Treatment of long COVID complicated by postural orthostatic tachycardia syndrome-Case series research.

Background: Coronavirus disease 2019 (COVID-19) sequelae, also known as long COVID, can present with various symptoms. Among these symptoms, autonomic dysregulation, particularly postural orthostatic tachycardia syndrome (POTS), should be evaluated. However, previous studies on the treatment of POTS complicated by COVID-19 are lacking. Therefore, this study aimed to investigate the treatment course of long COVID complicated by POTS. Methods: The medical records of patients who complained of fatigue and met the criteria for POTS diagnosis were reviewed. We evaluated the treatment days, methods and changes in fatigue score, changes in heart rate on the Schellong test, and social situation at the first and last visits. Results: Thirty-two patients with long COVID complicated by POTS were followed up (16 males; median age: 28 years). The follow-up period was 159 days, and the interval between COVID-19 onset and initial hospital attendance was 97 days. Some patients responded to ß-blocker therapy. Many patients had psychiatric symptoms that required psychiatric intervention and selective serotonin reuptake inhibitor prescription. Changes in heart rate, performance status, and employment/education status improved from the first to the last visit. These outcomes were believed to be because of the effects of various treatment interventions and spontaneous improvements. Conclusions: Our study suggests that the condition of 94% of patients with POTS complicated by long COVID will improve within 159 days. Therefore, POTS evaluation should be considered when patients with long COVID complain of fatigue, and attention should be paid to psychological symptoms and the social context.

Five cluster classifications of long COVID and their background factors: A cross-sectional study in Japan.

PURPOSE: The long-term symptoms of coronavirus disease 2019 (COVID-19), i.e., long COVID, have drawn research attention. Evaluating its subjective symptoms is difficult, and no established pathophysiology or treatment exists. Although there are several reports of long COVID classifications, there are no reports comparing classifications that include patient characteristics, such as autonomic dysfunction and work status. We aimed to classify patients into clusters based on their subjective symptoms during their first outpatient visit and evaluate their background for these clusters. METHODS: Included patients visited our outpatient clinic between January 18, 2021, and May 30, 2022. They were aged ≥ 15 years and confirmed to have SARS-CoV-2 infection and residual symptoms lasting at least 2 months post-infection. Patients were evaluated using a 3-point scale for 23 symptoms and classified into five clusters (1. fatigue only; 2. fatigue, dyspnea, chest pain, palpitations, and forgetfulness; 3. fatigue, headache, insomnia, anxiety, motivation loss, low mood, and forgetfulness; 4. hair loss; and 5. taste and smell disorders) using CLUSTER. For continuous variables, each cluster was compared using the Kruskal-Wallis test. Multiple comparison tests were performed using the Dunn's test for significant results. For nominal variables, a Chi-square test was performed; for significant results, a residual analysis was conducted with the adjusted residuals. RESULTS: Compared to patients in other cluster categories, those in cluster categories 2 and 3 had higher proportions of autonomic nervous system disorders and leaves of absence, respectively. CONCLUSIONS: Long COVID cluster classification provided an overall assessment of COVID-19. Different treatment strategies must be used based on physical and psychiatric symptoms and employment factors.

Need for revision of the ACMG/AMP guidelines for interpretation of X-linked variants.

The guidelines provided by American College of Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP) (ACMG/AMP guidelines) suggest a framework for the classification of clinical variants. However, the interpretations can be inconsistent, with each definition sometimes proving to be ambiguous. In particular, there can be difficulty with interpretation of variants related to the X-linked recessive trait. To confirm whether there are biases in the interpretation of inherited traits, we reanalyzed variants reported prior to the release of the ACMG/AMP guidelines. As expected, the interpretation ratio as pathogenic or likely pathogenic was significantly lower for variants related to the X-linked recessive trait. Evaluation of variants related to the X-linked recessive trait, hence, need to consider whether the variant is identified only in males in accordance with the X-linked recessive trait. The ACMG/AMP guidelines should be revised to eliminate the bias revealed in this study.

