Lingual adaptations of the Tarentola annularis with new insights into its papillary system adaptations: Ultrastructure, histochemistry, and immunohistochemical observations.

Our research aims to conduct a comprehensive ultrastructural, histochemical, and immunohistochemical examination of Tarentola annularis' tongue, utilizing various techniques such as light, scanning electron microscopy, and morphometric analysis. The complex papillary system consisted of four conical subtypes and one filiform type. The apex carried three conical subtypes (elongated, quadrilateral, and round); the midtongue carried two papillary types (quadrilateral conical and rectangular pointed filiform); and the hindtongue carried two conical subtypes (quadrilateral and elongated serrated). The dorsal papillary surface carried little taste pores on the foretongue and taste buds on the midtongue. The foretongue had a slightly stratum corneum that spread to coat the papillae, while the mid- and hindtongue did not. The glands are absent from the foretongue but are found in the interpapillary spaces of the mid- and hindtongue. Histochemical analysis reveals the presence of collagen fibers in the muscle bundles and the papillary core. The midtongue glands exhibited a strong reaction to AB and PAS, while the hindtongue showed moderate AB positivity and strong positive PAS. The cytokeratin expression in the foretongue papilla was positive, whereas the papillae in other regions were negative. The Tarentola annularis exhibits distinctive lingual structural characteristics due to its varied feeding habits influenced by available food particles.

A histological and immunohistochemical study on the parabronchial epithelium of the domestic fowl's (Gallus gallus domesticus) lung with special reference to its scanning and transmission electron microscopic characteristics.

The current study was designed to give complete histo-and immunohistochemical features of the parabronchial epithelium of domestic fowl's (Gallus gallus domesticus) lung with special reference to Scanning electron microscope (SEM) and mean transmission electron microscope (TEM) features. The lung exhibited variable-sized atrial openings encircled by exchange tissue zones. The parabronchial atrial chambers appeared as ovoid and polygonal-shaped that separated by the well-developed interatrial septum. The deep atrial lumens had blood vessels pierced by openings that represent the infundibula. The parabronchial blood capillaries meshwork was branched and exhibited ovoid-shaped air capillaries with numerous extravasated blood vessels. By TEM, there were several air capillaries and groups of squamous and endothelial respiratory cells and the squamous cells had oval nucleus with evenly distributed chromatin. The endothelial respiratory cells had few microvilli on their free surfaces. The parabronchial tubes opened into a group of widened atria that had smooth muscle bundles at the interatrial septa. The atrial chambers led to narrow infundibula. Moreover, the lining epithelium of parabronchi, atria, infundibula, and air capillaries was formed by simple squamous epithelium. Air capillary walls were lined by two types of respiratory cells (Types-I and II). Collagen fibers were concentrated within the tunica externa layers of the parabronchial blood vessels as well as, they were observed in CT interparabronchial septa. Immunohistochemically, the elastin immunoreactivity was detected around the parabronchial blood vessels, at the base of each parabronchial atria, and in the area encircling the alveolar-capillary walls. Our work concluded that there are a relation between the fowl's lifestyle and the surrounding environmental conditions.

Ameliorative effect of biosynthesized titanium dioxide nanoparticles using garlic extract on the body weight and developmental toxicity of liver in albino rats compared with chemically synthesized nanoparticles.

