Aberrant CREB1 activation in prostate cancer disrupts normal prostate luminal cell differentiation.

The molecular mechanisms of luminal cell differentiation are not understood well enough to determine how differentiation goes awry during oncogenesis. Using RNA-Seq analysis, we discovered that CREB1 plays a central role in maintaining new luminal cell survival and that oncogenesis dramatically changes the CREB1-induced transcriptome. CREB1 is active in luminal cells, but not basal cells. We identified ING4 and its E3 ligase, JFK, as CREB1 transcriptional targets in luminal cells. During luminal cell differentiation, transient induction of ING4 expression is followed by a peak in CREB1 activity, while JFK increases concomitantly with CREB1 activation. Transient expression of ING4 is required for luminal cell induction; however, failure to properly down-regulate ING4 leads to luminal cell death. Consequently, blocking CREB1 increased ING4 expression, suppressed JFK, and led to luminal cell death. Thus, CREB1 is responsible for the suppression of ING4 required for luminal cell survival and maintenance. Oncogenic transformation by suppressing PTEN resulted in constitutive activation of CREB1. However, the tumor cells could no longer fully differentiate into luminal cells, failed to express ING4, and displayed a unique CREB1 transcriptome. Blocking CREB1 in tumorigenic cells suppressed tumor growth in vivo, rescued ING4 expression, and restored luminal cell formation, but ultimately induced luminal cell death. IHC of primary prostate tumors demonstrated a strong correlation between loss of ING4 and loss of PTEN. This is the first study to define a molecular mechanism whereby oncogenic loss of PTEN, leading to aberrant CREB1 activation, suppresses ING4 expression causing disruption of luminal cell differentiation.

Full Outline of UnResponsiveness score and Glasgow Coma Scale in medical patients with altered sensorium: interrater reliability and relation to outcome.

PURPOSE: Full Outline of UnResponsiveness, or FOUR score (FS), is a recently described scoring system for evaluation of altered sensorium. This study examined interrater reliability for FS and Glasgow Coma Scale (GCS) among medical patients with altered mental status and compared outcome predictability of GCS, FS, and Sequential Organ Failure Assessment score. PATIENTS AND METHODS: Adult patients with altered mental status due to medical causes were rated by neurology consultants and internal medicine residents on FS and GCS. Interobserver reliability for GCS and FS was assessed using κ score. Relation with outcomes was explored using univariate and multivariate analyses. MAIN RESULTS: Of the 100 patients (age, 62 ± 17 years), 60 had neurologic conditions; 26, metabolic encephalopathy; 9, infections; and 7, others. Thirty-nine patients died at 3 months. κ Scores ranged from 0.71 to 0.85 for GCS and from 0.71 to 0.95 for FS. On multivariate analysis, GCS was predictive of outcome at 3 months; FS was predictive of mortality. Area under the receiver operating characteristic curves suggested equivalent performance of both scoring systems. CONCLUSIONS: Interrater reliability and outcome predictability for FS were comparable with those for GCS. This study supports the use of FS for evaluation of altered mental status in the medical wards.

c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression.

Despite 35 years of clinical trials, there is little improvement in 1-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg are elevated in primary melanomas (60%), in a subset of benign nevi (33%) and in some human melanoma cell lines. Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is requiredfor melanoma cell proliferation, survival and invasion. Significantly, we identify the mechanism by which activated c-Abl promotes melanoma invasion by showing that it transcriptionally upregulates matrix metalloproteinase-1 (MMP-1), and using rescue approaches we demonstrate that c-Abl promotes invasion through a STAT3 → MMP-1 pathway. Additionally, we show that c-Abl and Arg are not merely redundant, as active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Most importantly, c-Abl and Arg not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg kinase activity with the c-Abl/Arg inhibitor, nilotinib, dramatically inhibits metastasis in a mouse model. Taken together, these data identify c-Abl and Arg as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may be useful in preventing metastasis in patients with melanomas harboring active c-Abl and Arg.

Splenectomy for haematological disorders: a single center study in 150 patients from Oman.

