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2.  Countries with high circumcision prevalence have lower prostate cancer mortality 
Asian Journal of Andrology  2015;18(1):39-42.
The present study determined the relationship of male circumcision (MC) prevalence with prostatic carcinoma mortality rate in the 85 countries globally for which data on each were available. MC prevalence in different countries were obtained from a WHO report and allocated to WHO categories of 81%–100%, 20%–80%, and 0%–19%. Prostatic carcinoma mortality data were from Globoscan, gross national income per capita as well as male life expectancy were from a World Bank report, and percentages of Jews and Muslims by country were from the Pew Research Institute and the North American Jewish Data Bank. Negative binomial regression was used to estimate prostatic carcinoma mortality rate ratios. Compared to countries with 81%–100% MC prevalence, prostatic carcinoma mortality rate was higher in those with MC prevalence of 0%–19% (adjusted OR [adjOR] =1.82; 95% CI 1.14, 2.91) and 20%–80% (adjOR = 1.80; 95% CI, 1.16, 2.78). Higher Muslim percentage (adjOR = 0.92 [95% CI 0.87, 0.98] for each 10% increase) and longer life expectancy (adjOR = 0.82 [95% CI 0.72, 0.93] for each 5 additional years) were associated with lower prostatic carcinoma mortality. Higher gross national income per capita (adjOR = 1.10 [95% CI 1.01, 1.20] for double this parameter) correlated with higher mortality. Compared with American countries, prostatic carcinoma mortality rate was similar in Eastern Mediterranean countries (adjOR = 1.02; 95% CI 0.58, 1.76), but was lower in European (adjOR = 0.60; 95% CI 0.50, 0.74) and Western Pacific countries (adjOR = 0.54, 95% CI 0.37, 0.78). Thus, prostate cancer mortality is significantly lower in countries in which MC prevalence exceeds 80%.
PMCID: PMC4736355  PMID: 26323559
circumcision; country comparisons; epidemiology; global; prostate cancer; public health; urology
3.  Hormone Replacement Therapy, Likely Neither Angel Nor Demon 
PLoS ONE  2015;10(9):e0138556.
A decline in breast cancer incidence has been attributed to the reduction in hormone replacement therapy (HRT) prescriptions since the publication of the landmark WHIT paper in 2003. Concurrently, a relationship between HRT and cerebrovascular disease incidence has also been suggested. No generalized analysis of HRT prescription rates and breast cancer incidence rates that included more than seven years of data. We hypothesized that detailed analysis of SEER data would clarify the relationship between HRT use and breast cancer incidence. Given the large decline in HRT prescription rates uncovered, analyses of potential complications were also conducted, with the understanding that a small effect or one limited to a subpopulation, such as a single race, might not be detected.
Incidence rates (per 100,000 women) and standard errors for ductal and lobular breast carcinomas, and endometrioid /endometrial carcinomas in women over 50 years were obtained from the Surveillance, Epidemiology, and End Results (SEER) database 1992–2012. From the Medical Expenditure Panel Survey 1996–2012 weighted counts and standard errors of hormone replacement therapy (HRT) prescriptions for women over 50 years were obtained. Using the National Hospital Discharge Survey (NHDS), 1996–2010 weighted counts and standard errors of femoral neck fractures, total hip replacements, acute myocardial infarctions, and cerebral infarctions were obtained for 50+ year men and women. Weighted counts and standard errors were divided by US census figures and multiplied by 100,000. Joinpoint regression was used to analyze rates.
Main Results
Beginning 2001, HRT prescription rates dropped dramatically, 2001–2012 AAPC -14.9 (95% CI -17.4, -12.4). Breast cancer rates, which began to decline in 1999, increased after 2003; 2012 rates were similar to those seen in 2001 for both ductal, AAPC 0.1 (-0.4, 0.6) and lobular, AAPC 0.5 (-0.4, 1.5), carcinoma. Endometrial carcinoma rates increased, 2001–2012 AAPC 3.5 (3.1, 3.8), arguing against a negative effect of HRT discontinuation of endometrial carcinoma. Tests for parallelism failed to detect APC differences among genders for femoral neck fractures (P = 0.24), for total hip replacements (P = 0.11), for myocardial infarctions (P = 0.10), or for cerebral infarctions (P = 0.19), precluding any assignment of general effect on these disorders by HRT.
