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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

Quantitative evaluation of expression of iron-metabolism genes in ceruloplasmin-deficient mice.

Aceruloplasminemia is an autosomal recessive disorder caused by mutations in the ceruloplasmin (CP) gene, and is characterized by a unique combination of neurovisceral iron overload and iron deficiency anemia. We generated CP-deficient (CP(-/-)) mice to investigate the functional involvement of CP in iron metabolism. The mice showed a marked iron overload in the liver and mild iron deficiency anemia. We examined the expression of iron-metabolism genes in the duodenum and liver using TaqMan RT-PCR. The divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), and hephaestin (HEPH) genes were not up-regulated in the duodenum from CP(-/-) mice. These data suggest that the mechanism of hepatic iron overload in aceruloplasminemia is quite different from that in hemochromatoses and atransferrinemia. In the liver, CP(-/-) mice showed no increase of gene expression for DMT1 and transferrin receptors (TFR and TFR2), indicating that none of the known pathways of iron uptake is activated in hepatocytes of CP(-/-) mice. This result supports the hypothesis that CP mainly acts to release iron from cells in the liver.

Severe protein losing enteropathy with intractable diarrhea due to systemic AA amyloidosis, successfully treated with corticosteroid and octreotide.

This report concerns two patients with severe protein losing enteropathy and refractory diarrhea due to AA amyloidosis who were successfully treated with corticosteroid and octreotide. In these patients, biopsied tissues from the gastrointestinal (GI) tract showed extensive deposition of AA amyloid, which was caused by rheumatoid arthritis in one case and was of unidentified etiology in the other. Both patients manifested severe diarrhea unresponsive to conventional treatment with hypoproteinemia, and protein leakage from the small intestine to the ascending colon was confirmed by 99mTc-diethylene triamine pentaacetic acid human serum albumin (HSA-D) scintigraphy. Soon after starting a long-acting somatostatin analogue, octreotide, with co-administration of oral prednisolone, their general status improved in parallel with a rapid decrease in the volume of watery diarrhea and an increase in serum levels of albumin and IgG. Also on 99mTc-HSA-D scintigraphy protein leakage from the GI tract was apparently decreased in both patients. Combination therapy with a somatostatin analogue and corticosteroid may be effective for protein losing enteropathy with intractable diarrhea ascribable to GI amyloidosis. Because of the lack of specific therapies in this serious clinical situation, the described therapy should actively be considered as a therapeutic option not only in AA amyloidosis, but also in other types of systemic amyloidosis.

Acute respiratory distress syndrome due to systemic lupus erythematosus with hemophagocytic syndrome: an autopsy report.

This report concerns a patient with systemic lupus erythematosus (SLE) who died of acute respiratory distress syndrome (ARDS) 1 day after the onset of pulmonary symptoms. Autopsy demonstrated severe hemophagocytosis in the bone marrow and histopathology indicating a marked increase in vascular permeability in both lungs and kidneys. In this patient, active SLE and associated hemophagocytic syndrome may have induced an increase in the production of inflammatory cytokines, which immediately induced ARDS. Since fatal ARDS can occur as a life-threatening complication of SLE, careful observation is necessary, particularly when there are clinical findings suggestive of associated hemophagocytic syndrome.

Risk factors for hospital-acquired bacteremia.

OBJECTIVE: Bacteremia is one of the most serious health problems associated with high morbidity and mortality. The aim of this study was to identify risk factors for bacteremia in daily medical care to facilitate rapid and accurate clinical decisions about treatment. PATIENTS AND METHODS: We studied 306 inpatients retrospectively. Age, peripheral neutrophil count, C-reactive protein (CRP), platelets, serum total cholesterol, total protein, albumin and cholinesterase were compared in patients with positive- and negative-blood cultures. The associations between blood culture positivity and glucose tolerance, bedridden state, presence of a central venous catheter (CVC) or urinary catheter were examined. On October 14, 2002, strategies for prevention of catheter-related infection were altered in our hospital. We studied the impact of these changes on the risk of bacteremia. RESULTS: Sixty-seven patients had positive and 239 had negative blood cultures. Age, neutrophil, platelets, total protein, albumin, and cholinesterase were significantly different between the culture-positive patients and the culture-negative patients. Multivariate analysis showed albumin and platelets as independent predictors. The bedridden state and catheter-inserted states (central venous or urinary) conferred significantly higher positive blood culture rates. Multivariate analysis showed using urinary catheters and indwelling femoral CVCs as independent risk factors. There was no significant difference in the blood culture-positive rate before and after the change in prevention strategies; before the change, 6 of 9 catheter-inserted blood culture-positive cases yielded MRSA, while 4 of 12 cultures yielded Staphylococcus epidermidis after the change. CONCLUSION: Our study highlights the risk factors of bacteremia in vulnerable patients.

Astrocytic deformity and globular structures are characteristic of the brains of patients with aceruloplasminemia.

Aceruloplasminemia is an interesting disease, the study of which helps elucidate how iron-induced oxidative stress is involved in neuronal cell death. In order to study the neuropathological characteristics associated with oxidative stress, we scrutinized the brains of 5 patients with aceruloplasminemia histopathologically and immunohistochemically. The pathological findings were essentially similar in all patients. In the frontal cortices, iron deposition and neuronal cell loss were trivial, but in the basal ganglia (especially in the caudate nucleus and putamen), severe iron overload and extensive neuronal loss were noted. Iron deposition was more prominent in the astrocytes than in the neurons in both regions. 4-hydroxynonenal (HNE), one of the most physiologically active lipid peroxides, was strongly detected on neurons and astrocytes by immunostaining. Markedly deformed astrocytes were observed in the striatum. These astrocytes were similar to Alzheimer type 1 astrocytes. Globular structures were seen in proportion to the degree of iron deposition. They clearly reacted with anti-glial fibrillary acidic protein (GFAP) and anti-S-100 antibodies and contained glial fibril-like filaments, but showed no or only faint immunoreactivity to antibodies for neuronal marker proteins, such as neurofilament and synaptophysin. Therefore, the globular structures presumably originated from astrocytes. The structures also reacted positively to anti-HNE and anti-ubiquitin antibodies. We conclude that astrocytic deformities and globular structures are characteristic neuropathological features of aceruloplasminemia and are closely linked to iron overload and subsequent oxidative stress.