Treatment patterns and characteristics of headache in patients in Japan: A retrospective cross-sectional and longitudinal analysis of health insurance claims data.

BACKGROUND: The present study aimed to investigate prescription patterns for patients aged over 17 years with headaches in the REZULT database. METHODS: We conducted a cross-sectional study (Study 1) of the proportion of over-prescription of acute medications (≥30 tablets/90 days for triptans, combination non-steroidal anti-inflammatory drugs (NSAIDs) and multiple types; ≥45 tablets/90 days for single NSAIDs) among patients with headache diagnosed in 2020. We longitudinally studied (Study 2) patients for >2 years from initial headache diagnosis (July 2010 to April 2022). The number of prescribed tablets was counted every 90 days. RESULTS: In Study 1, headache was diagnosed in 200,055 of 3,638,125 (5.5%) patients: 13,651/200,055 (6.8%) received acute medication. Single NSAIDs were prescribed to 12,297/13,651 (90.1%) patients and triptans to 1710/13,651 (12.5%). Over-prescription was found in 2262/13,651 (16.6%) patients and 1200/13,651 (8.8%) patients received prophylactic medication. In Study 2, 408,183/6,840,618 (6.0%) patients were first diagnosed with headaches, which persisted for ≥2 years. Over time, the proportion of patients over-prescribed acute medications increased. Over 2 years, 37,617/408,183 (9.2%) patients were over-prescribed acute medications and 29,313/408,183 (7.2%) patients were prescribed prophylaxis at least once. CONCLUSIONS: According to real-world data, prophylaxis remains poorly prescribed, and both acute and prophylactic treatment rates for headaches have increased over time.

Treatment Patterns for and Characteristics of Headache in Children and Adolescents Aged 6-17 Years in Japan: A Retrospective Cross-Sectional and Longitudinal Analysis of Health Insurance Claims Data.

OBJECTIVE: To investigate the prescription patterns for patients aged 6-17 years with headaches in the REZULT database. METHODS: We cross-sectionally investigated (Study 1) the pattern of prescription and the proportion of triptan overprescription (≥30 tablets/90 d of triptans) among patients diagnosed with headaches in 2020. Next, we longitudinally studied patients (Study 2) for more than two years from the initial headache diagnosis (July 2010 to April 2022). The number of prescribed tablets was counted every 90 days. RESULTS: In Study 1, headache diagnoses were assigned to 62,568 of 543,628 (11.51%) patients, and 1524 of 62,568 (2.44%) patients received acute medication. Single nonsteroidal anti-inflammatory drugs and triptans were prescribed to 620/624 (99.36%) and 5/624 (0.80%) of patients aged 6-11 years, respectively, and 827/900 (91.89%) and 91/900 (10.11%) of patients aged 12-17 years, respectively. Triptan overprescription was observed in 11/96 (11.46%) patients, and 5/11 (45.45%) of those patients received prophylactic medication. In Study 2, 80,756/845,470 (9.55%) patients aged 6-17 years were diagnosed with headaches that persisted for at least two years. Over two years, 44/80,756 (0.05%) patients were overprescribed triptans, and 3408/80,756 (4.22%) patients were prescribed prophylaxis on at least one occasion. CONCLUSIONS: Based on real-world data, the appropriate use of prophylactic treatment is still problematic. Overprescription of triptans was observed, although the number of patients was small.

Developing an Artificial Intelligence-Based Pediatric and Adolescent Migraine Diagnostic Model.

Introduction Misdiagnosis of pediatric and adolescent migraine is a significant problem. The first artificial intelligence (AI)-based pediatric migraine diagnosis model was made utilizing a database of questionnaires obtained from a previous epidemiological study, the Itoigawa Benizuwaigani Study. Methods The AI-based headache diagnosis model was created based on the internal validation based on a retrospective investigation of 909 patients (636 training dataset for model development and 273 test dataset for internal validation) aged six to 17 years diagnosed based on the International Classification of Headache Disorders 3rd edition. The diagnostic performance of the AI model was evaluated. Results The dataset included 234/909 (25.7%) pediatric or adolescent patients with migraine. The mean age was 11.3 (standard deviation 3.17) years. The model's accuracy, sensitivity (recall), specificity, precision, and F-values for the test dataset were 94.5%, 88.7%, 96.5%, 90.0%, and 89.4%, respectively. Conclusions The AI model exhibited high diagnostic performance for pediatric and adolescent migraine. It holds great potential as a powerful tool for diagnosing these conditions, especially when secondary headaches are ruled out. Nonetheless, further data collection and external validation are necessary to enhance the model's performance and ensure its applicability in real-world settings.

Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice.

Aging is considered to be accelerated by insulin signaling in lower organisms, but it remained unclear whether this could hold true for mammals. Here we show that mice with skeletal muscle-specific double knockout of Akt1/2, key downstream molecules of insulin signaling, serve as a model of premature sarcopenia with insulin resistance. The knockout mice exhibit a progressive reduction in skeletal muscle mass, impairment of motor function and systemic insulin sensitivity. They also show osteopenia, and reduced lifespan largely due to death from debilitation on normal chow and death from tumor on high-fat diet. These phenotypes are almost reversed by additional knocking out of Foxo1/4, but only partially by additional knocking out of Tsc2 to activate the mTOR pathway. Overall, our data suggest that, unlike in lower organisms, suppression of Akt activity in skeletal muscle of mammals associated with insulin resistance and aging could accelerate osteosarcopenia and consequently reduce lifespan.

Chiral bifunctional sulfide-catalyzed asymmetric bromoaminocyclizations.

A BINOL-derived chiral bifunctional sulfide catalyst bearing a phenylurea moiety was applied to enantioselective bromoaminocyclization reactions of 2-allylaniline derivatives, which provide optically active 2-substituted indoline products as important motifs for biologically active compounds. A protecting group on the nitrogen of the 2-allylaniline substrate was carefully optimized, and highly enantioselective reactions were achieved by employing the p-biphenylsulfonyl-protected substrates. The origin of the good level of enantioselectivity for the present bromoaminocyclization was also investigated on the basis of DFT calculations. The resultant optically active 2-(bromomethyl)indoline products could be transformed to various 2-substituted indolines with no loss of the optical purity.

Alkyne aza-Prins cyclization of N-(hexa-3,5-diynyl)tosylamides with aldehydes using triflic acid and a binuclear aluminum complex.

The alkyne aza-Prins cyclization of 3,5-diynyl amides and various aldehydes was developed using TfOH with/without (Me2AlO)2SO2. This method, which could be applied to homopropargyl amides, provides TfO-substituted pyrrolidines with E-selectivities and exclusive regioselectivities. This work represents a first example of the aza-Prins cyclization with the introduction of TfO groups.

BINOL-derived bifunctional sulfide catalysts for asymmetric synthesis of 3,3-disubstituted phthalides via bromolactonization.

An efficient enantioselective synthesis of 3,3-disubstituted phthalides possessing a chiral quaternary carbon center was achieved via catalytic asymmetric bromolactonization that utilized BINOL-derived bifunctional sulfide catalysts. Transformations of the bromo group in optically active phthalide products were also performed to demonstrate the utility of this novel synthetic protocol.

Design of Chiral Bifunctional Dialkyl Sulfide Catalysts for Regio-, Diastereo-, and Enantioselective Bromolactonization.

Although a wide variety of chiral organocatalysts have been developed for asymmetric transformations, effective chiral dialkyl sulfide organocatalysts remain relatively rare and under-developed, despite the potential utility of dialkyl sulfide catalysts. Herein, we report the development of chiral bifunctional dialkyl sulfide catalysts possessing a urea moiety for regio-, diastereo-, and enantioselective bromolactonization. The importance of the bifunctional design of chiral sulfide catalysts was clearly demonstrated in the present work. The roles of both the sulfide and urea moieties of the catalyst were clarified based on the results of experimental and theoretical investigation.

Deregulation of pancreas-specific oxidoreductin ERO1ß in the pathogenesis of diabetes mellitus.

A growing body of evidence has underlined the significance of endoplasmic reticulum (ER) stress in the pathogenesis of diabetes mellitus. ER oxidoreductin 1ß (ERO1ß) is a pancreas-specific disulfide oxidase that is known to be upregulated in response to ER stress and to promote protein folding in pancreatic ß cells. It has recently been demonstrated that ERO1ß promotes insulin biogenesis in ß cells and thus contributes to physiological glucose homeostasis, though it is unknown if ERO1ß is involved in the pathogenesis of diabetes mellitus. Here we show that in diabetic model mice, ERO1ß expression is paradoxically decreased in ß cells despite the indications of increased ER stress. However, overexpression of ERO1ß in ß cells led to the upregulation of unfolded protein response genes and markedly enlarged ER lumens, indicating that ERO1ß overexpression caused ER stress in the ß cells. Insulin contents were decreased in the ß cells that overexpressed ERO1ß, leading to impaired insulin secretion in response to glucose stimulation. These data indicate the importance of the fine-tuning of the ER redox state, the disturbance of which would compromise the function of ß cells in insulin synthesis and thus contribute to the pathogenesis of diabetes mellitus.

