurological impairment and difficulty in swallowing. However, these patients often develop copper deficiency. This report describes a case of isolated neutropenia, which is a rare manifestation of copper deficiency. CASE SUMMARY: Our patient was a 19-year-old boy with neurological impairment and gastroesophageal reflux. He received PEG-J feeding, including an enteral supplement containing copper and zinc. However, as his serum zinc level was low (53 µg/dL) at the age of 19 years and 2 mo, we changed to a zinc-rich supplement containing 22 mg/d of zinc and 1.0 mg/d of copper. The supplement comprised a mixture of isocal 1.0 junior (5 packs/d), Tezon [2 packs (250 mL)/d], and cocoa powder. Seven months later, he had neutropenia (606/mm3) with a serum copper level of 16 µg/dL. There were no other manifestations of copper deficiency, including anemia. Copper deficiency and neutropenia both improved following the administration of cocoa powder and Tezon. CONCLUSION: In patients receiving long-term PEG-J feeds, white blood cell counts, hemoglobin, and serum levels of copper and zinc should be regularly monitored.

Effect of increased blood flow rate on renal anemia and hepcidin concentration in hemodialysis patients.

BACKGROUND: Increasing the blood flow rate (BFR) is a useful method for increasing Kt/V and the clearance for low molecular solutes. Hemodialysis patients are often anemic due to hypoerythropoiesis and their chronic inflammatory state. Hepcidin, a hormone that regulates iron homeostasis, is considered as an indicator of iron deficiency in patients with end-stage renal disease. This study aimed to investigate the effects of an increased BFR during hemodialysis on serum hepcidin levels and anemia. METHODS: Between April 2014 and March 2016, 22 chronic dialysis patients (11 men [50.0 %]; mean [± standard deviation] age, 72 ± 12 years) undergoing maintenance hemodialysis treatment, thrice weekly, were enrolled and followed prospectively for 24 months. In April 2014, the BFR was 200 mL/min; in April 2015 this was increased to 400 mL/min, which was within acceptable limits. The dialysate flow rate remained stable at; 500mlL/min. Blood samples were collected in March 2015 and 2016. The primary endpoint was the comparison of the amounts of erythropoiesis-stimulating agent (ESA) required. RESULTS: The increased BFR increased the Kt/V and contributed to significantly decreased urea nitrogen (UN) (p = 0.015) and creatinine (Cr) (p = 0.005) levels. The dialysis efficiency was improved by increasing the BFR. Ferritin (p = 0.038), hepcidin (p = 0.041) and high-sensitivity interleukin-6 (p = 0.038) levels were also significantly reduced. The ESA administered was significantly reduced (p = 0.004) and the Erythropoietin Resistant Index (ERI) significantly improved (p = 0.031). The reduction rates in UN (p < 0.001), Cr (p < 0.001), and beta-2 microglobulin (p = 0.017) levels were significantly greater post the BFR increase compared to those prior to the BFR increase. However, hepcidin was not affected by the BFR change. CONCLUSIONS: Increasing BFR was associated with hemodialysis efficiency, and led to reduce inflammatory cytokine interleukin-6, but did not contribute to reduce C-reactive protein. This reduced hepcidin levels, ESA dosage and ERI. Hepcidin levels were significantly correlated with ferritin levels, and it remains to be seen whether reducing hepcidin leads to improve ESA and iron availability during anemia management.

Deep Vein Thrombosis in Severe Motor and Intellectual Disabilities Patients and Its Treatment by Anticoagulants of Warfarin Versus Edoxaban.

Objective: Patients with severe motor and intellectual disabilities (SMID) often develop complications, including paralysis of the extremities due to abnormal muscular tonicity. Furthermore, the incidence of sudden death, which may be caused by pulmonary thromboembolism (PTE), is approximately 4.2%. Deep vein thrombosis (DVT) is attracting attention as an embolic source. In this study, DVT was confirmed in SMID patients by lower extremity venous ultrasound. The oral anticoagulant, warfarin, and novel oral anticoagulant, edoxaban tosilate hydrate, were administered, and their efficacies and safeties were evaluated. Materials and Methods: DVT patients were randomly allocated to warfarin and edoxaban groups. The frequency of hemorrhagic events and incidence of adverse events were investigated to evaluate efficacy and safety. Results: DVT was detected in 14 (8.4%) out of 167 patients. Four (0.067/person-month) hemorrhagic events occurred in the warfarin group from subcutaneous hemorrhage due to bruises caused by postural changes. Three (0.042/person-month) events occurred in the edoxaban group due to nasal hemorrhage caused by tracheal aspiration. There was no significant difference (p=0.5383) between groups. Conclusion: No significant differences were observed in hemorrhagic events between SMID patients with DVT treated with warfarin and edoxaban.

