Linum usitatissimum seeds oil down-regulates mRNA expression for the steroidogenic acute regulatory protein and Cyp11A1 genes, ameliorating letrezole-induced polycystic ovarian syndrome in a rat model.

The safety and effectiveness of nutricetics suggest that they may offer an alternative to pharmaceutical and surgical therapy for hormone-dependent disorders, such as polycystic ovarian syndrome (PCOS). We investigated the effects of Linum usitatissimum seed oil (LSO) on ovarian functionality, its molecular targets, and the oxidative response in hyperandrogenism-induced polycystic ovary. The composition of LSO has been analyzed using ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS). A well-established PCOS rat model orally administered with letrozole daily for 21 days was used to investigate the effect of LSO at doses of 1 and 2 mL/kg body weight for 28 days. The effect on hormonal profile and antioxidant status, histopathology (cell proliferation), and the expression ratio of the steroidogenic acute regulatory protein (StAR) and Cyp11A1 gene were evaluated. LSO exerted beneficial effects on PCOS rat models via restoring glutathione (GSH), malondialdehyde (MDA), beta subunit subunit luteinizing hormone (LH), testosterone levels, and histopathological scoring. Furthermore, LSO reversed the elevated StAR and Cyp11A1 genes in the PCOS rat model. This study demonstrated the molecular and cellular mechanisms of the beneficial effect of LSO against the reproductive and metabolic disorders of PCOS.

Laparoscopic and open inguinal hernia repair: Patient reported outcomes in the elderly from a single centre - A prospective cohort study.

BACKGROUND: With those over 65 making up over 16% of the UK's population, surgeons are counselling increasing numbers of elderly patients for hernia repair. Data is currently lacking comparing different repair methods of inguinal hernias in the elderly population with regards to patient reported outcomes. AIM: To compare open and laparoscopic hernia repair in patients >65 years old and those <65 years old with respect to patient reported outcomes. METHOD: As part of a quality assurance process patients receive a telephone consultation day 2 post procedure. This includes an optional survey with questions to quantify pain, general feeling, nausea, dizziness, drowsiness, satisfaction and vomiting since the operation. Patients were then classified into age ≥ 65 years or <65 years and subclassified into totally extraperitoneal (TEP) or open inguinal hernia repair (IHR). RESULTS: Data is presented from patients treated between January 2009 and August 2016, totalling those included 1167 of 2522 (55.5%). Only five patients (4.42%) reported moderate pain; in the >65 TEP group this was significantly lower (10.2% open IHR <65; 6.7% TEP <65; 12.8% open IHR >65). Patient satisfaction with the surgery was satisfied or very satisfied in all patients in all groups. CONCLUSION: Time off work is not an absolute appropriate measure of return to premorbid status with respect to the elderly as a substantial number of >65 year olds have retired. We therefore present this interesting insight into patient perceptions following hernia repair by age group. Overall patients over 65 can expect the same high levels of satisfaction and low levels of pain following either technique for inguinal hernia repair as younger patients.

Screening for amyloid in subcutaneous fat tissue of Egyptian patients with rheumatoid arthritis: clinical and laboratory characteristics.

OBJECTIVE: To screen for amyloid and to assess associated clinical and laboratory characteristics in Egyptian patients with rheumatoid arthritis (RA). METHODS: Abdominal subcutaneous fat aspirates were consecutively collected from 112 patients (103 women, nine men) having RA for five years or more. To detect amyloid, fat smears were stained with Congo red and the concentration of amyloid A protein in fat tissue was measured. Clinical, radiological, and laboratory characteristics of the patients were assessed. RESULTS: Amyloid was detected in eight (7%) of the fat smears stained with Congo red. Compared with the Congo red stain, the sensitivity for detecting amyloid by measurement of amyloid A protein in fat tissue was 75% and the specificity was 100%. The amount of amyloid found was small for both methods. The median disease duration of the eight amyloid patients was significantly longer (17 years) than that of the non-amyloid patients (10 years). Bronchopulmonary disease and constipation were more common, whereas proteinuria and chronic renal insufficiency were not. The number of swollen joints and the number of red blood cells were significantly lower in the amyloid group. CONCLUSIONS: Quantification of amyloid A protein and staining with Congo red are strongly concordant methods of screening for amyloid in fat tissue. The prevalence of amyloid in Egyptian patients with RA is 7%. Proteinuria is not a discriminating feature, whereas long disease duration, constipation, bronchopulmonary symptoms, and a moderate to low number of red blood cells may help to identify the arthritic patients with amyloid.

