RESUMEN
We report a case of inflammatory pseudotumor of the ureter. An 81-year-old man who had an operation of pelvic exenteration with ileal conduit presented with right flank pain. Computed tomography revealed a 16 mm mass of the right ureter with right hydronephrosis and renal atrophy. The mass increased in size during follow up. Right nephroureterectomy was performed with suspicion of ureteral cancer. Histopathological finding showed an inflammatory pseudotumor. No obvious recurrence has been observed for 33 months after the surgery.
Asunto(s)
Diagnóstico Diferencial , Enfermedades Ureterales/diagnóstico por imagen , Neoplasias Ureterales/diagnóstico por imagen , Anciano de 80 o más Años , Humanos , Masculino , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Enfermedades Ureterales/patología , Enfermedades Ureterales/cirugía , Neoplasias Ureterales/patologíaAsunto(s)
Cuerpo Calloso/diagnóstico por imagen , Encefalitis/líquido cefalorraquídeo , Encefalitis/diagnóstico por imagen , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Adolescente , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Niño , Preescolar , Encefalitis/sangre , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , MasculinoRESUMEN
Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal malignancy-related condition that involves rapidly progressing hypoxia and pulmonary hypertension. We report a case of PTTM caused by prostate carcinoma, which was diagnosed before autopsy in an 81-year-old man. Computed tomography showed diffuse ground-glass opacities, consolidation, and small nodules in the peripheral regions of the lung. Autopsy showed adenocarcinoma cells embolizing small pulmonary arteries with fibrocellular intimal proliferation, which was consistent with PTTM caused by prostate carcinoma.
RESUMEN
We report a case of recurrent breast cancer with involvement of the right adrenal grand, which was resected using laparoscopic surgery. The patient was a 41-year-old woman who underwent duct-lobular segmentectomy for ductal carcinoma in situ. Histopathology showed microinvasion, and tested positive for ER and PR, but negative for HER2, so we applied radiation to the remaining breast and administered tamoxifen. After 9 months, local recurrence was detected and quadrantectomy with axillary lymph node dissection was performed. One year and 10 months later, local recurrence was again detected and a tumorectomy was performed. The adjuvant therapy was changed to an LH-RH analog plus anastrozole and it was administered effectively for 5 years. Left ileal metastasis appeared in the 2nd month after completion of the adjuvant chemotherapy, so radiation was applied and an LH-RH analog plus exemestane administration was started. Three years passed without recurrence, but a right adrenal tumor appeared on computed tomography. The tumor grew over 6 months, so laparoscopic right adrenalectomy was performed. Histopathologically, the tumor tested positive for ER and PR, and negative for HER2 so we diagnosed metastasis of breast cancer, and administered an LH-RH analog plus exemestane. The patient's disease has not progressed in the 3 months since surgery.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/cirugía , Neoplasias de la Mama/patología , Neoplasias de las Glándulas Suprarrenales/secundario , Adrenalectomía , Adulto , Neoplasias de la Mama/cirugía , Femenino , Humanos , Laparoscopía , Mastectomía Segmentaria , Recurrencia , Resultado del TratamientoRESUMEN
BACKGROUND: There is not much information on established standard therapy for patients with severe methionine adenosyltransferase (MAT) I/III deficiency. CASE PRESENTATION: We report a boy with MAT I/III deficiency, in whom plasma methionine and total homocysteine, and urinary homocystine were elevated. Molecular genetic studies showed him to have novel compound heterozygous mutations of the MAT1A gene: c.191T>A (p.M64K) and c.589delC (p.P197LfsX26). A low methionine milk diet was started at 31 days of age, and during continuing dietary methionine restriction plasma methionine levels have been maintained at less than 750 µmol/L. He is now 5 years old, and has had entirely normal physical growth and psychomotor development. CONCLUSIONS: Although some severely MAT I/III deficient patients have developed neurologic abnormalities, we report here the case of a boy who has remained neurologically and otherwise normal for 5 years during methionine restriction, suggesting that perhaps such management, started in early infancy, may help prevent neurological complications.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Metionina Adenosiltransferasa/deficiencia , Metionina Adenosiltransferasa/genética , Errores Innatos del Metabolismo de los Aminoácidos/patología , Preescolar , Glicina N-Metiltransferasa/deficiencia , Heterocigoto , Homocisteína/sangre , Homocisteína/orina , Humanos , Masculino , Metionina/sangre , Mutación , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patologíaRESUMEN
The patient was a 60 year-old male who first visited a doctor because of back pain on the right side in May 2003. As a result of thorough examination, he was diagnosed with right renal pelvic cancer (cT4, N2, M1), and was referred to our department for treatment. In spite of systemic chemotherapy and radiation therapy in combination with cisplatinum on the primary tumor were performed from May 2003 to December 2005, the number and size of hepatic metastases increased. Consequently, considering hepatic metastasis as the specific prognosis factor, the patient was given a total of 14 cycles of hepatic arterial infusion chemotherapy (HAIC) from January to October 2006. As a result, the hepatic metastases completely disappeared. Then HAIC was tentatively discontinued and the patient was followed up. However, as new lung metastases were found by CT in March 2007, radiation therapy was performed on the lung metastases. As hepatic metastasis was recognized again by CT in April 2007, HAIC was resumed and the patient was given a total of 6 cycles starting from May 2007. During that period, two transurethral resection of bladder tumor were performed against the recurrence within the bladder while transarterial embolization was performed against the bleeding in the right kidney. The patient was regarded as a long-term survivor surviving for about five years after his initial consultation.
