Hepatoprotective effect of trypsin/chymotrypsin against olanzapine-induced non-alcoholic steatohepatitis in rats.

Metabolic side effects of atypical antipsychotics are an important cause of deterioration of cognitive function and failure of drug adherence. The antifatty effect trypsin/chymotrypsin (T/C) and their mechanisms of action remain unclear. To investigate possible therapeutic effect of T/C in rat model of chronic olanzapine (OLZ) - induced hepatic steatosis. Twenty rats were divided into two groups: control (C), given distilled water, and O, given 1 mg/kg of OLZ orally daily for 7 weeks. Then, both groups were given T/C 3 enzyme activity unit (EAU)/kg orally as an add-on treatment daily for the next 5 weeks and were named T/C or T/C+O groups. Rat performance in radial arm water maze was tested twice before and after T/C treatment. We measured liver enzymes, alpha-1 antitrypsin, albumin, total protein, direct and total bilirubin, inflammatory cytokines, and lipoprotein serum levels. Liver samples were collected for histopathology and Ki67 expression. The T/C add-on caused significant reduction in OLZ-induced elevation of alanine transaminase (ALT; P < 0.01), aspartate transaminase (AST; P < 0.001), alkaline phosphatase (ALP; P < 0.05), total cholesterol (Tc; P < 0.01), low-density lipoproteins (LDL-c; P < 0.05), steatosis score (P < 0.001), hepatocyte necrosis (P < 0.01), and significantly increased Ki67 expression (P < 0.01). The T/C add-on to OLZ provided protection against hepatic steatosis, elevated enzymes, and disturbed lipid profile and increased Ki67 without disturbing memory function.

Increased glomerular Bax/Bcl2 ratio is positively correlated with glomerular sclerosis in lupus nephritis.

INTRODUCTION: The role of intrinsic pathway of apoptosis in pathogenesis of lupus nephritis (LN) is still not clear. We investigated the relation between the expression of two major proteins of the intrinsic pathway of apoptosis; bcl2 as an antiapoptotic protein and bax as a proapoptotic one; in renal tissue of LN. METHODS: The study included fifty paraffin embedded renal tissue obtained from renal biopsy specimens of LN patients (8 cases class II, 10 cases class III, 21 cases class IV and 11 cases class V) and five paraffin embedded apparently normal renal tissue obtained from nephrectomy specimens due to renal neoplasms as a control group. Immunohistochemical staining for bcl2 and bax antibodies was done. Ki67 immunohistochemical staining was done for class III and IV to assess the degree of proliferation. The number of intraglomerular bcl2, bax and ki67 positive cells per glomerular cross section was evaluated for each case. The results were analysed in different LN classes and correlated to different glomerular lesions. RESULTS: The expression of bax and bcl2 proteins was higher in LN glomeruli compared to normal. The expression of bcl2 was significantly higher in class IV and was correlated to the degree of endocapillary hypercellularity. The bax to bcl2 ratio was significantly correlated to the percentage and degree of glomerular sclerosis. CONCLUSION: The intrinsic pathway of apoptosis interfere in the pathogenesis of lupus glomerulonephritis. The balance between bax and bcl2 proteins might have a role in regulating the progression of glomeruli from proliferative to sclerotic state.

Expression of p16 Tumor Suppressor Protein in Malignant Ovarian Germ Cell Tumors; Immunohistochemical Study.

BACKGROUND: Malignant ovarian germ cell tumors represent small percentage of malignant ovarian neoplasms but they affect significantly young age group. AIM OF THE STUDY: To investigate the immunohistochemical expression of p16 tumor suppressor protein in malignant ovarian germ cell tumors. MATERIALS AND METHODS: Twenty-two malignant ovarian germ cell tumors (five dysgerminoma, eight immature teratoma, and nine yolk sac tumors), twenty mature cystic teratoma tumors and twenty normal ovarian tissue were immunohistochemically stained with p16 monoclonal antibody. Ki67 immunohistochemical staining was done for malignant ovarian germ cell tumors to assess proliferation. RESULTS: We found that p16 tumor suppressor protein is overexpressed in all malignant ovarian germ cell tumors in both nuclear and cytoplasmic locations compared to control and to mature cystic teratoma (p-value <0.001). Cytoplasmic p16 expression was significantly correlated to Ki67 proliferation index in malignant ovarian germ cell tumors (p-value = 0.033, r = 0.445). CONCLUSION: Overexpression of p16 in malignant ovarian germ cell tumors denotes that dysfunction of the cyclin dependent kinase pathway is involved in tumorigenesis of malignant ovarian germ cell tumors.