Relationship between changes in symptoms and antibody titers after a single vaccination in patients with Long COVID.

Coronavirus disease 2019 (COVID-19) is spreading worldwide; there is a need to address its sequelae known as Long COVID. This study evaluated postvaccination changes in symptoms and antibody titers in patients with Long COVID. Patients visiting the outpatient department specializing in Long COVID at our hospital were enrolled. Changes in symptoms were evaluated before and 14-21 days after first vaccination. Antibody titers were measured using ARCHITECT SARS-CoV-2 IgG II Quant at the same time. This study included 42 patients (median age: 45 years; 17 [40.5%] men). Median pre- and postvaccination antibody titers were 456 and 28,963 AU/ml, respectively. Postvaccination symptoms (fatigue, joint pain, and taste and olfactory abnormalities) were relieved, worsened, and unchanged in 7 (16.7%), 9 (21.4%), and 26 (61.9%) patients, respectively. Ratios of pre- and postvaccination antibody titers were 53, 40, and 174 in the unchanged, relief, and worsened groups, respectively. The worsened group had the significantly highest antibody titer ratio (p = 0.02). The higher increased rate of the antibody titer in the worsened group than in the nonworsened group suggests an excessive immune response to vaccination associated with worsening of sequelae. Although patients with Long COVID should be vaccinated, additional concerns should be addressed.

Deletion of the gene encoding prostamide/prostaglandin F synthase reveals an important role in regulating intraocular pressure.

Prostamide/prostaglandin F synthase (PM/PGFS) is an enzyme with very narrow substrate specificity and is dedicated to the biosynthesis of prostamide F2α and prostaglandin F2α (PGF2α.). The importance of this enzyme, relative to the aldo-keto reductase (AKR) series, in providing functional tissue prostamide F2α levels was determined by creating a line of PM/PGFS gene deleted mice. Deletion of the gene encoding PM/PGFS (Fam213b / Prxl2b) was accomplished by a two exon disruption. Prostamide F2α levels in wild type (WT) and PM/PGFS knock-out (KO) mice were determined by LC/MS/MS. Deletion of Fam213b (Prxl2b) had no observed effect on behavior, appetite, or fertility. In contrast, tonometrically measured intraocular pressure was significantly elevated by approximately 4 mmHg in PM/PGFS KO mice compared to littermate WT mice. Outflow facility was measured in enucleated mouse eyes using the iPerfusion system. No effect on pressure dependent outflow facility occurred, which is consistent with the effects of prostamide F2α and PGF2α increasing outflow through the unconventional pathway. The elevation of intraocular pressure caused by deletion of the gene encoding the PM/PGFS enzyme likely results from a diversion of the endoperoxide precursor pathway to provide increased levels of those prostanoids known to raise intraocular pressure, namely prostaglandin D2 (PGD2) and thromboxane A2 (TxA2). It follows that PM/PGFS may serve an important regulatory role in the eye by providing PGF2α and prostamide F2α to constrain the influence of those prostanoids that raise intraocular pressure.

Component-resolved diagnostics can be useful for identifying hazelnut allergy in Japanese children.