Extensive brain pathology in a patient with aceruloplasminemia with a prolonged duration of illness.

We report the sixth autopsy case of a patient with aceruloplasminemia. He was the younger brother of the first reported autopsy case of this disease. Among autopsy cases with aceruloplasminemia reported to date, he had the longest duration of neurologic disorders. The neuropathologic findings showed that the basal ganglia and dentate nuclei were most severely affected. The most striking finding in the present case was that marked iron deposition was evident in the cerebral cortex. Many enlarged or deformed astrocytes and globular structures, both of which were heavily iron loaded, were found in the cerebral cortex as well as in the basal ganglia. Pyramidal neurons in his cerebral cortex were fewer in number than observed in the previous reported cases. There was a negative correlation between the number of cortical pyramidal neurons and globular structures. The present case clearly indicates that the neuropathologic process in aceruloplasminemia extends beyond the basal ganglia to the cerebral cortex with time.

Ceruloplasmin protects against rotenone-induced oxidative stress and neurotoxicity.

To clarify the neuroprotective property of ceruloplasmin and the pathogenesis of aceruloplasminemia, we generated ceruloplasmin-deficient (CP⁻/⁻) mice on the C57BL/10 genetic background and further treated them with a mitochondrial complex I inhibitor, rotenone. There was no iron accumulation in the brains of CP⁻/⁻ mice at least up to 60 weeks of age. Without rotenone treatment, CP⁻/⁻ mice showed slight motor dysfunction compared with CP⁺/⁺ mice, but there were no detectable differences in the levels of oxidative stress markers between these two groups. A low dose of rotenone did not affect the mitochondrial complex I activity in our mice, however, it caused a significant change in motor behavior, neuropathology, or the levels of oxidative stress markers in CP⁻/⁻ mice, but not in CP⁺/⁺ mice. Our data support that ceruloplasmin protects against rotenone-induced oxidative stress and neurotoxicity, probably through its antioxidant properties independently of its function of iron metabolism.

Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6-dependent pathway.

Insulin resistance is often associated with impeded insulin signaling due either to decreased concentrations or functional modifications of crucial signaling molecules including insulin receptor substrates (IRS) in the liver. Many actions of adiponectin, a well-recognized antidiabetic adipokine, are currently attributed to the activation of two critical molecules downstream of AdipoR1 and R2: AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). However, the direct effects of adiponectin on insulin signaling molecules remain poorly understood. We show here that adiponectin upregulates IRS-2 through activation of signal transducer and activator of transcription-3 (STAT3). Surprisingly, this activation is associated with IL-6 production from macrophages induced by adiponectin through NFκB activation independent of its authentic receptors, AdipoR1 and AdipoR2. These data have unraveled an insulin-sensitizing action initiated by adiponectin leading to upregulation of hepatic IRS-2 via an IL-6 dependent pathway through a still unidentified adiponectin receptor.

Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance.

Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class IB phosphoinositide-3 kinase (PI3Kγ) in inflammatory states, little is known about the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of PI3Kγ in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking p110γ (Pik3cg(-/-)), the catalytic subunit of PI3Kγ, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese Pik3cg(-/-) mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of PI3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that PI3Kγ plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that PI3Kγ can be a therapeutic target for type 2 diabetes.

Class IA phosphatidylinositol 3-kinase in pancreatic ß cells controls insulin secretion by multiple mechanisms.

Type 2 diabetes is characterized by insulin resistance and pancreatic ß cell dysfunction, the latter possibly caused by a defect in insulin signaling in ß cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in ß cells and the pik3r2 gene systemically (ßDKO mouse), results in glucose intolerance and reduced insulin secretion in response to glucose. ß cells of ßDKO mice had defective exocytosis machinery due to decreased expression of soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins and loss of cell-cell synchronization in terms of Ca(2+) influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of ßDKO mice, preserving insulin secretion in response to glucose. The class IA PI3K pathway in ß cells in vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes.

Adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway.

Adiponectin, one of the insulin-sensitizing adipokines, has been shown to activate fatty acid oxidation in liver and skeletal muscle, thus maintaining insulin sensitivity. However, the precise roles of adiponectin in fatty acid synthesis are poorly understood. Here we show that adiponectin administration acutely suppresses expression of sterol regulatory element-binding protein (SREBP) 1c, the master regulator which controls and upregulates the enzymes involved in fatty acid synthesis, in the liver of +Lepr(db)/+Lepr(db) (db/db) mouse as well as in cultured hepatocytes. We also show that adiponectin suppresses SREBP1c by AdipoR1, one of the functional receptors for adiponetin, and furthermore that suppressing either AMP-activated protein kinase (AMPK) via its upstream kinase LKB1 deletion cancels the negative effect of adiponectin on SREBP1c expression. These data show that adiponectin suppresses SREBP1c through the AdipoR1/LKB1/AMPK pathway, and suggest a possible role for adiponectin in the regulation of hepatic fatty acid synthesis.