Asunto(s)
Infusiones Intraarteriales , Neoplasias Renales/patología , Pelvis Renal , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Emphysematous cystitis is a rare lower urinary tract infection. A case of emphysematous cystitis with diabetes mellitus and transverse colon cancer is reported. The patient was an 81-year-old woman complaining of nausea and vomiting. Urinalysis showed hematopyuria. Plain abdominal film and CT scan showed gaseous shadow in the bladder wall. Urine culture contained Escherichia coli. A urethral catheterization and administration of antibiotics resulted in the marked improvement in the clinical course. To our knowledge, 53 cases of emphysematous cystitis have been reported in the Japanese literature including this case and the clinical features are reviewed.
Asunto(s)
Neoplasias del Colon/complicaciones , Cistitis/complicaciones , Enfisema/complicaciones , Anciano de 80 o más Años , Complicaciones de la Diabetes , Femenino , HumanosRESUMEN
BACKGROUND: Sorafenib is a multikinase inhibitor used as a second-line treatment for metastatic renal cell carcinoma (mRCC). However, it is very difficult to estimate sorafenib dosage because it is difficult to maintain stable administration and dosage intervals due to several side-effects. We examined the correlation between relative dose intensity (RDI) and clinical outcome of sorafenib therapy in a multi-institutional study. METHODS: A study population of 70 first-line therapy-refractory patients with pathologically confirmed RCC was eligible for this investigation. Clinical outcomes were evaluated according to clinicopathological features and RDI for 1 month (1M-RDI). RESULTS: There was significant difference in progression-free survival (PFS) time but not overall survival (OS) time when the 1M-RDI cut-off value was ≥ 50%. In 15 patients (21.4%) with 1M-RDI of <50%, median PFS time was 4.1 months (95% I collagen (95% CI): 2.0-6.2), whereas it was 10.5 months (95% CI: 7.6-13.4) in the patients with 1M-RDI of ⩾50% (P=0.022). Multivariate analysis showed 1M-RDI status to be significantly associated with PFS (HR: 3.838, 95% CI: 1.658-8.883, P=0.002) but not OS (P=0.328). CONCLUSION: Although this study was retrospective, a 1M-RDI cut-off value of ≥ 50% for sorafenib may be the first factor to predict PFS but not OS in cytokine pretreated mRCC patients. The data indicate that a dose of 400mg/day of sorafenib administered successively for the first one month was necessary to prolong disease stabilisation and could be tolerated by Japanese patients.
Asunto(s)
Antineoplásicos/administración & dosificación , Bencenosulfonatos/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Piridinas/administración & dosificación , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Análisis Multivariante , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Estudios Retrospectivos , Sorafenib , Resultado del TratamientoRESUMEN
We report a case of primary malignant lymphoma of the prostate. An 84-year-old man was referred to our hospital with a chief complaint of urinary retention. Magnetic resonance imaging showed a large mass below the bladder and in front of the rectum. Histological and immunocytochemical studies of transperineal biopsy of the prostate showed diffuse large B-cell non-Hogkin's lymphoma. Radiological assessment of the disease confirmed stage IV according to the Ann Arbor classification. Although the tumor was markedly reduced in size after four cycles of combination chemotherapy with cyclophosphamide, adriamycin, vincristine, and prednisolone, he died with brain metastasis 4 months after the diagnosis.