Contrasting molecular pathology of colorectal carcinoma in Egyptian and Western patients.

Colorectal carcinoma is uncommon in Egypt, but a high proportion of cases occurs before age 40 years and in the rectum. We compared the molecular pathology of 59 representative Egyptian patients aged 10-72 to Western patients with sporadic, young-onset, or hereditary non-polyposis colorectal cancer syndrome (HNPCC)-associated carcinoma and found significant differences. Most Egyptian cancers were rectal (51%) and poorly differentiated (58%). High levels of microsatellite instability (MSI-H) were frequent (37%) and attributable in some cases (36%) to methylation of the promoter of the hMLH1 mismatch repair gene, but no MSI-H cancer had loss of hMSH2 mismatch repair gene product of the type seen with germline hMSH2 mutation in HNPCC. K-ras mutation was uncommon (11%). In subset analyses, high frequencies of MSI-H in rectal carcinomas (36%) and p53 gene product overexpression in MSI-H cancers (50%) were found. MSI-H and K-ras mutation in Egyptians under age 40 were unusual (17% and 0%, respectively), and schistosomiasis was associated with MSI and K-ras mutation. Cluster analysis identified 2 groups: predominantly young men with poorly differentiated mucinous and signet-ring cell colorectal carcinoma lacking K-ras mutation; older patients who had well- or moderately differentiated adenocarcinoma often with MSI-H, K-ras mutation and schistosomiasis. Our findings show that the molecular pathology of colorectal cancer in older as well as younger Egyptians has unique differences from Western patients, and schistosomiasis influences the molecular pathogenesis of some tumours.

Planning cancer prevention strategies based on epidemiologic characteristics: an Egyptian example.

BACKGROUND AND METHODS: We describe the epidemiology, cancer prevention strategies, and educational messages to be learned from four characteristic cancers in Egypt: urinary bladder, liver, lung, and early-onset colorectal cancers. RESULTS: For bladder cancer, effective and convenient treatment of schistosomiasis, using social marketing and mass media in public and medical education has contributed dramatically to primary prevention of bladder cancer in Egypt. For liver cancer, educating hospital administrators to remove structural barriers to good practice may help the control of hepatitis transmission and related liver cancer. For lung cancer, the 50-year American experience for controlling tobacco smoking, beginning with physicians, could be very effective in Egypt and other countries with increasing smoking rates in the young so as to avert the expected epidemics of lung cancer. For colorectal cancer, more attention to physician and public education about the importance of interviewing colorectal cancer patients about a family history of cancer and the screening of at-risk families could be very effective in early detection of colorectal cancer. CONCLUSION: Countries with similar cancer epidemiology experience should make use of successful cancer prevention and education strategies that could be translated from the Egyptian experience.

Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt.

