Long‐Term Proton Pump Inhibitor Therapy and Falls and Fractures in Elderly Women: A Prospective Cohort Study

Proton pump inhibitors (PPIs) are widely used in the elderly. Recent studies have suggested that long‐term PPI therapy is associated with fractures in the elderly, however the mechanism remains unknown. We investigated the association between long‐term PPI therapy ≥1 year and fracture risk factors including bone structure, falls, and balance‐related function in a post hoc analysis of a longitudinal population‐based prospective cohort of elderly postmenopausal women and replicated the findings in a second prospective study of falling in elderly postmenopausal women. Long‐term PPI therapy was associated with increased risk of falls and fracture‐related hospitalizations; adjusted odds ratio (AOR) 2.17; 95% CI, 1.25–3.77; p = 0.006 and 1.95; 95% CI, 1.20–3.16; p = 0.007, respectively. In the replication study, long‐term PPI use was associated with an increased risk of self‐reported falling; AOR, 1.51; 95% CI, 1.00–2.27; p = 0.049. No association of long‐term PPI therapy with bone structure was observed; however, questionnaire‐assessed falls‐associated metrics such as limiting outdoor activity (p = 0.002) and indoor activity (p = 0.001) due to fear of falling, dizziness (p < 0.001) and numbness of feet (p = 0.017) and objective clinical measurement such as Timed Up and Go (p = 0.002) and Romberg eyes closed (p = 0.025) tests were all significantly impaired in long‐term PPI users. Long‐term PPI users were also more likely to have low vitamin B12 levels than non‐users (50% versus 21%, p = 0.003). In conclusion, similar to previous studies, we identified an increased fracture risk in subjects on long‐term PPI therapy. This increase in fracture risk in elderly women, already at high risk of fracture, appears to be mediated via increased falls risk and falling rather than impaired bone structure and should be carefully considered when prescribing long‐term PPI therapy. © 2014 American Society for Bone and Mineral Research.     

Intracellular calcium and calcineurin regulate neutrophil motility on vitronectin through a receptor identified by antibodies to integrins alphav and beta3

Buffering of intracellular calcium ([Ca2+]i) or inhibition of the calcium/calmodulin-dependent phosphatase, calcineurin, results in neutrophils being unable to detach from vitronectin with a consequent loss of motility. Treatment of [Ca2+]i-buffered or calcineurin- inhibited neutrophils with monoclonal antibodies (MoAbs) to beta3 or alphav beta3 integrins allowed neutrophils to detach and restored motility. Quantitative immunofluorescence and flow cytometry showed that MoAbs specific for beta3, alphav, or alphav beta3 integrins bind to neutrophils. Immunolocalization studies using antibodies to the highly conserved cytoplasmic domains of alphav and beta3 also identified the receptor on neutrophils. Whereas antibodies to alphav, alphav beta3, and beta3 recognized the receptor in intact cells, only the beta3 MoAb immunoprecipitated the receptor from a neutrophil cell lysate. The alpha subunit co-immunoprecipitated by the beta3 antibody reacted with an antibody to alphav by Western blot. Peptide maps of V8 protease digests showed a strong similarity in alpha and beta chains precipitated by antibodies to beta3 from neutrophils and endothelial cells. These results indicate that [Ca2+]i and calcineurin regulate neutrophil motility on vitronectin through an alphav beta3-like receptor. Although we cannot rule out the possibility that neutrophils have an isoform of alphav, such an isoform would have to be similar enough to react with alphav- and alphav beta3-specific MoAbs in intact cells.     

Plasma and urine cyclic nucleotide levels in patients with acute and chronic leukemia

Plasma and urine levels of cyclic adenosine 3',5'-monophosphate (cAMP) and of cyclic guanosine 3',5'-monophosphate (cGMP) were measured in 35 normal subjects, in 24 patients with nonneoplastic diseases (iron deficiency anemia, peptic ulcer, and cholelithiasis), and in 50 leukemic patients. The leukemic group included patients with acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. All patients were recently diagnosed and untreated, except for 5 patients with blastic transformation of chronic myelogenous leukemia who had been previously treated. There were no significant differences in plasma and urine cyclic nucleotide levels between normal subjects and patients with nonneoplastic diseases. In leukemic patients, plasma and urine cAMP levels were similar to those of normal subjects, whereas plasma and urine cGMP levels were markedly elevated. There were no significant differences in cGMP values between the various types of leukemia. After starting treatment, plasma cyclic nucleotide levels were periodically measured in 21 of the patients with acute leukemia; cGMP levels were normalized in all the 16 subjects who attained complete remission, whereas both cAMP and cGMP levels were apparently unaffected in the patients who did not respond to treatment. This suggests that plasma or urine cGMP could be used as an additional parameter to monitor the patient's response to treatment.     