Asunto(s)
Linfoma de Células B Grandes Difuso/complicaciones , Neoplasias de la Próstata/complicaciones , Retención Urinaria/etiología , Anciano de 80 o más Años , Antibióticos Antineoplásicos/administración & dosificación , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Prednisolona/administración & dosificación , Neoplasias de la Próstata/tratamiento farmacológico , Vincristina/administración & dosificaciónRESUMEN
PURPOSE: Since 2003, screening with prostate specific antigen (PSA) has been conducted to detect prostate cancer. We investigated the results between 2003 and 2007. PATIENTS AND METHODS: Screening with PSA alone was performed for males aged over 50 years who desired prostate cancer screening. We used a PSA cutoff value of 4.00 ng per milliliter. RESULTS: In 2003, there were 18,161 males aged over 50 years in Ikeda City. 3,738, 3,905, 4,129, 4,410, and 4,515 of the males underwent PSA screening in 2003, 2004, 2005, 2006, and 2007. The rate of elevated PSA levels was 7.9%-9.8% (median 9.1%). 161, 81, 70, 75 and 60 of the males visited us for secondary screening, and prostate biopsy was performed in 130 (80.7%), 57 (70.4%), 45 (64.3%), 38 (50.7%), and 42 (70.0%). Prostate cancer was detected in 91, 33, 29, 20 and 25 males, respectively. These values corresponded to 2.43%, 0.85%, 0.70%, 0.45% and 0.55% of the males who underwent primary screening. The incidence of prostate cancer was 0.96% during the 5 years. Clinical stage was B in 137 (69.2%), C in 52 (26.3%), D in 7 (3.5%), and unknown in 2. Surgery was performed in 87 (43.9%), endocrine therapy in 61 (30.8%), irradiation in 37 (18.7%), and follow up without treatment in 7 (3.5%). Treatment for 6 (3.0%) is unknown because they desired treatment at another hospital. CONCLUSIONS: 198 males were diagnosed with prostate cancer between 2003 and 2007. The clinical stage B was present in 137 (69.2%), and the early treatment was achieved. This may lead to a future decrease in the mortality rate.
Asunto(s)
Biomarcadores de Tumor/sangre , Tamizaje Masivo/estadística & datos numéricos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/diagnóstico , Anciano , Anciano de 80 o más Años , Diagnóstico Precoz , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Extractos Vegetales , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Tasa de Supervivencia , Factores de TiempoRESUMEN
We present the case of a patient with renal cell carcinoma treated preoperatively with sorafenib. Complete resection of the left renal mass measuring 7.2 x 6.6 cm seemed to be difficult at diagnosis because of large renal hilar lymph nodes. With a short period of sorafenib administration, marked shrinkage of the renal mass and lymphadenopathy was observed after the patient experienced fulminant hepatic failure and a severe hand-foot skin reaction. Two-dimensional computed tomography revealed 60%, 78% and 84% reduction in the primary renal tumor, lung metastatic nodules and lymph nodes, respectively. Tumor shrinkage allowed for complete resection of the left kidney and the lymphadenopathy. Pathological findings revealed that over 90% of the renal tumor was substituted by necrotic fibrotic tissue and that the residual neoplastic component was diagnosed as clear cell carcinoma. The lymph nodes that were resected were negative for malignancy. At 6 months after radical nephrectomy, a new computed tomography scan revealed no evidence of disease with the disappearance of lung nodules.
Asunto(s)
Antineoplásicos/administración & dosificación , Bencenosulfonatos/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/cirugía , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/cirugía , Piridinas/administración & dosificación , Anciano de 80 o más Años , Carcinoma de Células Renales/diagnóstico por imagen , Terapia Combinada , Femenino , Humanos , Neoplasias Renales/diagnóstico por imagen , Nefrectomía , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Cuidados Preoperatorios , Índice de Severidad de la Enfermedad , Sorafenib , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: In this retrospective study we reported the results of salvage external beam radiotherapy for patients with biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS: A total of 28 patients with biochemical recurrence after radical prostatectomy underwent salvage radiotherapy with (n=16) or without (n=12) hormonal therapy. Median radiation dose was 60 Gy. Biochemical recurrence after radiotherapy was defined as a single prostate-specific antigen (PSA) of at least 0.1 ng/ml. Potential risk factors were evaluated for significant associations with biochemical recurrence. RESULTS: The median follow-up period after salvage radiotherapy was 42 months. The actuarial biochemical recurrence free survival rate at 3 and 5 years was 81% and 74%, respectively. Addition of hormonal therapy to salvage radiotherapy did not alter biochemical recurrence rate (P = 0.56). Univariate analysis revealed that Gleason score of 8 to 10 (P = 0.026) and PSA before salvage therapy greater than 0.24 ng/ml (P = 0.0016) were significant risk factors for biochemical recurrence. On multivariate analysis, PSA before salvage therapy greater than 0.24 ng/ml (P = 0.017) maintained statistical significance. Of 28 patients 3 (11%) experienced late grade 3 toxicity of hematuria. CONCLUSION: Our data suggest that early use of salvage radiotherapy is beneficial for patients with biochemical recurrence after radical prostatectomy.
