Quality Evaluation of Gentamicin Sulfate Reference Standards in Japanese Pharmacopoeia Using Hydrophilic Interaction Chromatography Combined With Tandem Mass Spectrometry.

BACKGROUND: Through the recent development of analytical technology, antibiotics quantification in the Japanese Pharmacopoeia (JP) has changed from traditional microbiological assays to physicochemical methods with high specificity and precision. However, for several multicomponent antibiotics without typical UV absorption, potency cannot be directly determined using instrumental methods such as high-performance liquid chromatography; therefore, traditional microbiological assays are still used. Gentamicin sulfate (GmS), which consists of three major components, C1, C1a, and C2, is such a typical antibiotic, and its antimicrobial potency continues to be assayed using microbiological methods in JP monographs. Introduction of a physicochemical assay for GmS is needed to help ensure its quality and quantity. OBJECTIVE: This study aimed to develop quality control measures for GmS that could be complementary to quantitative assays and purity tests specified in the JP. METHODS: For each gentamicin C component (C1, C2, and C1a), theoretical potencies were determined based on the quantitative relationship between purity and potency, as measured by quantitative 1H NMR and microbiological assays, respectively. Two lots of the JP reference standard (RS) were used as test samples, with the contents of each component and impurity (sisomicin and garamine) being determined using hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS). RESULTS: The ratios of theoretical potency for C1, C2, and C1a were 1.00, 1.21, and 1.80, respectively. The potencies of the GmS JP RSs, which were estimated based on the contents and theoretical potency of each C component, corresponded well with those determined through microbiological assays. Marked differences in impurities (%) between the two RS lots were highlighted by quantifying sisomicin and garamine. CONCLUSIONS: The developed analytical procedure enabled the characterization of two different JP RSs in terms of content ratio, potencies, and impurities. HIGHLIGHTS: Novel analytical procedures useful for routine quality control of GmS were developed using HILIC-MS/MS.

Treatment of new-onset primary central nervous system lymphoma in elderly patients using RMPV chemotherapy: a single-institution experience.

The prognosis of primary central nervous system lymphoma (PCNSL) in the elderly remains poor. We aimed to evaluate the outcome of rituximab, methotrexate, procarbazine, and vincristine (RMPV) chemotherapy in elderly patients with new-onset PCNSL. Twenty-eight patients aged ≥ 70 years treated for PCNSL between 2010 and 2020 were examined retrospectively. Nineteen patients received RMPV and nine did not qualify. Patients received five to seven cycles of RMPV plus response-adapted whole-brain radiotherapy (WBRT) and cytarabine. Ten of the 19 patients who received RMPV (52.6%) completed the induction, but only four patients (21.1%) completed RMPV chemotherapy, WBRT 23.4 Gy, and cytarabine. Median progression-free survival (PFS) and overall survival (OS) in the RMPV group was 54.4 and 85.0 months, respectively. Both PFS and OS were significantly longer in patients who received RMPV chemotherapy than in those who did not, and in patients who started but did not complete RMPV than in those who did not receive RMPV. Patients who received incomplete RMPV tended to have a favorable prognosis. Initial treatment with RMPV chemotherapy was effective in elderly patients with PCNSL. Adjusting the number of courses of RMPV may improve the prognosis of elderly patients with PCNSL, but further verification is necessary.

Endovascular treatment of an aneurysm arising from the minor limb of an upper basilar artery fenestration: illustrative case.

BACKGROUND: An aneurysm arising in an upper basilar artery (BA) fenestration is extremely rare. The authors reported a case involving successful endovascular treatment of an aneurysm arising from the minor limb of an upper BA fenestration. OBSERVATIONS: A 65-year-old woman presented with an incidentally detected upper BA aneurysm arising from the minor limb of an upper BA fenestration. The irregularly shaped aneurysm was 6.0 × 2.7 mm in diameter, and the minor limb had several perforators. The aneurysm was nearly completely occluded with a catheter-assisted technique. The authors preserved both limbs of the BA fenestration. The postoperative course was uneventful, and the patient had an excellent clinical course with no neurological deficits or aneurysmal recanalization. LESSONS: The case is the first report of an unruptured aneurysm arising at the minor limb of an upper BA fenestration. In this case, the authors preserved the minor limb with endovascular treatment. The authors believe catheter-assisted coil embolization to be a feasible endovascular technique in such cases.