Prevalence and Characteristic Features of Deep Venous Thrombosis in Patients with Severe Motor and Intellectual Disabilities.

Sudden death associated with patients with severe motor and intellectual disabilities (SMID) have been thought to be caused in part by venous thromboembolism (VTE), but actual situation of VTE in SMID is not clear. We examined the prevalence and location of deep venous thrombosis (DVT), and the relation of the development of crural veins in 16 patients with SMID, using ultrasonography. The maximum diameter of soleal vein was 1.6±0.5 mm. In most cases, DVT was found in the femoral veins. We could not detect thrombus in the soleal veins. In the present study, the detection ratio of DVT was high in patients with SMID who had restricted mobility capability and were bedridden, and we found the veins centrally from popliteal veins in DVT in SMID, not soleal veins, as the initial sites of the DVT. In the literature, the mean diameter of soleal veins, in healthy adults is 6.7±1.8 mm, that in contrast in SMID being smaller. Underdevelopment of intramuscular veins is possibly related to the mechanism of DVT in SMID. In the current guidelines for the management of VTE, there is limited in scope of ambulatory adults and no application cases who exhibit to SMID restricted mobility of the lower extremities and are bedridden associated with cerebral palsy and developmental motor disabilities, and such patients have associated high risk of the complications of DVT. According to our present study, it is necessary to provide appropriate guidelines for DVT in SMID considering characteristic features. (This is a translation of Jpn J Phlebol 2017; 28: 29-34.).

Multicenter, Open-Label, Randomized Controlled Trial of Warfarin and Edoxaban Tosilate Hydrate for the Treatment of Deep Vein Thrombosis in Persons with Severe Motor Intellectual Disabilities.

Sudden death in patients with severe motor and intellectual disabilities (SMID) is sometimes caused in part by pulmonary thromboembolism (PTE), and deep venous thrombosis (DVT) has drawn attention as a possible embolic source. Warfarin, which is a conventional therapeutic agent, is not easy to control appropriately, and daily management can be especially difficult in SMID patients. On the other hand, edoxaban tosilate hydrate, which has been newly approved for insurance coverage for the treatment of DVT, is not listed in the Guidelines for the Diagnosis, Treatment and Prevention of Pulmonary Thromboembolism and Deep Vein Thrombosis (DVT-PTE guidelines). The aim of this study is to evaluate the efficacy and safety of anticoagulation therapy (warfarin vs. edoxaban) in DVT treatment in SMID patients by means of an open-label, randomized controlled trial. The primary endpoint is the incidence of hemorrhagic events during 12 months of follow up.

KL-6 as a biomarker of respiratory complications in severely disabled children.

BACKGROUND: The aim of this study was to assess the importance of KL-6 level in evaluating the status of stabilized chronic pneumonia in children in the severe motor and intellectual disabilities-medical care-dependent (SMID-MCD) category. METHODS: A total of 20 SMID-MCD children were enrolled in this study. Serum KL-6, white blood cell count, C-reactive protein, chest computed tomography (CT) and other factors related to respiratory complications were analyzed in all children under stable respiratory conditions. RESULTS: Mean age was 5.8 ± 1.0 years (mean ± SE). Serum KL-6 was significantly higher in those SMID-MCD children with abnormal CT than in those with normal CT: 316 ± 39 U/mL versus 190 ± 11, respectively (P = 0.0075). CONCLUSIONS: Measures of serum KL-6 level provide valuable information for determining the respiratory management of SMID-MCD children with occult chronic pneumonia.

