Analysis of TACI mutations in CVID & RESPI patients who have inherited HLA B*44 or HLA*B8

Background  

Recent reports have suggested that Common Variable Immunodeficieny (CVID) can present as an autosomal dominant trait dependent on the inheritance of a set of uncommon mutations/alleles of TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) involving exons 3 or 4. Penetrance, however, appears to be incomplete. Among our clinic population, the greatest genetic linkage for CVID is to the major histocompatibility complex (MHC) on chromosome 6. The majority of our patients have inherited HLA *DQ2, *DR7, *DR3(17), *B8, and/or *B44. Of these, HLA*B44 was present in almost half of the patients and was thus the most common susceptibility allele. HLA *B44 was also found to be over-represented among patients who presented to our clinic with adult-onset recurrent sinopulmonary infections (RESPI) and normal serum immunoglobulin levels, a cohort that included first and second degree relatives of patients with CVID. One of the two original reports of the association between TACI and CVID also reported Human Leukocyte Antigen (HLA) haplotypes. Of 13 affected subjects, nine had inherited HLA *B8 and six had inherited HLA B44. This raised the possibility that TACI mutations might synergize with MHC class I alleles to enhance susceptibility to humoral immune deficiency.     

N,N'-Alkane-diyl-bis-3-picoliniums as nicotinic receptor antagonists: inhibition of nicotine-evoked dopamine release and hyperactivity

The current study evaluated a new series of N,N'-alkane-diyl-bis-3-picolinium (bAPi) analogs with C6-C12 methylene linkers as nicotinic acetylcholine receptor (nAChR) antagonists, for nicotine-evoked [3H]dopamine (DA) overflow, for blood-brain barrier choline transporter affinity, and for attenuation of discriminative stimulus and locomotor stimulant effects of nicotine. bAPi analogs exhibited little affinity for alpha4beta2* (* indicates putative nAChR subtype assignment) and alpha7* high-affinity ligand binding sites and exhibited no inhibition of DA transporter function. With the exception of C6, all analogs inhibited nicotine-evoked [3H]DA overflow (IC50 = 2 nM-6 microM; Imax = 54-64%), with N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; C12) being most potent. bPiDDB did not inhibit electrically evoked [3H]DA overflow, suggesting specific nAChR inhibitory effects and a lack of toxicity to DA neurons. Schild analysis suggested that bPiDDB interacts in an orthosteric manner at nAChRs mediating nicotine-evoked [3H]DA overflow. To determine whether bPiDDB interacts with alpha-conotoxin MII-sensitive alpha6beta2-containing nAChRs, slices were exposed concomitantly to maximally effective concentrations of bPiDDB (10 nM) and alpha-conotoxin MII (1 nM). Inhibition of nicotine-evoked [3H]DA overflow was not different with the combination compared with either antagonist alone, suggesting that bPiDDB interacts with alpha6beta2-containing nAChRs. C7, C8, C10, and C12 analogs exhibited high affinity for the blood-brain barrier choline transporter in vivo, suggesting brain bioavailability. Although none of the analogs altered the discriminative stimulus effect of nicotine, C8, C9, C10, and C12 analogs decreased nicotine-induced hyperactivity in nicotine-sensitized rats, without reducing spontaneous activity. Further development of nAChR antagonists that inhibit nicotine-evoked DA release and penetrate brain to antagonize DA-mediated locomotor stimulant effects of nicotine as novel treatments for nicotine addiction is warranted.     