Screening and quantification of undeclared PGF2α analogs in eyelash-enhancing cosmetic serums using LC-MS/MS.

In recent years, cosmetics deemed equivalent to pharmaceutical products containing prostaglandin F2α (PGF2α) analogs have been distributed overseas in the form of eyelash serums that can be purchased via the internet. The purpose of this study was to investigate the presence or absence of PGF2α analogs in eyelash serums procured in Japan via the internet to elucidate the actual composition. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) measurement system was developed for the determination of 14 PGF2α analogs in cosmetic serums. In total, 64 eyelash serum samples were purchased from 34 websites. After pretreatment, eyelash serum samples were screened for PGF2α analogs using the LC-MS/MS system. Products containing PGF2α analogs were subjected to quantification of these compounds. Of the 64 products, four were found to contain bimatoprost, among which, three did not indicate their contents on their package labels. In contrast, no samples were found to contain latanoprost, travoprost, or tafluprost, which are prescribed for glaucoma treatment. Additionally, eight products contained other PGF2α analogs, which have not been used as pharmaceuticals. The ease of access to cosmetic serums containing PGF2α analogs via online purchases presents a risk of serious side effects, particularly when consumers are not informed of their contents on the packages. This issue requires serious consideration to avoid the incorporation of pharmaceutical substances into cosmetic products.

A Spontaneous Extracranial Internal Carotid Artery Dissection with Autosomal Dominant Polycystic Kidney Disease: A Case Report and Literature Review.

Background and Objectives: Non-cystic manifestation of autosomal dominant polycystic kidney disease (ADPKD) is an important risk factor for cerebral aneurysms. In this report, we describe a rare spontaneous internal carotid artery (ICA) dissection in a patient with ADPKD. Observations: A 38-year-old woman with a history of ADPKD and acute myocardial infarction due to coronary artery dissection experienced severe spontaneous pain on the left side of her neck. Magnetic resonance imaging (MRI) revealed a severe left ICA stenosis localized at its origin. Carotid plaque MRI showed that the stenotic lesion was due to a subacute intramural hematoma. Close follow-up by an imaging study was performed under the diagnosis of spontaneous extracranial ICA dissection, and spontaneous regression of the intramural hematoma was observed uneventfully. Conclusions: When patients with a history of ADPKD present with severe neck pain, it is crucial to consider the possibility of a spontaneous ICA dissection. A carotid plaque MRI is beneficial in the differential diagnosis. Conservative management may benefit patients without ischemic symptoms.

A new biomarker of cardiac resynchronization therapy response: cGMP to mature BNP ratio.

BACKGROUND: Biomarkers that can predict cardiac resynchronization therapy (CRT) response have not yet been identified. The purpose of this study was to assess whether individual measurements of four brain/B-type natriuretic peptide (BNP) forms, coupled with cyclic guanosine monophosphate (cGMP) might contribute to the prediction of echocardiographic CRT responders. METHODS: A BNP precursor (proBNP) and total BNP (= proBNP + mature BNP) were measured with newly developed kits, while an N-terminal fragment of proBNP (NT-proBNP) and cGMP were measured with commercial kits on the day before CRT implantation. Estimated mature BNP (emBNP = total BNP-proBNP), and the ratio of cGMP to each BNP form, as well as the concentrations of three other BNP forms, were prospectively investigated for their capability in predicting a response to CRT. A CRT responder was defined as an improvement in left ventricular ejection fraction >10% and/or a reduction in left ventricular end-systolic volume >15% at 6-month follow-up. RESULTS: Out of 77 patients, 46 (60%) were categorized as CRT responders. Among the measurement parameters, only the highest quartile of the cGMP to emBNP ratio was an independent predictor of CRT responders (odds ratio 4.87, 95% confidence interval 1.25-18.89, p = 0.02). The cGMP to emBNP ratio was associated with the cumulative events of heart failure hospitalization within one year following CRT implantation (log-rank p = 0.029). CONCLUSIONS: The cGMP to emBNP ratio could be utilized as a predictive biomarker of CRT responders. (Clinical Study on Responder Prediction in Cardiac Resynchronization Therapy Using Individual Molecular Measurement of Natriuretic Peptide: UMIN R000038927).