The application of metallic nanoparticles poses risks to human and animal health. Titanium dioxide nanoparticles (TiO2NPs) are the most commonly synthesized metallic oxides in the world. Exposure to TiO2NPs can cause toxicity in the target organisms. This study aimed to evaluate the effects of green and chemical TiO2NPs on maternal and embryo-fetal livers. Green TiO2NPs using garlic extract (GTiO2NPs) and chemical TiO2NPs (CHTiO2NPs) were synthesized and characterized by x-ray powder diffraction and high-resolution transmission electron microscopy. The cytotoxicity of both chemical and green TiO2NPs was determined against HepG2 cell lines. Fifty pregnant female Albino rats were equally and randomly divided into five groups. Group 1 was kept as a control. Groups 2 and 3 were orally treated with 100 and 300 mg/kg body weight of CHTiO2NPs, respectively. Groups 4 and 5 were orally treated with 100 and 300 mg/kg of GTiO2NPs, respectively, from day 6 to 19 of gestation. All dams were euthanized on gestation day 20. All live fetuses were weighed and euthanized. Blood and tissue samples were collected for biochemical, histopathological, and Bax-immunohistochemical expression analyses. Our results indicated that garlic could be used as a reducing agent for the synthesis of TiO2NPs, and the produced NPs have no toxic effect against HepG2 cells compared with CHTiO2NPs. The maternal and fetal bodyweights were greatly reduced among the chemically TiO2NPs induced animals. The mean serum level of AST and ALT activities and the total protein level significantly increased when TiO2NPs were administered at high doses. Histologically, the CHTiO2NPs-treated groups revealed vacuolated and necrotized hepatocytes with congested and dilated blood vessels in the fetal and maternal livers. The immunohistochemistry revealed distinct positive staining of Bax expressed in the hepatocytes. Nevertheless, the biosynthesis of TiO2NPs using garlic extract had a minimal effect on the normal architecture of the liver. It could be concluded that the bioactivity of TiO2NPs can be modified by green synthesis using garlic extract. Compared to the CHTiO2NPs, the exposure to GTiO2NPs showed reduced liver damage in maternal and embryo-fetal rats.

Carcinoma Pulmonar: estudio clínico patológico / Pulmonary carcinoma: clinical pathological study

Clasificar los carcinomas de pulmón según criterios establecidos por la OMS 2015 en biopsias de la sección de patología respiratoria del Instituto Anatomopatológico "Dr. José Antonio O`Daly" en el período enero 2006-diciembre 2016. Se realizó estudio descriptivo y retrospectivo, en el que se evaluaron todos los casos de carcinomas pulmonares recibidos entre enero 2006 diciembre 2016. La edad de presentación del carcinoma pulmonar fue 61 ± 11,45 años. Fue más frecuente en el sexo masculino 56,57 %. El tipo histológico más frecuente fue el adenocarcinoma 61,6 %. El adenocarcinoma el patrón predominantemente sólido fue el más constante 57,3 %, seguido de patrón predominantemente acinar 18,2 % y patrones mixtos. El carcinoma de células escamosas fue el segundo tipo más frecuente con 30,3 % de los casos representando el carcinoma de células escamosas poco diferenciado no queratinizante un 40 %. El carcinoma neuroendocrino fue el tercer tipo de carcinoma más común y el carcinoma de células pequeñas representó el 80 % de estos casos. Al menos 10,8 % de los casos fueron carcinomas no clasificables por necrosis o muestra escasa. Los casos previamente diagnosticados como adenocarcinoma poco diferenciado se corresponden con patrón sólido. Es importante el uso de inmunohistoquímica para el diagnóstico definitivo especialmente de adenocarcinoma patrón predominantemente sólido. El uso de la actual clasificación permite definir pronóstico y tratamiento personalizado(AU)

To classify the lung carcinomas according to criteria established by WHO 2015 in the biopsies of the section of respiratory pathology of the Anatomo Pathological Institute "Dr. José Antonio O`Daly" in the period January 2006 December 2016. A study will be carried out descriptive and retrospective, in which all cases of the pulmonary carcinomas received between January 2006 and December 2016 were evaluated. The age of presentation of the lung carcinoma was 61 ± 11.45 years old. It was more frequent in the male sex 56.57 %. The most frequent histological type was the adenocarcinoma 61.6 %. The predominantly solid adenocarcinoma pattern was the most constant 57.3 % followed by predominantly acinar pattern 18.2 % and the mixed patterns. The squamous cell carcinoma was the second most frequent type 30.3 %, and the poorly differentiated and non-keratinizing type was a 40 %. The neuroendocrine carcinoma was the third most common type of it the small cell carcinoma accounted an 80 %. At least 10.8 % of the cases were carcinomas unclassifiable due to necrosis or scarce sample. The cases previously diagnosed as poorly differentiated adenocarcinoma correspond to a solid pattern. The immunohistochemically use is important for the definitive diagnosis, especially for the adenocarcinoma predominantly solid pattern. The use of the current classification allowsdefining the prognosis and the personalized treatment(AU)

Solitary primary intracranial leptomeningeal glioblastoma invading the normal cortex: Case report.