Using SEER data, we demonstrated that changes in breast cancer rates cannot be explained by HRT prescription rate changes.
PMCID: PMC4575090  PMID: 26384022
4.  Treatment of Hepatic Epithelioid Hemangioendothelioma: Finding Uses for Thalidomide in a New Era of Medicine 
Hepatic epithelioid hemangioendothelioma (HEH) is extremely rare, occurring in 1 to 2 per 100,000, with chemotherapy options not well defined. Our case involved a 49-year-old female who had hepatic masses and metastasis to the lungs with a liver biopsy revealing HEH. After developing a rash from sorafenib, thalidomide was started with the progression of disease stabilized. Resection is only an option in 10% of the cases; therefore, chemotherapy is the only line of treatment. Newer chemotherapy alternatives are targeting angiogenesis via the vascular endothelial growth factor. Thalidomide was first used as an antiemetic, but, sadly, soon linked to phocomelia birth defects. Given the mechanism of action against angiogenesis, thalidomide has a valid role in vascular tumors. In conclusion, the use of thalidomide as chemotherapy is novel and promising, especially in the setting of a rare vascular liver tumor such as HEH.
PMCID: PMC4488146  PMID: 26167310
5.  Odds of death after glioblastoma diagnosis in the United States by chemotherapeutic era 
Cancer Medicine  2014;3(3):660-666.
Bevacizumab (BZM) and temozolomide (TMZ) have been shown to be beneficial in the treatment of patients with glioblastoma. We sought evidence for the benefit of BZM in the general patient population at large. The Surveillance, Epidemiology, and End Results SEER database was queried for patients diagnosed with glioblastoma between 2000 and 2009, divided into a pre-TMZ era (January 2000–June 2003), a transitional era (July 2003–March 2005), a TMZ era (April 2005–October 2007), and a BZM-TMZ era (November 2007–December 2009). Binomial logit regression analyzed odds of death, taking into account age at diagnosis, tumor size, gender, race, marital status, radiotherapy, and extensive surgery. Compared with the pre-TMZ era, odds of death were decreased in the TMZ era by 12% (97.5% CI [confidence interval] 3–20%) 6 months after diagnosis and 36% (30–42%) a year after diagnosis; corresponding values for BZM-TMZ were 31% (24–37%) and 50% (45–55%). For era comparisons, decreases in odds of death were larger at 12 than 6 months; the opposite was true for extensive surgery and radiotherapy (P < 0.025, Wald χ2 test, for each analysis). For both 6 and 12 month comparisons, odds of death in the BZM-TMZ era were lower than in the TMZ era (P < 0.025, Wald χ2 test, for each analysis). The results provide evidence that TMZ positively impacted survival of glioblastoma patients and that the addition of BZM further improved survival, this lends support to the addition of BZM to the chemotherapeutic armamentarium. Evaluation of odds of death is an attractive alternative to Cox regression when proportional hazards assumptions are violated and follow-up is good.
PMCID: PMC4101757  PMID: 24610705
Bevacizumab; glioblastoma; odds of death; population database; SEER; temozolomide
6.  Osteoclastic giant cell tumor of the pancreas☆ 
Pancreatic giant cell tumors are rare, with an incidence of less than 1% of all pancreatic tumors. Osteoclastic giant cell tumor (OGCT) of the pancreas is one of the three types of PGCT, which are now classified as undifferentiated carcinoma with osteoclast-like giant cells.