BACKGROUND: Cor a 9 and Cor a 14 are effective markers for predicting hazelnut allergy. However, there have been no reports on the component-resolved diagnostics (CRD) of hazelnut allergy using an oral food challenge (OFC) for diagnosis in Asia. We hypothesized that CRD would improve the accuracy of diagnosing hazelnut allergies in Japanese children. METHODS: We recruited 91 subjects (median age: 7.3 years) who were sensitized to hazelnuts and had performed a hazelnut OFC at the National Hospital Organization Sagamihara National Hospital between 2006 and 2017. All subjects were classified as allergic or asymptomatic to 3 g of hazelnuts. The sIgE levels (hazelnut/Cor a 1/Cor a 8/Cor a 9/Cor a 14/alder pollen) were measured using ImmunoCAP. We aimed to determine the predictive factors of hazelnut allergy. RESULTS: Nine subjects (10%) were allergic to ≤3 g of hazelnuts. Levels of sIgE for Cor a 9 in hazelnut-allergic subjects were significantly higher than those in asymptomatic subjects (4.47 vs. 0.76 kUA/L, p = 0.039). Levels of sIgE to alder pollen and Cor a 1 in hazelnut-allergic subjects were significantly lower than those in asymptomatic subjects (<0.10 vs 13.0 kUA/L, p = 0.004; <0.10 vs 5.03 kUA/L, p = 0.025). The area under the receiver operating characteristics curve for hazelnut/alder/Cor a 1/Cor a 9 was 0.55/0.78/0.72/0.71, respectively, with p = 0.651/0.006/0.029/0.040, respectively. CONCLUSIONS: The findings of a high sIgE level for Cor a 9 and a low sIgE level for Cor a 1 can improve the diagnostic accuracy to better identify Japanese children sensitized to hazelnuts.

Development of Ion Mobility Spectrometry with Novel Atmospheric Electron Emission Ionization for Field Detection of Gaseous and Blister Chemical Warfare Agents.

Drift tube ion mobility spectrometry with a novel atmospheric electron emission (AEE) source was developed for determination of gaseous and blister chemical warfare agents (CWAs) in negative mode. The AEE source was fabricated from an aluminum substrate electrode covered with 1 µm silver nanoparticle-dispersed silicone resin and a thin gold layer. This structure enabled stable tunneling electron emission upon the application of more than 11 V potential under atmospheric pressure. The reactant ion peak (RIP) was observed for the reduced mobility constant ( K0) of 2.18 and optimized at the charging voltage of 20 V. This RIP was assigned to O2- by using a mass spectrometer. Hydrogen cyanide was detected as a peak ( K0 = 2.47) that was discriminatively separated from the RIP (resolution = 1.4), with a limit of detection (LOD) of 0.057 mg/m3, and assigned to CN- and OCN-. Phosgene was detected as a peak ( K0 = 2.36; resolution = 1.2; and LOD = 0.6 mg/m3), which was assigned to Cl-. Lewisite 1 was detected as two peaks ( K0 = 1.68 and 1.34; LOD = 12 and 15 mg/m3). The K0 = 1.68 peak was ascribed to a mixture of adducts of molecules or the product of hydrolysis with oxygen or chloride. Cyanogen chloride, chlorine, and sulfur mustard were also well detected. The detection performance with the AEE source was compared with those under corona discharge and 63Ni ionizations. The advantage of the AEE source is the simple RIP pattern (only O2-), and the characteristic marker ions contribute to the discriminative CWAs detection.

Measurement of Exhaled Nitric Oxide in Children: A Comparison Between NObreath® and NIOX VERO® Analyzers.

PURPOSE: Few studies have compared fractional exhaled nitric oxide (FeNO) measurement by NIOX VERO® (NOV) and other devices in children. Moreover, there is no agreement between differences in FeNO values obtained using different devices in adults. Here, we compared FeNO values obtained using NOV and NObreath® (NOB) systems to derive a correction equation for children. METHODS: Eighty-eight participants (age 7-15 years) who were diagnosed with atopic bronchial asthma and visited Sagamihara National Hospital as outpatients between January and April of 2017 were included. We measured FeNO values obtained using NOB and NOV, and analyzed them using Wilcoxon tests and Altman-Bland plots. RESULTS: The median age of the participants was 11.5 years, and the scored Asthma Control Test (ACT) or Childhood ACT (C-ACT) was 25 (interquartile range, 24-25) or 26 (24-27). NOB and NOV values were significantly different (31 [14-52] versus 36 [20-59] ppb; P = 0.020) and strongly correlated (r = 0.92). An equation to convert NOB values into NOV values was derived using linear regression as follows: log NOV = 0.7329 × log NOB + 0.4704; NOB for 20, 40, 58, 80 and 100 ppb corresponded to NOV for 27, 44, 59, 73 and 86 ppb. Thus, NOB < 58 ppb suggested NOB < NOV, whereas NOB > 58 ppb suggested NOB > NOV. CONCLUSIONS: NOB and NOV values were strongly correlated. Participants whose FeNO values were relatively low represented NOB < NOV, whereas those whose FeNO values were relatively high represented NOB > NOV.