Memory impairment, oxidative damage and apoptosis induced by space radiation: ameliorative potential of alpha-lipoic acid

Exposure to high-energy particle radiation (HZE) may cause oxidative stress and cognitive impairment in the same manner that seen in aged mice. This phenomenon has raised the concerns about the safety of an extended manned mission into deep space where a significant portion of the radiation burden would come from HZE particle radiation. The present study aimed at investigating the role of alpha-lipoic acid against space radiation-induced oxidative stress and antioxidant status in cerebellum and its correlation with cognitive dysfunction. We observed spontaneous motor activities and spatial memory task of mice using pyroelectric infrared sensor and programmed video tracking system, respectively. Whole body irradiation of mice with high-LET (56)Fe beams (500 MeV/nucleon, 1.5 Gy) substantially impaired the reference memory at 30 day post-irradiation; however, no significant effect was observed on motor activities of mice. Acute intraperitoneal treatment of mice with alpha-lipoic acid prior to irradiation significantly attenuated such memory dysfunction. Radiation-induced apoptotic damage in cerebellum was examined using a neuronal-specific terminal deoxynucleotidyl transferase-mediated nick end-labeling method (NeuroTACS). Radiation-induced apoptotic and necrotic cell death of granule cells and Purkinje cells were inhibited significantly by alpha-lipoic acid pretreatment. Alpha-lipoic acid pretreatment exerted a very high magnitude of protection against radiation-induced augmentation of DNA damage (comet tail movement and serum 8-OHdG), lipid proxidation products (MDA+HAE) and protein carbonyls in mice cerebellum. Further, radiation-induced decline of non-protein sulfhydryl (NP-SH) contents of cerebellum and plasma ferric reducing power (FRAP) was also inhibited by alpha-lipoic acid pre-treatment. Results clearly indicate that alpha-lipoic acid is a potent neuroprotective antioxidant. Moreover, present finding also support the idea suggesting the cerebellar involvement in cognition.     

Whole sheep ovary cryopreservation: evaluation of a slow freezing protocol with dimethylsulphoxide

Purpose  

To evaluate a slow freezing method for whole ovary cryopreservation by evaluating effects of added cryoprotectant.     

Revisiting the interaction between birth weight and current body size in the foetal origins of adult disease

The four models proposed for exploring the foetal origins of adult disease (FOAD) hypothesis use the product term between size at birth and current size to determine the relative importance of pre- and post-natal growth on disease in later life. This is a common approach for testing the interaction between an exposure (in this instance size at birth) and an effect modifier (in this instance current size)—incorporating the product term obtained by multiplying the exposure and effect modifier variables within a statistical regression model. This study examines the mathematical basis for this approach and uses computer simulations to demonstrate two potential statistical flaws that might generate misleading findings. The first of these is that the expected value of the partial regression coefficient for the product term (between exposure and effect modifier) will be zero when the outcome, exposure and effect modifier are all continuously distributed and follow a multivariate normal distribution. This is because testing the product interaction term amounts to testing for multivariate normality among the three variables, irrespective of the pair-wise correlations amongst them. The second flaw is that it is possible to generate a statistically significant interaction between exposure and effect modifier, even when none exists, simply by categorising either or both of these variables. These flaws pose a serious challenge to the four models approach proposed for exploring the FOAD hypothesis. The interaction between exposure and effect modifier variables should be interpreted with caution both here and elsewhere in epidemiological analyses.     

Statistical profiling of hospital performance using acute coronary syndrome mortality

Background

In order to improve the quality of care delivered to patients and to enable patient choice, public reports comparing hospital performances are routinely published. Robust systems of hospital ‘report cards’ on performance monitoring and evaluation are therefore crucial in medical decision-making processes. In particular, such systems should effectively account for and minimise systematic differences with regard to definitions and data quality, care and treatment quality, and ‘case mix’.

Methods

Four methods for assessing hospital performance on mortality outcome measures were considered. The methods included combinations of Bayesian fixed- and random-effects models, and risk-adjusted mortality rate, and rank-based profiling techniques. The methods were empirically compared using 30-day mortality in patients admitted with acute coronary syndrome. Agreement was firstly assessed using median estimates between risk-adjusted mortality rates for a hospital and between ranks associated with a hospital’s risk-adjusted mortality rates. Secondly, assessment of agreement was based on a classification of hospitals into low, normal or high performing using risk-adjusted mortality rates and ranks.