BACKGROUND: Haematological disorders, in particular sickle cell disease (SCD) and thalassaemia, are relatively common in Oman. We report our experience of splenectomy for haematological disorders and review the literature on splenectomy role in their management. OBJECTIVES: To review our experience in the management of 150 patients with haematological disorders undergoing splenectomy with emphasis on indications and outcome. To compare our experience with those reported from outside this region. METHODS: The records of 150 patients who underwent splenectomy over a thirteen year period were reviewed retrospectively, analyzing the age and sex of the patients, indication for splenectomy, operative procedures, complications, peri-operative management and outcome. RESULTS: Of the 150 patients, 96 (64%) had SCD and 34 (22.6%) had beta-thalassaemia; the rest comprised patients with refractory idiopathic thrombocytopenic purpura (ITP) n=12, hereditary spherocytosis (HS) n=6, and auto-immune haemolytic anaemia (AHA) n=2. In SCD patients, the main indications for splenectomy were recurrent splenic sequestration (60.4%) and hypersplenism (36.4%), whereas in thalassaemic patients it was increased requirement of packed red blood cells (PRBC) transfusion (mean 310 ml, range 242-372 of PRBC/kg/year). All patients received prophylactic antibiotics and vaccination against pneumococcal infection and when the vaccine was available for Haemophilus influenzae. PRBC and platelet concentrates as well as intravenous fluids were infused preoperatively as per protocol. Concomitant procedures at laparotomy included liver biopsy (14.6%) and cholecystectomy (8.6%). The postoperative morbidity was low (8.6%) and there was no mortality. All patients were maintained on long term penicillin and proguanil, and the mean follow-up was 4.6 years. In SCD patients splenectomy eliminated the risks of life threatening acute splenic sequestration and improved significantly the blood counts of the hypersplenic cases, while in thalassaemic patients it reduced significantly the mean transfusion requirement by 100ml PRBC/kg/year (p<0.0001). Of the patients with refractory ITP, two thirds had a good response to splenectomy (p<0.0001). All HS and AHA patients benefited from splenectomy. CONCLUSION: The predominant indications for splenectomy were recurrent acute splenic sequestration and hypersplenism in SCD patients, and increased transfusion demand in the thalassaemics. Overall, splenectomy proved beneficial in eliminating the risk of splenic sequestration in SCD patients, in improving the blood counts in SCD with hypersplenism and in reducing transfusion requirement in thalassaemic patients, while in ITP group two thirds of the patients benefited.

Epidemiological transition of some diseases in Oman: a situational analysis.

During the past 35 years Oman has undergone a rapid socioeconomic and epidemiological transition leading to a steep reduction in child and adult mortality and morbidity due to the decline of various communicable diseases, including vaccine-preventable diseases. Good governance and planning, together with leadership and commitment by the government, has been a critical factor in this reduction. However, with increasing prosperity, lifestyle-related noncommunicable diseases have emerged as new health challenges to the country, with cardiovascular diseases, diabetes and obesity in the lead among other chronic conditions. Appropriate prevention strategies for reducing the burden of noncommunicable diseases are discussed.

Epidemiological transition of some diseases in Oman: a situational analysis.

During the past 35 years Oman has undergone a rapid socioeconomic and epidemiological transition leading to a steep reduction in child and adult mortality and morbidity due to the decline of various communicable diseases, including vaccine-preventable diseases. Good governance and planning, together with leadership and commitment by the government, has been a critical factor in this reduction. However, with increasing prosperity, lifestyle-related noncommunicable diseases have emerged as new health challenges to the country, with cardiovascular diseases, diabetes and obesity in the lead among other chronic conditions. Appropriate prevention strategies for reducing the burden of noncommunicable diseases are discussed.

