[Cervical Spinal Epidural Hematoma].

A woman in her 60s was admitted to our hospital because of sudden-onset right hemiparesis, paresthesia, and neck pain. At first, a head CT scan was performed to rule out stroke, which did not detect any abnormalities. Subsequently, a neck CT scan was performed, which revealed a mild high-density structure compressing the dural sac within the cervical spinal canal. She was suspected to have a spinal hematoma. A MRI scan revealed a spindle-shaped structure with a heterogeneous high signal on T2-weighted and a mild high signal on T1-weighted sagittal images, which led to the diagnosis of a spontaneous spinal epidural hematoma. The patient was treated with conservative therapy upon which her symptoms improved. She was discharged seven days after admission. Spontaneous cervical spinal epidural hematoma often causes neck pain followed by unilateral spinal cord compression symptoms(such as hemiparesis and paresthesia)and can be misdiagnosed as a stroke. In cases of hemiparesis with sudden-onset neck pain, cervical lesions should be considered in the differential diagnoses in addition to stroke.

Reinterpretation of magnetic resonance imaging findings with magnetoencephalography can improve the accuracy of detecting epileptogenic cortical lesions.

OBJECTIVE: This study examined whether the application of magnetoencephalography (MEG) to interpret magnetic resonance imaging (MRI) findings can aid the diagnosis of intractable epilepsy caused by organic brain lesions. METHODS: This study included 51 patients with epilepsy who had MEG clusters but whose initial MRI findings were interpreted as being negative for organic lesions. Three board-certified radiologists reinterpreted the MRI findings, utilizing the MEG findings as a guide. The degree to which the reinterpretation of the imaging results identified an organic lesion was rated on a 5-point scale. RESULTS: Reinterpretation of the MRI data with MEG guidance helped detect an abnormality by at least one radiologist in 18 of the 51 patients (35.2%) with symptomatic localization-related epilepsy. A surgery was performed in 7 of the 51 patients, and histopathological analysis results identified focal cortical dysplasia in 5 patients (Ia: 1, IIa: 2, unknown: 2), hippocampal sclerosis in 1 patient, and dysplastic neurons/gliosis in 1 patient. CONCLUSIONS: The results of this study highlight the potential diagnostic applications of MEG to detect organic epileptogenic lesions, particularly when radiological visualization is difficult with MRI alone.

Prediction of unilateral hyperaldosteronism on adrenal vein sampling using captopril challenge test in patients with primary aldosteronism.

Captopril challenge test (CCT) is a simple and safe confirmatory test for primary aldosteronism (PA). We investigated the effectiveness of the indices after captopril administration for prediction of unilateral hyperaldosteronism (UHA) on adrenal vein sampling (AVS). We studied 238 patients with PA who had CCT and successful AVS between July 2007 and December 2019 in Sapporo City General Hospital. Receiver operating characteristic (ROC) curve analysis showed that the diagnostic performance for prediction of UHA on AVS in regard to the reduction rate of plasma aldosterone concentration (PAC) after captopril administration was inferior to aldosterone to renin ratio (ARR) and PAC (area under the ROC curve 0.72 vs. 0.84, 0.72 vs. 0.89, respectively, both p < 0.01). Based on the optimal cut-off values in ARR (897 pg/mL/ng/mL/h, sensitivity 64.6%, specificity 93.0%) and PAC (203 pg/mL, sensitivity 73.9%, specificity 93.0%) after captopril administration, the patients were divided into three groups: (1) both positive, (2) one positive, and (3) both negative. The prevalence of UHA on AVS in the three groups were 90.0%, 52.9%, and 7.3%, respectively. In the first group, 31 of 32 patients with unilateral nodular lesion on CT had an ipsilateral unilateral AVS. In conclusion, the combination of post-captopril ARR and PAC is useful for prediction of laterality diagnosis on AVS. AVS is strongly recommended in patients with both positive or one positive results for the optimal cut-off values of post-captopril ARR and PAC and is weakly recommended in patients with both negative results.

Relationships of drooling with motor symptoms and dopamine transporter imaging in drug-naïve Parkinson's disease.