Loss of X-linked Protocadherin-19 differentially affects the behavior of heterozygous female and hemizygous male mice.

Mutations in the X-linked gene Protocadherin-19 (Pcdh19) cause female-limited epilepsy and mental retardation in humans. Although Pcdh19 is known to be a homophilic cell-cell adhesion molecule, how its mutations bring about female-specific disorders remains elusive. Here, we report the effects of Pcdh19 knockout in mice on their development and behavior. Pcdh19 was expressed in various brain regions including the cerebral cortex and hippocampus. Although Pcdh19-positive cells were evenly distributed in layer V of wild-type cortices, their distribution became a mosaic in Pcdh19 heterozygous female cortices. In cortical and hippocampal neurons, Pcdh19 was localized along their dendrites, showing occasional accumulation on synapses. Pcdh19 mutants, however, displayed no detectable abnormalities in dendrite and spine morphology of layer V neurons. Nevertheless, Pcdh19 hemizygous males and heterozygous females showed impaired behaviors including activity defects under stress conditions. Notably, only heterozygous females exhibited decreased fear responses. In addition, Pcdh19 overexpression in wild-type cortices led to ectopic clustering of Pcdh19-positive neurons. These results suggest that Pcdh19 is required for behavioral control in mice, but its genetic loss differentially affects the male and female behavior, as seen in human, and they also support the hypothesis that the mosaic expression of Pcdh19 in brains perturbs neuronal interactions.

A hairy-leaf gene, BLANKET LEAF, of wild Oryza nivara increases photosynthetic water use efficiency in rice.

BACKGROUND: High water use efficiency is essential to water-saving cropping. Morphological traits that affect photosynthetic water use efficiency are not well known. We examined whether leaf hairiness improves photosynthetic water use efficiency in rice. RESULTS: A chromosome segment introgression line (IL-hairy) of wild Oryza nivara (Acc. IRGC105715) with the genetic background of Oryza sativa cultivar 'IR24' had high leaf pubescence (hair). The leaf hairs developed along small vascular bundles. Linkage analysis in BC5F2 and F3 populations showed that the trait was governed by a single gene, designated BLANKET LEAF (BKL), on chromosome 6. IL-hairy plants had a warmer leaf surface in sunlight, probably due to increased boundary layer resistance. They had a lower transpiration rate under moderate and high light intensities, resulting in higher photosynthetic water use efficiency. CONCLUSION: Introgression of BKL on chromosome 6 from O. nivara improved photosynthetic water use efficiency in the genetic background of IR24.

Phosphorylation of the centrosomal protein, Cep169, by Cdk1 promotes its dissociation from centrosomes in mitosis.

Cep169 is a centrosomal protein conserved among vertebrates. In our previous reports, we showed that mammalian Cep169 interacts and collaborates with CDK5RAP2 to regulate microtubule (MT) dynamics and stabilization. Although Cep169 is required for MT regulation, its precise cellular function remains largely elusive. Here we show that Cep169 associates with centrosomes during interphase, but dissociates from these structures from the onset of mitosis, although CDK5RAP2 (Cep215) is continuously located at the centrosomes throughout cell cycle. Interestingly, treatment with purvalanol A, a Cdk1 inhibitor, nearly completely blocked the dissociation of Cep169 from centrosomes during mitosis. In addition, mass spectrometry analyses identified 7 phosphorylated residues of Cep169 corresponding to consensus phosphorylation sequence for Cdk1. These data suggest that the dissociation of Cep169 from centrosomes is controlled by Cdk1/Cyclin B during mitosis, and that Cep169 might regulate MT dynamics of mitotic spindle.

