Guided stem cell cardiopoiesis: discovery and translation

Over 1000 patients have participated worldwide in clinical trials exploring the therapeutic value of bone marrow-derived cells in ischemic heart disease. Meta-analysis evaluation of this global effort indicates that adult stem cell therapy is in general safe, but yields a rather modest level of improvement in cardiac function and structural remodeling in the setting of acute myocardial infarction or chronic heart failure. Although promising, the potential of translating adult stem cell-based therapy from bench to bedside has yet to be fully realized. Inter-trial and inter-patient variability contribute to disparity in the regenerative potential of transplanted stem cells with unpredictable efficacy on follow-up. Strategies that mimic the natural embryonic program for uniform recruitment of cardiogenic progenitors from adult sources are currently tested to secure consistent outcome. Guided cardiopoiesis has been implemented with mesenchymal stem cells obtained from bone marrow of healthy volunteers, using a cocktail of secreted proteins that recapitulate components of the endodermal secretome critical for cardiogenic induction of embryonic mesoderm. With appropriate validation of this newly derived cardiopoietic phenotype, the next generation of trials should achieve demonstrable benefit across patient populations.     

A proteomic analysis on human sperm tail: comparison between normozoospermia and asthenozoospermia

Purpose

Asthenozoospermia is a common cause of human male infertility characterized by reduced sperm motility. The molecular mechanism that impairs sperm motility is not fully understood. This study proposed to identify novel biomarkers by focusing on sperm tail proteomic analysis of asthenozoospermic patients.

Methods

Sperm were isolated from normozoospermic and asthenozoospermic semen samples. Tail fractions were obtained by sonication followed by Percoll gradient. The proteins were extracted by solubilization and subjected to two-dimensional gel electrophoresis (2-DE); then, the spots were analyzed using Image Master 2D Platinum software. The significantly increased/decreased amounts of proteins in the two groups were exploited by matrix-assisted laser desorption-ionization time-of-flight/time-of-flight (MALDI-TOF-TOF) mass spectrometry.

Results

Three hundred ninety protein spots were detected in both groups. Twenty-one protein spots that had significantly altered amounts (p < 0.05) were excised and exploited using MALDI-TOF-TOF mass spectrometry. They led to the identification of the following 14 unique proteins: Tubulin beta 2B; glutathione S-transferase Mu 3; keratin, type II cytoskeletal 1; outer dense fiber protein 2; voltage-dependent anion-selective channel protein 2; A-kinase anchor protein 4; cytochrome c oxidase subunit 6B; sperm protein associated with the nucleus on the X chromosome B; phospholipid hydroperoxide glutathione peroxidase-mitochondrial; isoaspartyl peptidase/L-asparaginase; heat shock-related 70 kDa protein 2; stress-70 protein, mitochondrial; glyceraldehyde-3-phosphate dehydrogenase, testis-specific and clusterin.

Conclusion

Fourteen proteins present in different amounts in asthenozoospermic sperm tail samples were identified, four of which are reported here for the first time. These proteins might be used as markers for the better diagnosis of sperm dysfunctions, targets for male contraceptive development, and to predict embryo quality.     

A relatively high prevalence and severity of asthma,allergic rhinitis and atopic eczema in schoolchildren in the Sultanate of Oman

OBJECTIVES: Although asthma, allergic rhinitis and eczema are among the most common chronic diseases in children worldwide, there is very limited information about the burden of these conditions in Oman. The aim of this study was to determine the prevalence and severity of symptoms of asthma, allergic rhinitis and eczema in Omani schoolchildren using the International Study of Asthma and Allergies in Childhood (ISAAC) Phase I questionnaire. METHODS: An Arabic version of the ISAAC Phase I questionnaire was completed by parents of 3893 children aged 6-7 years and self-completed by 3174 children aged 13-14 years, randomly selected from a nationwide sample of public schools. RESULTS: The prevalence rates of reported diagnoses of asthma, allergic rhinitis and eczema were higher in older children (20.7%, 10.5% and 14.4% compared with 10.5%, 7.4% and 7.5%, respectively, in young children). In young children, 277 were current wheezers and of these 40.8% had sleep-disturbing wheeze at least once a week and 45.1% had speech-limiting wheeze during the past year. Similarly, 283 older children were current wheezers, and of these 30.0% had sleep-disturbing wheeze at least once a week and 37.5% had speech-limiting wheeze during the past year. Exercise-induced wheeze was higher in older children (19.2% vs 6.9%; P < 0.001). Allergic rhinitis and eczema were also associated with significant sleep disturbance and limitation of activity in both age groups. CONCLUSION: Allergic conditions in Omani schoolchildren are common and associated with significant morbidity. Further research is required to identify the local risk factors for allergy to allow better understanding and management of these conditions.     