An unusual case of Klippel-Trénaunay-Weber syndrome presenting with portosystemic encephalopathy.

We report a unique male patient presenting with portosystemic encephalopathy (PSE) due to intrahepatic portohepatic venous (PHV) shunts. He was diagnosed as having Klippel-Trénaunay-Weber syndrome (KTWS) based on the findings of a hemitruncal port-wine stain with subcutaneous arteriovenous fistulae and varicose veins in the legs. However, limb-hypertrophy, which is one of the most cardinal manifestations of KTWS, was absent, and in KTWS, PSE is quite a rare clinical manifestation. Hence, the clinical picture of this patient was unusual. Our clinical observation suggests that KTWS can be one of the underlying disorders causing PSE.

Increased vulnerability to rotenone-induced neurotoxicity in ceruloplasmin-deficient mice.

Ceruloplasmin (Cp) is the strongest ferroxidase in human plasma. Hereditary deficiency of this protein, named aceruloplasminemia, is an interesting model to elucidate the pathogenesis and pathophysiology of neurodegeneration induced by oxidative stress. Enhanced oxidative stress due to excessive iron accumulation is observed in the brains of aceruloplasminemia patients. Rotenone, a selective mitochondrial complex I inhibitor, induces neurodegeneration mimicking Parkinson's disease. We investigated the influence of Cp deficiency upon neurodegeneration using rotenone-treated, Cp-deficient mouse brains. Immunohistochemical examination showed that acrolein, one of the products of lipid peroxides, and ubiquitin were more markedly immunoreacted in the brains of rotenone-treated, Cp-deficient mice than in rotenone-untreated, Cp-deficient or rotenone-treated, wild-type mice. These molecules were localized in neuronal cells. These results suggested that rotenone-induced lipid peroxidation and accumulation of ubiquitin immunoreactivity were enhanced in the absence of Cp. Therefore, Cp may protect neuronal cells from oxidative stress-induced neurodegeneration.

Lupus erythematosus profundus (lupus panniculitis) induced by interferon-beta in a multiple sclerosis patient.

We report a patient with multiple sclerosis (MS) who developed subcutaneous nodules on the face, shoulders and extremities while being treated with interferon (IFN)-beta-1b. These nodules fluctuated in parallel with myelopathy, and were diagnosed as lupus erythematosus profundus (LEP) based on histopathological findings. The patient showed no relapse of either neurological symptoms or subcutaneous nodules after cessation of IFN-beta-1b. This agent can cause induration and necrosis in the sites of injection but also systemic skin lesions such as LEP ascribable to its immunomodulatory effects.

Henoch-Schönlein purpura nephritis complicated by reversible posterior leukoencephalopathy syndrome.

We report a young female patient with Henoch-Schönlein purpura (HSP) nephritis complicated by reversible posterior leukoencephalopathy syndrome (RPLS). The patient suddenly showed generalized seizures and cortical blindness with severe hypertension due to renal insufficiency approximately 1 year after cessation of corticosteroid treatment for HSP nephritis. Magnetic resonance imaging (MRI) demonstrated bilateral abnormal signals mainly in the cerebellum and white matter of the occipital lobe. Clinical symptoms quickly improved in conjunction with disappearance of abnormal signals on brain MRI after starting control of hypertension and continuous hemodiafiltration with steroid pulse therapy and plasmapheresis. RPLS may be caused by vasculitis and also by hemodynamic change due to severe hypertension in HSP, particularly in patients with nephropathy. In such cases intensive treatment should be performed as soon as possible to avoid neurological sequelae.

Isaacs' syndrome associated with myasthenia gravis, showing remission after cytoreductive surgery of pleural recurrence of thymoma.

We report a patient with Isaacs' syndrome associated with myasthenia gravis and pleural recurrence of thymoma, who showed severe limb pain attributed to hyperexcitability of sensory nerves. Myokymia and severe pain were successfully treated with cytoreductive surgery and intraoperative hyperthermic intrathoracic perfusion chemotherapy, but neither pharmacotherapy nor plasma exchange showed obvious clinical effects. Pleural thymoma in our patient may have caused Isaacs' syndrome, probably by unconfirmed humoral immune mechanisms. Cytoreductive treatment for recurrent thymoma should be actively considered as a potent therapeutic option in refractory patients with disabling neuromyotonia symptoms.