Results

There was poor agreement between the point estimates of risk-adjusted mortality rates, but better agreement between ranks. However, for categorised performance, the observed agreement between the methods’ classification of the hospital performance ranged from 90 to 98%. In only two of the six possible pair-wise comparisons was agreement reasonable, as reflected by a Kappa statistic; it was 0.71 between the methods of identifying outliers with the fixed-effect model and 0.77 with the hierarchical model. In the remaining four pair-wise comparisons, the agreement was, at best, moderate.

Conclusions

Even though the inconsistencies among the studied methods raise questions about which hospitals performed better or worse than others, it seems that the choice of the definition of outlying performance is less critical than that of the statistical approach. Therefore there is a need to find robust systems of ‘regulation’ or ‘performance monitoring’ that are meaningful to health service practitioners and providers.     

Relation of left ventricular sphericity to 10-year survival after acute myocardial infarction

After ST-elevation myocardial infarction, the association between left ventricular sphericity (measured by biplane ventriculography) and survival rate at a median of 6.5 years was determined in 825 patients. The highest tertile of sphericity (vs the lowest and middle tertiles) was associated with a decreased 10-year survival rate in patients who had anterior myocardial infarction (p = 0.002), inferior myocardial infarction (p = 0.011), Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow (p = 0.005), or TIMI grade 0 to 2 flow (p = 0.001) in the infarct artery. The independent multivariate predictors of a 10-year survival rate were ejection fraction (p = 0.002), treadmill exercise duration (p = 0.004), biplane left ventricular sphericity index (p = 0.032), age (p = 0.043), and end-systolic volume index (p = 0.047), but not TIMI flow grade.     

New Q waves on the presenting electrocardiogram independently predict increased cardiac mortality following a first ST-elevation myocardial infarction.

AIMS: The prognostic significance of pathological Q waves appearing in the acute phase of myocardial infarction has not been determined. We investigated whether new Q waves on the presenting electrocardiogram of patients with acute ST-segment elevation were independently associated with a worse outcome after a first myocardial infarction. METHODS AND RESULTS: The presence or absence of new Q waves on the presenting electrocardiogram was assessed in 481 patients who presented within 4 h of symptom onset and were randomized to receive either captopril or placebo within 2 h of streptokinase therapy for myocardial infarction. Ventriculography was performed at 22+/-6 days and mortality status was obtained at a median follow-up of 5.6 years. New Q waves were associated with a lower ejection fraction (51+/-13% vs 61+/-12%, P<0.0001), a larger end-systolic volume index (37 ml vs 28 ml, P<0.001), and increased cardiac mortality at 30 days (7% vs 2%, P=0.01) and at follow-up (17% vs 7%, P=0.002). On multivariate analysis, age (P<0.01), new Q waves at presentation (P<0.01) and a history of angina (P=0.046) were independent predictors of cardiac mortality, whereas randomization to captopril and the time from symptom onset to streptokinase administration were not. CONCLUSION: New Q waves at presentation are independently associated with a worse outcome after a first myocardial infarction. The presence of new Q waves on the presenting electrocardiogram allows very early identification of patients at risk of increased cardiac mortality.     

A novel technique to facilitate laparoscopic repair of large paraesophageal hernias

BACKGROUND: Laparoscopic repair of large paraesophageal hernias (LPEH) is technically challenging, and requires advanced laparoscopic skills. We have developed a novel technique for facilitating laparoscopic repair of LPEHs safely and easily, using a Nelaton catheter. PATIENTS AND METHODS: Seven patients with LPEHs were operated on through a laparoscopic approach. During surgery, the left lobe of the liver and right diaphragmatic crus were elevated using a suspended thread covered by a Nelaton catheter. RESULTS: All patients were operated on laparoscopically using this technique. No patient required conversion to open method. The median operating time was 205 minutes and the range was from 155 to 295 minutes. No intraoperative or early complications occurred in any patient. Late complications occurred in 2 patients due to a small sliding hernia: a slipped fundoplication in 1 patient, and a gastric ulcer in the other. CONCLUSIONS: In conclusion, laparoscopic repair of LPEH is a challenging procedure that requires wide experience in laparoscopic gastroesophageal surgery. Further refinement for this operation may be necessary.