The patient is a 57 year old woman who presented with a 3 week history of epigastric pain and a palpable abdominal mass. Imaging studies revealed an 18 cm × 15 cm soft tissue mass with cystic components which involved the pancreas, stomach and spleen. Exploratory laparotomy with distal pancreatectomy, partial gastrectomy and splenectomy was performed. Histology revealed undifferentiated pancreatic carcinoma with osteoclast-like giant cells with production of osteoid and glandular elements.
OGCT of the pancreas resembles benign-appearing giant cell tumors of bone, and contain osteoclastic-like multinucleated cells and mononuclear cells. OGCTs display a less aggressive course with slow metastasis and lymph node spread compared to pancreatic adenocarcinoma. Due to the rarity of the cancer, there is a lack of prospective studies on treatment options. Surgical en-bloc resection is currently considered first line treatment. The role of adjuvant therapy with radiotherapy or chemotherapy has not been established.
Pancreatic giant cell tumors are rare pancreatic neoplasms with unique clinical and pathological characteristics. Osteoclastic giant cell tumors are the most favorable sub-type. Surgical en bloc resection is the first line treatment. Long-term follow-up of patients with these tumors is essential to compile a body of literature to help guide treatment.
PMCID: PMC3980420  PMID: 24631915
Giant cell; Pancreas; Osteoclastic; CEA, carcinoembryonic antigen; cGy, centigray; CT, computerized tomography; GCT, giant cell tumor; MV, megavolts; OGCT, osteoclastic giant cell tumor; PD, pancreaticoduodenectomy; PR, pancreatic resection; PGCT, pleomorphic giant cell tumor; RFA, radio frequency ablation; RT, radiotherapy
7.  Outcomes for patients who are diagnosed with breast and endometrial cancer 
Oncology Letters  2013;6(4):1103-1107.
The present study sought to determine the survival outcomes for women diagnosed with breast and endometrial cancer. Using SEER data, a population-based cohort study of women diagnosed with breast and endometrial cancer was conducted. Kaplan-Meier survival curves were created for disease-specific survival rates. A total of 2,027 women diagnosed with breast and endometrial cancer were identified. Of these, 1,296 (63.9%) developed breast cancer first and 731 (36.1%) developed endometrial cancer first. Regional lymph node involvement was significantly more common with a breast cancer diagnosis [522 (25.8%) women] compared with an endometrial cancer diagnosis [87 (4.3%) women] (P<0.05). Factors associated with decreased survival included a high tumor grade in endometrial cancer, nodal positivity and estrogen receptor-negative breast cancer (P<0.05 for each). There were 83 (4.1%) mortalities due to breast cancer, 63 (3.1%) mortalities due to endometrial cancer and 178 (8.8%) mortalities due to other causes (P<0.05). In conclusion, for women diagnosed with breast and endometrial cancer, the cumulative risk of mortality at five years following the second cancer diagnosis is nearly four times more likely to be due to breast cancer than endometrial cancer.
PMCID: PMC3796420  PMID: 24137471
breast cancer; endometrial cancer; survival
8.  Serum albumin alters the expression of iron-controlled genes in Pseudomonas aeruginosa 
Microbiology  2012;158(Pt 2):353-367.
Pseudomonas aeruginosa, which causes serious infections in immunocompromised patients, produces numerous virulence factors, including exotoxin A and the siderophore pyoverdine. As production of these virulence factors is influenced by the host environment, we examined the effect serum has on global transcription within P. aeruginosa strain PAO1 at different phases of growth in an iron-deficient medium. At early exponential phase, serum significantly enhanced expression of 138 genes, most of which are repressed by iron, including pvdS, regA and the pyoverdine synthesis genes. However, serum did not interfere with the repression of these genes by iron. Serum enhanced regA expression in a fur mutant of PAO1 but not in a pvdS mutant. The serum iron-binding protein apotransferrin, but not ferritin, enhanced regA and pvdS expression. However, in PAO1 grown in a chemically defined medium that contains no iron, serum but not apotransferrin enhanced pvdS and regA expression. While complement inactivation failed to eliminate this effect, albumin absorption reduced the effect of serum on pvdS and regA expression in the iron-deficient medium chelexed tryptic soy broth dialysate. Additionally, albumin absorption eliminated the effect of serum on pvdS and regA expression in the chemically defined medium. These results suggest that serum enhances the expression of P. aeruginosa iron-controlled genes by two mechanisms: one through apotransferrin and another one through albumin.