OBJECTIVES: The aim of the present study was to determine the relationships of drooling with motor symptoms and nigrostriatal neuron loss in drug-naïve patients with Parkinson's disease (PD). We therefore examined the relationships of drooling with motor symptoms and striatal dopamine transporter (DAT) binding measured by [123-Iodine]-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenylnortropane) dopamine transporter single-photon emission computed tomography(123I-FP-CIT SPECT). PATIENTS AND METHODS: Thirty-five untreated PD patients (14 men and 21 women with a mean age of 71.9 ±â€¯7.2 years) were included in this study. The patients were divided into a drooler group and non-drooler group. They underwent clinical assessments and 123I-FP-CIT SPECT imaging. Motor symptoms were assessed using Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: The results showed that UPDRS motor score (p = 0.002) and akinetic-rigid score (p = 0.008) were higher and that striatal DAT availability (p = 0.03) was lower in the drooler group than in the non-drooler group. However, tremor score, age, and duration of PD showed no significant differences between the drooler group and non-drooler group. CONCLUSIONS: Drooling in untreated PD is related to an increase in motor symptoms (especially bradykinesia and axial symptoms) and to reduction of striatal DAT availability.

Relations of clinical symptoms with dopamine transporter imaging in drug-naïve Parkinson's disease.

OBJECTIVES: The aim of the present study was to determine the relations of clinical symptoms with nigrostriatal neuron loss in drug-naïve patients with Parkinson's disease (PD). We examined the severity of motor symptoms and freezing of gait (FOG), falls and overactive bladder (OAB) in PD patients and their relations with striatal dopamine transporter (DAT) binding. PATIENTS AND METHODS: Thirty-two untreated PD patients (14 men and 18 women with a mean age of 71.4 ±â€¯7.2 years) were included in this study. Clinical assessments were performed by using Unified Parkinson's Disease Rating Scale (UPDRS) and overactive bladder symptom score (OABSS), and striatal dopamine transporter (DAT) binding was measured by123I-FP-CIT SPECT. RESULTS: The results showed that striatal DAT availability was significantly lower in the high UPDRS motor score group, high akinetic-rigid score group, FOG group, and OAB group than in the low UPDRS motor score group, low akinetic-rigid score group, non-FOG group, and non-OAB group. However, the results also showed that there was no significant difference in striatal DAT availability between the high tremor score group and low tremor score group or between the faller group and non-faller group. CONCLUSIONS: The severity of bradykinesia and axial symptoms and the existence of FOG and OAB in untreated PD patients are related to a decrease in striatal DAT availability. Severity of tremors and occurrence of falls are not related to a decrease in striatal DAT availability. The mechanisms underlying the clinical symptoms of PD involve not only dopaminergic pathways but also non-dopaminergic pathways.

Progressive Multifocal Leukoencephalopathy during Tocilizumab Treatment for Rheumatoid Arthritis.

A 61-year-old woman was diagnosed with rheumatoid arthritis 12 years ago and received multiple treatment regimens before achieving symptomatic stability with methotrexate plus tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, about 2 years prior to the current presentation. Sixteen months after tocilizumab initiation, she exhibited dysarthria and disorientation; five months later, she was hospitalized with movement difficulties. Her neurological symptoms deteriorated thereafter, accompanied by enlarged cerebral white matter lesions on magnetic resonance imaging. A biopsy of the right frontal lesion confirmed progressive multifocal leukoencephalopathy (PML). While several therapeutic monoclonal antibodies have been linked to PML, this is the first case associated with tocilizumab.

The risk factors for hepatic steatosis in patients with primary aldosteronism.

Patients with primary aldosteronism (PA) are complicated by metabolic syndrome more frequently than those without PA. Hyperaldosteronism has been reported to be associated with a higher prevalence of non-alcoholic fatty liver disease (NAFLD). We aimed to clarify the risk factors for hepatic steatosis in the two subtypes of PA, comparing the status of hepatic steatosis in each of these subtypes. This was a retrospective observational study. We enrolled patients with an aldosterone producing adenoma (APA) (n = 33) or idiopathic hyperaldosteronism (IHA) (n = 56). Hepatic fat content was evaluated using the ratio of liver to spleen (L/S) X-ray attenuation on unenhanced computed tomography. L/S ratio <1.0 was utilized for assessing as hepatic steatosis. Age, sex distribution, visceral fat percentage (VF%), and visceral fat area (VFA) did not differ between patients with the two PA subtypes. The percentages of patients with L/S ratio <1.0 was not different between the two subtypes (APA: 21.2 % (7/33) vs. IHA: 19.6 % (11/56), p = 1.00). In both subtypes, the L/S ratio negatively correlated with VF% (APA: r = -0.66, p < 0.001; IHA: r = -0.66, p < 0.001) and with VFA (APA: r = -0.44, p < 0.01; IHA: r = -0.37, p < 0.01). The status of hepatic steatosis, evaluated using L/S ratio, did not differ between patients with APA or IHA. Hepatic steatosis was affected by the amount of visceral fat.