8The effect of food on electrical and mechanical activity of the canine antrum

Cyclic vomiting syndrome (CVS) is an unexplained disorder characterized by recurrent attacks of nausea and vomiting. The aim of this study was to investigate the characteristics of gastric myoelectrical activity in patients meeting Rome II criteria for CVS and studied between cycles using cutaneous electrogastrography (EGG). Methods: 11 patients (6M, 5F, mean age: 31 years, range: 16–60) with CVS (5 symptomatic and 6 asymptomatic at the time of the study) underwent EGG between acute CVS attacks. EGG recordings were made for 30 minutes in the fasting state and for 60 minutes after ingestion of a caloric liquid meal (Boost, 360 kcal). Power spectral analysis methods were used to extract quantitative EGG parameters: EGG dominant frequency/power, change in postprandial EGG power, percentages of normal slow waves (2 to 4 cpm) and dysrythmias including tachygastria (slow‐wave frequency >4 cpm) and bradygastria (slow‐wave frequency <2 cpm) in each recording session. Patients were asked to score their symptoms of nausea, vomiting and abdominal pain (0 = none, 4 = constant) during both pre‐ and postprandial periods. Data are expressed as mean ± SE. Results: 7/11 demonstrated an abnormal EGG (dysrhythmia >30% in 4 patients and a decrease in postprandial EGG power in 6 patients). 5/11 patients had symptoms (nausea) during EGG recording and all had an abnormal EGG. The major abnormalities of EGG were tachygastria and a decrease in EGG postprandial power change. In comparison with asymptomatic patients at the time of the study, symptomatic patients had significantly more tachgastria (20.4 ± 3.9% vs. 6.7 ± 2.7%, P = 0.01) and significantly less normal slow waves (67.6 ± 2.0% vs. 86.7 ± 2.8%, P < 0.05) in the fed state. The increase in EGG postptandial power in symptomatic patients was also significantly less than asymptomatic patients (­2.55 ± 1.01 dB vs. 1.14 ± 0.54 dB, P < 0.05). Conclusions: 1) Abnormalities of EGG are presented in CVS between acute episodes and could explain some of the symptoms present; 2) Abnormal gastric myoelectrical activity is part of the spectrum of the CVS patients.     

Hormonal control of diabetes type 2 after surgery: Clinical and experimental evaluation

Diabetes mellitus (DM) type 2 now afflicts over 170 million people worldwide, a number expected to surpass 220 million by 2010. DM and its associated complications is a significant burden to public health care funding. In 2007, $US174 billion was spent in the United States, according to the American Diabetic Society. The morbidly obese have high serum leptin and insulin levels and low ghrelin levels, which have been associated with altered satiety. Exercise, medical therapy and dieting usually do not result in long‐term weight loss or euglycemia. Bariatric surgery yields euglycemia for many patients, but its mechanism has yet to be fully elucidated. Our preliminary studies showed resolution of DM after both gastric bypass (GBP) and sleeve gastrectomy (SG), more so than after gastric banding. GBP significantly reduces ghrelin levels in the morbidly obese, perhaps as a result of exhausting ghrelin production in the stomach. A reduction in serum ghrelin levels would be expected after SG, which extirpates the ghrelin‐producing cells by removing the fundus. This question has not, to our knowledge, been fully explored with regard to the relationship between ghrelin and other hormones.     

Two common mitochondrial DNA polymorphisms are highly associated with migraine headache and cyclic vomiting syndrome

Mitochondrial dysfunction is a hypothesized component in the multifactorial pathogenesis of migraine without aura (MoA, 'common migraine') and the related condition of cyclic vomiting syndrome (CVS). In this study, the entire mitochondrial genome was sequenced in 20 haplogroup-H CVS patients, a subject group studied because of greater genotypic and phenotypic homogeneity. Sequences were compared against haplogroup-H controls. Polymorphisms of interest were tested in 10 additional CVS subjects and in 112 haplogroup-H adults with MoA. The 16519C→T polymorphism was found to be highly disease associated: 21/30 CVS subjects [70%, odds ratio (OR) 6.2] and 58/112 migraineurs (52%, OR 3.6) vs. 63/231 controls (27%). A second polymorphism, 3010G→A, was found to be highly disease associated in those subjects with 16519T: 6/21 CVS subjects (29%, OR 17) and 15/58 migraineurs (26%, OR 15) vs. 1/63 controls (1.6%). Our data suggest that these polymorphisms constitute a substantial proportion of the genetic factor in migraine pathogenesis, and strengthen the hypothesis that there is a component of mitochondrial dysfunction in migraine.     

Neuroactive neurosteroids: dehydroepiandrosterone (DHEA) and DHEA sulphate

Dehydroepiandrosterone (DHEA) and its sulphate ester (DHEAS) are neuroactive and are both imported into the brain from the circulation and produced in the nervous system. These neurosteroids have neurotrophic and excitatiory effets, and further study is needed to delineate their physiological and pathological functions.     

Fetal hyaloid artery: timing of regression with US

Large-aperture, dynamically focused ultrasonic imaging permits noninvasive, anatomic study of the eye at the millimeter level in the second and third trimesters of pregnancy. The authors report their observations of the hyaloid artery in 210 of 219 fetuses examined with this technique. This vessel is seen in fetuses of 20 weeks gestational age or less and regresses spontaneously at the start of the third trimester. The 210 subjects included 100 who were examined at gestational ages of 16-32 weeks or more and 85 healthy fetuses and 25 with pathologic findings at birth who were examined at 34 weeks gestational age to term. The presence of the hyaloid artery in the mid third trimester was uncommon in healthy subjects (less than 1%) and was not seen in any beyond 29.9 weeks gestational age. However, in nine of the 25 fetuses with abnormalities (five with trisomy syndromes), the vessel was seen at 30.8-36.8 weeks gestational age. The temporarily delayed regression of the hyaloid artery may occur with trisomy 21 syndrome and other forms of retarded brain development.