Relationship between vitamin D and coronary artery disease in Egyptian patients.

BACKGROUND: Previous studies have reported conflicting results about the association of vitamin D (VD) level with coronary artery disease (CAD). We aimed to study the association of VD with atherosclerotic CAD in Egyptian individuals. RESULTS: We prospectively enrolled 188 consecutive CAD patients with a median age of 55(50-62) years; 151(80.3%) were male. All patients were diagnosed by cardiac catheterization and were compared with 131 healthy controls. VD levels were measured in serum samples of all participants. Compared to controls, CAD patients had a significantly lower median VD level, 14.65 (9.25-21.45) versus 42.0 (32.0-53.0) ng/mL, p < 0.001. VD was correlated with the number of diseased coronary arteries and lipid profile (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, p < 0.001 for each). By multivariate analyses, VD was an independent predictor of CAD [OR 1.22 (95% CI 1.07-1.4), p = 0.003, optimal cut-off value 30 ng/mL (AUC 0.92, sensitivity 81% and specificity 81.4%), p < 0.001], and the number of diseased coronary arteries, p < 0.001, especially three-vessel disease [OR 0.83 (95% CI 0.72-0.95), p = 0.008]. CONCLUSIONS: We have shown that low VD should be considered a non-traditional risk factor for CAD in Egyptian individuals. Low VD was correlated with coronary atherosclerosis, especially in patients with multivessel effects.

The protective effect of olanzapine on ketamine induced cognitive deficit and increased NR1 expression in rat model of schizophrenia.

BACKGROUND: Impaired cognitive flexibility is the core manifestation of schizophrenia (SZ). Previous literature raised a claim against the effect of atypical antipsychotic drugs (AAD) on cognitive and executive functions whose cause needs further investigation. Attention set-shifting task (ASST) tests the prefrontal cortex's (PFC) executive and flexibility functions. GOALS: To examine Olanzapine (OLZ) effect on ASST, expression of N-methyl-D-aspartate receptor 1 (NMDR-NR1) in prefrontal cortex (PFC), and metabolic comorbidity in ketamine (KET) model of SZ. METHODS: Sixty-two male rats were divided into three groups: 8 for ASST and 30 for open field, ELISA and immunohistochemistry sub-chronic study, and 24 for regular serological and histopathological examination. Rats treated with V: vehicle; K: KET and KO: OLZ plus KET. RESULTS: KET caused significant increase in time, trials, and errors to reach criterion. OLZ co-administration reversed effects of KET in ASST with no reduction of locomotor activity. OLZ normalized KET-induced rise of NR1 expression and protected against KET-induced degenerative changes in hippocampus and PFC. Significant increase in serum liver enzymes, total bilirubin, and lipids with chronic compared to sub-chronic OLZ administration. In contrast, insignificant difference between sub-chronic OLZ and vehicle was found. CONCLUSIONS: Current study demonstrated the efficacy of OLZ to reverse KET-induced cognitive deficits in ASST with neither reduction in NR1 expression in PFC nor metabolic malfunction in the sub-chronic study. It also showed the protective effect of OLZ on KET induced neuronal degeneration and necrosis. We suggest that chronic OLZ treatment-induced-metabolic malfunction might be the cause of time-dependent cognitive deterioration.

Challenge in the Pathological Diagnosis of the Follicular- Patterned Thyroid Lesions.

