A Clinical Trial to Introduce Voluntary Medical Male Circumcision for HIV Prevention in Areas of High Prevalence in the Dominican Republic

Background

Voluntary Medical Male Circumcision (VMMC) is an effective strategy to reduce the risk of HIV infection. Studies conducted in the Dominican Republic (DR) suggest that acceptability of VMMC among men may be as high as 67%. The goal of this clinical trial was to assess the acceptability, uptake and safety for VMMC services in two areas of high HIV prevalence in the country.

Methods

This was a single-arm, non-randomized, pragmatic clinical trial. Study personnel received background information about the risks and benefits of VMMC and practical training on the surgical technique. A native speaking research assistant administered a questionnaire of demographics, sexual practices and knowledge about VMMC. One week after the surgery, participants returned for wound inspection and to answer questions about their post-surgical experience.

Results

539 men consented for the study. Fifty seven were excluded from participation for medical or anatomical reasons and 28 decided not to have the procedure after providing consent. A total of 454 men were circumcised using the Forceps Guided Method Under Local Anesthesia. The rate of adverse events (AE) was 4.4% (20% moderate, 80% mild). There were no serious AEs and all complications resolved promptly with treatment. Eighty eight percent of clients reported being “very satisfied” and 12% were “somewhat satisfied” with the outcome at the one-week postoperative visit.

Conclusions

Recruitment and uptake were satisfactory. Client satisfaction with VMMC was high and the rate of AEs was low. Roll out of VMMC in targeted areas of the DR is feasible and should be considered.

Trial Registration

ClinicalTrials.gov NCT02337179     

The Enfacement Illusion Is Not Affected by Negative Facial Expressions

Enfacement is an illusion wherein synchronous visual and tactile inputs update the mental representation of one’s own face to assimilate another person’s face. Emotional facial expressions, serving as communicative signals, may influence enfacement by increasing the observer’s motivation to understand the mental state of the expresser. Fearful expressions, in particular, might increase enfacement because they are valuable for adaptive behavior and more strongly represented in somatosensory cortex than other emotions. In the present study, a face was seen being touched at the same time as the participant’s own face. This face was either neutral, fearful, or angry. Anger was chosen as an emotional control condition for fear because it is similarly negative but induces less somatosensory resonance, and requires additional knowledge (i.e., contextual information and social contingencies) to effectively guide behavior. We hypothesized that seeing a fearful face (but not an angry one) would increase enfacement because of greater somatosensory resonance. Surprisingly, neither fearful nor angry expressions modulated the degree of enfacement relative to neutral expressions. Synchronous interpersonal visuo-tactile stimulation led to assimilation of the other’s face, but this assimilation was not modulated by facial expression processing. This finding suggests that dynamic, multisensory processes of self-face identification operate independently of facial expression processing.     

Differential Expression of Non-Shelterin Genes Associated with High Telomerase Levels and Telomere Shortening in Plasma Cell Disorders

Telomerase, shelterin proteins and various interacting factors, named non-shelterin proteins, are involved in the regulation of telomere length (TL). Altered expression of any of these telomere-associated genes can lead to telomere dysfunction, causing genomic instability and disease development. In this study, we investigated the expression profile of a set of non-shelterin genes involved in essential processes such as replication (RPA1), DNA damage repair pathways (MRE11-RAD50-NBS1) and stabilization of telomerase complex (DKC1), in 35 patients with monoclonal gammopathy of undetermined significance (MGUS) and 40 cases with multiple myeloma (MM). Results were correlated with hTERT expression, TL and clinical parameters. Overall, a significant increase in DKC1, RAD50, MRE11, NBS1 and RPA1 expression along with an upregulation of hTERT in MM compared with MGUS was observed (p≤0.032). Interestingly, in both entities high mRNA levels of non-shelterin genes were associated with short TLs and increased hTERT expression. Significant differences were observed for DKC1 in MM (p ≤0.026), suggesting an important role for this gene in the maintenance of short telomeres by telomerase in myeloma plasma cells. With regard to clinical associations, we observed a significant increase in DKC1, RAD50, MRE11 and RPA1 expression in MM cases with high bone marrow infiltration (p≤0.03) and a tendency towards cases with advanced ISS stage, providing the first evidence of non-shelterin genes associated to risk factors in MM. Taken together, our findings bring new insights into the intricate mechanisms by which telomere-associated proteins collaborate in the maintenance of plasma cells immortalization and suggest a role for the upregulation of these genes in the progression of the disease.     