PMCID: PMC3352286  PMID: 22053004
9.  Sonographic and Clinical Features of Upper Extremity Deep Venous Thrombosis in Critical Care Patients 
Background-Aim. Upper extremity deep vein thrombosis (UEDVT) is an increasingly recognized problem in the critically ill. We sought to identify the prevalence of and risk factors for UEDVT, and to characterize sonographically detected thrombi in the critical care setting. Patients and Methods. Three hundred and twenty patients receiving a subclavian or internal jugular central venous catheter (CVC) were included. When an UEDVT was detected, therapeutic anticoagulation was started. Additionally, a standardized ultrasound scan was performed to detect the extent of the thrombus. Images were interpreted offline by two independent readers. Results. Thirty-six (11.25%) patients had UEDVT and a complete scan was performed. One (2.7%) of these patients died, and 2 had pulmonary embolism (5.5%). Risk factors associated with UEDVT were presence of CVC [(odds ratio (OR) 2.716, P = 0.007)], malignancy (OR 1.483, P = 0.036), total parenteral nutrition (OR 1.399, P = 0.035), hypercoagulable state (OR 1.284, P = 0.045), and obesity (OR 1.191, P = 0.049). Eight thrombi were chronic, and 28 were acute. We describe a new sonographic sign which characterized acute thrombosis: a double hyperechoic line at the interface between the thrombus and the venous wall; but its clinical significance remains to be defined. Conclusion. Presence of CVC was a strong predictor for the development of UEDVT in a cohort of critical care patients; however, the rate of subsequent PE and related mortality was low.
PMCID: PMC3359658  PMID: 22655181
10.  Sonographic Lobe Localization of Alveolar-Interstitial Syndrome in the Critically Ill 
Introduction. Fast and accurate diagnosis of alveolar-interstitial syndrome is of major importance in the critically ill. We evaluated the utility of lung ultrasound (US) in detecting and localizing alveolar-interstitial syndrome in respective pulmonary lobes as compared to computed tomography scans (CT). Methods. One hundred and seven critically ill patients participated in the study. The presence of diffuse comet-tail artifacts was considered a sign of alveolar-interstitial syndrome. We designated lobar reflections along intercostal spaces and surface lines by means of sonoanatomy in an effort to accurately localize lung pathology. Each sonographic finding was thereafter grouped into the respective lobe. Results. From 107 patients, 77 were finally included in the analysis (42 males with mean age = 61 ± 17 years, APACHE II score = 17.6 ± 6.4, and lung injury score = 1.0 ± 0.7). US exhibited high sensitivity and specificity values (ranging from over 80% for the lower lung fields up to over 90% for the upper lung fields) and considerable consistency in the diagnosis and localization of alveolar-interstitial syndrome. Conclusions. US is a reliable, bedside method for accurate detection and localization of alveolar-interstitial syndrome in the critically ill.
PMCID: PMC3357508  PMID: 22645669
11.  Derivation and validation of murine histologic alterations resembling asthma, with two proposed histologic grade parameters 
BMC Immunology  2009;10:58.
The objective was to define murine histologic alterations resembling asthma in a BALB/c OVA model and to suggest grading criteria. Identified were six salient histologic findings in lungs with putative allergic inflammation: 1) bronchoarterial space inflammation; 2) peri-venular inflammation; 3) inflammation about amuscular blood vessels; 4) inter-alveolar space inflammation, not about capillaries; 5) pleural inflammation; and 6) eosinophils within the inflammatory aggregates. An initial study comprised six groups of twelve mice each: 1) stressed, control; 2) stressed, sensitized; 3) stressed, challenged; 4) not physically stressed, control; 5) not physically stressed, sensitized; 6) not physically stressed, challenged. A second study comprised four experimental groups of twenty mice each: 1) stressed, control; 2) stressed, challenged; 3) not physically stressed, control; 4) not physically stressed, challenged. A third study evaluated two grading criteria, 1) the proportion of non-tracheal respiratory passages with inflammatory aggregates and 2) mitoses in the largest two non-tracheal respiratory passages, in five groups of five mice each, evaluated at different times after the last exposure.