Solitary primary intracranial leptomeningeal glioma (PLG) is a rare entity of glioma. PLG arises from the heterotopic glial tissue in the subarachnoid space and usually grows there without parenchymal invasion. The present study reported a case of solitary PLG, pathologically diagnosed as glioblastoma, that invaded the temporal cortex and finally disseminated to the spinal cord. A 55-year-old woman had headaches and visited Nihon University, Itabashi Hospital. Head magnetic resonance imaging showed a solid mass mainly located in the right middle fossa extending to the frontal base with strong enhancement effect after contrast medium injection. A conventional angiogram showed a tumor arising from the middle meningeal artery. Fronto-temporal craniotomy was performed to remove the tumor. During reflection of the dura matter, there were numerous small vessels connecting the dura matter and the cortical surface. The tumor was located in the Sylvian fissure and extended around the middle cerebral artery. The border between the tumor and the normal temporal lobe was unclear. Temporal lobectomy was done, but the tumor was left around the perforators of the middle cerebral artery. Hematoxylin and eosin staining showed typical glioblastoma with high cellularity, mitosis, pseudopallisading and vascular proliferation. The tumor cells were immunohistochemically negative for isocitrate dehydrogenase (IDH)1-R132H indicating glioblastoma, IDH-wild type. The patient received chemotherapy and radiation therapy, and was discharged from the hospital. Six months later, local regrowth and spinal dissemination were found. Despite additional chemotherapy and radiation therapy, the tumor became uncontrollable and the patient succumbed. Only 15 cases of solitary PLGs have been reported previously. The IDH status of these tumors have not been investigated in most cases; however, pathological grading varies from lower to higher grade glioma. Together with the pathological difference of astrocytic or oligodendrocytic tumors, solitary PLGs may develop due to various gene alterations similar to intra-axial gliomas.

[Occurrence pattern and impact of lymph node micrometastasis in pancreatic head cancer].

Objective: To investigate the occurrence of lymph node micrometastasis in pancreatic head carcinoma and analyze its effect on the prognosis of patients. Methods: The lymph nodes in 40 patients who received pancreatoduodenectomy with regional lymphadenectomy were dissected by surgical magnification microscopy. The expression of cytokeration(AE1/E3) were detected by immunohistochemical staining in the pathologically negative lymph nodes. The frequency of lymph nodes metastases and micrometastases, as well as the relationship between metastasis and prognosis were analyzed. Results: 1 550 lymph nodes were dissected from 40 patients. Lymph node metastases was pathologically detected in 27 patients (67.5%) and in 199 lymph nodes(12.8%). No.13(24.1%, 68/282), No.14(18.1%, 58/321), No.12(12.7%, 31/245), No.16(12.3%, 30/243) and No.17(11.4%, 12/105) lymph nodes groups had higher frequency of metastases. Lymph node micrometastases was immunohistochemically detected in 6 patients and 130 lymph nodes. No.14(16.5%, 53/321), No.13(15.2%, 43/282), No.16(6.2%, 15/243), No.12(4.9%, 12/245) and No.8(5.0%, 7/141) lymph nodes groups had higher frequency of micrometastases. The total ratio of patients with postive lymph nodes invasion and the ratio of positive lymph nodes invasion were 82.5% and 21.2%. 11 patients survived more than one year. 29 patients died of recurrence or metastasis within 8~11 months after surgery. The 1-year survival rate was 27.5%. 1-year survival rate was 14.9% in HE (+ ) patients, and 33.3% in HE (-) AE1/E3 (+ ) patients (P=0.632). AE1/E3 (-) HE (-) patients had a 1-years survival rate of 71.4%, which was statistically higher than that in HE (+ ) group patients (P=0.010). Conclusions: AE1/E3 combined with pathological examination can significantly improve the detection rate of lymph nodes micrometastasis in pancreatic head carcinoma patients. Micrometastasis is commonly found in No 13, 14, 12, 16, 8 lymph nodes groups. Lymph nodes micrometastasis had a significant effect on the prognosis of patients. Special attention should be payed to No 13, 14, 16, 12, 17 lymph nodes groups during radical duodenopancreatectomy.

Pretreatment Serum Concentration of Vitamin D and Breast Cancer Characteristics: A Prospective Observational Mediterranean Study.

