Genetic and Epigenomic Modifiers of Diabetic Neuropathy

Diabetic neuropathy (DN), the most common chronic and progressive complication of diabetes mellitus (DM), strongly affects patients’ quality of life. DN could be present as peripheral, autonomous or, clinically also relevant, uremic neuropathy. The etiopathogenesis of DN is multifactorial, and genetic components play a role both in its occurrence and clinical course. A number of gene polymorphisms in candidate genes have been assessed as susceptibility factors for DN, and most of them are linked to mechanisms such as reactive oxygen species production, neurovascular impairments and modified protein glycosylation, as well as immunomodulation and inflammation. Different epigenomic mechanisms such as DNA methylation, histone modifications and non-coding RNA action have been studied in DN, which also underline the importance of “metabolic memory” in DN appearance and progression. In this review, we summarize most of the relevant data in the field of genetics and epigenomics of DN, hoping they will become significant for diagnosis, therapy and prevention of DN.     

Screening for cervical cancer: experience from the Colposcopy Clinic at Harare Hospital

A study was carried out to determine the prevalence of cervical intra-epithelial neoplasia (CIN) among women referred to Harare Hospital Colposcopy Clinic with a history of an abnormal smear. During the period, 132 patients were seen and 79 (60 pc) had colposcopic findings suggestive of CIN and 17 (13 pc) had inflammatory changes and 36 (27 pc) had normal findings. Electrocautery was used to treat low grade CIN lesions, cone biopsy was performed for higher grades of CIN and a selected group underwent hysterectomy.     

Conformation and activity of mannose- and N-acetylgalactosamine-specific lectins from Vicia villosa seeds

The conformation of two Vicia villosa lectins specific for mannose and N-acetylgalactosamine, respectively, was studied by circular dichroism. Both showed a broad negative CD band around 220 nm and a positive one above 190 nm. CD data analysis indicated that they were rich in beta-sheet. However, they differed in conformational stability against extreme pH, at elevated temperature, and in guanidine hydrochloride and sodium dodecyl sulfate solutions. The unusual feature was that the conformation of N-acetylgalactosamine-specific lectin was virtually unaltered in 6 M guanidine hydrochloride and 7.5 mM surfactant.     

Performance of ultra wide band system using nonlinear receiver in the presence of interference

The performance of a time hopping combined with pulse position modulation ultra wide band system with a nonlinear receiver using an adaptive filter and a soft-limiter in the presence of narrowband interference has been considered. This system brings a significant performance improvement compared with the system that uses an adaptive filter and a linear receiver, particularly in the case of high-interference power where its absence leads to the reception loss. Also, the proposed receiver has much better interference rejection performance compared with minimal mean-square error interference rejection, in case of high-interference power (interference to signal ratios from 30 to 65 dB).     

(+)-CC-1065 as a structural probe of Mu transposase-induced bending of DNA: overcoming limitations of hydroxyl-radical footprinting

Phage Mu transposase (A-protein) is primarily responsible for transposition of the Mu genome. The protein binds to six att sites, three at each end of Mu DNA. At most att sites interaction of a protein monomer with DNA is seen to occur over three minor and two consecutive major grooves and to result in bending up to about 90 degrees. To probe the directionality and locus of these A-protein-induced bends, we have used the antitumor antibiotic (+)-CC-1065 as a structural probe. As a consequence of binding within the minor groove, (+)-CC-1065 is able to alkylate N3 of adenine in a sequence selective manner. This selectivity is partially determined by conformational flexibility of the DNA sequence, and the covalent adduct has a bent DNA structure in which narrowing of the minor groove has occurred. Using this drug in experiments in which either gel retardation or DNA strand breakage are used to monitor the stability of the A-protein--DNA complex or the (+)-CC-1065 alkylation sites on DNA (att site L3), we have demonstrated that of the three minor grooves implicated in the interaction with A-protein, the peripheral two are 'open' or accessible to drug bonding following protein binding. These drug-bonding sites very likely represent binding at at least two A-protein-induced bending sites. Significantly, the locus of bending at these sites is spaced approximately two helical turns apart, and the bending is proposed to occur by narrowing of the minor groove of DNA. The intervening minor groove between these two peripheral sites is protected from (+)-CC-1065 alkylation. The results are discussed in reference to a proposed model for overall DNA bending in the A-protein att L3 site complex. This study illustrates the utility of (+)-CC-1065 as a probe for protein-induced bending of DNA, as well as for interactions of minor groove DNA bending proteins with DNA which may be masked in hydroxyl radical footprinting experiments.     

Effect of pulmonary artery stenoses on the cardiopulmonary response to exercise following repair of tetralogy of Fallot

Data from exercise tests, echocardiograms, and lung perfusion scans were analyzed to determine whether the excessive minute ventilation (VE) often encountered among patients with tetralogy of Fallot is due to ventilation-perfusion mismatch secondary to branch pulmonary artery stenoses. Patients with branch PA stenoses had lower peak oxygen consumptions and higher VE during exercise than did patients without stenoses, and a strong correlation existed between the degree of pulmonary blood flow maldistribution on lung perfusion scan and the amount of excessive VE during exercise.