Patients under age 40 constitute 35.6% of all colorectal cancer cases in Egypt, an unusual disease pattern to which both environmental exposures and inefficient DNA repair may contribute. While a number of polymorphisms in DNA repair genes have been recently identified, their role as cancer risk modifiers is yet to be determined. In a pilot case-control study, we tested the hypothesis that polymorphisms in the gene for the DNA repair enzyme XRCC1 are associated with increased risk of colorectal cancer among Egyptians. Using a multiplex polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology, allelic variants of the XRCC1 gene at codons 194 (Arg-->Trp) (194Trp) and 399 (Arg-->Gln) (399Gln), were analyzed in DNA from lymphocytes of 48 newly-diagnosed colorectal cancer cases and 48 age- and sex-matched controls. Overall, the inheritance of 194Trp allele (Arg/Trp genotype) and 399Gln allele (combined Arg/Gln and Gln/Gln genotypes) was associated with increased colorectal cancer risk (odds ratio (OR)=2.56, 95% confidence limits (CL) 0.73-9.40, and P=0. 08 for 194Trp allele and OR=3.98, 95% CL 1.50-10.6, and P<0.001 for 399Gln allele). Interestingly, the frequencies of 194Trp and 399Gln genotypes were higher in colorectal cancer cases under age 40 than in corresponding controls, and an association between both polymorphisms and early age of disease onset was observed (OR=3.33, 95% CL 0.48-35.90, and P=0.16 for 194Trp and OR=11.90, 95% CL 2.30-51.50, and P=0.0003 for 399Gln). Analysis of the data after adjustment for place of residence indicated that the frequencies of the genotypes with the 194Trp and the 399Gln alleles were higher among urban residents (OR=3.33, 95% CL 0.48-35.90, and P=0.16 for 194Trp and OR=9.97, 95% CL 1.98-43.76, and P<0.001 for 399Gln) than among rural residents (OR=2.00, 95% CL 0.36-26.00, and P=0.30 for 194Trp and OR=1.90, 95% CL 0.50-7.53, and P=0.20 for 399Gln). These findings support our hypothesis and suggest that polymorphisms in the XRCC1 gene, in conjunction with place of residence, may modify disease risk. This first demonstration that polymorphisms in DNA repair genes may contribute to colorectal cancer susceptibility and may increase the risk of early onset of the disease opens the door for future studies in that direction.

Polymorphism of glutathione S-transferase loci GSTM1 and GSTT1 and susceptibility to colorectal cancer in Egypt.

Egypt has an unusually high proportion of early-onset colorectal cancer under age 40 years. Environmental exposures and low DNA repair capacity are among the risk factors. Because GSTM1 and GSTT1 gene deficiencies may act as risk modifiers for colorectal cancer risk, we investigated the relationship between genetic polymorphism in these genes and colorectal cancer risk in Egyptians. Sixty-six patients and 55 controls were included. Genotyping for GSTM1 and GSTT1 was conducted using PCR techniques and the results were related to epidemiologic and clinical information. No overall association was observed between GSTM1 or GSTT1 null genotypes and colorectal cancer risk. However, the data suggest a possible role for GSTM1 genotype in influencing tumor site. Furthermore, GSTM1 and GSTT1 genotypes, in conjunction with gender and place of residence, may play a role in modifying disease risk. Further studies on a larger population in Egypt are needed to generalize the results of this study.

Familial aggregation of colorectal cancer in Egypt.

We have investigated the familial aggregation of colorectal cancer and hereditary nonpolyposis colorectal cancer (HNPCC) in Egypt because of the high incidence of colorectal cancer in Egyptian children and young adults and the prevalence of consanguinity there. In a pilot study, we conducted detailed interviews with 111 Egyptian colorectal cancer patients and 111 healthy Egyptian controls about their family histories of colorectal cancer, and other cancers, consanguinity, age at diagnosis, symptoms and recurrence. Eight patients (7.2%) had one or more first- or second-degree relatives under age 40 with colorectal cancer, suggestive of HNPCC by the Amsterdam criteria. One of these families had a typical history of HNPCC, with 4 relatives having colorectal cancer in 3 generations; 3 of these relatives were younger than age 45 at colon cancer diagnosis, and other relatives had extracolonic tumors. Another 14 patients (12.6%) had a first- or second-degree relative with a family history of other neoplasms such as endometrial, urinary and hepatobiliary cancers that could also be related to HNPCC. Four patients with early-onset colon cancer and a family history of other HNPCC-related cancers reported that their parents were first-degree cousins.

Depression and depressive symptoms in rheumatoid arthritis patients: an analysis of their occurrence and determinants.

