Albumin‐binding of diclofenac and the effect of a site II inhibitor in the aqueous humor of cataract patients with the instillation of diclofenac

Diclofenac instillation has been used widely in cataract surgery to prevent postoperative inflammation. Since diclofenac binds strongly to albumin in the circulation, it does not have a sufficient effect on patients in whom diclofenac binds strongly to albumin in the aqueous humor. A decrease in diclofenac binding and an increase in free diclofenac levels are necessary in these patients. The binding of diclofenac to albumin was investigated in the aqueous humor. In a diclofenac binding assay with albumin in the aqueous humor of individual patients, diclofenac was extracted from aliquots of the aqueous humor, and its total levels were measured using ultra high performance liquid chromatography (UHPLC). Free diclofenac levels were measured using ultrafiltration and UHPLC. The albumin‐binding fraction of diclofenac was 0.8 or higher in the aqueous humor of some patients. Ibuprofen significantly inhibited diclofenac binding to site II of albumin in mimic aqueous humor, but not in pooled aqueous humor. This difference may have been due to the weak binding of diclofenac to site II in the pooled aqueous humor. Flurbiprofen was used instead of diclofenac. Flurbiprofen has been shown to bind more strongly than diclofenac to the same site of albumin. Thus, the inhibitory effect of ibuprofen on the binding of flurbiprofen to albumin was investigated in pooled aqueous humor. The results indicated that ibuprofen significantly inhibited the flurbiprofen binding. An effective diclofenac administration method may be established for clinical application by the instillation of an appropriate inhibitor of binding to the albumin site II. Copyright © 2014 John Wiley & Sons, Ltd.     

Association of crossing capillaries in the finger nailfold with diabetic retinopathy in type 2 diabetes mellitus

Aims/IntroductionCrossing capillaries in the finger nailfold might potentially be a novel diabetic retinopathy (DR) biomarker that could be assessed non‐invasively in the clinical setting. However, the association between crossing capillaries and DR is controversial. This study aimed to investigate the association between the percentage of crossing capillaries in the finger nailfold and DR in patients with type 2 diabetes mellitus.Materials and MethodsThis cross‐sectional study enrolled 108 type 2 diabetes mellitus patients (aged 40–75 years) who visited the outpatient diabetic clinic at Osaka University Hospital, Osaka, Japan, between May and October 2019. Capillary morphology was assessed using nailfold capillaroscopy based on the simple capillaroscopic definitions of the European League Against Rheumatism Study Group. Details of DR and other laboratory data were obtained from medical records. The association between the tertile of the percentage of the crossing capillary and DR was analyzed using multivariable logistic regression.ResultsAfter adjusting for age, sex, diabetes duration, glycated hemoglobin, systolic blood pressure, body mass index, and use of renin–angiotensin system inhibitor and antihyperlipidemic medication, the percentage of crossing capillaries was significantly associated with DR (multivariable‐adjusted odds ratios for increasing tertiles of the percentage of crossing capillary: 1 [reference], 2.05 [95% confidence interval 0.53–7.94], and 4.33 [95% confidence interval 1.16–16.21]; P‐trend = 0.028).ConclusionsA higher percentage of crossing capillaries in the nailfold was associated with a higher risk of DR, independent of traditional risk and inhibiting factors, in patients with type 2 diabetes mellitus.     

Fatal overwhelming postsplenectomy infection due to Streptococcus pneumoniae serotype 10A with atypical polysaccharide capsule in a patient with chromosome 22q11.2 deletion syndrome: A case report

We report the first case of a teenage patient with chromosome 22q11.2 deletion syndrome who died of overwhelming postsplenectomy infection (OPSI) by Streptococcus pneumoniae despite appropriate prevention by pneumococcal vaccine. He had congenital heart disease and underwent several surgeries. Immunodeficiency had not been noticed clinically. Two years prior to death, splenectomy was performed for a drug-resistant idiopathic thrombocytopenic purpura and he was immunized with 23-valent pneumococcal polysaccharide vaccine (PPV23) 4 months after splenectomy. He died suddenly after a mild flu-like symptom. Autopsy was performed and OPSI was diagnosed. Blood culture was positive for S. pneumoniae. This isolated S. pneumoniae strain was serotypically un-typable by polyvalent serum agglutination test. On the contrary, multilocus sequence typing followed by DNA sequencing indicated the molecular serotype as 10A. Additional testing using monovalent and factor-specific sera confirmed the strain as serotype 10A. Ultrastructural observation of this S. pneumoniae strain showed that the polysaccharide capsule was thin and sparse. We speculate that the abnormal morphology of the capsule may have accounted for the polyvalent serum agglutination failure and may possibly be associated with severity of OPSI observed in this case. Chromosome 22q11.2 deletion syndrome is associated with certain immunodeficiency, especially susceptible to S. pneumoniae infections; however, fatal OPSI has not been reported. In addition to vaccination, prophylactic antibiotics may be necessary for these patients who are at risk of immunodeficiency.     