Epidemiological transition of some diseases in Oman: a situational analysis

During the past 35 years Oman has undergone a rapid socioeconomic and epidemiological transition leading to a steep reduction in child and adult mortality and morbidity due to the decline of various communicable diseases, including vaccine-preventable diseases. Good governance and planning, together with leadership and commitment by the government, has been a critical factor in this reduction. However, with increasing prosperity, lifestyle-related noncommunicable diseases have emerged as new health challenges to the country, with cardiovascular diseases, diabetes and obesity in the lead among other chronic conditions. Appropriate prevention strategies for reducing the burden of noncommunicable diseases are discussed

Measurement of circulating levels of VEGF-A, -C, and -D and their receptors, VEGFR-1 and -2 in gastric adenocarcinoma.

AIM: To analyze the serum levels and prognostic significance of vascular endothelial growth factor (VEGF) -A, -C, and -D, and their receptors, VEGFR-1 and -2 in gastric adenocarcinomas. METHODS: The serum levels of VEGF family members were measured in 76 control subjects and 76 patients with gastric adenocarcinoma using an enzyme-linked immunosorbent assay (ELISA). These measurements were correlated with clinco-pathological features and survival rates. RESULTS: The serum levels of VEGF-A and its receptor, VEGFR-1, were significantly higher in patients with gastric cancer than in healthy donors (t = 2.3, P = 0.02 and t = 4.2, P < 0.0001, respectively). In contrast, the serum levels of VEGF-D were significantly higher in control subjects than in patients (t = 2.9, P = 0.004). There was no significant difference in serum levels of VEGF-C and VEGFR-2 between patients and controls. VEGF-C was associated with advanced tumor stage and presence of metastasis. VEGFR-1 was associated with metastasis, advanced overall stage, tumor differentiation and survival. VEGFR-2 levels were associated with poor tumor differentiation. There was no significant prognostic value for any of the VEGF family members or their receptors except for VEGFR-1 where high levels were associated with a poor overall survival. CONCLUSION: Serum VEGF levels vary significantly in the same cohort of patients with variable clinico-pathological features and prognostic values. The simultaneous measurement of VEGF receptors levels in sera may overcome the limitations of a single biomarker assay.

[Conceiving and implementing an ISO 9001:2000 quality management system: quality improvement and efficiency increase over 3 years at the Dept. of Ophthalmology, Sultan Qaboos University in Oman]. / Konzeption und Implementierung eines Qualitätsmanagementsystems nach ISO 9001:2000: Qualitäts- und Effizienzsteigerung über 3 Jahre an der Augenklinik der Sultan Qabbos Universität in Oman.

BACKGROUND: Oman is a developing country of the Middle East with a University Hospital in a national health system. Problems related to documentation, structure, and procedure prevailing in a multicultural environment result in a lack of productivity. The aim of this study was to test the feasibility of introducing a quality management system according to ISO 9001:2000 into a university department of ophthalmology with special reference to quality and efficiency data over 3 years. MATERIALS AND METHODS: Standardized types of documentation (35 documents, 183 forms and formats, and 453 registers) under a formal roof (booklets for work instructions, quality management, procedures) were conceived in 2001 and implemented, and were evaluated by descriptive statistics over the years 2002-2005 with respect to quality and efficiency. In 2005, the departmental QMS was merged into the QMS of the whole hospital. RESULTS: Establishment of "responsibility clusters" with structured surveillance tasks, procedural improvements, and continuous audits resulted in a significant quality improvement already during the implementation until ISO 9001:2000 certification in 2002, and over the following 3 years. The data were assessed by non-conformities documented monthly (total inpatients: -50%, outpatients: -20%, operating theater: -100%, teaching: -10%; p <0.05) and increased efficiency assessed by the most important performance indicators (before QMS vs a median of 3 years with QMS): major surgery: +459%, inpatient stay: -49.7%, occupancy rate: +63.9%, technical diagnostics: +292.9%, postgraduate teaching total: +740%, research output total: +330% (p <0.05). CONCLUSIONS: It is feasible to introduce the quality management system according to ISO 9001:2000 into a developing country in the Middle East. It has an immediate effect on the increase of efficiency (measured by performance indicators) and quality in all systems providing the possibility for regional benchmarking.

The prognostic determinants of gastric cancer treatment outcome in Omani Arab patients.