Cep169, a Novel Microtubule Plus-End-Tracking Centrosomal Protein, Binds to CDK5RAP2 and Regulates Microtubule Stability.

The centrosomal protein, CDK5RAP2, is a microcephaly protein that regulates centrosomal maturation by recruitment of a γ-tubulin ring complex (γ-TuRC) onto centrosomes. In this report, we identified a novel human centrosomal protein, Cep169, as a binding partner of CDK5RAP2, a member of microtubule plus-end-tracking proteins (+TIPs). Cep169 interacts directly with CDK5RAP2 through CM1, an evolutionarily conserved domain, and colocalizes at the pericentriolar matrix (PCM) around centrioles with CDK5RAP2. In addition, Cep169 interacts with EB1 through SxIP-motif responsible for EB1 binding, and colocalizes with CDK5RAP2 at the microtubule plus-end. EB1-binding-deficient Cep169 abolishes EB1 interaction and microtubule plus-end attachment, indicating Cep169 as a novel member of +TIPs. We further show that ectopic expression of either Cep169 or CDK5RAP2 induces microtubule bundling and acetylation in U2OS cells, and depletion of Cep169 induces microtubule depolymerization in HeLa cells, although Cep169 is not required for assembly of γ-tubulin onto centrosome by CDK5RAP2. These results show that Cep169 targets microtubule tips and regulates stability of microtubules with CDK5RAP2.

Soybean ß-Conglycinin Prevents Age-Related Hearing Impairment.

Obesity-related complications are associated with the development of age-related hearing impairment. ß-Conglycinin (ß-CG), one of the main storage proteins in soy, offers multiple health benefits, including anti-obesity and anti-atherosclerotic effects. Here, to elucidate the potential therapeutic application of ß-CG, we investigated the effect of ß-CG on age-related hearing impairment. Male wild-type mice (age 6 months) were randomly divided into ß-CG-fed and control groups. Six months later, the body weight was significantly lower in ß-CG-fed mice than in the controls. Consumption of ß-CG rescued the hearing impairment observed in control mice. Cochlear blood flow also increased in ß-CG-fed mice, as did the expression of eNOS in the stria vascularis (SV), which protects vasculature. ß-CG consumption also ameliorated oxidative status as assessed by 4-HNE staining. In the SV, lipofuscin granules of marginal cells and vacuolar degeneration of microvascular pericytes were decreased in ß-CG-fed mice, as shown by transmission electron microscopy. ß-CG consumption prevented loss of spiral ganglion cells and reduced the frequencies of lipofuscin granules, nuclear invaginations, and myelin vacuolation. Our observations indicate that ß-CG ameliorates age-related hearing impairment by preserving cochlear blood flow and suppressing oxidative stress.

Protocadherin-17 mediates collective axon extension by recruiting actin regulator complexes to interaxonal contacts.

In the process of neuronal wiring, axons derived from the same functional group typically extend together, resulting in fascicle formation. How these axons communicate with one another remains largely unknown. Here, we show that protocadherin-17 (Pcdh17) supports this group extension by recruiting actin polymerization regulators to interaxonal contact sites. Pcdh17 is expressed by a subset of amygdala neurons, and it accumulates at axon-axon boundaries because of homophilic binding. Pcdh17 knockout in mice suppressed the extension of these axons. Ectopically expressed Pcdh17 altered the pattern of axon extension. In in-vitro cultures, wild-type growth cones normally migrate along other axons, whereas Pcdh17 null growth cones do not. Pcdh17 recruits the WAVE complex, Lamellipodin, and Ena/VASP to cell-cell contacts, converting these sites into motile structures. We propose that, through these mechanisms, Pcdh17 maintains the migration of growth cones that are in contact with other axons, thereby supporting their collective extension.

Adiponectin ameliorates endotoxin-induced acute cardiac injury.