Ultrasound biomicroscopic study of the stability of intraocular lens implants after phacoemulsification cataract surgery

Purpose: To assess the postoperative stability of three‐piece intraocular lens (IOL) implants using ultrasound biomicroscopy (UBM). Methods: This is a prospective observational cohort case series. Best‐corrected visual acuity (BCVA) assessment, slit lamp examination, refraction and UBM evaluation were performed preoperatively and at 1, 6, 12, 18 and 24 months postoperatively. The anterior chamber depth (ACD) and IOL tilt angles at the 12, 6, 3 and 9 o’clock meridians were assessed. Results: Twenty‐one consecutive adult patients (21 study eyes) were recruited, but two dropped out from the study. The average age during cataract surgery was 71.7 years (60–83, SD 6.0). There were very slight changes in the refraction and IOL stability characteristics at all the postoperative follow‐up time points. These were not found to be statistically significant, apart from the increase in ACD from months one (3.85 ± SD 0.29) to six (3.91 ± SD 0.26) (p = 0.01, paired t‐test). Conclusion: There was a small but statistically significant increase in ACD between the first and sixth postoperative month, but ACD remained stable thereafter. This was not associated with any significant changes in refraction or BCVA. In contrast, IOL optic tilt remained statistically unchanged throughout the 24‐month study duration.     

Heart-After-Liver Transplantation Attenuates Rejection of Cardiac Allografts in Sensitized Patients

BackgroundIn patients undergoing heart transplantation, significant allosensitization limits access to organs, resulting in longer wait times and high waitlist mortality. Current desensitization strategies are limited in enabling successful transplantation.ObjectivesThe purpose of this study was to describe the cumulative experience of combined heart-liver transplantation using a novel heart-after-liver transplant (HALT) protocol resulting in profound immunologic protection.MethodsReported are the results of a clinical protocol that was instituted to transplant highly sensitized patients requiring combined heart and liver transplantation at a single institution. Patients were dual-organ listed with perceived elevated risk of rejection or markedly prolonged waitlist time due to high levels of allo-antibodies. Detailed immunological data and long-term patient and graft outcomes were obtained.ResultsA total of 7 patients (age 43 ± 7 years, 86% women) with high allosensitization (median calculated panel reactive antibody = 77%) underwent HALT. All had significant, unacceptable donor specific antibodies (DSA) (>4,000 mean fluorescence antibody). Prospective pre-operative flow cytometric T-cell crossmatch was positive in all, and B-cell crossmatch was positive in 5 of 7. After HALT, retrospective crossmatch (B- and T-cell) became negative in all. DSA fell dramatically; at last follow-up, all pre-formed or de novo DSA levels were insignificant at <2,000 mean fluorescence antibody. No patients experienced >1R rejection over a median follow-up of 48 months (interquartile range: 25 to 68 months). There was 1 death due to metastatic cancer and no significant graft dysfunction.ConclusionsA heart-after-liver transplantation protocol enables successful transplantation via near-elimination of DSA and is effective in preventing adverse immunological outcomes in highly sensitized patients listed for combined heart-liver transplantation.     

Central auditory processing and word discrimination in patients with multiple sclerosis

Many multiple sclerosis (MS) patients with normal pure tone threshold suffer from difficulties in their hearing especially speech perception in background noise, which is possibly because of incompetence of central auditory processing in this group. Three audiologic tests including gap in noise test (GIN), duration pattern sequence test (DPST) and word discrimination score (WDS) were used for comparing a number of aspects of central auditory processing between patients with MS and normal subjects. Approximate threshold and percent of correct answers in GIN test, percent of correct answers in DPST test and monosyllabic discrimination in WDS test were obtained through cross-sectional non-invasive study conducted on 26 subjects with relapsing-remitting multiple sclerosis who had mean age of 28.9 (SD 4.1) years, and 26 18–40-year-old ones with normal hearing and mean age of 27.7 (SD 5.2). Results of this study demonstrate increased approximate threshold and reduction of percent of correct answers obtained from GIN test in patients with multiple sclerosis (Pv = 0.0001). Furthermore in patients with MS, the average of correct answers in DPST was lower than normal subjects and finally performance of MS subjects in WDS test in quiet environment was correlated with GIN threshold (r = ?/624, Pr = /003). Results of the present study showed that patients with MS had defect in aspects of central auditory processing consisting of temporal resolution, auditory pattern and the memory for auditory task and difficulty in discrimination of speech in noisy environment that are related to the involvement of central nervous system.     

Growth hormone response to clonidine predicts aggression in Alzheimer's disease

OBJECTIVE: The neurobiology of aggression in Alzheimer's Disease (AD) remains unknown. The objective of this study was to determine if altered central noradrenergic (NE) responsiveness is related to aggression in AD. METHODS: Fifteen institutionalized, non-depressed elderly (11 males, four females, mean age 81.5 +/- 5.5) with probable AD, severe cognitive impairment (MMSE mean 3.3 +/- 4.6) and significant behavioral disturbances (Neuropsychiatric Inventory (NPI) score > or = 8) were studied. Growth Hormone (GH) response to clonidine challenge (5 microg/kg) was used as an index of central alpha(2)-adrenergic function. RESULTS: When patients were divided into those with preserved GH response (GH maximum change from baseline > 0, n = 6) and those with blunted GH response (GH maximum change from baseline < or = 0, n = 9) there were significant differences in levels of aggression as measured by the Cohen-Mansfield Agitation Inventory (CAMI) physical aggression subscale (p = .026). Patients with blunted GH response also had significantly higher levels of aggression against others on the retrospective Overt Aggression Scale (p = 0.027). CONCLUSIONS: Certain types of physically aggressive behaviors are associated with a blunted GH response to clonidine challenge. This finding is consistent with compensatory down-regulation of post-synaptic alpha(2)-adrenergic receptors in response to enhanced NE outflow in aggressive AD patients.