Left-right differences in adrenal vein sampling for primary aldosteronism.

In adrenal venous sampling (AVS) for patients with primary aldosteronism (PA), adrenocorticotropic hormone (ACTH) stimulation generally increased the success rate. The effect of ACTH stimulation on the left-right differences of laterality diagnosis in AVS remains unclear. A total of 167 patients with PA underwent successful AVS were examined. Patients with autonomous cortisol secretion were excluded. The proportion of dominant side in AVS was compared before and after ACTH stimulation. Unilateral disease on AVS was defined as a lateralization index of more than 4, both before and after ACTH stimulation. Before ACTH stimulation, unilateral disease was more frequently observed on the right side than the left side (right 33.5% vs. left 13.8%, p < 0.01). After ACTH stimulation, unilateral disease was more frequently observed on the left side than the right side, without statistical significance (left 15.6% vs. right 10.8%, p = 0.20). Among the 56 patients who had right unilateral disease before ACTH stimulation, 17 patients (30.0%) also had right unilateral disease after ACTH stimulation. The affected side of AVS was changed from right unilateral to bilateral after ACTH stimulation in 34 (60.7%) out of 56 patients. These patients had milder PA and CT scans showed no nodular lesions on the right side. In AVS, ACTH stimulation not only decreased unilateral results but also shifted to the dominant side. Overestimation should be carefully considered when the surgical indication for the right adrenal gland was decided based on AVS results without ACTH stimulation.

A case of Williams syndrome with suspected coexisting ectopic aldosterone-producing tumor in the liver.

SUMMARY: A 31-year-old man with Williams syndrome (WS) was referred to our hospital because of a 9-year history of hypertension, hypokalemia, and high plasma aldosterone concentration to renin activity ratio. A diagnosis of primary aldosteronism (PA) was clinically confirmed but an abdominal CT scan showed no abnormal findings in his adrenal glands. However, a 13-mm hypervascular tumor in the posterosuperior segment of the right hepatic lobe was detected. Adrenal venous sampling (AVS) subsequently revealed the presence of an extended tributary of the right adrenal vein to the liver surrounding the tumor. Segmental AVS further demonstrated a high plasma aldosterone concentration (PAC) in the right superior tributary vein draining the tumor. Laparoscopic partial hepatectomy was performed. The resected tumor histologically separated from the liver was composed of clear cells, immunohistochemically positive for aldesterone synthase (CYP11B2), and subsequently diagnosed as aldosterone-producing adrenal adenoma. After surgery, his blood pressure, serum potassium level, plasma renin activity and PAC were normalized. To the best of our knowledge, this is the first report of WS associated with PA. WS harbors a high prevalence of hypertension and therefore PA should be considered when managing the patients with WS and hypertension. In this case, the CT findings alone could not differentiate the adrenal rest tumor. Our case, therefore, highlights the usefulness of segmental AVS to distinguish adrenal tumors from hepatic adrenal rest tumors. LEARNING POINTS: Williams syndrome (WS) is a rare genetic disorder, characterized by a constellation of medical and cognitive findings, with a hallmark feature of generalized arteriopathy presenting as stenoses of elastic arteries and hypertension. WS is a disease with a high frequency of hypertension but the renin-aldosterone system in WS cases has not been studied at all. If a patient with WS had hypertension and severe hypokalemia, low PRA and high ARR, the coexistence of primary aldosteronism (PA) should be considered. Adrenal rest tumors are thought to arise from aberrant adrenal tissues and are a rare cause of PA. Hepatic adrenal rest tumor (HART) should be considered in the differential diagnosis when detecting a mass in the right hepatic lobe. Segmental adrenal venous sampling could contribute to distinguish adrenal tumors from HART.