Regulation of vascular tone by the modulation of Ca2+ sensitivity

The contractile tone of the vascular smooth muscle plays an important role on the regulation of the blood pressure as well as the local perfusion of the important organs such as the heart and brain. The importance of the Ca(2+) sensitivity in the regulation of the vascular tone has been established by the development of the simultaneous measurements of intracellular Ca(2+) concentration ( [Ca(2+)](i) ) and tension as well as that of the receptor coupled permeabilized preparation in the late 1980s. Recently, the mechanisms underlying the regulation of Ca(2+) sensitivity have been revealed. The increase in the Ca(2+) sensitivity involves the myosin phosphatase (MLCP) inhibition mediated by rhoA-rho kinase system and PKC-CPI system. The decrease in the Ca(2+) sensitivity involves the PKA-mediated inhibition of myosin light chain kinase, the PKG-mediated activation of MLCP, and PKA- or PKG-mediated inactivation of rhoA. In this article, the regulation of the Ca(2+) sensitivity of the contractile apparatus of the vascular smooth muscle will be briefly reviewed.     

Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia

Predicting the response to immunosuppressive therapy could provide useful information to help the clinician define treatment strategies for patients with aplastic anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with aplastic anemia, using flow fluorescence in situ hybridization. Median age of patients was ten years (range 1.5–16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies using antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at six months was 52% (33 of 64). The probability of 5-year failure-free survival and overall survival were 56% (95% confidence interval (CI): 41–69%) and 97% (95%CI: 87–99%), respectively. Median telomere length in responders was −0.4 standard deviation (SD) (−2.7 to +3.0 SD) and −1.5 SD (−4.0 to +1.6 (SD)) in non-responders (P<0.001). Multivariate analysis showed that telomere length shorter than −1.0 SD (hazard ratio (HR): 22.0; 95%CI: 4.19–115; P<0.001), platelet count at diagnosis less than 25×10⁹/L (HR: 13.9; 95%CI: 2.00–96.1; P=0.008), and interval from diagnosis to immunosuppressive therapy longer than 25 days (HR: 4.81; 95%CI: 1.15–20.1; P=0.031) were the significant variables for poor response to immunosuppressive therapy. Conversely to what has been found in adult patients, measurement of the telomere length of lymphocytes at diagnosis is a promising assay in predicting the response to immunosuppressive therapy in children with aplastic anemia.     

First-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy

The current treatment approach for severe aplastic anemia in children is based on studies performed in the 1980s, and updated evidence is required. We retrospectively compared the outcomes of children with acquired severe aplastic anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation from an HLA-matched family donor registered in the Japanese Society for Hematopoietic Cell Transplantation Registry. Between 1992 and 2009, 599 children (younger than 17 years) with severe aplastic anemia received a bone marrow transplant from an HLA-matched family donor (n=213) or immunosuppressive therapy (n=386) as first-line treatment. While the overall survival did not differ between patients treated with immunosuppressive therapy or bone marrow transplantation [88% (95% confidence interval: 86–90) versus 92% (90–94)], failure-free survival was significantly inferior in patients receiving immunosuppressive therapy than in those undergoing bone marrow transplantation [56% (54–59) versus 87% (85–90); P<0.0001]. There was no significant improvement in outcomes over the two time periods (1992–1999 versus 2000–2009). In multivariate analysis, age <10 years was identified as a favorable factor for overall survival (P=0.007), and choice of first-line immunosuppressive therapy was the only unfavorable factor for failure-free survival (P<0.0001). These support the current algorithm for treatment decisions, which recommends bone marrow transplantation when an HLA-matched family donor is available in pediatric severe aplastic anemia.     