Mechanical load regulates bone growth via periosteal Osteocrin.

Mechanical stimuli including loading after birth promote bone growth. However, little is known about how mechanical force triggers biochemical signals to regulate bone growth. Here, we identified a periosteal-osteoblast-derived secretory peptide, Osteocrin (OSTN), as a mechanotransducer involved in load-induced long bone growth. OSTN produced by periosteal osteoblasts regulates growth plate growth by enhancing C-type natriuretic peptide (CNP)-dependent proliferation and maturation of chondrocytes, leading to elongation of long bones. Additionally, OSTN cooperates with CNP to regulate bone formation. CNP stimulates osteogenic differentiation of periosteal osteoprogenitors to induce bone formation. OSTN binds to natriuretic peptide receptor 3 (NPR3) in periosteal osteoprogenitors, thereby preventing NPR3-mediated clearance of CNP and consequently facilitating CNP-signal-mediated bone growth. Importantly, physiological loading induces Ostn expression in periosteal osteoblasts by suppressing Forkhead box protein O1 (FoxO1) transcription factor. Thus, this study reveals a crucial role of OSTN as a mechanotransducer converting mechanical loading to CNP-dependent bone formation.

Current status of a helicopter transportation system on remote islands for patients undergoing mechanical thrombectomy.

BACKGROUND: Mechanical thrombectomy (MT) is standard treatment for acute ischemic stroke (AIS) with large-vessel occlusion within 6 h of symptom onset to treatment initiation (OTP). Recent trials have extended the therapeutic time window for MT to within 24 h. However, MT treatment remains low in remote areas. Nagasaki Prefecture, Japan has many inhabited islands with no neurointerventionalists. Our hospital on the mainland is a regional hub for eight island hospitals. We evaluated clinical outcomes of MT for patients with AIS on these islands versus on the mainland. METHODS: During 2014-2019, we reviewed consecutive patients with AIS who received MT at our hospital. Patients comprised the Islands group and Mainland group. Patient characteristics and clinical outcomes were compared between groups. RESULTS: We included 91 patients (Islands group: 15 patients, Mainland group: 76 patients). Seven patients (46.7%) in the Islands group versus 43 (56.6%) in the Mainland group achieved favorable outcomes. Successful recanalization was obtained in 11 patients (73.3%) on the islands and 67 (88.2%) on the mainland. The median OTP time in the Islands was 365 min. In both the Islands and Mainland groups, the OTP time and successful recanalization were associated with functional outcome. The modified Rankin Scale (mRS) score at 90 days ≤2 was obtained in two patients and mRS = 3 in four patients among eight patients with OTP time >6 h. CONCLUSIONS: Few patients with AIS on remote islands have received MT. Although patients who underwent MT on the islands had longer OTP, the clinical outcomes were acceptable. OTP time on remote islands must be shortened, as this is related to functional outcome. In some cases with successful recanalization, a favorable outcome can still be obtained even after 6 h. Even if OTP exceeds 6 h, it is desirable to appropriately select patients and actively perform MT.

[A Case of M2 Segment Dissection of the Middle Cerebral Artery Presenting with Deep White Matter Infarction Triggered by Minor Head Injury].

Herein, we report a rare case of a dissecting aneurysm of the M2 segment of the middle cerebral artery(MCA), presenting with a deep white matter infarction triggered by minor head injury. A 31-year-old woman was admitted to our hospital with headache and vomiting 3 hours after a mild head impact. A magnetic resonance angiogram obtained 10 months earlier, when the patient had complained of sudden headache, showed mild fusiform dilatation of the left M2 segment. On admission, computed tomography angiography(CTA)revealed irregular fusiform dilatation of the superior trunk of the left M2. Magnetic resonance imaging showed an intramural hematoma on the wall of the left M2 and acute infarction in the left deep white matter. Eight days after admission, CTA revealed further dilation of the aneurysm, and it was diagnosed as a dissecting aneurysm. The patient was successfully treated with proximal clipping and superficial temporal artery(STA)-MCA(M4)bypass on day 15. Bypass to a cortical M4 recipient was performed after the efferent M4 was identified using indocyanine green videoangiography. Four weeks postoperatively, the patient was discharged without any neurological deficits. The M2 dissecting aneurysm gradually regressed, and the bypass remained patent for 10 months postoperatively. To our knowledge, this is the first case of a dissecting M2 aneurysm treated by proximal clipping and STA-MCA bypass. This procedure seems a feasible option when the distal portion of the dissected MCA is difficult to expose.