Relationship Between Visceral Fat and Plasma Aldosterone Concentration in Patients With Primary Aldosteronism.

CONTEXT: The involvement of visceral fat in aldosterone secretion has not been reported in patients with primary aldosteronism (PA). Patients with PA are complicated by metabolic syndrome more frequently than those without PA. An excess of visceral fat has been hypothesized to cause an elevation of aldosterone secretion in patients with PA. OBJECTIVES: To clarify the role of visceral fat in the pathophysiology of PA, we investigated the correlation between plasma aldosterone concentration (PAC) and visceral fat parameters in patients with PA. DESIGN: This retrospective observational study comprised 131 patients diagnosed with PA between April 2007 and April 2017 at Sapporo City General Hospital. We divided participants into two PA subtypes, aldosterone-producing adenoma (APA; n = 47) and idiopathic hyperaldosteronism (IHA, n = 84), utilizing adrenal venous sampling. We analyzed the correlations of PAC with visceral fat percentage (VF%), visceral fat area (VFA), and subcutaneous fat area, by evaluating computed tomography studies in each subtype group. RESULTS: Patients with IHA showed a positive correlation of PAC with VF% (r = 0.377, P < 0.001) and VFA (r = 0.443, P < 0.001). The correlation was not evident in patients with APA. CONCLUSIONS: This study revealed a relationship between visceral adipose tissue and aldosterone production only in patients with IHA.

Relation of overactive bladder with motor symptoms and dopamine transporter imaging in drug-naïve Parkinson's disease.

OBJECTIVES: The aim of the present study was to determine the relation of urinary dysfunction with motor symptoms and nigrostriatal neuron loss in drug-naïve patients with Parkinson's disease (PD). We therefore examined the relation of overactive bladder (OAB) symptoms with motor symptoms and striatal dopamine transporter (DAT) binding measured by [123-Iodine]-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenylnortropane) dopamine transporter single-photon emission computed tomography (123I-FP-CIT SPECT). PATIENTS AND METHODS: Thirty-one untreated PD patients (12 men and 19 women with a mean age of 71.2 ±â€¯6.7 years) were included in this study. Patients were evaluated with overactive bladder symptom score (OABSS) and divided into an OAB group and Non-OAB group. They underwent clinical assessments and 123I-FP-CIT SPECT imaging. Motor symptoms were assessed using Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: The results showed that UPDRS motor score (p = 0.01) and akinetic-rigid score (p = 0.002) were higher and that striatal DAT availability (p = 0.01) was lower in the OAB group than in the Non-OAB group. However, tremor score, age, and duration of PD showed no significant differences between the OAB group and Non-OAB group. CONCLUSIONS: Urinary dysfunction in untreated PD is related with increase in motor symptoms (especially bradykinesia and axial symptoms) and reduction of striatal DAT availability.

Improvement of cerebral hypometabolism after resection of radiation-induced necrotic lesion in a patient with cerebral arteriovenous malformation.

A 55-year-old woman underwent radiosurgery for a left cerebral hemisphere arteriovenous malformation (AVM) and developed radiation-induced necrosis causing a massive edema in the surrounding brain tissues. Despite various therapies, the edema expanded to the ipsilateral hemisphere and induced neurological symptoms. The radiation-induced necrotic lesion was surgically removed 4 years after radiosurgery. While the preoperative FDG PET revealed severe hypometabolism in the left cerebrum, the necrotomy significantly ameliorated the brain edema, glucose metabolism (postoperative FDG PET), and symptoms. This case indicates that radiation necrosis-induced neurological deficits may be associated with brain edema and hypometabolism, which could be reversed by appropriate necrotomy.

Bilateral breast MRI by use of dual-source parallel radiofrequency excitation and image-based shimming at 3 Tesla: improvement in homogeneity on fat-suppression imaging.