BACKGROUND: Recent studies of the correlation between breast cancer (BC) and vitamin D yielded contrasting results. Although preclinical and clinical evidence has implicated vitamin D in BC prevention and outcome, little is known about the link between vitamin D and specific BC histologically defined subtypes. In the attempt to clarify this association we correlated vitamin D levels with BC characteristics. PATIENTS AND METHODS: We enrolled 220 pre- and postmenopausal women with early BC in this prospective observational trial. Data on the patients' clinical and specific BC pathological characteristics were collected and related to vitamin D levels, stratified in deficient (< 20 ng/mL), insufficient (20-30 ng/mL), and sufficient (> 30 ng/mL). BC subtypes were defined according to the 14th St Gallen Breast Cancer Conference. RESULTS: Deficient vitamin D levels were correlated with Grade 3 (P = .015) and node-positive (P = .043) BC, and with a higher body mass index (P = .017). Insufficient vitamin D levels were associated with estrogen receptor expression in the primary tumor (P = .033). Vitamin D levels were unrelated to the histological molecular subtypes of BC. CONCLUSION: Deficient vitamin D levels were correlated with more aggressive disease, namely, node-positive high grade BC, and with obesity. Should our findings be confirmed in larger prospective studies, nutritional programs designed to reduce body weight, and vitamin D supplementation might be considered a BC prevention strategy.

Occurrence pattern and impact of lymph node micrometastasis in pancreatic head cancer / 中华肿瘤杂志

Objective@#To investigate the occurrence of lymph node micrometastasis in pancreatic head carcinoma and analyze its effect on the prognosis of patients.@*Methods@#The lymph nodes in 40 patients who received pancreatoduodenectomy with regional lymphadenectomy were dissected by surgical magnification microscopy. The expression of cytokeration(AE1/E3) were detected by immunohistochemical staining in the pathologically negative lymph nodes. The frequency of lymph nodes metastases and micrometastases, as well as the relationship between metastasis and prognosis were analyzed.@*Results@#1 550 lymph nodes were dissected from 40 patients. Lymph node metastases was pathologically detected in 27 patients (67.5%) and in 199 lymph nodes(12.8%). No.13(24.1%, 68/282), No.14(18.1%, 58/321), No.12(12.7%, 31/245), No.16(12.3%, 30/243) and No.17(11.4%, 12/105) lymph nodes groups had higher frequency of metastases. Lymph node micrometastases was immunohistochemically detected in 6 patients and 130 lymph nodes. No.14(16.5%, 53/321), No.13(15.2%, 43/282), No.16(6.2%, 15/243), No.12(4.9%, 12/245) and No.8(5.0%, 7/141) lymph nodes groups had higher frequency of micrometastases. The total ratio of patients with postive lymph nodes invasion and the ratio of positive lymph nodes invasion were 82.5% and 21.2%. 11 patients survived more than one year. 29 patients died of recurrence or metastasis within 8~11 months after surgery. The 1-year survival rate was 27.5%. 1-year survival rate was 14.9% in HE (+ ) patients, and 33.3% in HE (-) AE1/E3 (+ ) patients (P=0.632). AE1/E3 (-) HE (-) patients had a 1-years survival rate of 71.4%, which was statistically higher than that in HE (+ ) group patients (P=0.010).@*Conclusions@#AE1/E3 combined with pathological examination can significantly improve the detection rate of lymph nodes micrometastasis in pancreatic head carcinoma patients. Micrometastasis is commonly found in No 13, 14, 12, 16, 8 lymph nodes groups. Lymph nodes micrometastasis had a significant effect on the prognosis of patients. Special attention should be payed to No 13, 14, 16, 12, 17 lymph nodes groups during radical duodenopancreatectomy.

Screening for lynch syndrome in endometrial carcinoma / 临床与实验病理学杂志

Purpose To evaluate the application of mismatch repair (MMR) genes proteins expression and methylationspecific to screen for Lynch syndrome patients.Methods 126 endometrial carcinoma patients were tested the protein expression of hMSH2,hMSH6h,hMLH1,hPMS2 by immunohistochemically of SP,and the methylation status of hMLH1 genes by the methylation-specific PCR.Results The result of MMR immunocytochemistry showed that 22％ (28/126) cases lacked MMR protein expression,including hMLH1-/hPMS2-in 12 cases,4 hMSH2-/hMSH6-,6 hPMS2-,3 hMLH6-and 3 hMLH1-.Meanwhile,the methylation-specific PCR test showed that 9 cases was methylation status of hMLH1 genes in 15 cases hMLH1-,and suggested the patients might be sporadic endometrial carcinoma.Conclusion Immunohistochemical of SP staining for MMR proteins in endometrial carcinoma patients,accompanied by testing for the methylation status of hMLH1 genes,may be an effective approach to screen for Lynch syndrome.