[Early Development of a Symptomatic Expanding Porencephalic Cyst in the Hematoma Cavity after Subcortical Hematoma Removal in an Adult:A Case Report].

A 69-year-old woman presented on an emergency basis, with headache and left hemiparesis. Initial head CT at the time of admission revealed a large subcortical hematoma with perihematomal edema extending from the right parietal to the occipital lobe. A small part of the hematoma extended toward the trigone of the right lateral ventricle. CT angiography revealed no vascular abnormalities. Emergency craniotomy was erformed, and the patient's initial postoperative course was unremarkable. However, the patient's neurological symptoms worsened 10 days postoperatively, and CT revealed a new low-density cystic lesion with perifocal edema at the site of hematoma removal, in addition to severe cerebral compression. We performed a reoperation, and intraoperatively we observed hematoma fluid mixed with cerebrospinal fluid without any abnormal blood vessels or neoplastic lesions in the hematoma cavity. We identified the choroid plexus deep within the surgical field, and slight leakage of cerebrospinal fluid was detected from the ventricular aspect, indicating the formation of a small passage between the hematoma cavity and the ventricle. After the second operation, her postoperative course was uneventful without recurrent cyst formation. An early symptomatic expanding porencephalic cyst in the hematoma cavity after removal of an intracerebral hematoma is rare, and only a few cases have been reported in the literature. Based on literature review and considering the likely mechanism of cyst development, we speculated that progressive cyst expansion could be attributed to a check valve mechanism between the ventricle and the cavity from which the hematoma was removed, as observed in the present case.

[Ruptured Cerebral Aneurysm Associated with Arachnoid Cyst].

Cerebral aneurysms and arachnoid cysts are relatively common cerebral malformations and the use of recent modalities has increased their detection rates. However, cerebral aneurysms associated with arachnoid cysts are unusual. We describe two cases of ruptured cerebral aneurysms associated with arachnoid cysts. According to previous reports, clinical presentation may sometimes be unusual, as cysts can prevent subarachnoid hemorrhage. Moreover, in some cases, CT may reveal typical arachnoid cysts without subarachnoid hemorrhage, without intracystic hematoma, or with subdural hematoma alone. These clinical presentations and radiologic findings can lead to delayed diagnosis of subarachnoid hemorrhage. Therefore, we should consider the coexistence of arachnoid cyst in case of a warning sign of aneurysm rupture.

[Task-shifting Carried out by an Emergency Department's Stroke Hotline and Medical Care Support Conducted by Nurse Practitioners].

Our hospital serves as the main hub for eight remote island hospitals(RIHs)in Nagasaki Prefecture, Japan. The shortage of stroke physicians, which has led to overwork, is a major concern. Several "task-shifting" systems were adopted to avoid physician burnout. First, the emergency department established a hotline system for receiving emergency calls regarding a stroke, and which managed initial care until the stroke physicians arrived(called the Nagasaki Medical Center stroke hotline system: N-SHOT)in 2014. The rt-PA administration rate increased from 3.3% in the Pre-N-SHOT group to 6.7% in the N-SHOT group. Second, the 'isolated islands stroke hotline system(I-SHOT)', with which physicians in RIHs participate in cooperation with N-SHOT, was started in 2017. After I-SHOT was introduced, the number of patients treated with the drip and ship method using teleradiology and 24-h helicopter transportation increased from 20(2010-2016)to 29 cases in 2017-2018. Additionally, new information and communication technology(ICT)using smart devices was introduced into the teleradiology system for task support. Third, on behalf of stroke physicians, nurse practitioners(NP)helped bedridden patients who had been delivered from RIHs and who had received acute treatment, and returned to their islands by helicopter or airplane as transitions of care. N-SHOT is smoothly operated by each hospital department without reducing the quality of the stroke hotline. It has contributed to an increase in rt-PA and mechanical thrombectomy cases; I-SHOT has had the same effect. Task-shifting and task support with N- & I-SHOT, the smooth transfer system by NP, and the new ICT are considered to be useful for reducing the overall burden of stroke physicians.