Asunto(s)
Recurrencia Local de Neoplasia/radioterapia , Prostatectomía , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/cirugía , Terapia Recuperativa , Anciano , Biomarcadores de Tumor/sangre , Terapia Combinada , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/tratamiento farmacológico , Dosificación Radioterapéutica , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
A 26-year-old man was admitted to our hospital with a chief complaint of left cervical lymphadenopathy. He was diagnosed as having seminoma by needle biopsy. Computed tomography revealed an aorto-caval retroperitoneal tumor. Levels of lactic deydrogenase, human beta-chorionic gonadotropin, alpha-fetoprotein were not elevated. No abnormal findings were present on palpation and ultrasonography of the testes. The patient was diagnosed as having a retroperitoneal extragonadal germ cell tumor (EGCT). Three courses of chemotherapy (bleomycin, etoposide and cisplatin) and another course of chemotherapy (etoposide, ifosfamide and cisplatin) were performed. Complete remission was achieved. Seven years later, the patient noticed an enlargement of his right scrotal contents. Neither distant metastasis nor lymph node metastasis was detected by computed tomography. Right radical orchiectomy was performed and histology revealed seminoma with yolk sac tumor components. No recurrence has been seen after 10 months.
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Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Primarias Secundarias/patología , Neoplasias Retroperitoneales/patología , Seminoma/patología , Neoplasias Testiculares/patología , Adulto , Humanos , Masculino , Factores de TiempoRESUMEN
Cases 1 and 2 were a 84-year-old, 64-year-old female relatively. Case 2 had a history of uncontrolled diabetes mellitus. Both cases were referred to our hospital with a chief complaint of high fever. Initial diagnosis was acute pyelonephritis based on the findings of pyuria and right costovertebral angle knock pain. Abdominal computed tomography (CT) scan revealed a gas shadow in the right renal pelvis and calyx with right ureteral stone. The definitive diagnosis was emphysematous pyelonephritis (EPN). We selected transureteral catheterization into the right ureter immediately. Escherichia coli was identified from urine culture. Conservative therapy with antibiotics was also effective and general condition improved. Herein we discussed the etiology, symptomatology, choice of treatment and prognosis of emphysematous pyelonephritis. Recently CT is an effective imaging method for diagnosis at an early stage. Antibiotics therapy combined with transureteral drainage of gas-forming urolithiasis is effective as the initial conservative therapy.
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Enfisema/terapia , Pielonefritis/terapia , Stents , Cateterismo Urinario , Anciano de 80 o más Años , Cefotiam/administración & dosificación , Enfisema/diagnóstico , Enfisema/diagnóstico por imagen , Infecciones por Escherichia coli , Femenino , Humanos , Persona de Mediana Edad , Pielonefritis/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
We herein report four cases of sarcomatoid renal cell carcinoma. These cases comprised 4.1% of the 98 patients with renal cell carcinoma treated in our department during the past 13 years. It is confirmed that renal cell carcinoma with a sarcomatoid component often shows local invasion, distant metastasis, rapid growth and poor prognosis. In Mian's series, the percentage of sarcomatoid component (< 25% vs > or = 25%) was associated with decreased survival time, but was independent of stage. The pathological stage was pT3b N0 M0 in case 1, pT1b N0 M1 in case 2, pT3b N0 M1 in case 3 and pT1a N0 M1 in case 4. The pT1 sarcomatoid renal cell carcinoma in case 2 and case 4, who developed poor prognosis, was composed of 60 and 80% sarcomatoid change, respectively. However in case 3 with a pathological stage of pT3, the patient is alive 35 months after resection, because the extent of sarcomatoid component was 25%. The prognosis of patients with sarcomatoid renal cell carcinoma depends on not only disease stage and tumor grade but also the pathological extent of sarcomatoid component.