In this study, we aimed to compare fat-suppression homogeneity on breast MR imaging by using dual-source parallel radiofrequency excitation and image-based shimming (DS-IBS) with single-source radiofrequency excitation with volume shim (SS-Vol) at 3 Tesla. Twenty patients were included. Axial three-dimensional T1-weighted turbo-field-echo breast images with DS-IBS and SS-Vol were obtained. Fat suppression was scored with four grade points. The contrast of the pectoral muscle and the fat in each breast area was obtained in the head medial, head lateral, foot medial, and foot lateral areas. The axillary space was calculated and compared between DS-IBS and SS-Vol. The average DS-IBS score was significantly higher than that of SS-Vol. The mean contrasts of fat in the foot lateral areas and axillary spaces on DS-IBS images were significantly higher than on SS-Vol images.

Earlier and better high-resolution single breast imaging during bilateral breast dynamic scans at 3-T MRI: comparison with post dynamic high-resolution imaging.

BACKGROUND: Breast MRI protocols have been improved by using a combination of dynamic scans for bilateral breasts and high-resolution imaging for a single breast which can be obtained during dynamic scans by recent technological advances. The purpose of this study was to compare high-resolution imaging during dynamic scans (HR-intra) with high-resolution imaging obtained post dynamic scans (HR-post). METHODS: Fifty-five women with pathologically proven breast cancer who underwent breast dynamic scans at 3-T MRI from February to September 2009 were enrolled in this study. Tumoral contrasts to the background breast tissue were compared by three radiologists independently in a blinded fashion. Results of visual assessment were categorized into three groups as follows: HR-intra being better (IB), equal (E), and HR-post being better (PB). The contrast to noise ratio (CNR) of the tumor and the signal to noise ratio of the normal breast gland (SNR) were compared between HR-intra and HR-post. RESULTS: Two patients were excluded because of poor MR imaging quality. Three radiologists separately categorized 64.2, 79.2, and 77.4 % of lesions as IB. The CNR of the tumor of HR-intra (mean ± SD = 6.9 ± 4.0) was significantly higher than that of HR-post (6.0 ± 3.7, p < 0.0001). The SNR of the normal breast gland of HR-intra (9.5 ± 1.7) was significantly lower than that of HR-post (10.0 ± 1.9, p < 0.0001). CONCLUSION: HR-intra during dynamic MRI provided earlier and better tumor to normal breast gland contrast than HR-post.

The value of 4-month neurocognitive function as an endpoint in brain metastases trials.

To investigate whether the neurocognitive function at 4 months could be a relevant primary endpoint in clinical trials dealing with brain metastases, we created a Japanese neurocognitive battery and examined the changes in patients' neurocognitive function for 1 year after their brain radiotherapy. In this prospective pilot study, we enrolled 27 patients (20 patients who received whole-brain radiation therapy [WBRT] and seven who received stereotactic irradiation [STI] alone) between March 2009 and December 2010. The follow-up neurocognitive data at 4, 8 and 12 months were available in 22 (17 WBRT, 5 STI), 19 patients (14 WBRT, 5 STI) and 13 patients (9 WBRT, 4 STI), respectively. Among the patients who received WBRT, significant deterioration in delayed memory compared to the baseline (p = 0.04) was observed at 4 months, and at 8 months, significant improvements were observed in immediate memory compared to the baseline (p = 0.008) and 4-months scores (p = 0.005). At 12 months, however, the immediate memory scores had returned to the baseline. Similar trends were observed in other functions (delayed memory, attention and executive functions). In these patients, the correlations between 4-months scores of neurocognitive functions and 12-months scores were significant in immediate memory (γ = 0.68, p = 0.004), delayed memory (γ = 0.738, p = 0.023) and attention (γ = 0.817, p = 0.007). Among the patients who received STI, no significant changes were observed in any functions. These results suggest that 4-months changes in neurocognitive functions were transient but could also be a premonitory index for predicting the neurocognitive function 1 year or later after brain radiation therapy.

Isolated posterior fossa involvement in posterior reversible encephalopathy syndrome.

Posterior reversible encephalopathy syndrome (PRES) is characterized by reversible vasogenic edema affecting the subcortical white matter of bilateral occipital and parietal lobes. We describe a case of isolated posterior fossa involvement of PRES which occurred during remission induction chemotherapy for T-cell acute lymphoblastic leukemia. Both the brainstem and cerebellum were extensively involved, but the supratentorial structures were completely spared. The follow-up magnetic resonance images revealed reversibility of most lesions. The knowledge of atypical radiological features of PRES is essential for prompt diagnosis.