BACKGROUND: Gastric cancer is the most common cancer in Oman and a leading cause of cancer death. The variation in survival rates between countries and ethnic groups has been attributed to early detection policies, differences in clinicopathological features, treatment approaches, and biological characteristics. There were no previous reports on gastric cancer from Oman and very few studies on Asian Arabs. AIM: To evaluate the impact of clinicopathological and treatment variables on the survival prospects of Omani Arab patients diagnosed with gastric cancer. METHODS: The medical records of 339 Omani Arab patients diagnosed with invasive gastric adenocarcinoma during the period 1993-2004 were retrospectively reviewed. The relative importance of clinicopathological features and surgical and medical treatments were assessed using univariate and multivariate analyses. RESULTS: Most patients had distal ulcerating-type gastric cancer and presented at advanced stages. The median survival time for the entire cohort was 12 months (95% CI 9.7-14.4) with a 5-year overall survival rate of 16.7%. On univariate analysis of 237 patients who underwent surgical resection, the following positive prognostic factors emerged as significant: early overall TNM stage, early T stage, negative lymph nodes, tumor size <5 cm, ulcerating macroscopic appearance, and curative surgical attempt. The independent prognostic factors on multivariate analysis were T stage and lymph node involvement. CONCLUSION: The overall T and N stages are the most important determining factor for survival in Omani Arab patients. More efforts need to be made for the early detection of gastric cancer in developing countries such as Oman, while continuing to employ the standard surgical and medical treatments.

The prognostic significance of p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67 proteins expression in gastric cancer: a clinicopathological and immunohistochemical study of 121 Arab patients.

BACKGROUND: The variability of prognosis within a pathological stage of gastric cancer (GC) at presentation, underscores the need for specific biological markers to identify subgroups of patients with aggressive course for intensive treatment. To our knowledge, this is the first study from an Arab population reporting on the relationship of p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67 expression, and clinicopathological features and their prognostic significance. METHODS: Formalin-fixed paraffin-embedded tumors were studied by immunohistochemistry, using monoclonal antibodies to p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67. The results were correlated with clinicopathological features and survival. RESULTS: M:F = 80:41; median age = 60 years; stage III and IV = 71%; and median follow-up = 34.4 months. Positive expression rates of p53, p27 kip1, p21 waf1, Ki67, and HER-2/neu were 54%, 40%, 8.3%, 70%, and 12% respectively. p53 expression correlated with age <60 years (P = 0.03), tumor size >5 cm (P = 0.01), p27 kip1 and Ki67 expression (P = 0.0001), and HER-2/neu (P = 0.04). p21 waf1 correlated inversely with T-stage (P = 0.008) and Her-2/neu expression correlated with histological grade (P = 0.04) and T-stage (P = 0.008). Univariate analysis showed that p53 overexpression (P = 0.01), fungating and infiltrative macroscopic appearance (P = 0.02), size >5 cm (P = 0.0001), lymph node metastasis (P = 0.0001), p T3 and T4 disease (P = 0.01), and overall stage III and IV (P = 0.0001) disease were adverse prognostic factors. Patients with tumor profiles p53 (-)/p27 (+) had better survival than those with p53 (+)/p27 kip1 (-)(P = 0.02). On multivariate analysis by Cox regression model, the expression of p53 (P = 0.03) and lymph node involvement (P = 0.01) were significant adverse prognostic factors for overall survival. CONCLUSIONS: The expression of p53 in Arab patients with GC correlates with aggressive tumor characteristics and is an independent prognostic factor. The combined analysis of p53 and p27 kip1 is of added prognostic value.

The outcome of treatment of breast cancer in a developing country--Oman.