BACKGROUND: Obesity is a risk factor for cardiovascular disease. Increasing evidence suggests that reduced levels of the adipocyte-derived plasma protein adiponectin are associated with an increased cardiovascular risk. Here, we examined the effects of adiponectin on lipopolysaccharide- (LPS-) induced acute cardiac injury in vivo. METHODS AND RESULTS: A single dose of LPS (10 mg/kg) was intraperitoneally injected into wild-type (WT) and adiponectin-knockout (APN-KO) mice. Following LPS administration, APN-KO mice had exacerbation of left ventricular (LV) systolic dysfunction compared with WT mice. Administration of LPS to WT and APN-KO mice led to an increased expression of inflammatory cytokines including TNF-α and IL-6 in the heart, but the magnitude of this induction was greater in APN-KO mice compared to WT mice. Systemic delivery of an adenoviral vector expressing adiponectin (Ad-APN) improved LPS-induced LV dysfunction in APN-KO mice, and this effect was accompanied by the reduced expression of TNF-α and IL-6 in the heart. Administration of etanercept, a soluble TNF receptor abolished the reduced LV contractile function in response to LPS in APN-KO mice. CONCLUSION: These results suggest that adiponectin protects against LPS-induced acute cardiac injury by suppressing cardiac inflammatory responses, and could represent a potential therapeutic target in sepsis-associated myocardial dysfunction.

Multilayered adipose-derived regenerative cell sheets created by a novel magnetite tissue engineering method for myocardial infarction.

BACKGROUND: Adipose-derived regenerative cells (ADRCs) are a promising source of autologous stem cells for regeneration and repair of damaged tissue. Herein, we investigated the therapeutic potential of ADRC sheets created by a magnetite tissue engineering technology (Mag-TE) for myocardial infarction. METHODS AND RESULTS: Adipose tissue was obtained from wild-type (WT) mice and ADRCs were isolated. ADRCs incubated with magnetic nanoparticle-containing liposomes (MCLs) were cultured. MCL-labeled ADRCs were mixed with a diluted extracellular matrix (ECM) precursor, and a magnet was placed on the reverse side. Magnetized ADRCs formed multilayered cell sheets after a 24-h incubation. WT mice were subjected to myocardial infarction by permanent ligation of the left anterior descending artery. We then transplanted the constructed ADRC sheet or a cell-free collagen gel sheet, as a control, onto the infarcted myocardium using an Alnico magnet before skin closure. Cardiac parameters were measured by echocardiogram, and angiogenesis was determined by tissue capillary density. ADRC sheet-treated mice showed significant improvements in systolic function, infarct wall thinning, and fibrotic length after myocardial infarction. ADRC sheet implantation also promoted angiogenesis in both the infarct area and the border zone in WT mice after myocardial infarction. The angiogenic effects of ADRC sheets were attributed to an increased expression of VEGF and bFGF mRNA in ischemic hearts. CONCLUSIONS: ADRC sheets created by this Mag-TE method protect the heart against pathological cardiac remodeling. Our ADRC sheets have the potential to be a novel regenerative strategy for ischemic heart disease.

A Japanese region-wide survey of the knowledge, difficulties and self-reported palliative care practices among nurses.

OBJECTIVE: We investigated palliative care knowledge, difficulty and self-reported practice among a region-wide sample of nurses who cared for cancer patients in Japan. METHODS: A cross-sectional questionnaire survey was distributed to 9 designated cancer centers, 17 community hospitals and 73 district nurse services across 4 regions in 2008. We used the Palliative Care Knowledge Test, the Palliative Care Difficulty Scale (five-point Likert scale) and the Palliative Care Self-Reported Practices Scale (five-point Likert scale). RESULTS: In total, 2378 out of 3008 nurses (79%) responded. The knowledge, difficulty and self-reported practice scores were 51 ± 20%, 3.2 ± 0.7 and 3.7 ± 0.6, respectively. In the knowledge test, philosophy scored highest (88 ± 26%) and psychiatric problems scored lowest (37 ± 29%). In the difficulty test, alleviating symptoms scored most difficult (3.5 ± 0.8) and providing expert support scored least difficult (2.9 ± 1.3). In the self-reported practice questionnaire, pain and delirium relief were most frequently (4.0 ± 0.8) and least frequently (3.1 ± 0.9) provided, respectively. Knowledge was significantly poorer in community hospitals (P = 0.035); difficulty scores were significantly higher in community hospitals (P < 0.001) and district nurse services (P = 0.013); and self-reported practice scores were significantly poorer in community hospitals (P < 0.001) but superior in district nurse services (P < 0.001) than in designated cancer centers. CONCLUSIONS: Knowledge, difficulty and self-reported practice for symptom management, particularly psychological symptoms, were insufficient, particularly in community hospitals. Education, expert support and adequate clinical experiences would help provide quality palliative care.