The first study suggested the six histological findings might reliably indicate the presence of alterations resembling asthma: whereas 82.4% of mice with a complete response had detectable interleukin (IL)-5, only 3.8% of mice without one did; whereas 77.8% of mice with a complete response were challenged mice, only 6.7% of mice without complete responses were. The second study revealed that the six histological findings provided a definition that was 97.4% sensitive and 100% specific. The third study found that the odds of a bronchial passage's having inflammation declined 1) when mitoses were present (OR = 0.73, 0.60 - 0.90), and 2) with one day increased time (OR = 0.75, 0.65 - 0.86).
A definition of murine histologic alterations resembling asthma in the BALB/c OVA mouse was developed and validated. The definition will be of use in experiments involving this model to ensure that all mice said to have undergone an asthmatic attack did indeed reveal allergic pulmonary inflammation. Proposed grading criteria should be further evaluated with additional studies using physiologic measures of attack severity and increased airway resistance.
PMCID: PMC2777149  PMID: 19878549
12.  Pancreas Cancer Survival in the Gemcitabine Era 
Clinical Medicine. Oncology  2008;2:405-413.
After multiple positive studies, gemcitabine, approved for the treatment of pancreas cancer by the FDA in 1977, became standard of care. Whether this therapeutic advance has translated into longer survival for pancreas cancer patients in general has not been established. This study, derived from SEER (Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute) data, compared the survival experiences of the gemcitabine (1998–2004) and pre-gemcitabine (1988–1997) eras for 7,151 patients who had metastatic disease and did not undergo extirpative surgery, 14,369 patients who had not undergone surgery and had metastases, 5,042 patients who had undergone surgery and did not have metastases, and 5,011 patients who had undergone surgery and had metastases. Calculated survival time ratios (TR) were adjusted for radiotherapy history, grade, nodal status, loco-regional extent of disease, age, race, and gender. For those who did not undergo extirpative surgery, improvements in survival in the gemcitabine era (1998–2004) versus the prior time period (1988–1997) seen for patients with metastatic cancer (TR = 1.20, 95% c.i. 1.15–1.25) were not seen for those without metastatic cancer (TR = 1.05, 95% c.i. 1.00–1.15). For those who did undergo extirpative surgery, improvements were much more dramatic for those with metastatic cancer (TR = 1.61, 95% c.i. 1.45–1.80) than those without metastases (TR = 1.23, 95% c.i. 1.15–1.31). The results are consistent with the notion that the promising findings with respect to gemcitabine in the controlled clinical trials have found expression in the general population of patients with pancreas cancer.
PMCID: PMC3161658  PMID: 21892307
gemcitabine; pancreas cancer; survival; metastatic disease
13.  Combined Hepatocellular Cholangiocarcinomas; Analysis of a Large Database 
Combined hepatocellular cholangiocarcinoma (combined tumor) has been described as either a variant of hepatoma or a variant of cholangiocarcinoma. Prior studies evaluated fewer than 50 patients with combined tumors, precluding multivariate analyses. Posited was the notion that analysis of a large database would yield more definite answers.
This study used SEER (Surveillance, Epidemiology, and End Results Program of the National Cancer Institute) to analyze 282 combined tumors, 2,035 intrahepatic cholangiocarcinomas, and 19,336 hepatomas between the years 1973–2003. Multinomial logit regression calculated point estimates and 95% confidence intervals (c.i.) for relative risk (rr). Cox regression calculated point estimates and 95% confidence intervals (c.i.) for hazard ratios (ĥ).