Deep Vein Thrombosis in Patients with Severe Motor and Intellectual Disabilities, Especially Diagnosis and Prevention of Recurrence for Chronic Thrombosis-Serial Changes of Sonography and D-Dimer.

Most patients with severe motor and intellectual disabilities (SMID) have restricted mobility capability and have been bedridden for long periods because of paralysis of the extremities caused by abnormal muscular tonicity due to cerebral palsy and developmental disabilities. Such patients are associated with a high risk of complications like deep vein thrombosis (DVT). Here, we report twelve patients (42.9%) with DVT among 28 patients with SMID during prolonged bed rest. However, we did not detect thrombosis in the soleal veins, finding it mostly in the femoral and common femoral veins. We applied anticoagulant therapy (warfarin), and carefully followed up the cases with DVT, regulating the warfarin dosage at prothrombin time-international normalized ratio (PT-INR) values around two to prevent recurrence of chronic thrombosis. Regarding laboratory data for the coagulation system, there were no cases above 5 µg/ml for the D-dimer and there were significant differences between the DVT and non-DVT groups in the D-dimer levels. The plasma levels of D-dimer in patients with DVT diminished to less than 1.0 µg/ml after warfarin treatment. Concerning sudden death (4.2%) in patients with SMID, we have to be very careful of the possibility of pulmonary thromboembolism due to DVT. Therefore, we should consider the particularity of the underdeveloped vascular system from underlying diseases for the evaluation of DVT. A detailed study of DVT as a vascular complication is very important for the smooth medical care of SMID, and serial assessment of compression Doppler ultrasonography of the lower extremities, as a noninvasive examination and measurement of D-dimer, is very helpful. (This article is a translation of Jpn J Phlebol 2014; 25: 34-42.).

Association of increased indoleamine 2, 3-dioxygenase with impaired natural killer cell activity in hemodialysis patients.

Indoleamine 2, 3-dioxygenase (IDO) suppresses adaptive immune response. However, there was no study to examine whether IDO activity is associated with immune parameters in dialysis patients. In this study, we estimated serum IDO activity by the kynurenine/tryptophan ratio (KTR), and compared KTR with natural killer (NK) cell activity, soluble interleukin-2 receptor (sIL-2R) and serum levels of trace elements such as selenium (Se) and zinc (Zn) that affect T-cell function in 28 hemodialysis (HD) patients (age: 72 ± 13 years old, time on HD: 79 ± 89 months). NK cell activity was decreased in 35.7% of the patients. KTR values were almost 10-times higher in HD patients (380.81 ± 385.46 mM/M) than those in the referred controls (32.9 ± 9.10 mM/M). KTR was lower in patients with impaired NK cell activity than those without (279 ± 111 vs. 565 ± 603 mM/M, P = 0.07). There was no relationship between KTR and sIL-2R and Zn, while KTR was significantly and negatively correlated with serum Se levels that can impair cellular immunity (r = -0.41, P < 0.05). Our findings suggest that increased IDO activity with Se deficiency may be associated with impaired NK cell function in HD patients.

Deep vein thrombosis in patients with severe motor and intellectual disabilities.

Most patients with severe motor and intellectual disabilities (SMID) have restricted mobility capability and have been bedridden for long periods because of paralysis of the extremities caused by abnormal muscular tonicity due to cerebral palsy and developmental disabilities, and such patients are associated with a high risk for the complications of deep vein thrombosis (DVT). Here, we report 8 patients (34.8%) with DVT among 23 patients with SMID during prolonged bed rest. However, we did not detect thrombosis in the soleal veins, finding it mostly in the superficial femoral and common femoral veins. Regarding laboratory data for the coagulation system, there were no cases with D-dimer above 5 µg/ml. Concerning sudden death in patients with SMID, we have to be very careful of the possibility of pulmonary thromboembolism due to DVT. Therefore, we should consider the particularities of an underdeveloped vascular system from underlying diseases for the evaluation of DVT in patients with SMID. A detailed study of DVT as a vascular complication is very important for smooth medical care of SMID and compression Doppler ultrasonography of the lower extremities, as noninvasive examination, is very helpful. (English translation of Jpn J Phlebol 2012; 23: 17-24).