The aim of the present study was to evaluate the outcome of treatment of breast cancer in Oman with an analysis of clinico-pathological features, treatment modalities utilized, and prognostic factors. One hundred fifty-two breast cancer patients diagnosed between January 1996 and June 2002 were evaluated retrospectively. Their mean age was 48.5 (S.D. +/- 10.8) years, and 48% of the female patients were premenopausal. The mean tumor size according to pathology was 4.6 (S.D. 3.29)cm, and 34.9% and 15.8% of patients had stage III or IV disease, respectively. Only 26.3% of the patients had breast-conserving surgery, and neoadjuvant chemotherapy was underutilized. The overall 5-year relapse-free survival (RFS) and overall (OS) survival rates were 62% and 64%, respectively. On multivariate analysis, axillary lymph node involvement and tumor differentiation were predictive of RFS and OS, respectively. Thus, breast cancer patients in Oman present with advanced stages of the disease at younger ages than their counterparts in the West and have lower survival rates. Increasing awareness and the introduction of screening programs and of a multidisciplinary approach are essential in Oman and other developing countries to improve the outcome of treatment.

MATERNAL RISK FACTORS AS DETERMINANTS OF LOW BIRTH WEIGHT AMONG ARMED FORCES FAMILIES.

Low birth weight (LBW) is responsible for a significant proportion of child morbidity and mortality apart from its possible role in the occurrence of chronic disease in adult life. This study highlights the overall low incidence of LBWs at 13.6% among the Armed Forces families. The Other Ranks had a proportionally higher incidence of LBW at 24.14%. 82.14% of the LBWs occurred in the age group of 20-29 yrs, with only 6.93% of the births being teenage pregnancies. Primiparous women accounted for 54.95% of births but 75% of the LBWs. Smoking was not a significant factor. The findings underscore the need for special attention to other rank families and primiparas. A continued effort at updating the health care facilities provided to the Armed Forces families, and a concerted health and dietary advice by the authorised medical attendants, directed at the primiparous women, will further help lower the incidence of LBWs. The National LBW target of less than 10% by 2000 AD is definitely achievable by the Armed Forces.

Evaluation of some risk factors for ischaemic heart disease under a matched pairs case-control design.

A pair-wise matched case-control study was carried out in 200 male patients of ischaemic heart disease (IHD). The cases were matched with an equal number of controls in respect of the variables viz., age and socio-economic status. The objective was to quantify the risk of developing IHD for some of the leading risk factors under the univariate and multivariate situations. The analysis revealed that of the factors (smoking, overweight, hypertension, diabetes, serum cholesterol and family history) considered, the smoking habit of the individual, presence of family history of the disease and overweight were the significant risk factors responsible for the development of the disease. The estimated odds ratios were found to be 3.29, 2.60 and 2.00 respectively.

Analysis of ordinal data in a study of endometrial cancer under a matched pairs case-control design.

While estimating odds ratios (ORs) in the context of dose levels of conjugated oestrogen exposure and development of endometrial cancer, the categories formed by the levels of the exposure are ordinal in nature. In the literature, the binary logistic model is used for estimating OR for each category relative to the baseline category. We describe the use of two ordinal logistic models, the cumulative logit and continuation-ratio logit models, to estimate the ORs for the matched pairs case-control data set of the Los Angeles endometrial cancer study. A test for equality of the cumulative ORs across the exposure levels is proposed. The test statistic follows asymptotically the chi-square distribution.

Evaluation of susceptibility status of Culex quinquefasciatus larvae to few organophosphorus insecticides based on logistic regression analysis.

A laboratory trial was carried out at Pune to evaluate the effectiveness of five types of larvicides viz. Malathion, Temephos, Fenthion, Dichlorvos and Fenitrothion against Culex quinquesfasciatus larvae. The expected number of mortality at various dose levels for the five types of insecticides were estimated separately using logistic regression model. Based on the fitted model, the estimated dose level corresponding to the 90 percent mortality (LC90) was obtained for each insecticide. Approximate 95 percent confidence intervals for the LC90 dose, in each case, has been provided. The analysis revealed that out of all the five types of insecticides included in the study, fenthion was the most effective. The estimated value of LC90 in this case was the lowest and is equal to 0.007 mg/L. The effectiveness of temephos, dichlorvos and fenitrothion was found to be approximately same and malathion was the least effective. The results were found to be comparable with that obtained under probit method.

