BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts.

BACKGROUND: Germline mutations of the BRCA tumour suppressors have been associated with increased risk of pancreatic cancer. Clinical evidence suggests that these patients may be more sensitive to treatment with cisplatin. As the frequency of germline BRCA mutations is low, definitive experimental data to support the clinical observations are still missing. METHODS: We tested gemcitabine and cisplatin sensitivity of four BRCA1 and BRCA2 mutant and three BRCA1 and BRCA2 wild-type (WT) patient-derived pancreatic cancer xenografts. RESULTS: We observed treatment sensitivity to gemcitabine and cisplatin in the BRCA WT and mutant models. The BRCA1 and BRCA2 mutant xenografts were significantly more sensitive to cisplatin although these models also showed sensitivity to gemcitabine. The BRCA1 and BRCA2 WT models showed sensitivity to gemcitabine but not cisplatin. Treatment sensitivity in the xenograft models closely resembled treatment response in the corresponding patients. DISCUSSION: We have characterised a panel of xenografts derived from pancreatic cancer patients carrying germline BRCA mutations, and shown that their genetic features resemble the patient donor. Our results support further clinical testing of treatment regimens combining gemcitabine and platinum drugs in this patient population, as well as preclinical research aiming to identify mechanisms of cisplatin resistance in BRCA mutant pancreatic cancers.

Prevalence of Dirofilaria immitis (Nematoda: Filarioidea) in mosquitoes from northeast Arkansas, the United States.

A mosquito survey was conducted to identify which species of mosquitoes carry Dirofilaria immitis (Leidy) (Nematoda: Filarioidea), dog heartworm, in northeast Arkansas. Using polymerase chain reaction, mosquitoes were analyzed for D. immitis, Dirofilaria repens Railliet & Henry, and Acanthocheilonema dracunculoides Cobbold. Mosquitoes were collected from April to October 2009 using black light ultraviolet traps baited with dry ice. Sixteen mosquito species were identified. D. immitis was identified in nine mosquito species, which included Aedes vexans (Meigen), Anopheles quadrimaculatus Say, Anopheles punctipennis (Say), Culex pipiens quinquefasciatus Say, Culex erraticus (Dyer & Knab), Culiseta inornata (Williston), Psorophora columbiae (Dyer & Knab), Psorophora ferox (Humboldt), and Psorophora howardii Coquillett. No D. repens or A. dracunculoides DNA was amplified. Of the 1,212 mosquito pools tested, 7.3% were positive for D. immitis. Frequency of D. immitis infections from six collection sites ranged from 2.1 to 19.4%. Ae. vexans and An. quadrimaculatus were the two most abundant species, composing 58.7 and 23.7% of the total mosquitoes collected, with 9.6 and 6.9% of pools positive for D. immitis, respectively. To investigate localized vector infection rates of D. immitis, mosquitoes were collected from inside the kennel of a heartworm-positive dog. Of the 114 mosquitoes collected, 84 (73.7%) were positive for D. immitis. The frequency of D. immitis-infected mosquitoes collected near a heartworm-positive dog was considerably higher than in the original six collection sites, suggesting a single heartworm-positive dog potentially increases infection pressure on susceptible animals sharing mosquito exposure.

Subjective satisfaction and quality of life in patients prior to listing for liver transplantation.

OBJECTIVES: Differences in health-related quality of life (HR-QoL) perception between alcohol abusing and non-substance-dependent subjects with liver cirrhosis could depend on differences in personality profile and influence management of patients awaiting liver transplant. METHODS: We compared the perceptions of disease state in 78 male patients of similar disease severity divided into 2 groups based on etiology of cirrhosis: 47% had alcoholic cirrhosis, and 53% had hepatitis C virus(HCV)-related cirrhosis without alcohol abuse. Patients' perception of disease state was determined using the SAT-P questionnaire (a self-administered questionnaire that provides a global assessment of perceived HR-QoL and subjective well-being). The assessment yields 2 scales: an analytic scale based on 32 variables and a synthetic scale based on 5 factors. RESULTS: In patients with alcohol-related disease, ''psychological function'' was found to be more impaired,while ''sleep, diet, and free time'' was less impaired compared with subjects with HCV-related cirrhosis, suggesting dysfunction related to substance abuse with personality disturbance. CONCLUSIONS: The perception of disease state is different in alcohol-abusing patients with cirrhosis compared with those with cirrhosis unrelated to alcohol.

