Effects of antimuscarinics on voiding function after cerebral infarction in a rat model of overactive bladder

Muscarinic receptor antagonists are used clinically for their therapeutic peripheral effects on bladder function. However, these agents may also act on central muscarinic receptors, especially in individuals with compromised blood-brain barrier function. We compared the effects of atropine and tolterodine, agents that do and do not readily cross the blood-brain barrier, respectively, administered peripherally (intravenous [i.v.]) and centrally (intracerebroventricular [i.c.v.]) on cystometrography in conscious rats after cerebral infarction induced by middle cerebral artery occlusion or sham surgery. We hypothesized that tolterodine would produce greater improvement in bladder capacity and less impairment in bladder contractility and that the effects of both agents would be greater in rats with cerebral infarction and sham-operated rats after peripheral administration, but that tolterodine and atropine would exert similar effects after central administration. Bladder capacity was markedly reduced following cerebral infarction. Low-dose i.v. tolterodine (or=20 nmol/kg) significantly increased bladder capacity but also significantly increased residual volume and decreased bladder contraction pressure. Tolterodine was significantly more efficacious than atropine in increasing bladder capacity, whereas atropine produced significantly greater increases in residual volume and reductions in bladder contraction pressure; these treatment group differences were also observed in sham-operated animals. Tolterodine and atropine administered i.c.v. significantly increased bladder capacity following cerebral infarction or sham surgery; however, this was accompanied by significantly increased residual volume and decreased bladder contraction time. The decrease in bladder contraction time was significantly smaller after tolterodine vs atropine. Peripherally acting muscarinic receptor antagonists may be preferable to centrally acting agents for minimizing adverse events, such as incomplete bladder emptying, even in individuals with compromised blood-brain barrier function.     

Age-related comparison of the profiles of patients with hepatocellular carcinoma

BACKGROUND/AIMS: It is not known whether the putative etiologic factors and clinical and pathological features of hepatocellular carcinoma differ between young adults and older patients. Therefore this study aims to evaluate whether the clinicopathological features in young patients with HCC significantly differ from those of elderly patients. METHODOLOGY: A total of 1014 consecutive patients with HCC were divided into two groups based on age. Among them, 73 patients younger than 50 years of age comprised the first group and 941 patients 50 years and older made up the second. Clinical, laboratory, and pathological characteristics were compared between the two age groups. RESULTS: The male: female ratio and the incidence of positive hepatitis B surface antigen were significantly higher in young patients than in elderly patients. Tumor size, pathological grading of the tumor, and the severity of liver disease did not differ between the two groups. Especially in those patients demonstrating positive antibody to hepatitis C virus, alanine aminotransferase was higher in the younger, and platelet count was lower. Younger patients also had a higher ratio of alcohol consumption compared to elderly patients. CONCLUSIONS: There were age-related differences in the clinicopathological characteristics of HCC patients. Concerning hepatocarcinogenesis, male and HBsAg positive patients were at high risk in young. Of the HCV-related HCC patients, heavy drinking may accelerate the progression from chronic hepatitis to cirrhosis and HCC.     

Rituximab treatment for resistant antiphospholipid syndrome

Antiphospholipid syndrome (APS) and catastrophic antiphospholipid syndrome (CAPS) can be challenging to treat. As they are rare, clinicians are not often exposed to these complex diseases. For the patient resistant to standard treatments new therapeutic directions can be perplexing, especially in the context of ongoing thromboses and bleeding episodes. We describe 3 patients, 2 with APS and one with CAPS, resistant to conventional medications, who responded to treatment with rituximab, an anti-CD20 monoclonal antibody. Since rituximab infusion, all the patients have had stable platelet counts and no further episodes of bleeding or thromboses.     