The objectives were to determine the differences in depressive symptoms and depression between rheumatoid arthritis (RA) and osteoarthritis (OA) patients, and to analyse the contribution of sociodemographic and clinical variables to depression in RA patients. The responses of 60 Egyptian RA patients and 40 patients with OA of the knees to the Symptom Checklist-90-R Depression subscale were compared. The proportions of patients from both groups confirmed by a psychiatric interview to be clinically depressed according to the DSM-III-R criteria were also compared. The contributions of sociodemographic and disease variables to depressive symptoms and clinical depression in RA patients were explored by multiple linear and logistic regression, respectively. RA patients showed significantly higher depression scores than OA patients (P = 0.001). The difference was unaffected by controlling for the effects of age, sex, disease duration and the sociodemographic covariates. A depressive disorder was clinically confirmed in 23% of RA patients and 10% of OA patients. The erythrocyte sedimentation rate (ESR), being unmarried and an urban residence were significant predictors of depressive symptoms (P < 0.05), while being unmarried (P < 0.05, OR = 2.1) and HAQ disability (P < 0.01, OR = 3.8) were significant predictors of clinical depression in RA patients. RA patients have significantly more depressive symptoms and tend to be more clinically depressed than OA patients. The contribution of some sociodemographic and clinical variables to depression in RA patients was modest, albeit significant.

Effect of radiation dose rate and cyclophosphamide on pulmonary toxicity after total body irradiation in a mouse model.

PURPOSE: Interstitial pneumonitis (IP) is still a major complication after total body irradiation (TBI) and bone marrow transplantation (BMT). It is difficult to determine the exact role of radiation in this multifactorial complication, especially because most of the experimental work on lung damage was done using localized lung irradiation and not TBI. We have thus tested the effect of radiation dose rate and combining cyclophosphamide (CTX) with single fraction TBI on lung damage in a mouse model for BMT. METHODS AND MATERIALS: TBI was given as a single fraction at a high dose rate (HDR, 0.71 Gy/min) or a low dose rate (LDR, 0.08 Gy/min). CTX (250 mg/kg) was given 24 h before TBI. Bone marrow transplantation (BMT) was performed 4-6 h after the last treatment. Lung damage was assessed using ventilation rate (VR) and lethality between 28 and 180 days (LD(50/28-180)). RESULTS: The LD50 for lung damage, +/- standard error (SE), increased from 12.0 (+/- 0.2) Gy using single fraction HDR to 15.8 (+/- 0.6) Gy using LDR. Adding CTX shifted the dose-response curves towards lower doses. The LD50 values for the combined treatment were 53 (+/- 0.2) and 3.5 (+/- 0.2) Gy for HDR and LDR, respectively. This indicates that the combined effect of CTX and LDR was more toxic than that of combined CTX and HDR. Lung damage evaluated by VR demonstrated two waves of VR increase. The first wave of VR increase occurred after 6 weeks using TBI only and after 3 weeks in the combined CTX-TBI treatment, irrespective of total dose or dose rate. The second wave of VR elevation resembled the IP that follows localized thoracic irradiation in its time of occurrence. CONCLUSIONS: Lung damage following TBI could be spared using LDR. However, CTX markedly enhances TBI-induced lung damage. The combination of CTX and LDR is more toxic to the lungs than combining CTX and HDR.

Late renal damage after total body irradiation and bone marrow transplantation in a mouse model: effect of radiation fractionation.

In response to the accumulating evidence that renal damage is now becoming an important late complication after total body irradiation (TBI) and bone marrow transplantation (BMT), we have tested the effect of fractionated and hyperfractionated TBI on late kidney damage in a mouse model. TBI was given as fractionated (three fractions in 3 days, Fx 3), or hyperfractionated (nine fractions in 3 days, Fx 9) treatment. Kidney damage was evaluated using [51Cr]EDTA residual activity, blood urea nitrogen (BUN) and percentage haematocrit (%Hct) as end-points. We were able to detect progressive renal damage with no evidence of recovery or plateau in the Fx 3 and Fx 9 schedules. The time latency before the expression of renal damage was dependent on both total dose and end-point and it was shorter the higher the dose. [51Cr]EDTA detected renal damage at the same doses as BUN but earlier in time whereas %Hct detected renal damage at doses lower than both BUN and [51Cr]EDTA. Reducing the dose per fraction spared the kidney from TBI damage. The dose-response curves for renal damage (using the [51Cr]EDTA end-point) were steep, and tended to shift towards lower doses with longer follow-up times. The dose-modifying factors defined as the dose needed to cause renal damage in 50% of the animals (ED50) using single fraction TBI divided by the ED50 using fractionated TBI were 1.3 and 1.9 for the Fx 3 and Fx 9, respectively. These results may indicate that patients treated with TBI and BMT should be assessed for late kidney damage and that fractionation and particularly hyperfractionation may protect the kidneys from TBI-induced renal damage.