Stratified mucin-producing intraepithelial lesion with invasive carcinoma: 12 cases with immunohistochemical and ultrastructural findings.

Stratified mucin-producing intraepithelial lesion (SMILE) is considered to be a variant of adenocarcinoma in situ (defined as intraepithelial malignant glandular epithelium without invasion) or adenosquamous carcinoma in situ of the uterine cervix. However, recent study suggested that SMILE is more similar to high-grade squamous epithelial lesion by their immunohistochemical findings. An invasive form of SMILE "invasive stratified mucin-producing carcinoma (ISMC)" has been also proposed, but immunohistochemical features are not well documented. Therefore, this study aimed to clarify the immunohistochemical characteristics of SMILE and ISMC. Twelve cases of SMILE were found among 445 patients (2.7%) with high-grade intraepithelial lesions or invasive carcinomas, 3 of whom had solely intraepithelial disease with SMILE component (mean age, 37 years; range, 30-48 years) and 9 with invasive carcinomas (mean age, 47 years; range, 37-66 years; including ISMC). Immunohistochemically, SMILE and ISMC were diffusely positive for p16 and CAM5.2, focally for IMP3, and almost negative or only focally positive for p63. Nuclear signals in SMILE and invasive carcinomas were detected by human papillomavirus (HPV) in situ hybridization; 5 cases showed HPV16 and/or HPV18 polymerase chain reaction products. The ultrastructural study of 1 case showed surface microvilli and small vacuolar structure in SMILE; ISMC had mucous-like vacuoles, many mitochondria and intracytoplasmic lumen but lacked tonofilament. These findings were more similar to adenocarcinoma in situ or adenocarcinoma than squamous intraepithelial lesion or squamous cell carcinoma. We suggest that SMILE is an intraepithelial neoplasm and ISMC is an invasive form of SMILE.

Morphological Analysis for Neuron-Like Cells in the Vomeronasal Organ of Human Fetuses at the Middle of Gestation.

The vomeronasal organ (VNO) of 5-month-old fetuses was examined immunohistochemically by the use of an antiserum to protein gene product 9.5 (PGP). The purpose was to identify if the human fetal VNO is lined by neuroepithelium. The PGP antiserum labeled abundant cells within the vomeronasal epithelium (VE), nerve fiber bundles in its lamina propria, and cells associated with these bundles. PGP-immunoreactive (ir) vomeronasal epithelial cells were classified into three subtypes. Type I cells, about 44% of the total cells observed, did not have any processes and tended to be located in the basal layer of the VE. Type II cells, about 37% had a single apical process that projected toward the lumen, ending at the epithelial surface. Type III cells sent a prominent process mainly toward the basement membrane, and occupied about 19% of the total cells observed. In the lamina propria, a considerable number of PGP-ir cells was observed. Some of them were present in nerve fiber bundles and contained processes parallel to the bundles. In addition, PGP-ir nerve fiber bundles and cells associated with them were even present in the portion of the nasal septal mucosa that was very close to the brain. The present results strongly suggested that the VE in human fetuses at mid-gestation is a neuroepithelium and that the VE may produce migrating cells toward the brain.

Clinicopathologic analysis of 3 patients with metaplastic thymoma / 肿瘤研究与临床

Objective To investigate the clinicopathologic characteristics of metaplastic thymoma.Methods The histological features and immunophenotype of three cases with metaplastic thymoma were studied, and the literatures were reviewed.Results There were 2 females and 1 male of 3 patients with 45, 52 and 40 years old, respectively.All tumors were characterized by a biphasic pattern composed of epithelial components and spindle cells.The epithelial areas consisted of anastomosing cords and islands or broad trabeculae of cohesive neoplasia cells.Some epithelial cells showed mild cytologic atypia, the presence of prominent nuclear grooves or pseudoinclusion body, and very low mitotic activity.The cells appeared bland and a fine nuclear chromatin pattern, and the mitoses were not found.The epithelial cells were diffusely and strongly positive for AE1/AE3.The spindle cells were diffusely positive for Vimentin.The Ki-67 fraction was low (＜5 ％) in both components.Conclusions Metaplastic thymoma is a rare primary thymic epithelial tumor, and its biologic behavior is likely benign or lowly malignant process.Occasionally, the tumor invades adjacent tissue or recurrence.With complete tumor resection, the patients have good prognosis.The diagnosis of metaplastic thymoma mainly relies on its morphologic features and immunohistochemical profiles.