The mental health status of children who have been evacuated or migrated from rural areas in Fukushima prefecture after the Fukushima daiichi nuclear power station accident: results from the Fukushima health management survey

Introduction: We evaluated the mental health status of children residing in Kawauchi village (Kawauchi), Fukushima Prefecture, after the 2011 accident at the Fukushima Daiichi Nuclear Power Station, based on the children’s experience of the nuclear disaster. Methods: We conducted this cross-sectional study within the framework of the Fukushima Health Management Survey (FHMS); FHMS data on age, sex, exercise habits, sleeping times, experience of the nuclear disaster, and the “Strengths and Difficulties Questionnaire (SDQ)” scores for 156 children from Kawauchi in 2012 were collected. Groups with and without experience of the nuclear disaster — “nuclear disaster (+)” and “nuclear disaster (−)” — were also compared. Results: Our effective response was 93 (59.6%); the mean SDQ score was 11.4±6.8 among elementary school-aged participants and 12.4±6.8 among junior high school-aged ones. We statistically compared the Total Difficulties Scores (TDS) and sub-item scores of the SDQ between “elementary school” and “junior high school” or “nuclear disaster” (+) and (−). There was no significant difference between these items. Conclusions: We found indications of poor mental health among elementary and junior high school-aged children in the disaster area immediately following the accident, but no differences based on their experience of the nuclear disaster. These results indicate the possibility of triggering stress, separate to that from experiences related to the nuclear disaster, in children who lived in affected rural areas and were evacuated just after the nuclear disaster.     

Common peroneal nerve rupture with multiple ligament knee injury: A case report

In peroneal nerve palsy with closed knee injury, most of the case improves by follow‐up. We present a case of peroneal nerve rupture with closed multiple ligament knee injury, requiring nerve transplantation. In multiple ligament knee injury, it is necessary to consider the possibility of peroneal nerve rupture.     

Oxa-Michael-based divergent synthesis of artificial glutamate analogs

Herein we report stereoselective generation of two skeletons, 1,3-dioxane and tetrahydropyranol, by oxa-Michael reaction as the key reaction from δ-hydroxyenone. The construction of the 1,3-dioxane skeleton, achieved through hemiacetal formation followed by oxa-Michael reaction from δ-hydroxyenone, was exploited to access structurally diverse heterotricyclic artificial glutamate analogs. On the other hand, formation of a novel tetrahydro-2H-pyranol skeleton was accomplished by the inverse reaction order: oxa-Michael reaction followed by hemiacetal formation. Thus, this study succeeded in showing that structural diversity in a compound collection can be acquired by interchanging the order of just two reactions. Among the skeletally diverse, heterotricyclic artificial glutamate analogs synthesized in this study, a neuronally active compound named TKM-50 was discovered in the mice in vivo assay.

By interchanging the order of reactions, two types of skeletons were created and a neuroactive artificial glutamate analog was developed.