Late tissue reactions after single-fraction sequential half-body irradiation (HBI) in patients with non-Hodgkin's lymphomas.

Lung and hepatic toxicities constituted the main radiation-related damage after half-body irradiation (HBI) used as the treatment for patients with non-Hodgkin's lymphomas (NHL). Liver damage was mostly transient after a single dose of 8 Gy and could be well monitored by serum enzyme levels. A dose-response relationship could be shown for lung damage in the single dose range of 6.25-9.25 Gy, but the relationship did not reach statistical significance. A significant dose-rate effect could be shown. Mediastinal involvement by lymphoma seemed to increase the risk of pneumonitis. In a radical setting half-body irradiation is recommended to be used at a low dose-rate or as a multifraction irradiation in order to reduce the risk of liver and lung toxicities.

Pharmacokinetics of etanidazole (SR-2508) in bladder and cervical cancer: evidence of diffusion from urine.

Following an IV infusion of 2.0 g/m2 of Etanidazole, the mean tumor concentration 40 min after injection was 126 micrograms/g in bladder cancer and 65 micrograms/g in cervical cancer. The tumor/plasma concentration ratio was 1.88 in bladder and 0.85 in cervical cancer. This high tumor concentration in bladder cancer could be accounted for by diffusion from a highly concentrated urine. This renders bladder cancer a suitable clinical model for testing this sensitizer.

Postoperative radiotherapy of carcinoma in bilharzial bladder using a three-fractions per day regimen.

Patients with T3 bladder cancer who survived surgery and proved to have P3a, P3b or P4a tumors were randomized to either no further treatment (61 patients) or postoperative total pelvic irradiation (55 patients). A three-fraction per day regime was adopted with a dose per fraction of 125 cGy and an interval of 3 h between fractions. The total dose amounted to 3750 cGy divided into 30 fractions over 12 days. Patients of the postoperative radiotherapy group were re-randomized to radiotherapy alone or radiotherapy plus misonidazole (MISO) in a daily dose of 1 g/m2 given orally 2 h before the first daily fraction. The 2-year disease-free survival rate in the cystectomy alone group was 33 +/- 6% compared to 65 +/- 6% in the postoperative radiotherapy group. The therapeutic benefit applied to the two cell types, all histological grades and stages and to patients with or without nodal metastases. The benefit of postoperative irradiation was also verified by the Cox's multivariant analysis which adjusts for the relative representation of the important prognostic factors particularly pathological stage and nodal involvement. MISO did not seem to add to the therapeutic gain. No late complications were encountered in the wall of the rectum, small bowel or uretero-intestinal anastomotic sites. This is suggested to be due to the small dose per fraction used. However, early small bowel reactions were dose-limiting.

Schistosomiasis and inflammatory polyarthritis: a clinical, radiological and laboratory study of 96 patients infected by S. mansoni with particular reference to the diarthrodial joint.

Patients with active Schistosoma mansoni infection attending a medical clinic in an endemic area, 100 miles from Cairo, were asked to participate in this study. Ninety-six patients are reported, 72 of whom presented with musculoskeletal complaints. Nine of these presented with an enthesitis alone; 16 had an inflammatory peripheral polyarthritis alone; the remaining 47 were suffering from the combination of both an arthritis and an enthesitis. Alpha-1-acid glycoprotein was significantly lowered in those patients with musculoskeletal manifestations.

Experience in the radical radiotherapy of cancer in the bilharzial bladder: the use of misonidazole.