Trypanocidal structure-activity relationship for cis- and trans-methylpluviatolide.

The trypanocidal activity of racemic mixtures of cis- and trans-methylpluviatolides was evaluated in vitro against trypomastigote forms of two strains of Trypanosoma cruzi, and in the enzymatic assay of T. cruzi gGAPDH. The cytotoxicity of the compounds was assessed by the MTT method using LLC-MK2 cells. The effect of the compounds on peroxide and NO production were also investigated. The mixture of the trans stereoisomers displayed trypanocidal activity (IC50 approximately 89.3 microM). Therefore, it was separated by chiral HPLC, furnishing the (+) and (-)-enantiomers. Only the (-)-enantiomer was active against the parasite (IC50 approximately 18.7 microM). Despite being inactive, the (+)-enantiomer acted as an antagonistic competitor. Trans-methylpluviatolide displayed low toxicity for LLC-MK2 cells, with an IC50 of 6.53 mM. Furthermore, methylpluviatolide neither inhibited gGAPDH activity nor hindered peroxide and NO production at the evaluated concentrations.

Reliance on prothrombin time ratios causes significant errors in anticoagulation therapy.

BACKGROUND: The intensity of warfarin anticoagulation in the United States may be inappropriate if the international normalized ratio (INR) is not used, or if the international sensitivity index (ISI) of the thromboplastin is outside the range of 2.2 to 2.6. METHODS: Fifty-three hospital laboratories provided data on the sensitivity of their thromboplastin and whether they reported INR values. Additional data on thromboplastin sensitivity were obtained from 140 laboratories involved in the Stroke Prevention in Atrial Fibrillation study. The three major manufacturers of thromboplastin confirmed the range of thromboplastin sensitivity reported by the laboratories. RESULTS: Of 53 laboratories surveyed, 16 (30%) could not provide ISI data and only 11 (21%) reported INR results. Unlabeled thromboplastin was being used by 20% to 24% of laboratories, and only 8% to 20% were using thromboplastins with an ISI of 2.2 to 2.6. At the time the three manufacturers were contacted, they reported marketing thromboplastins with ISI values from 1.2 to 2.8, but none of the thromboplastins at that time had ISI values between 2.2 and 2.6. CONCLUSION: Warfarin therapy in the United States is managed inappropriately because most laboratories do not report INRs and the variability in thromboplastin sensitivity produces misleading prothrombin time ratio results. Additionally, recent research may require reexamination if INR or ISI data were not provided.

Surgical complications of carotid body tumors surgery: a review.

Carotid body tumor (CBT) is a rare neoplasm, although it represents about 65% of head and neck paragangliomas. Surgical excision is considered the appropriate therapy for CBTs. The aim of this study was to evaluate surgical outcomes on a large scale. We reviewed 19 studies between 2004 to 2014 with a total of 625 procedures. We observed a higher number of cases in women (62%). Only 3 (0,48%) deaths were reported as surgical complication. Total cranial nerve injuries were 302 (48,32%) of which 194 (31,04%) were transient and 108 (17,28%) were permanent. We found a total of 174 (27,84%) arterial injuries, most of which are external carotid artery (ECA) injuries. Cerebrovascular accident due to surgery were 15 (2,4%). We concluded that surgical resection remains the treatment of choice for these disease despite the related morbidity.

Long-term survival after curative resection for pancreatic ductal adenocarcinoma--Surgical treatment.