Ionotropic glutamate receptors (iGluRs) mediate the majority of the excitatory neurotransmissions such as learning, memory, and nociception in the mammalian central nervous system (CNS).¹ To study and control the function of iGluRs, specific glutamate analogs have been developed in natural product chemistry² and in medicinal chemistry.^3,4 IKM-159 (Fig. 1A) is an artificial glutamate analog designed and developed based on dysiherbaine^5,6 and kainic acid⁷ in our laboratories as an antagonist selective to (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA)-type iGluR.^8–12 The AMPA receptor consists of four subunits: GluA1, GluA2, GluA3, and GluA4.³In vitro, IKM-159 selectively inhibits the GluA1/GluA2 heterodimer and GluA4 homodimer.¹⁰In vivo, IKM-159 inhibits voluntary action of mice for 50 min to several hours upon intracerebroventricular injection. The potency and selectivity of IKM-159 are, however, not very satisfactory to selectively modulate the function of AMPA-type iGluR. As an attempt to improve the biological profiles of IKM-159, we have been studying its structural modification.Open in a separate windowFig. 1Background (A) and summary (B) of this work. (A) AMPA-type iGluR antagonist IKM-159. (B) Artificial glutamate analogs 1 and 2, generated by oxa-Michael-based transformations (this work). The gray circle in 1 denotes the position for the structural diversity.From the first-generation studies on structure–activity relationships (SARs) of IKM-159, it had been shown that the ring size and the heteroatom of the C-ring were important for neuroactivity of IKM-159.^10,13 We then studied the second-generation SAR on the oxa analogs generated by a Prins-Ritter three-component coupling strategy, although all analogs were found to lose the original neuronal activity of IKM-159.¹⁴ Herein, we report our continuous effort along this line employing the homoallylic alcohol such as 5 and 7 (see Scheme 2) as the common intermediates.¹⁵Open in a separate windowScheme 2Preparation of the common intermediate 7 (racemate).One of the strategies in this work is the thermodynamically controlled, stereoselective formation of 1,3-dioxane (1 in Fig. 1B) by hemiacetal formation followed by oxa-Michael reaction from δ-hydroxyenone derivative that we recently developed (Scheme 1).¹⁶ The other strategy is the novel stereoselective formation of tetrahydropyranol (2 in Fig. 1B) by the inverse reaction order; oxa-Michael reaction followed by hemiacetal formation (see Scheme 5). Thus, this study succeeded in showing that structural diversity in a compound collection can be acquired by interchanging the order of just two reactions; hemiacetal formation and oxa-Michael reaction. Among the skeletally diverse, heterotricyclic artificial glutamate analogs thus synthesized, a compound named TKM-50 (1ar) was discovered to be neuronally active in the mice in vivo assay.Open in a separate windowScheme 1Our recent work regarding stereoselective 1,3-dioxane formation.¹⁶ For clarity and comparison, enantiomers of the reported compounds are shown in this scheme.Open in a separate windowScheme 5The heterotricyclic artificial glutamate analog 2, constructed by intermolecular oxa-Michael reaction of MeOH followed by acetalization.The substrate used for the 1,3-dioxane formation was prepared from the known dimethyl ester 5 (Scheme 2).¹⁷ Exposure of dimethyl ester 5 to hydrochloric acid (6 M) at 65 °C provided dicarboxylic acid 6.¹⁷ Without purification, dicarboxylic acid 6 was treated with BnBr and Cs₂CO₃ to furnish the common intermediate 7 in 72% yield (2 steps).¹⁸The alkene 7 was subjected to cross metathesis with methyl vinyl ketone (8) mediated by Hoveyda-Grubbs second generation catalyst (9)¹⁹ to provide enone 10 in 82% yield (Scheme 3). Upon exposure to paraformaldehyde as an equivalent of formaldehyde and 1,3,5-trioxane¹⁶ in the presence of MsOH, 1,3-dioxane ring formed smoothly by oxa-Michael reaction to give rise to desired (7R*)-heterotricycle 11r and the (7S*) epimer 11s (structure not shown) in the ratio of >9 : 1, as well as the N-hydroxymethylated product 12r (see Scheme 3) and the (7S*) epimer 12s (structure not shown). Since we had found that alkaline hydrolysis is of use to remove the N-hydroxymethyl group, the mixture of hemiaminals (12r/12s) and free amides (11r/11s) was treated with ammonium hydroxide²⁰ to obtain free amide 11r in 73% isolated yield (2 steps), and free amide 11s in 10% yield (estimated by NMR, 2 steps). The formation of 1,3-dioxane ring of 11r was determined by the HMBC correlations (Fig. 2A), and the stereochemical configuration was established by a ³J_H,H value and NOESY correlations denoted in Fig. 2B. Both configuration and conformation of 11r are identical to those we observed recently in the simple case (3 → 4, see Scheme 1),¹⁶ showing that the 1,3-dioxane formation in this study is also thermodynamically controlled (see below for the mechanism).Open in a separate windowScheme 3Stereoselective 1,3-dioxane formation leading to heterotricyclic artificial glutamate analog 1ar.^{a a}dr denotes the diastereoselectivity in the 1,3-dioxane formation.Open in a separate windowFig. 2Structure analysis of 1,3-dioxane 11r. (A) HMBC correlations in 11r indicates formation of the 1,3-dioxane ring. (B) Small ³J_H,H value and NOESY correlations show the configuration and the conformation of 11r.The proposed mechanism for the 1,3-dioxane formation is shown in Scheme 4A. Reaction of alcohol 10 and paraformaldehyde would form hemiacetal intermediate A under acidic conditions, which, then undergoes intramolecular oxa-Michael reaction to give 11r and 11s. Since the second conjugate addition is generally a thermodynamically controlled, reversible process, production of more stable (7R*) isomer 11r predominated over the (7S*) epimer 11s, as discussed also in our preliminary study.