Men less often had cholangiocarcinomas than they had combined tumors (rr = 0.63, c.i. = 0.49–0.81). Hepatomas less often than combined tumors presented with distant spread (rr = 0.56, c.i. = 0.43–0.72). Men (rr = 1.50, c.i. = 1.17–1.93) and patients with a known Asian or Pacific birthplace (rr = 2.36, c.i. = 1.56–3.56) more often had hepatomas than they had combined tumors. Among patients not known to have an Asian/Pacific birthplace, a diagnosis of cholangiocarcinoma (ĥ = 0.72, c.i. = 0.63–0.82) or hepatoma (ĥ = 0.75, c.i. = 0.66–0.86) provided a better prognosis than did a diagnosis of combined tumor.
Combined tumors differ from hepatomas and cholangiocarcinomas in terms of distribution and survival patterns in the population; they should be considered neither cholangiocarcinomas nor hepatomas.
PMCID: PMC3160004  PMID: 21876650
hepatoma; cholangiocarcinoma; combined hepatocellular cholangiocarcinoma; multinomial logit; survival analysis
14.  Modulation of gastrointestinal permeability of low-molecular-weight heparin by l-arginine: in-vivo and in-vitro evaluation 
l-Arginine is the principal physiological precursor of nitric oxide (NO, a key neurotransmitter) that plays a versatile role in the physiology of the gastrointestinal tract. In this study, the efficacy of l-arginine in enhancing intestinal absorption of ardeparin, a low-molecular-weight heparin (LMWH) was investigated in Caco-2 cell monolayers and a rat model. Regional permeability studies using rat intestine were performed using a modified Ussing chamber. Cell viability in the presence of various concentrations of enhancer was determined by MTT assay. Furthermore, the eventual mucosal epithelial damage was histologically evaluated. LMWH formulated with l-arginine was administered orally to mate Sprague-Dawley rats and the absorption of LMWH was determined by measuring plasma anti-factor Xa activity. Higher ardeparin in-vitro permeability (~3 fold) compared with control was observed in the presence of 2% l-arginine. Regional permeability studies indicated predominant absorption in the colon region. Cell viability studies showed no significant cytotoxicity below 0.8% l-arginine. The oral bioavailability of ardeparin formulated with l-arginine (250 mg kg−1) was increased by ~2 fold compared with control. The formulation was well tolerated by the rats and no abnormal histopathological findings were observed in intestinal tissues of rats exposed to l-arginine. These results suggest that l-arginine may be useful in enhancing the intestinal absorption of LMWHs.
PMCID: PMC1557380  PMID: 16640827
15.  Zonula occludens toxin synthetic peptide derivative AT1002 enhances in vitro and in vivo intestinal absorption of low molecular weight heparin 
Journal of drug targeting  2006;14(5):321-329.
Zonula occludens toxin (Zot) is an enterotoxin obtained from the bacterium vibrio cholerae that has been shown to reversibly and safely open the tight junctions and enhance paracellular transport. AT1002 is a novel synthetic hexapeptide derived from Zot. The hypothesis to be tested in this study is that AT1002 enhances the oral absorption of ardeparin, a low molecular weight heparin (LMWH). To test this hypothesis, drug transport through Caco-2 cell monolayers was monitored in the presence and absence of AT1002. Regional permeability studies using rat intestine were performed. Cell viability in the presence of various concentrations of enhancer was determined. The absorption of ardeparin after oral administration in rats was measured by anti-factor Xa assay. Furthermore, the eventual mucosal and epithelial damage was histologically evaluated. Higher ardeparin permeability (~2-fold) compared to control was observed in the presence of 0.025% of AT1002. Regional permeability studies revealed that the permeability of ardeparin across the duodenal membrane was improved by the AT1002. Cell viability studies showed no significant cytotoxicity below 0.0028% of AT1002. In the presence of 100 μg/kg of AT1002, ardeparin oral bioavailability was significantly increased (Frelative/s.c ~ 20.5%). Furthermore, AT1002 at a dose of 100 μg/kg did not induce any observable morphological damage on gastrointestinal (GI) tissues in vivo. These in vivo and in vitro results suggest that the co-administration of LMWH with AT1002 may be a useful delivery strategy to increase its permeability and hence oral absorption.