INTRODUCTION: Recent reports have demonstrated improvement in the 5-years serviva with resecate ductal adenocarcinoma. The aim of study is to determinate the factor influencing long-term survival after DCP. MATERIALS AND METHODS: We have critically reviewed a group of 85 patients how were admitted to our department with diagnosis of ductal adenocarcinoma of the head of pancreas between January 1974 and January 1998. RESULTS: Patients were stratified according to stage using TNM classification; in stage I 31 patients with 5 T1aN0M0 disease, 11 patients with T1bN0M0 and 15 patients T2N0M0 disease. By contrast, in stage III 54 patients with 48 patients T2N1M0 and 6 patients with T3N1M0. Tumour size was recorded for 72 patients with a median of 3.8 cm. The R1 dissection was performed in 67 patients. The R2 resection was performed in 18 patients. In our series we verified and analysed the histopathologic features of 5 patients with 15-years survival (5.8%). The features regard age, male or female, tumours size, stage and positive lymph node resection. DISCUSSION: We found a specifically subset of patients where the combination of prognostic factors, in particular, negative surgical margins R0, tumour size ≤ 30 mm and the absence of lymph node metastasis independently reduced the mortality indicating that earlier tumour detection and histologically curative resection are important factors contributing to long term survival and healing of ductal adenocarcinoma of the head of the pancreas.

Potential warfarin-ciprofloxacin interaction in patients receiving long-term anticoagulation.

This study prospectively evaluated the potential interaction between the oral anticoagulant warfarin and the quinolone antimicrobial agent ciprofloxacin. After a 10-day placebo lead-in phase, 16 patients stabilized with long-term warfarin therapy were randomized to receive ciprofloxacin 500 mg or a matching placebo twice/day for 10 days. International normalized ratios (INRs) measured by both standard laboratory analysis and by Coumatrak (finger-stick) methods were evaluated at 3- to 5-day intervals. No patient experienced a significant increase in INR. No patient experienced a bleeding event. These data support the fact that a warfarin-ciprofloxacin interaction does not routinely occur at this dosage and duration of ciprofloxacin therapy.

A statistical and clinical evaluation of fingerstick and routine laboratory prothrombin time measurements.

STUDY OBJECTIVE: To compare prothrombin time measurements by fingerstick and routine laboratory methods. DESIGN: Prospective cohort study. SETTING: University-affiliated anticoagulation clinic. PATIENTS: Thirty-three patients receiving warfarin with stable anticoagulation for 3 months preceding the two studies. INTERVENTIONS: Groups 1 (17 patients) and 2 (16 patients) provided 150 and 125 paired samples, respectively, for fingerstick and routine laboratory analysis. The fact that no patient required a dosage change allowed for a clinical assessment. MEASUREMENTS AND MAIN RESULTS: Correlation and agreement between methods were good in group 1 but poor in group 2. Fingerstick results were less variable (smaller standard deviation and smaller coefficient of repeatability) in both groups. By analysis of discrepant pairs (25 in group 1, 63 in group 2), the routine laboratory results indicated dosage changes erroneously more often than did the fingerstick method. CONCLUSIONS: In these two trials, the fingerstick system was superior to the routine laboratory method in that it was more reliable (less variability and more repeatable) and less likely to indicate dosage changes erroneously.

Peptic ulcer inheritance in patients with elevated serum pepsinogen group A levels and without infection of Helicobacter pylori.

BACKGROUND: Peptic ulcer has multifactorial aetiology, including genetic factors. We have identified a family with pepsinogen Group A levels higher than normal, with a high prevalence of ulcer disease and a low prevalence of Helicobacter pylori infection. AIMS: Performing linkage analysis in the identified family PATIENTS AND METHODS: We examined the segregation of pepsinogens with microsatellite dinucleotide repeat DNA markers along chromosome 11 (D11S480, PYGM) for pepsinogen Group A and along chromosome 6 [D6S105, D6S 1610, TRMI) for pepsinogen Group C. RESULTS: In markers examined along chromosome 11, linkage analysis provided no evidence for significant causal mutation but, controlling for some risk factors we observed that the probability of falling ill, increases. The linkage analysis along chromosome 6 for pepsinogen Group C did not show a uniform genetic profile. CONCLUSIONS: This study evaluates the hypothesis of peptic ulcer inheritance at least in a small group of patients without the common risk factors.