¹⁶ It should be also noted here that, in that preliminary study employing a simple substrate, the (7S) epimer had not been obtained.¹⁶ Generation of the less stable (7S*) epimer 11s in this study would be due to unfavorable steric interactions between the acetyl group and the benzyl ester on the near side in 11r (Scheme 4B), that make the energy difference between the two diastereomers (11r and 11s) smaller.Open in a separate windowScheme 4The plausible mechanism of 1,3-dioxane ring formation. (A) Stepwise mechanism that consists of hemiacetal formation followed by intramolecular oxa-Michael reaction. (B) The steric repulsion included in the stable isomer 11r.Then two benzyl groups of 11r were removed by hydrogenolysis²¹ to cleanly provide glutamate analog 1ar ((2R*,7R*)-TKM-50) in 86% yield (Scheme 3).With the same reaction sequences for 1ar (Scheme 3), two more analogs 1br and 1cr were furthermore synthesized (Fig. 3). The marked decrease in diastereoselectivity in these oxa-Michael reactions (see Fig. 3) suggests that the steric repulsion between the pentyl/methoxyphenyl group and the benzyl ester on the near side is extremely large. The minor (7S*) diastereomers obtained in these oxa-Michael reactions were also isolated and deprotected to give 1bs and 1cs (see the ESI^†), which were subjected to in vivo assay (see below).Open in a separate windowFig. 3Other 1,3-dioxane analogs synthesized by the intramolecular oxa-Michael reaction.^{a a}dr denotes the diastereoselectivity in the 1,3-dioxane formation.We also found that another skeleton can be constructed from δ-hydroxyenone being used for 1,3-dioxane formation, under alkaline hydrolytic conditions. Thus, as shown in Scheme 5, the δ-hydroxyenone 13 derived from homoallylic alcohol 5 by cross metathesis was selectively transformed into cyclic hemiacetal 2 in 53% yield (1 M LiOH in water, MeOH, rt). In this transformation, dimethyl ester and δ-hydroxyenone moiety independently suffer hydrolysis and cyclization, respectively, to generate glutamate analog 2 efficiently. The configuration of 2 was determined by combined analysis of NMR and DFT calculation (see the ESI^†).²²The plausible mechanism for the hemiacetal formation is shown in Scheme 6. In view of the fact that the hydroxy and carbonyl groups are located apart in 13, the six-membered-ring formation should take place after saturation of the trans-alkene. It is, therefore, supposed that oxa-Michael reaction of MeOH to enone 13 first generates saturated ketone Cvia enolate B.²³ Under alkaline conditions, the alkoxide C intramolecularly attacks carbonyl group to give rise to hemiacetal 2. Considering the fact that oxa-Michael reaction and the acetalization are thermodynamically controlled, reversible processes, energetically favorable diastereomer 2 would have been obtained predominantly (see the ESI^† for discussions on thermodynamic stability of 2). A related example had been reported in 1992 by Shing et al.²⁴Open in a separate windowScheme 6The plausible mechanism for hemiacetal formation under alkaline conditions.Behavioral activities of all six compounds upon intracerebroventricular (i.c.v.) injection were evaluated in mice (Fig. 4).²⁵ Injection of 1ar (TKM-50, 50 μg per mouse) resulted in loss of voluntary motor activity for 10 min after injection and then ataxia-like motions were recorded, thus annotated as hypoactive. The hypoactivity observed for 1ar (TKM-50) is thus somewhat weaker than IKM-159 which causes loss of mice spontaneous activity for up to 4 h.¹² Other congeners, however, did not cause any noticeable behavioral changes at the same dose tested.Open in a separate windowFig. 4The in vivo activities on mice.     

Medical,welfare, and educational challenges and psychological distress in parents caring for an individual with 22q11.2 deletion syndrome: A cross-sectional survey in Japan

Parents of children with 22q11.2 deletion syndrome (22q11DS) experience distress not only due to multimorbidity in the patients, but also due to professionals' lack of understanding about 22q11DS and insufficient support systems. This study investigated relationships between medical, welfare, and educational challenges and parental psychological distress. A cross-sectional survey was conducted on primary caregivers of children with 22q11DS. Participants included 125 parents (114 mothers, 91.2%; average age = 44.3 years) who reported their challenges, psychological distress, and child's comorbidities of 22q11DS. Results showed that the difficulty in going to multiple medical institutions (β = 0.181, p < 0.05) and lack of understanding by welfare staff and insufficient welfare support systems for 22q11DS (β = 0.220–0.316, all p < 0.05) were associated with parental psychological distress, even after adjusting for child's comorbidities. In the subsample of parents whose child attended an educational institution, inadequate management in classroom and mismatch between service and users in educational settings were associated with psychological distress (β = 0.222–0.296, all p < 0.05). This study reveals the importance of assessing not only severity of comorbidities in 22q11DS, but also the medical, welfare, and educational challenges for parental mental health.