The results of application of a protracted split-course radiotherapy regimen in T3 carcinoma in the bilharzial bladder are presented. A total dose of 70 Gy spread over 61 days was divided into four courses separated by gaps of 1, 2 and 1 week, respectively. Each of the first three sessions comprised eight fractions, 2.5 Gy each, while four such fractions were given during the fourth course. Patients were randomized between radiotherapy alone (32 patients) and radiotherapy plus misonidazole (MIS) (30 patients). The drug was given in a daily oral dose of 0.5 g/m2, 3.5 h prior to each radiation treatment. The treatment was well tolerated and MIS did not augment the radiation reaction. Mild or moderate peripheral neuropathy was experienced by 63% of patients of the group. Age and degree of upper obstructive uropathy were the most important determinants of the risk of neuropathy. The 2-year disease-free actuarial survival rates amounted to 58% and 44% in the MIS and radiotherapy alone groups respectively; the difference is not significant. The results were significantly better in case of transitional cell (67%) than squamous cell cancer (29%) but were independent of the histological grade. A strong correlation was found between the magnitude of tumour volume reduction after 40 Gy and the long-term end results.

The use of misonidazole in association with a three-fractions per day regimen in advanced head and neck epidermoid cancer. A pilot study.

Twenty-one patients with Stage III or IV head and neck epidermoid cancer were treated by a three-fractions per day radiotherapy regime plus misonidazole (MIS). An initial course of 45 Gy was used, spread over 12 days and divided into 30 fractions 1.5 Gy each with a 3-hour interval between fractions. A daily MIS dose of 1 g/m2 was given 2 hours prior to the first fraction. A boost dose of 22.5 Gy/5 days was given to 10 patients, 4 weeks after the initial course, using the same fractionation scheme. The local acute and chronic reactions were acceptable. Eight patients suffered mild reversible peripheral neuropathy. The mean MIS blood level corresponded to an enhancement ratio of about 1.45. The 1-year disease-free survival rate was 9/21 and was significantly greater in patients receiving the boost irradiation. The control rate of nodal disease was encouraging. Based on this pilot study, a prospective trial is proposed aiming at testing the usefulness of MIS in MDF regimens in advanced head and neck cancer, either as the sole method of treatment or as a preoperative measure.

Misonidazole in the preoperative and radical radiotherapy of bladder cancer.

Measurement of intercapillary distances suggests the presence of significant cell hypoxia in Bilharzial bladder cancer. This tumor seems to be capable of reoxygenation in view of the existence of a correlation between prognosis and immediate tumor shrinkage after irradiation. Two programs are presented: 1) Use of misonidazole with concentrated preoperative irradiation where the reoxygenation properties are not used fully. A prospective randomized study is presented whereby cystectomy alone is compared with cystectomy plus preoperative irradiation (6.5 Gy X 2F/1 week) with or without misonidazole. the drug is given either orally (in two doses 3 g/m2 each given 3.5 hours prior to each fraction; blood levels: 90-110 micrograms/ml) or intravesically. The intravesical administration is designed in the light of penetration studies and seems to have the advantage of the complete lack of systemic drug toxicity. Twenty-eight patients were included in this study and no drug toxicity was recorded. A second preoperative irradiation study is presented whereby cystectomy alone is compared with cystectomy plus preoperative irradiation (4.0 Gy X 5F) with or without misonidazole in individual doses of 2 g/m2. 2) Two radical radiotherapy regimes are presented. One protocol involves a split course (SC) protracted regime making full use of spontaneous reoxygenation. The drug is given in 0.5 g/m2 daily doses (total dose 14 g/m2 spread over 61 days, blood level: 15-20 micrograms/ml). A second protocol involves hyperfractionation stimulating continuous low-dose-rate irradiation. Higher blood levels are attained (60-80 micrograms/ml) after daily doses of 2 g/m2 (total dose: 14 g/m2 spread over 35 days). In a phase II study using SC technic, reversible grade 1 peripheral neuropathy was encountered in 5 of 22 patients. Complete tumor regression 3 months after irradiation was achieved in 18 of 22 patients with 3T tumors. No neuropathy was encountered in four patients subjected to the HF regimen who also showed complete tumor regression.