Compared kinetics of 2-(2,3-dihydro-5-acetoxy-4,6,7-trimethylbenzofuranyl) acetic acid (IRFI 016) and its active metabolite 2-(2,3-dihydro-5-hydroxy-4,6,7-trimethylbenzofuranyl) acetic acid (IRFI 005) in plasma and bronchial alveolar liquid in mice.

The concentration of 2-(2,3-dihydro-5-acetoxy-4,6,7-trimethylbenzofuranyl) acetic acid (IRFI 016) and its active metabolite 2-(2,3-dihydro-5-hydroxy-4,6,7-trimethylbenzofuranyl) acetic acid (IRFI 005) in bronchial alveolar liquid (BAL) and plasma of mice were studied. IRFI 016 and its active metabolite IRFI 005 are both present in BAL and plasma after oral administration of IRFI 016. In BAL no delay times were noted, in comparison with plasma, regarding Cmax time nor significant variation of t1/2 and the elimination constant (Kel). IRFI 016, orally administered, is very rapidly absorbed and, both in unaltered form and as its active metabolite, reaches the anatomic site where it carries out its principal pharmacological activity, according to the same kinetic course observed in plasma.

Gastric bicarbonate secretion in high-relapsing, smoking duodenal ulcer patients.

Gastric bicarbonate secretion has been evaluated by Feldman's method in 48 duodenal-ulcer patients. The relationship between smoking, clinical ulcer outcome (healing and recurrence) and bicarbonate secretion has been analysed. Heavy smokers secreted higher bicarbonate ions than did non-smokers. High-relapsing patients produced lower bicarbonate output. These preliminary data suggest that an impaired gastric bicarbonate secretion is associated with smoking, a well-known ulcer-associated factor; further-more, it may single out high-relapsing duodenal ulcer patients.

[Prevalence of surface antigens (HBsAg), surface antibody (HBsAb) and anticore antibody (HBcAb) in hospital personnel and patients with and without hepatic pathology]. / Prevalenza dell'antigene di superficie (HBsAg), dell'anticorpo di superficie (HBsAb) e dell'anticorpo anticore (HBcAb) in personale ospedaliero e in pazienti con e senza patologia epatica.

We studied hepatitis B virus surface antigen (HBsAg), surface antibody (HBsAb) and "core" antibody (HBcAb) prevalence in 166 among hospital personell and patients with and without liver disease. Results show there is a very high prevalence of hepatitis B virus markers in such populations and the presence of HBcAb in absence of the other markers varies from 6% in "high risk" subjects to 30.3% in cirrhotic patients. We conclude that HBcAb seems to be, at moment, the most sensitive serological marker either for epidemiological studies or diagnosis and, in some instances, for prognosis of hepatitis B virus liver diseases.

[Alcohol-dependent mast cell activation in ulcer]. / Attivazione delle mastcellule alcol-dipendente nella malattia ulcerosa.

Numerous studies have shown that alcohol causes both acute and chronic damage to gastroduodenal mucosa. The methods of damage differ however, and experimental studies in animals have shown that the degranulation of mast cells in gastric mucosa causes acute hemorrhagic lesions after the consumption of alcohol. It is not known whether this mechanism also operates in man. The aim of the present study was therefore to evaluate whether there is a correlation between mast-cell activation, determined by assaying tryptase levels in gastric mucosa, and the consumption of alcohol in patients with ulcerative diseases. Thirty-one patients with cicatrized ulcerative lesions (13 gastric ulcers, 18 duodenal ulcers) were included in the study. Biopsies at the level of the gastric fundus and antrum and the duodenal bulb were performed in all patients to determine tryptase levels. Biopsy material was frozen and subsequently homogenized; the enzyme was assayed in the supernatant using a radioimmunometric method. The mean daily alcohol consumption was calculated in clinical terms for each patient over the past 5 years and patients were subdivided into non-drinkers and moderate (< 60 g alcohol/day) and excessive (> 60 g alcohol/day) drinkers. It was found that tryptase concentrations were higher in the fundus compared to the gastric antrum and duodenal bulb, irrespective of alcohol consumption both in patients with gastric ulcer and duodenal ulcer. The importance of mast cells in provoking alcohol-dependent damage was studied at a gastric level. Alcohol leads to their degranulation and therefore contributes to the formation of gastric lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug interactions.