Differences in automated analyzers for assessing the use of imprecise serum chloride concentrations as indirect predictors of serum bromide concentrations.

Although bromide (Br) is used to treat intractable epilepsy, serum Br concentrations are not routinely analyzed. The present study measured serum Br(-) and Cl(-) concentrations in Br-treated epileptic patients, showing a significant correlation between Br(-) and imprecise Cl(-) concentrations, which suggested the use of a unique correlating equation for each diagnostic tool. Results indicated that imprecise Cl(-) concentrations are useful markers for measuring appropriate serum Br(-) levels in epileptic patients.

Idiopathic childhood occipital epilepsy of Gastaut: report of 12 patients.

This study sought to present clinical and outcome data of patients with idiopathic childhood occipital epilepsy of Gastaut, to validate previously reported characteristics of this epilepsy. The study group was comprised of 12 affected children (three boys and nine girls), with a median age of onset at 10.3 years. Common ictal manifestations included elementary visual hallucinations (75.0%), blindness or blurring of vision (50.0%), headache (50.0%), and secondarily generalized tonic-clonic seizures (58.3%). Interictal electroencephalography revealed occipital spike-wave paroxysms reactive to eye closure and opening in all patients, accompanied by spike-wave activity in the extra-occipital areas in four (33.3%), and by generalized spike-wave discharges in two (16.7%). One patient exhibited the onset of occipital lobe seizures 1 year after manifesting absence epilepsy. Seizure remission occurred in 81.8% of cases, in half of which medication was discontinued by late adolescence. This study confirmed the previously delineated electroclinical features of epilepsy syndrome, with additional aspects including the frequent association of generalized tonic-clonic seizures and atypical evolution from childhood absence epilepsy.

Atypical childhood absence epilepsy with preceding or simultaneous generalized tonic clonic seizures.

OBJECTIVE: Although the current diagnostic criteria for childhood absence epilepsy (CAE) do not specifically exclude children with generalized tonic clonic seizures (GTCSs) occurring before or early in the course of the active absence seizures, some workers have suggested that they should be interpreted as doing so. The aim of this study was to compare the clinical features between children with typical CAE and those with atypical CAE with preceding or simultaneous episodes of GTCS (atypical CAE-GTCS). METHODS: A total of 11 patients with atypical CAE-GTCS and 30 with typical CAE were identified by using the current CAE criteria. Their clinical data, including age, sex, family history of epilepsy, personal history of febrile convulsions, onset ages of absences and GTCS, treatment, and outcome were statistically analyzed. RESULTS: The two groups had the same mean onset age of absences (6years), and their seizure outcome was comparably favorable in terms of both absences and GTCS. There was no significant difference in other clinical data except for the onset age of GTCS between the groups. CONCLUSION: These findings show the similarity in the main clinical features between the groups, suggesting that some patients with atypical CAE-GTCS may have a variant form of CAE with early onset of GTCS.

Positron emission tomography with glucose hypermetabolism of a hypothalamic hamartoma in infantile spasms associated with Pallister-Hall syndrome.

Although hypothalamic hamartomas (HHs) have been shown to be intrinsically epileptogenic and to participate in the generation of gelastic seizures, no evidence has been reported regarding its contribution to the pathogenesis of infantile spasms. We describe a male infant with Pallister-Hall syndrome who had a large HH presenting with infantile spasms without hypsarrhythmia. [(18)F]fluoro-deoxyglucose positron emission tomography scan performed during the period of epileptic spasms demonstrated glucose hypermetabolism of the HH, which resolved after cessation of the spasms with adrenocorticotropin hormone treatment. No concurrent increased metabolic activity in the lenticular nuclei or brainstem was observed in the ictal or interictal states. The present case suggests that HHs may be involved in the pathogenesis of infantile spasms, possibly with propagation of epileptic discharges from the hamartoma to the descending spinal pathway.

Reversible coma associated with prolonged high-dose phenobarbital therapy in bilateral Sturge-Weber syndrome.