Protective effects of a nicotinamide derivative, isonicotinamide, against streptozotocin-induced ß-cell damage and diabetes in mice.

OBJECTIVE: Nicotinamide rescues ß-cell damage and diabetes in rodents, but a large-scale clinical trial failed to show the benefit of nicotinamide in the prevention of type 1 diabetes. Recent studies have shown that Sirt1 deacetylase, a putative protector of ß-cells, is inhibited by nicotinamide. We investigated the effects of isonicotinamide, which is a derivative of nicotinamide and does not inhibit Sirt1, on streptozotocin (STZ)-induced diabetes in mice. RESEARCH DESIGN AND METHODS: Male C57BL/6 mice were administered with three different doses of STZ (65, 75, and 100 mg/kg BW) alone or in combination with subsequent high-fat feeding. The mice were treated with isonicotinamide (250 mg/kg BW/day) or phosphate-buffered saline for 10 days. The effects of isonicotinamide on STZ-induced diabetes were assessed by blood glucose levels, glucose tolerance test, and immunohistochemistry. RESULTS: Isonicotinamide effectively prevented hyperglycemia induced by higher doses of STZ (75 and 100mg/kg BW) alone and low-dose STZ (65 mg/kg BW) followed by 6-week high-fat diet in mice. The protective effects of isonicotinamide were associated with decreased apoptosis of ß-cells and reductions in both insulin content and insulin-positive area in the pancreas of STZ-administered mice. In addition, isonicotinamide inhibited STZ-induced apoptosis in cultured isolated islets. CONCLUSIONS: These data clearly demonstrate that isonicotinamide exerts anti-diabetogenic effects by preventing ß-cell damage after STZ administration. These findings warrant further investigations on the protective effects of isonicotinamide and related compounds against ß-cell damage in diabetes.

Cystatin C as a predictor of mortality and cardiovascular morbidity after cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) has been reported to improve symptoms and cardiac performance in patients with severe heart failure (HF), but CRT recipients with advanced HF do not always experience improved mortality rates. Cystatin C has recently been involved in HF, but the association of serum cystatin C level with adverse events and long-term prognosis after CRT is unknown. This study investigated whether cystatin C level can predict mortality and cardiovascular events after CRT. METHODS AND RESULTS: A total of 117 consecutive patients receiving a CRT device for the treatment of advanced HF were assessed according to cystatin C level and long-term outcome after implantation of the device. Over a median follow-up of 3.2 years, 34 patients (29.1%) died and 59 patients (50.4%) developed cardiovascular events. Kaplan-Meier survival analysis indicated that elevated cystatin C level was significantly associated with higher all-cause mortality and prevalence of cardiovascular events, including hospitalization for progressive HF. After multivariate Cox regression analysis, serum cystatin C level and QRS duration, but not conventional echocardiographic parameters, were found to independently predict all-cause death or cardiovascular events. Of importance, only cystatin C level was an independent predictor of all-cause mortality after CRT. CONCLUSIONS: Cystatin C level independently predicts cardiac mortality or morbidity in patients receiving CRT. The assessment of cystatin C level could provide valuable information about long-term prognosis after CRT.