Outcomes after up-front surgery and metronomic neoadjuvant chemotherapy with S-1 or UFT for early tongue squamous cell carcinoma

Background

Our aim was to investigate the disease-free survival in patients with tongue squamous cell carcinoma receiving metronomic neoadjuvant chemotherapy with 5-fluorouracil prodrugs (UFT or S-1) plus bleomycin compared with those who had up-front surgery retrospectively.

Methods

In this retrospective study, 108 patients with stages I to II tongue squamous cell carcinoma who had undergone surgery were divided into the “surgery group” or “neoadjuvant chemotherapy group.”

Results

A total of 41 patients received up-front surgery; 67 received metronomic neoadjuvant chemotherapy with UFT plus bleomycin (39) or S-1 plus bleomycin (28). The rate of disease-free survival was the primary outcome measure. Neoadjuvant 5-fluorouracil prodrugs did not correlate higher with improved disease-free survival than up-front surgery (72 and 54%, respectively; hazard ratio for recurrence or death, 0.54; 95% confidence interval [CI], 0.28 to 1.03; P = 0.06). Patients who received S-1 were more likely than those who received UFT to have pathological complete response (46% vs. 15%; P = 0.007). Neoadjuvant S-1 significantly improved disease-free survival as compared with up-front surgery (79% vs. 54%; hazard ratio, 0.41; 95% CI, 0.15 to 0.98; P = 0.04). However, neoadjuvant UFT did not improve disease-free survival as compared with up-front surgery (67% vs. 54%, respectively; hazard ratio, 0.66; 95% CI, 0.31 to 1.33; P = 0.24).

Conclusions

Neoadjuvant S-1 chemotherapy, as compared with up-front surgery, significantly improved disease-free survival among patients with tongue squamous cell carcinoma.

Clinical relevance

A choice of drugs before neoadjuvant metronomic chemotherapy is needed.

     

Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition

GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2^−/−) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2^−/− mice show cortical PV⁺ interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2^−/− mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2^−/− caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.Precursors of most γ-aminobutyric acid (GABA)-releasing interneurons of the cerebral cortex and the hippocampus originate in the embryonic medial ganglionic eminence (MGE) (1–3). A subpopulation of MGE-derived cells differentiates into fast-spiking, parvalbumin-expressing (PV⁺) interneurons that tightly regulate the activity and synchronization of cortical projection neurons (2, 4). Structural and functional deficits in PV⁺ interneurons are hypothesized as a pathophysiological mechanism in schizophrenia and psychotic disorders (4–6).Although psychotic disorders are clearly heterogeneous in etiology, disinhibition within temporolimbic cortical circuits is postulated as a core pathophysiology underlying positive symptoms (e.g., delusions and hallucinations) and a subset of cognitive disturbances that manifest with psychosis (4, 5, 7). Postmortem studies of brains from individuals with psychotic disorders show reduced molecular markers of the number and/or function of PV⁺ interneurons in the hippocampus (6, 8). Consistent with these observations, basal metabolic activity in the hippocampus, as measured with functional magnetic resonance imaging (fMRI), is increased in schizophrenia, a phenotype that predicts psychosis and positive symptom severity (5, 7). This abnormal resting activity is postulated to underlie abnormal recruitment of hippocampal circuits during cognitive performance (5, 9). Striatal dopamine (DA) release capacity is also increased and correlated with positive symptoms in schizophrenia and its risk states (10, 11). Importantly, hippocampal hyperactivity may contribute to DA dysregulation (12), because rodent studies show that caudoventral hippocampal (in the primate, anterior hippocampal) efferents regulate the activity of DA neurons and medial striatal DA release (13, 14).Thus, converging evidence implicates hippocampal disinhibition in the abnormal striatal DA transmission and cognitive impairment in schizophrenia. However, the role of hippocampal inhibitory interneurons in psychosis-relevant circuitry remains to be established. To this end, we used the cyclin D2 (Ccnd2) knockout mouse model (15), which displays a relatively selective deficit in cortical PV⁺ interneurons, and transplantation of interneuron precursors from the MGE to elucidate relationships between reduced hippocampal GABA interneuron function and multiple psychosis-relevant phenotypes, and to explore a novel treatment strategy for psychosis.