High-dose phenobarbital therapy is an effective treatment for refractory status epilepticus in children. The advantages of this therapy include milder adverse effects without limits for maximal phenobarbital levels or doses during the initial phase of treatment. However, little is known about the safety of continuing the treatment. We describe an infant with intractable epilepsy associated with bilateral Sturge-Weber syndrome who became comatose after 1(2/3) months of high-dose phenobarbital treatment. The patient regained consciousness as serum phenobarbital concentration decreased to below 40 microg/mL. The progression and recovery were also documented by electroencephalogram and brainstem auditory evoked potentials. The present case suggests that prolonged high-dose phenobarbital therapy may cause cerebral and brainstem dysfunction in patients with severe cerebrovascular diseases. The underlying baseline metabolic and perfusion deficit related to the disease can precipitate the neurological complication during long-term high-dose phenobarbital therapy.

Failure-tolerant performance stabilization of the generic large-scale system by decentralized linear output feedback.

Most of the existing results on the decentralized stabilization of large-scale systems consider systems in the input-output-decentralized form, i.e., systems whose input and output matrices are block diagonal. The controller synthesis for such systems is less involved than that for input-output-centralized ones. In this paper, a transformation is proposed for the input-output decentralization of the generic large-scale system. Using the transformed system, a sufficient condition for failure-tolerant performance stabilization of the original large-scale system in a desirable performance region under decentralized linear output feedback is established. The problem is then reformulated as a constrained nonlinear optimization problem. The proposed methodology results in the optimal reconciliation of failure-tolerant performance stabilization of the overall system, and reliability and low actuator gains of the isolated subsystems. The effectiveness of the proposed approach is demonstrated by an example.

Identification and characterization of a novel Pyk2/related adhesion focal tyrosine kinase-associated protein that inhibits alpha-synuclein phosphorylation.

alpha-Synuclein is a presynaptic protein involved in the pathogenesis of several neurodegenerative diseases, such as Parkinson's disease. Pyk2/related adhesion focal tyrosine kinase (RAFTK) tyrosine kinase is an upstream regulator of Src family kinases in the central nervous system that is involved in alpha-synuclein phosphorylation. The present study reports the cloning and characterization of a novel adaptor protein, Pyk2/RAFTK-associated protein (PRAP), that specifically binds to Pyk2/RAFTK and inhibits alpha-synuclein tyrosine phosphorylation. PRAP contains a coiled-coil domain, a pleckstrin homology domain, and a SH3 domain; the SH3 domain binds to the proline-rich domain of Pyk2/RAFTK. PRAP was observed to be present throughout the brain, including substantia nigra dopaminergic neurons, in which it localized to the cytoplasm. PRAP was found to function as a substrate for Src family kinases, such as c-Src or Fyn, but not for Pyk2/RAFTK. Hyperosmotic stress induced phosphorylation of tyrosine 125 of alpha-synuclein via Pyk2/RAFTK, which acted through Src family kinases. Such phosphorylation was inhibited by PRAP expression, suggesting that PRAP negatively regulates alpha-synuclein phosphorylation following cell stress. In conclusion, PRAP functions as a downstream target for Pyk2/RAFTK and plays a role in alpha-synuclein phosphorylation.

Neurotoxic damage of granule cells in the dentate gyrus and the cerebellum and cognitive deficit following neonatal administration of phenytoin in mice.

The use of antiepileptic drugs during human gestation probably increases the risk of causing CNS disorders in later life. In brain, granule cells in the dentate gyrus (DG) and cerebellum are still developing in the last trimester of human gestation and a similar development is taking place during the mouse perinatal period. We treated newborn C57BL/6 mice orally with 35 mg/kg phenytoin (PHT) daily during postnatal days (PD) 5 to 14. Histopathological investigation revealed that the layer of mature granule cells in the DG that was immunoreactive to anti-calbindin D28k was thinner in PHT-treated mice. Purkinje cells in the treated group also had poor, immature arbors with an irregular arrangement. A number of TUNEL-positive cells were observed in the DG and cerebellum during the treatment. PHT-treated mice were impaired in the acquisition of a hidden platform task in the water maze and committed significantly more errors during the learning process in theradial arm maze. These findings demonstrate that neonatal administration of PHT interferes with the development of granule cells in the hippocampus and the cerebellum and causes spatial leaning deficits in later life. Cautious clinical use of this drug for pregnant patients is warranted, especially in the last trimester.