An atypical case of intracerebral schwannoma.

We report a case of intracerebral cystic schwannoma in the temporal fossa manifested as a gradually worsening headache in a 49-years-old woman. Computed Tomography (CT) and magnetic resonance imaging (MRI) showed a left temporal partly cystic, partly solid mass. The preoperative diagnosis was astrocytoma or glioblastoma multiforme (GBM), but microscopic examination of the mass showed the characteristic pattern with cellular Antony A component. Immunohistochemically, the tumor was positive for S-100 protein. These findings are consistent with a schwannoma. Intracerebral schwannomas not related to cranial nerves are rare and most reported cases involved young patients.

SHOULD FISH TEST BE PERFORMED TO ALL PATIENTS WITH BREAST CANCER?

CerbB2 receptor determination is very important for the prognosis and treatment of breast cancer. The most used two methods for CerbB2 receptor determination are immunohistochemistry and FISH methods. FISH method is recommended for immunohistochemically CerbB2 (++) patient group. Therefore, even though the immunohistochemically CerbB2 (++) patients are in the same group, FISH test divides the results into two separate groups. Our study compared these two groups in terms of relaps duration. Total of 85 patients from The Kayseri Research and Training Hospital in Kayseri, Kayseri Erciyes University Hospital and Mersin State Hospital were included in this study. The relaps duration of the patients were determined and then compared statistically. When the mean disease free survival was compared for FISH(+) and FISH(-) groups, the mean DFS was 46±5 and 73±8 months. However, the median DFS was 38±9 months for the FISH positive group. No median PFS was reached for FISH (-) group. Immunohistochemically CerbB2 (++) breast cancer patients are considered as in the same group, however actually they have different prognostic features. Similarly, when the immunohistochemical tests and FISH tests are compared for CerbB2 positivity, different results are obtained. As a consequence of that, the therapy alternatives will be changed. Therefore, we conclude that the FISH test should be performed to all patients.

Two Cases of Primary Ovarian Transitional Cell Carcinoma / 대한산부인과학회잡지

Primary ovarian transitional cell carcinoma (TCC) is extremely rare tumor and recently it has been recognized as one of histologic subtype of ovarian epithelial carcinomas. Primary ovarian TCC has been classified as a different subtype from malignant Brenner tumor for it's histologic and clinical characteristics. Several recent studies repoert immunohistochemical stains are helpful to differentiate this tumor from TCC of bladder. Primary ovarian TCC usually presents at an advanced stage and behaves aggressively however, these tumors appear to be more sensitive to chemotherapy than other ovarian carcinomas and may have a better prognosis. We experienced two cases where operation and chemotherapy have made for primary ovarian TCC patients and report our own case studies with a brief literature review.

The association of p21ras expression and microvascular density (MVD) in pancreatic carcinoma and its clinicopathological significance / 解放军医学杂志

Objective To investigate the expression of p21ras and microvascular density (MVD) in pancreatic carcinoma and to identify their clinico-pathological significance. Methods Expressions of p21ras and MVD were immunohistochemically assessed in 48 cases of pancreatic carcinomas. Results The expression rate of p21ras in pancreatic carcinomas was 60.40%, the MVD was (22.207?5.815) and (18.053?5.502) respectively in the p21ras-positive group and p21ras-negative group (P

Expression of p21ras and VEGF in pancreatic cancer and its clinicopathological implication / 解放军医学杂志

Objective To investigate the expression of p21ras and vascular endothelial growth factor (VEGF) in pancreatic carcinoma, and to elucidate its clinicopathological implication. Methods Expressions of p21ras and VEGF were immunohistochemically examined in 48 cases of pancreatic carcinomas. Results The expressions of p21ras and VEGF in pancreatic carcinomas were 60.40% and 64.58%, respectively, and they were significantly higher than those in adjacent tissues (P