Drug-drug interactions are most likely to occur in patients receiving multiple medications and with drugs that have a narrow therapeutic window. The outcome may be harmful or beneficial, but the relative incidence of clinically important adverse drug interactions remains unknown. Many interactions may be minimized or avoided; the prescriber must be aware of this potential in order to take the necessary precautions.

Modern diagnostic imaging of lumbar spondylosis.

The authors retrospectively analyzed 205 patients affected with low back pain and submitted to conventional radiology, CT scan, MR. The purpose of the study was that of gaining a better understanding of the mechanisms caused by the occurrence of spondylosis and its evolution. In light of the most recent literature, the authors conclude: 1) the degenerative process nearly always initiates with laceration of the anulus; 2) dysfunction of the disc then has repercussions on the posterior structures at varying times and with different modalities; 3) symptoms do not always coincide with radiological findings. Thus, the authors believe that for a more complete understanding of the etiopathogenesis and the evolution of spondylosis, further studies involving long-term follow-up of a young population, in relation to clinical and MR findings are needed. MR is the method of choice in determining disc degeneration.

The anchor nail in osteosynthesis of fractures of the humerus.

Osteosynthesis with a humeral anchor nail may be listed along with other methods of intramedullary fixation for the treatment of diaphyseal fractures. The authors report their experience with 33 cases of humeral fractures treated between July 1987 and July 1991. Results were excellent in 61% of the cases, good in 24%, and fair in 15%; no particular complications were reported. The authors believe that the anchor nail constitutes a system of osteosynthesis involving only a small amount of trauma, and allowing for positive elastic stability for the consolidation of the fracture, as well as being a sufficiently safe system so that immobilization in plaster may be avoided. When compared with other systems of intramedullary fixation, the anchor nail is more effective than the Rush nail from a mechanical point of view, and the Kuntscher nail from a biological one.

Arthroplasty in the sequelae of congenital hip dysplasia.

The authors report their experience in the surgical treatment of the sequelae of congenital hip dysplasia, more specifically, 125 arthroplasties performed in 116 patients, with specific reference to the technical difficulties encountered and the various surgical methods used. This review suggests that prosthetization yields a high percentage of good results (77%) and constant remission of pain. Nonetheless, joint function, particularly when motion was severely compromised before surgery, or when dislocation was very severe (Crowe grades III and IV), is not always restored.

Indications and limits of CT scan in prosthetic loosening.

The authors attempt to define the role of computed tomography (CT) in the study of loosened hip prosthesis. To this purpose they have studied 30 patients with clinical and/or radiographic findings of loosening, carrying out a conventional radiographic assessment and a CT scan of the hip in question, and then comparing them. They conclude that CT scan when carried out according to the correct procedures described is very useful. Despite the presence of technical artefacts due to the presence of the metal prosthesis, the test makes a considerable contribution, not so much to the diagnosis of loosening in itself, which continues to be a clinical-radiologic diagnosis, rather to the evaluation of the morphostructural states of the acetabular bone for correct planning of surgery.

Evaluation of several immunological parameters in patients with aseptic loosening of hip arthroplasty.

The authors evaluated several immunological parameters in patients with loosened hip arthroplasty in order to determine the state of sensitization with regard to the metallic constituents of the prosthesis. The results obtained by in vivo epicutaneous testing did not reveal a correlation between loosening and sensitization, as the patch test was positive in only 1 out of 16 cases examined. An evaluation of the lymphocyte subpopulation on peripheral blood demonstrated that patients with prostheses in Cr, Co, Mo, Ni alloy present significant lymphopenia, with a reduction in subpopulations CD4 and CD8 and a decrease in in vitro cytotoxic activity. The meaning of these modifications could be interpreted to be either a toxic effect products released from the implant, or as the recruitment of lymphocytes in the site of loosening, due to lymphocyte sequestration phenomena consequent to a cell-mediated hypersensitivity reaction.