[A Case of Radiation-induced Glioblastoma 29 Years after Treatments for Germinoma].

Intracranial germinomas are considered one of the most radiosensitive tumors and are curable by radiotherapy alone. Although patients can expect long-term survival, the adverse effects of radiotherapy and late sequelae in survivors are a major concern. Radiation-induced secondary neoplasms are one of those sequelae and are a serious concern because they are often connected directly with life prognosis. We describe a case of radiation-induced glioblastoma after radiotherapy for germinoma. An 11-year-old boy with basal ganglia germinoma was successfully treated with postoperative cranial irradiation. At the age of 40 years, he was admitted to our hospital for aphasia and memory disturbance. CT and MRI revealed a tumor in the left parietal lobe with dissemination. The tumor of the parietal lobe was removed surgically, and pathohistologically, it was diagnosed as glioblastoma. Long-term survivors who receive radiotherapy for germinomas in childhood are at risk for late complications, including radiation-induced neoplasms. Therefore, careful follow-up neurological examinations are recommended in these patients, even 20-30 years after radiotherapy.

[A Rare Case of Communicating Hydrocephalus with Intraparenchymal Pericatheter Cyst and Surrounding Edema in an Adult due to Accidental Change in the Pressure Setting of the Programmable Shunt System].

A 59-year-old woman suffering from memory impairment visited our hospital. She was discharged nine years ago without complications after undergoing neck clipping surgery for intracranial aneurysm rupture and a right ventricular peritoneal shunt using the CODMAN® HAKIM® programmable valve system(CHPV)for hydrocephalus. Initial CT/MRI revealed a cystic lesion with surrounding edema in the right frontal lobe around the proximal catheter, and a left frontal subacute subdural hematoma. The right ventricle was shown as a slit as before. The cystic portion presented with an MRI signal of the same intensity as the cerebrospinal fluid(CSF), and no enhancement effect was observed. It was thought to be a CSF cyst around the shunt catheter with interstitial CSF edema. Skull radiographs showed an accidental change in the CHPV pressure setting(100 to 190mmH2O), possibly due to head impact. We concluded that the newly set valve pressure caused sudden shunt dysfunction, resulting in CSF cyst formation and surrounding edema. Image findings and her symptoms were immediately improved on adjusting the shunt valve. This complication in adults associated with shunt dysfunction is very rare and only 10 cases have been reported to date. This is the first report of this complication due to an accidental reset of CHPV. To prevent the risk of misdiagnosing this condition as a tumor or abscess and performing unnecessary surgery, it is always necessary to suspect the possibility of this complication. For that purpose, detailed images, including diffusion-weighted images and contrast-enhanced MRI, should be done early in clinical practice.

[Falx Meningioma Presenting with Intratumoral Hemorrhage and Interhemispheric Acute Subdural Hematoma:A Case of Report].

A 68-year-old male with a sudden headache while defecation was transferred to our hospital. He was initially diagnosed with intracerebral hemorrhage in the right occipital lobe and acute subdural hematoma(ASDH)in the right interhemispheric fissure. A CT angiography(CTA)showed stenosis in the superior sagittal sinus(SSS)and the vein of Galen(VG)near the hematoma, which were considered to be due to compression of the hematoma. In the source image of CTA, the enhancement effect of the hematoma part was not clear. MRI revealed a heterogeneous mixed signal intensity in the hematoma area, suggesting a mixture of hematoma components that had bled at different times. Cerebral angiography performed two weeks after onset showed a tumor shadow imaged from the middle meningeal artery. Therefore, the presence of hemorrhagic meningioma was suspected. This was confirmed by contrast-enhanced MRI. One month after the onset, tumor resection was performed after the embolization of the feeding artery. Part of the tumor around the SSS and VG was left due to severe adhesion. Postoperatively, stenosis of the SSS and VG significantly improved. In this case, the increase in venous pressure may be related to the bleeding mechanism. Hemorrhagic onset meningioma with interhemispheric ASDH is extremely rare, and only 4 cases have been reported. It is easy to misdiagnose if only non-contrast CT is used. It should be noted that in cases of intratumoral hemorrhage, CTA may not show an enhancing effect in the acute phase. Since contrast-enhanced MRI may be useful for a definitive diagnosis, it should be performed at the time of initial imaging.