PMCID: PMC1994914  PMID: 16882552
AT1002; low molecular weight heparin; enhancer; oral delivery; zonula occludens toxin
16.  Oral delivery of low-molecular-weight heparin using sodium caprate as absorption enhancer reaches therapeutic levels 
Journal of drug targeting  2005;13(10):573-583.
The primary objective of this study was to evaluate sodium caprate as an oral penetration enhancer for low molecular weight heparin (LMWH), ardeparin. In vitro studies using Caco-2 cell monolayer indicated that 0.0625% of sodium caprate gave approximately 2-fold enhancement of ardeparin compared to negative control with almost 100% cell survival as evaluated by MTT cytotoxicity assay. In vivo studies in rats with ardeparin (1200 IU/kg) and sodium caprate (100 mg/kg) led to a relative bioavailability of 27% with plasma anti-factor Xa levels within the therapeutic range (> 0.2 IU/ml). Moreover, under these conditions, histological examination provided evidence that there was no damage to the gastrointestinal wall. Regional permeability studies using rat intestine indicated the colon as the region of maximum permeation. These results suggest that, at the dose administered, sodium caprate acts as a relatively safe and efficient absorption enhancer in the quest for alternatives for the oral delivery of LMWH.
PMCID: PMC1993550  PMID: 16390818
Sodium caprate; low molecular weight heparin; Caco-2 cell monolayer; absorption enhancer; ardeparin; oral absorption
17.  Evaluation of the Oral Bioavailability of Low Molecular Weight Heparin Formulated With Glycyrrhetinic Acid as Permeation Enhancer 
Drug development research  2006;67(2):166-174.
Low molecular weight heparin (LMWH) is the agent of choice for anticoagulant therapy and prophylaxis of thrombosis and coronary syndromes. However, its therapeutic use is limited due to poor oral bioavailability. The aim of this study was to investigate the oral delivery of LMWH, ardeparin formulated with 18-β glycyrrhetinic acid (GA), as an alternative to currently used subcutaneous (sc) delivery. Drug transport through Caco-2 cell monolayers was monitored in the presence and absence of GA by scintillation counting and transepithelial electrical resistance. Regional permeability studies using rat intestine were performed using a modified Ussing chamber. Cell viability in the presence of various concentrations of enhancer was determined by MTT assay. The absorption of ardeparin after oral administration in rats was measured by an anti-factor Xa assay. Furthermore, the eventual mucosal epithelial damage was histologically evaluated. Higher ardeparin permeability (~7-fold) compared to control was observed in the presence of 0.02 % GA. Regional permeability studies indicated predominant absorption in the duodenal segment. Cell viability studies showed no significant cytotoxicity below 0.01 % GA. Ardeparin oral bioavailability was significantly increased (Frelative/S.C. = 13.3%) without causing any damage to the intestinal tissues. GA enhanced the oral absorption of ardeparin both in vitro and in vivo. The oral formulation of ardeparin with GA could be absorbed in the intestine. These results suggest that GA may be used as an absorption enhancer for the oral delivery of LMWH.
PMCID: PMC1948842  PMID: 17710191
glycyrrhetinic acid; LMWH; Caco-2 cells; absorption enhancer; oral delivery
18.  Different regression equations relate age to the incidence of Lauren types 1 and 2 stomach cancer in the SEER database: these equations are unaffected by sex or race 
BMC Cancer  2006;6:65.
Although impacts upon gastric cancer incidence of race, age, sex, and Lauren type have been individually explored, neither their importance when evaluated together nor the presence or absence of interactions among them have not been fully described.