i-Motif formation and spontaneous deletions in human cells

Concatemers of d(TCCC) that were first detected through their association with deletions at the RACK7 locus, are widespread throughout the human genome. Circular dichroism spectra show that d(GGGA)_n sequences form G-quadruplexes when n > 3, while i-motif structures form at d(TCCC)_n sequences at neutral pH when n ≥ 7 in vitro. In the PC3 cell line, deletions are observed only when the d(TCCC)_n variant is long enough to form significant levels of unresolved i-motif structure at neutral pH. The presence of an unresolved i-motif at a representative d(TCCC)_n element at RACK7 was suggested by experiments showing that that the region containing the d(TCCC)₉ element was susceptible to bisulfite attack in native DNA and that d(TCCC)₉ oligo formed an i-motif structure at neutral pH. This in turn suggested that that the i-motif present at this site in native DNA must be susceptible to bisulfite mediated deamination even though it is a closed structure. Bisulfite deamination of the i-motif structure in the model oligodeoxynucleotide was confirmed using mass spectrometry analysis. We conclude that while G-quadruplex formation may contribute to spontaneous mutation at these sites, deletions actually require the potential for i-motif to form and remain unresolved at neutral pH.     

Neurite Extension Occurs in the Absence of Regulated Exocytosis in PC12 Subclones

We have investigated the process leading to differentiation of PC12 cells. This process is known to include extension of neurites and changes in the expression of subsets of proteins involved in cytoskeletal rearrangements or in neurosecretion. To this aim, we have studied a PC12 clone (trk-PC12) stably transfected with the nerve growth factor receptor TrkA. These cells are able to undergo both spontaneous and neurotrophin-induced morphological differentiation. However, both undifferentiated and nerve growth factor-differentiated trk-PC12 cells appear to be completely defective in the expression of proteins of the secretory apparatus, including proteins of synaptic vesicles and large dense-core granules, neurotransmitter transporters, and neurotransmitter-synthesizing enzymes. These results indicate that neurite extension can occur independently of the presence of the neurosecretory machinery, including the proteins that constitute the fusion machine, suggesting the existence of differential activation pathways for the two processes during neuronal differentiation. These findings have been confirmed in independent clones obtained from PC12-27, a previously characterized PC12 variant clone globally incompetent for regulated secretion. In contrast, the integrity of the Rab cycle appears to be necessary for neurite extension, because antisense oligonucleotides against the neurospecific isoform of Rab-guanosine diphosphate-dissociation inhibitor significantly interfere with process formation.     

Potential therapeutic effect of yeast killer toxin

Experimental infections were produced in guinea pigs, rabbits and dogs with lesions similar to those seen in human seborrheic dermatitis and otitis externa by cutaneous application of cultures of Malassezia furfur and M. pachydermatis. Infected animals were treated by topical application of a concentrated yeast killer toxin (Hansenula anomala UCSC 25F). Clinical recovery as well as negative mycological test cultures of infected animals proved to the clearly associated with the treatment by the killer toxin.     

Activation of Dopamine D2 Receptors Linked to Voltage-Sensitive Potassium Channels Reduces Forskolin-Induced Cyclic AMP Formation in Rat Pituitary Cells

3,4-Dihydroxyphenylethylamine (dopamine) D2 receptor agonists, including BHT 920 and bromocriptine, and the potassium channel opener minoxidil share the property of hyperpolarizing the plasma membrane by activating voltage-dependent potassium channels. These drugs were tested for their ability to inhibit the cyclic AMP formation induced by forskolin either in intact or in broken pituitary cells. In contrast to bromocriptine, which was active in both experimental systems, BHT 920 and minoxidil inhibited the forskolin-induced cyclic AMP formation in intact-cell but not in broken-cell preparations. The effects of BHT 920 were (a) concentration dependent, with a calculated IC50 of 0.7 microM, (b) dopaminergic in nature, being specifically antagonized by sulpiride, (c) not additive with those induced by minoxidil, and (d) less effective in the presence of potassium channel blockers, such as 4-aminopyridine and tetraethylammonium. These data indicate that the inhibition of forskolin-induced cyclic AMP formation by BHT 920 in intact pituitary cells is not a primary consequence of receptor occupation, but a late event, possibly related to the opening of voltage-dependent potassium channels elicited by this drug through the activation of a subtype of dopamine D2 receptors uncoupled to adenylyl cyclase.