Asunto(s)
Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Adulto , Anciano , Carcinoma de Células Renales/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Sarcoma/mortalidad , Sarcoma/patologíaRESUMEN
A 15-year-old girl presented to a clinic with an asymptomatic macrohematuria. Cystoscopy revealed a bladder tumor. The next day she was admitted to our hospital because of preshock status with macrohematuria. Abdominal computed tomography (CT) revealed a solid tumor in the left anterior to lateral wall. Urinary cytology was negative. She received a transfusion and transurethral resection of bladder tumor as an emergent operation. Histopathological examination revealed inflammatory myofibroblastic tumor. Anaplastic lymphoma kinase immunohistopathological studies revealed cytoplasmic staining of the myofibroblasts. To our knowledge, this is the 35th reported case of inflammatory myofibroblastic tumor of the bladder in Japan. She has been followed up for 13 months without any evidence of local recurrence.
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Neoplasias de Tejido Muscular/patología , Neoplasias de la Vejiga Urinaria/patología , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de Tejido Muscular/cirugía , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
Segmental infarction of the testis represents a rare entity in that there have been fewer than 40 cases documented in the literature. Like global infarction, segmental infarction of the testis can masquerade as a mass lesion or torsion of the testis. Reported herein is a very rare case of segmental testicular infarction due to atheroembolism in a 58-year-old man. The patient presented with severe left testicular pain and underwent left high orchiectomy on the clinical diagnosis of testicular torsion. The testis had a segmental hemorrhagic necrosis around which many cholesterol emboli were observed. This is the first report to describe cholesterol embolism-associated segmental testicular infarction.
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Embolia por Colesterol/patología , Infarto/patología , Enfermedades Testiculares/patología , Testículo/irrigación sanguínea , Diagnóstico Diferencial , Embolia por Colesterol/complicaciones , Embolia por Colesterol/cirugía , Humanos , Infarto/etiología , Infarto/cirugía , Masculino , Persona de Mediana Edad , Torsión del Cordón Espermático/patología , Enfermedades Testiculares/etiología , Enfermedades Testiculares/cirugía , Testículo/patología , Testículo/cirugíaRESUMEN
Each heavy chain of dimeric chick brain myosin V (BMV) has a neck domain consisting of six IQ motifs with different amino acid sequences. The six IQ motifs form binding sites for five calmodulin (CaM) molecules and one essential light chain (either 17 or 23 kDa). When the calcium concentration is high, a small fraction of the 10 total CaM molecules dissociates from one molecule of BMV, resulting in loss of actin-based motor activity. At low Ca2+ concentrations, two molecules of exogenous CaM associate with one molecule of CaM-released BMV. This suggests that there is a single specific IQ motif responsible for the calcium-induced dissociation of CaM. In this study, we identify the specific IQ motif to be IQ2, the second IQ motif when counted from the N-terminal end of the neck domain. In addition, we showed that the essential light chains do not reside on IQ1 and IQ2. These findings were derived from proteolysis of BMV at high Ca2+ concentrations specifically at the neck region and SDS-PAGE analyses of the digests.
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Calcio/farmacología , Calmodulina/metabolismo , Miosina Tipo V/química , Miosina Tipo V/metabolismo , Citoesqueleto de Actina/metabolismo , Secuencias de Aminoácidos , Animales , Biotinilación , Calcio/metabolismo , Calmodulina/análisis , Bovinos , Pollos , Electroforesis en Gel de Poliacrilamida , Endopeptidasa K/metabolismo , Fragmentos de Péptidos/metabolismo , Unión Proteica/efectos de los fármacos , ConejosRESUMEN
Mast cells are the major effector-cell type for immediate hypersensitivity and other forms of allergic reactions. Expression of 4-1BB, a member of the tumor necrosis factor receptor superfamily, is induced at mRNA and protein levels on stimulation through the high-affinity receptor for immunoglobulin E (IgE; FcepsilonRI). In this study, we present evidence that agonistic anti-4-1BB antibodies can enhance FcepsilonRI-induced cytokine production and secretion. Consistent with this, 4-1BB-deficient mast cells exhibit reduced degranulation and cytokine production on FcepsilonRI stimulation. Analysis of 4-1BB ligand (4-1BBL)-deficient cells supported this notion. As a potential mechanism for these defects, we identified a defect in Ca2+ flux induced by FcepsilonRI stimulation. The defective Ca2+ flux could be accounted for by the reduced activity of Lyn/Btk/phospholipase C-gamma2 pathway and constitutive interactions between 4-1BB and Lyn. Therefore, FcepsilonRI-inducible 4-1BB plays a costimulatory function together with FcepsilonRI stimulation.