BACKGROUND: The follicular-patterned thyroid lesions (FPTLs) include hyperplastic nodules (HN), follicular adenoma (FA), non-invasive follicular neoplasm with papillary-like nuclear features (NIFTP), follicular carcinoma (FC), and the follicular variant of papillary carcinoma (FVPTC). Sometimes the pathologists cannot accurately separate these lesions from each others on a histological basis. AIMS: To evaluate the utility of immunohistochemistry in the diagnosis of FPTLs. MATERIALS AND METHODS: Immunohistochemical analysis, incorporating 83 cases of histologically confirmed FPTLs out of which 20 carcinomas, 51 benign FPTLs (38 HN and 13 FA), and 12NIFTP were separated from each others using four immunostains (HBME-1, CK19, Galectin-3, and CD56). RESULTS: We found statistically significantly more frequent expression of HBME-1, CK19, Galectin-3 proteins in carcinomas as compared to benign FPTLs (p = <0.01). HBME-1 and Galectin-3 were the most sensitive markers for the diagnosis of malignant FPTLs (75%). Galectin-3 was the most specific marker for the diagnosis of carcinoma (90.3%). CONCLUSIONS: The histomorphological features remain the cornerstone of the diagnosis of FPTN. Although HBME-1, Galectin-3, and CK19 immunostains have some diagnostic value in the separation of malignant from benign FPTLs, they are variably expressed in the benign and malignant FPTLs. No single immunostain has sufficient sensitivity and specificity and therefore their diagnostic use is controversial. Future studies are mandated to find more reliable markers that can separate between benign and malignant FPTLs.

Role of the endometrial tripod interleukin-18, -15, and -12 in inadequate uterine receptivity in patients with a history of repeated in vitro fertilization-embryo transfer failure.

OBJECTIVE: To document in the endometrium the correlation among the interleukin (IL)-12, -15, and -18 mRNA and the correlation between cytokine levels, vascular status, and endometrial natural killer (NK) cell count in the context of recurrent implantation failure. DESIGN: A pilot study. SETTING: Department of Reproductive Immunology. PATIENT(S): Women who failed to become pregnant after repeated IVF-embryo transfer and fertile control subjects. INTERVENTION(S): Ultrasonic evaluation and endometrial biopsy in luteal phase. MAIN OUTCOME MEASURE(S): Uterine artery Doppler, count of uterine CD56 bright cells/field, and quantification by real-time polymerase chain reaction (PCR) to monitor IL-12 family (IL-12p40, IL-12p35, EBI3, IL-23), the IL-18 system (IL-18, IL-18R, IL18BP), and the IL-15 mRNA ratio. RESULT(S): The uterine artery Doppler and the CD56 bright cell counts were significantly different in fertile and infertile patients. The mean uterine artery pulsatility index correlated significantly negatively with the IL-18/actin ratio suggesting a defect of the cytokine-dependent vascular remodeling pathway. The number of uterine CD56 bright cells was significantly correlated with the IL-15/actin and IL-18/IL-18BP ratios. Thus, IL-18 and IL-15 seems to be involved in the local recruitment and the activation of uterine natural killer (uNK) cells. IL-18 was itself correlated with IL-15 and IL-12, suggesting a local control of uNK cells activation. CONCLUSION(S): The assessment of the tripod IL-12/-15/-18 shows distinct immune-related mechanisms that are involved in the broader context of inadequate uterine receptivity.

Premenstrual administration of gonadotropin-releasing hormone antagonist coordinates early antral follicle sizes and sets up the basis for an innovative concept of controlled ovarian hyperstimulation.

OBJECTIVE: To investigate whether premenstrual administration of a GnRH antagonist coordinates early antral follicle sizes during the subsequent follicular phase. DESIGN: Prospective, longitudinal study. SETTING: University Hospital in France PATIENT(S): Twenty-five women, 50 cycles. INTERVENTION(S): On cycle day 2 (control/day 2), women underwent measurements of early antral follicles by ultrasound and serum FSH and ovarian hormones. On day 25, they received a single cetrorelix acetate administration, 3 mg. On the subsequent day 2 (premenstrual GnRH antagonist/day 2), participants were re-evaluated as on control/day 2. MAIN OUTCOME MEASURE(S): Magnitude of follicular size discrepancies. RESULT(S): Follicular diameters (4.1 +/- 0.9 vs. 5.5 +/- 1.0 mm) and follicle-to-follicle size differences decreased on premenstrual GnRH antagonist/day 2 as compared with control/day 2. Consistently, FSH (4.5 +/- 1.9 vs. 6.7 +/- 2.4 mIU/mL), E(2) (23 +/- 13 vs. 46 +/- 26 pg/mL), and inhibin B (52 +/- 30 vs. 76 +/- 33 pg/mL) were lower on GnRH antagonist/day 2 than on control/day 2. CONCLUSION(S): Premenstrual GnRH antagonist administration reduces diameters and size disparities of early antral follicles on day 2, likely through the prevention of luteal FSH elevation and early follicular development. This simple, original approach may be used to coordinate multifollicular development in controlled ovarian hyperstimulation.