Validity of dual MRI and F-FDG PET imaging in predicting vulnerable and inflamed carotid plaque.

BACKGROUND: Vulnerable and inflamed plaques in the carotid artery are at high risk of ischemic stroke, suggesting the importance of diagnostic modalities to detect them in patients with carotid stenosis with high sensitivity and specificity. Although many investigators have reported that magnetic resonance imaging (MRI) is a useful tool to predict the vulnerable components of carotid plaque, its validity is not established. On the other hand, (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) may be an alternative modality to directly identify the inflamed plaque in carotid artery stenosis. Therefore, this study aimed at evaluating the validity of MRI and FDG-PET to predict vulnerable and inflamed carotid plaque. METHODS: This prospective study totally included 25 patients who underwent carotid endarterectomy (CEA) for carotid artery stenosis at our institute between January 2009 and January 2012. Prior to CEA, FDG-PET, black-blood T1-weighted imaging (BB-T1WI), and 3-dimensional time-of-flight (TOF) imaging were performed. The specimens were stained with hematoxylin-eosin to assess the different plaque components (lipid, hemorrhage, calcification, and fibrous tissue). In addition, they were stained with primary antibodies against CD68 (activated macrophages) and matrix metalloproteinase (MMP)-9. RESULTS: High FDG uptake was detected in 13 (52.0%) of 25 patients. All of them had lipid-rich plaque. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) to identify the lipid-rich plaques were all 100% for FDG-PET. More importantly, all of the FDG-positive plaques had strong immunoreactivity against both CD68 and MMP-9. There was a significant correlation between the findings on FDG-PET and those on immunohistochemistry against CD68 and MMP-9 (p = 0.006 and 0.004, respectively). On the other hand, 16 (64.0%) of 25 patients had high signal intensity plaque on BB-T1WI. In 7 of these 16 patients, the lesions also showed high signal intensity on TOF imaging. All of them had a large intraplaque hemorrhage. The sensitivity, specificity, PPV, and NPV to identify a large intraplaque hemorrhage were 70, 100, 100, and 83%, respectively, for MRI. CONCLUSIONS: These findings suggest that FDG-PET and MRI are complementary to predict high-risk carotid plaque, such as lipid-rich or hemorrhagic plaque. FDG-PET can accurately predict the lipid-rich and inflamed plaque. MRI is valuable to identify unstable plaque with a large intraplaque hemorrhage. The combination of these two modalities may play an important role in predicting carotid plaque at high risk of ischemic stroke.

Imaging characteristics of cardiac dominant diffuse large B-cell lymphoma demonstrated with MDCT and PET/CT.

PURPOSE: To investigate the specific imaging findings of multidetector row CT (MDCT) and PET/CT with(18)F-FDG in cardiac dominant diffuse large B-cell lymphoma (DLBCL) in comparison with other cardiac tumours. METHODS: Five patients with DLBCL and 12 patients with other cardiac tumours including pericardial tumours were retrospectively reviewed. Among the patients with other cardiac tumours, seven had metastatic tumours, three had benign tumours, and two had other malignant cardiac tumours. The location of the cardiac mass, the encasement of the coronary artery surrounded by the mass, and pericardial effusion were evaluated using MDCT. The disease activity of the cardiac tumour was also evaluated by PET/CT. RESULTS: Four of the five DLBCL patients had primarily right-sided cardiac lesions, which was seen significantly more frequently in DLBCL than in other cardiac tumours (p = 0.028). All cardiac DLBCL lesions were located around the atrioventricular groove and encased the coronary arteries. ECG-gated cardiac MDCT showed that there was no apparent stenosis of the coronary arteries. Large amounts of pericardial effusion were seen in all DLBCL patients. PET/CT revealed significantly higher FDG uptake in DLBCL than in other cardiac malignant tumours, with no overlap (p = 0.0007). CONCLUSION: The combination of a right-sided cardiac mass with a large pericardial effusion and no apparent stenosis of the encased coronary artery revealed by MDCT and a high maximum standard uptake value were the specific findings in cardiac dominant DLBCL.