Calcium channel blockers and the CVS reflex responses during lower body suction.

Nine normal men (mean age 27.6 yr) were exposed to continuous lower-body suction pressure (LBSP) of -20 to -50 mmHg (for 5 min at each level) on four different occasions after having consumed a single oral therapeutic dose of either diltiazem, nifedipine, verapamil, or a placebo, randomly, in a single blind manner. The suction was applied at 12.30 pm in all experiments, while the medications were administered in such a manner so that their expected peak plasma levels would have been achieved at the time of suction application. The cardiovascular reflex effects commenced at a pressure of -30 mmHg, and peaked at -50 mmHg. The increases in the heart rate for all treatments at -50 mmHg was statistically similar (about 16-20 beats/min). The systolic BP fell by about 9 mmHg for the placebo experiments, and this change was not different from the changes produced by the 3 Calcium channel blocker treatments. The diastolic BP increase was about 3 mmHg. The Cardiac index did not vary significantly. Our results suggest that the commonly used Ca++ channel blockers do not adversely affect orthostatic tolerance.

Laboratory evaluation of some larvicidal agents against Anopheles culicifacies in Pune.

A laboratory study to evaluate some larvicidal agents against Anopheles culcifacies was carried out. The findings of this study brought out that the larvae of this species were highly susceptible to temephos, fenthion, Paris green and Mosquito Larvicidal Oil (MLO) in that order. The LC50 values in respect of these larvicides were 0.0009 ppm, 0.0081 ppm, 0.029 ppm and 0.015 ml respectively and LC90 values were 0.0018 ppm, 0.022 ppm, 0.11 ppm and 0.046 ml respectively.

A case control study of cancer cervix patients attending Command Hospital, Pune.

A case control study was undertaken with the objective to determine the association of certain host factors like marital status, age at first marriage, duration of married life, parity, literary status and genital hygiene, in the subsequent development of cancer cervix. A total number of ninety-two cases and an equal number of control subjects, under matched case control design, were studied at Command Hospital, Pune over a period of nine months. Salient findings of this epidemiological study have been highlighted in this communication. Few of the risk factors viz early age at first marriage, longer duration of married life, increased and early parity, low educational status and poor genital hygiene were found to have played significant role in the subsequent development of carcinoma cervix.

Medico-social profile of male teenager STD patients attending a clinic in Pune.

A study of 250 male teenager STD cases was carried out to determine the association between certain medicosocial factors e.g. age, type of infection, educational status, source of infection, knowledge about mode of acquiring infection and prophylaxis etc. Salient findings of the study such as gonorrhoea being the commonest type of STD, curiosity being the main reason for first sexual exposure and prostitutes being the major source of infection have been highlighted in this communication.

PIP: Diagnosis and social characteristics of 250 male adolescents attending a sexually transmitted disease (STD) clinic in Pune, Maharashtra State, India in April-August 1985 are described. 75% of the teens were 18-19 years old. their diagnoses were gonorrhea 37.6% chancroid 36.0%, primary syphilis 11.2%, balano-prosthitis 4.8%, condyloma acuminata 3.6%, lymphogranuloma venereum 3.2%, herpes genitalis 2.8% and secondary syphilis 0.8%. 99.2% were single. 56% were employed and 31.2% were students. Of the types of families reported, most lived in nuclear, joint or 3-generation families. 18% were illiterate, the rest had completed either 6th or 9th standard or high school. 22.0% had incorrect knowledge, and 64.4% no knowledge about STDs. 80.8% were ignorant of prevention and 13.6 had inaccurate knowledge, reporting folk methods such as application urine after intercourse or avoiding intercourse with menstruating women or those that did not look clean. 69% reported that they contracted their infection from their 1st sexual contact, while 90% reported that they had done so during a subsequent contact. Most of their sexual contacts had been prostitutes, although some paid in meals or gifts rather than money. These young men also reported that they knew about sexual intercourse at the age of 14 (85%), and had their 1st experience between age 15 and 18 years old. Most stated that curiosity or peer pressure was the chief reason for their 1st sexual experience.