This study, derived from SEER (Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute) data, analyzed the incidences of gastric cancer between the years 1992–2001. There were 7882 patients who had developed gastric cancer. The total denominator population was 145,155, 669 persons (68,395,787 for 1992–1996, 78,759,882 for 1997–2001). Patients with multiple tumors were evaluated as per the default of the SEER*Stat program. 160 age-, five year period (1992–1996 vs 1997–2001)-, sex-, race (Asian vs non-Asian)-, Lauren type- specific incidences were derived to form the stratified sample evaluated by linear regression. (160 groups = 2 five year periods × 2 race groups × 2 sexes × 2 Lauren types × 10 age groups.) Linear regression was used to analyze the importance of each of these explanatory variables and to see if there were interactions among the explanatory variables.
Race, sex, age group, and Lauren type were found to be important explanatory variables, as were interactions between Lauren type and each of the other important explanatory variables. In the final model, the contribution of each explanatory variable was highly statistically significant (t > 5, d.f. 151, P < 0.00001). The regression equation for Lauren type 1 had different coefficients for the explanatory variables Race, Sex, and Age, than did the regression equation for Lauren type 2.
The change of the incidence of stomach cancer with respect to age for Lauren type 1 stomach cancer differs from that for Lauren type 2 stomach cancers. The relationships between age and Lauren type do not differ across gender or race. The results support the notion that Lauren type 1 and Lauren type 2 gastric cancers have different etiologies and different patterns of progression from pre-cancer to cancer. The results should be validated by evaluation of other databases.
PMCID: PMC1479359  PMID: 16539725
19.  The incidence of lower mid-trunk hyperpigmentation (linea nigra) is affected by sex hormone levels. 
The incidence of linea nigra was studied in 1,550 Nigerians of both sexes and of different age groups and among pregnant women and men with benign and malignant prostatic diseases over a nine-month period. From the study, it would appear that linea nigra increases in incidence from the age group 0-15 years (31.4%) to the age group 16-30 years (47.3%) before starting to fall in clinically normal individuals >30 years to 19.2%. For age groups 0-5 years, 6-10 years and 16-30 years, females more often than males have a linea nigra. For age group 11-15, males are equally as likely as females to have a linea nigra. The results suggest that women over 30 are more likely to have a linea nigra than men, but there are too few patients to make a definite statement, given the number of statistical tests performed. Pregnant women far more often have a linea nigra than nonpregnant women of the same age. The findings suggest that the likelihood of having a linea nigra depends on the level of sex hormones. This means that changes in the levels of hormones, either due to disease or drugs, may be reflected in changes in the incidence of a linea nigra. If this finding is confirmed, the linea nigra may serve as a convenient, noninvasive, free marker of alterations in sex hormones.
PMCID: PMC2569341  PMID: 15926645
20.  Family poverty accounts for differences in lower-extremity amputation rates of minorities 50 years old or more with diabetes. 
Rates of leg amputations in diabetics are known to differ among racial/ethnic groups, but the relationship between family poverty and the risk of amputation has not been fully addressed. One-hundred-seven diabetic patients, all 50 or more years old and all from ZIP code tabulation area 778, underwent their first amputations at one hospital. Linear regression evaluated differences in age and atherosclerosis severity among African-American, Hispanic-American and other patients. chi2 statistics evaluated differences among African-American, Hispanic-American and other patients, with respect to sex and type of amputation. chi2 statistics evaluated differences among fractions of African- American, Hispanic-American and other patients, with respect to those residents 50 years old and older and those of poor families. Patient groups did not differ in regard to age, atherosclerosis severity, sex or type of amputation (P>0.05). The percents who were African-American, Hispanic-American, and other (33%, 21%, and 47%, respectively) differed markedly from those of persons 50 or more years old [13%, 7%, and 79%, (w=0.81, P<0.00001)] and mirrored those of poor families [37%, 19%, and 44% (w=0.08, P>0.05)]. Family poverty accounts for differences in diabetic amputation rates of African Americans, Hispanic Americans and other persons 50 or more years old.
PMCID: PMC2568625  PMID: 15779497

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