[Aplastic or Twig-like Middle Cerebral Artery with Cortical Subarachnoid Hemorrhage and Reversible Cerebral Vasoconstriction Syndrome during the Postpartum Period in a Juvenile Female:A Case Report].

A 17-year-old female in a lethargic state with mild dysarthria was transferred to our hospital after experiencing a generalized tonic seizure immediately after giving birth. Head CT showed a cortical subarachnoid hemorrhage(cSAH)in the left frontoparietal convexity. Three-dimensional rotational angiography(3D-RA)revealed multifocal narrowing of the cortical branches of the left middle cerebral artery(MCA)and severe stenosis of the left M1 segment with plexiform collateral networks, suggesting the presence of reversible vasoconstriction syndrome(RCVS)and aplastic or twig-like MCA(Ap/T-MCA). When 3D-RA was repeated on day 17, the narrowing of the cortical artery had resolved, and a new constriction of more proximal blood vessels was observed. The arterial spasm disappeared within 3 months, confirming the diagnosis of RCVS and Ap/T-MCA. Although non-aneurysmal SAH due to Ap/T-MCA is extremely rare, RCVS often complicates cSAH in the frontal/parietal region. It is suggested that RCVS triggers cSAH in the presence of incidental Ap/T-MCA. Ap/T-MCA is thought to be caused by developmental abnormalities during the embryonic period, but only 11 cases in children or adolescents have been reported. This suggests that there are a considerable number of asymptomatic young patients whose condition has not been detected. The majority of patients with Ap/T-MCA are from East Asia, suggesting that racial and genetic background differences are a factor. As this anomaly is more likely to present as a stroke in adulthood, long-term follow-up is recommended if it is found at a young age. There is no evidence that revascularization is effective in preventing stroke. Further studies are needed on how to manage this condition appropriately.

[Two Cases of Late-onset Brain Edema after Craniotomy for Unruptured Intracranial Aneurysms Suspected to be due to an Allergic Reaction to Arachnoid Plasty Material].

We report two rare cases of late-onset brain edema after craniotomy for clipping or coating of unruptured intracranial aneurysms, possibly due to an allergic reaction to topically applied fibrin glue or gelatin sponge used for arachnoid plasty to cover the opened sylvian cistern. Both patients were women in their 60s with an allergic predisposition and both followed a similar clinical course. A slight fever and headache persisted during the postoperative period. Five to six weeks after surgery without complications, MR images showed an extensive T2 prolongated region in the white matter around the operative field, indicative of vasogenic edema, with mass effect and meningeal enhancement around the sylvian fissure that had been covered with gelatin sponge and sprayed fibrin glue. Swelling of the cerebral cortex around the sylvian fissure subjected to arachnoid plasty was also observed. Blood tests showed the absence of an inflammatory reaction and cerebrospinal fluid examination showed lymphocytosis that was considered to be due to an aseptic meningeal reaction or meningitis. Clinical symptoms and imaging findings steadily improved with the administration of steroids and antiallergic agents. Delayed brain edema may occur around the arachnoid plasty area despite an uneventful chronic postoperative period, which could be due to an allergic reaction to locally administered fibrin glue or gelatin sponge. Thus, the application of arachnoid plasty using fibrin glue and gelatin sponge in patients with a predisposition to allergies needs to be carefully considered.

[Significance of Existence and Future Prospects of Nurse Practitioners in Neurosurgical Teams].

Recently, hospitals and medical facilities have been experiencing a shortage of doctors along with heavy workload. The role of a mid-level provider may be important as a potential solution to these problems. A nurse practitioner(NP)is the most famous mid-level provider, and in our institution, the neurosurgery department has 3 NPs. Contrary to America, in Japan, the job of an NP is not an occupation independent from doctors or nurses. NPs perform 38 specific procedures according to doctors' instructions. Their activities include assisting with operations, writing prescriptions, participation in neurosurgical rounds and conferences, transportation of patients by helicopter, etc. The safe transportation of patients to isolated islands by a helicopter is especially a representative activity in our institution. Inclusion of NPs in clinical settings may bring forth medical improvements and superior work efficiency. According to regional characteristics, the job profile of a NP presents a potential scope for added capabilities.