A peptide nucleic acid-neamine conjugate that targets and cleaves HIV-1 TAR RNA inhibits viral replication

The neamine part of the aminoglycoside antibiotic neomycin B was conjugated to a 16 mer peptide nucleic acid (PNA) targeting HIV-1 TAR RNA. Attachment of the neamine core allows cellular uptake of the PNA and results in potent inhibition of HIV-1 replication. The polycationic neamine moiety imparts greater solubility to the PNA and also confers a unique RNA cleavage property to the conjugate which is specific to its target site and functional at physiological concentrations of Mg(2+). These properties suggest a potential therapeutic application for this class of compounds.     

Endogenous peptide: Met-enkephalin-Arg-Phe, differently regulate expression of opioid receptors on chronic treatment

Endogenous peptide, Met-enkephalin-Arg-Phe (Tyr-Gly-Gly-Phe-Met-Arg-Phe; MERF) induces effects like antinociception, inhibit contraction of guinea pig ileum, mouse vas deferens and anti-tussive action. However, results regarding its functional efficiency and selectivity are controversial. Therefore, present study was undertaken to investigate whether MERF on systemic (intra-peritoneal, i.p.) route of administration induce any antinociception or not; to scrutinize the effect of 6 days chronic i.p. treatment of MERF on expression of μ (MOR1), δ (DOR1) and κ (KOR1) opioid receptors; and finally, the antinociceptive effect of two synthetic peptides, MERFamide and (D-Ala²)-MERFamide was compared with MERF on intracerebroventricular administration in order to understand the role of FMRF moiety in analgesic effect of MERF.Pharmacological results revealed that only 68.4 and 91.2 μmol/kg dose induce significant antinociception among various doses. Further, on 6 days chronic treatment, MERF induced significant antinociception in comparison to saline. Differential expression of MOR1 and KOR1 showed continuous up-regulation throughout the treatment whereas DOR1 showed down-regulation in initial 3 days followed by subsequently up-regulation during the latter observable period. Moreover, variation in opioid receptors expression had not affected the MERF antinociception.In conclusion, present study discursively demonstrates that MERF during chronic treatment interacts with all three opioid receptors (μ, δ and κ) in rats and differently regulates their expression. Further, the interaction was such that the induction was mainly observed at molecular/expression level and not at pharmacological level to affect antinociception.     

Velocardiofacial syndrome with single central incisor

Three siblings and their mother are reported who all had cytogenetically proven velocardiofacial syndrome (VCFS). One boy had normal dental and craniofacial findings, except for an increased cranial base angle. His sister had only one central incisor in the maxilla. One central incisor had also been missing in the primary dentition. She had no labial frenulum present. Cephalometry showed a small maxillary unit length indicating mild maxillary hypoplasia, an increased anterior face height, steep mandibular plane angle, retruded chin, and a large cranial base angle. Dental measurements showed retroclined lower incisors and increased interincisal angle. A second sister had a cleft of the secondary palate. All permanent teeth were present with the exception of a missing central incisor in the lower jaw: the single lower central incisor was situated in the midline. Her cephalometry showed similar findings as in her sister. All three siblings required palate surgery for speech. Mother was not available for detailed dental and other oral investigations. A single maxillary central incisor has previously been reported in VCFS, but to our knowledge a single central incisor in the mandible has not been reported previously in this entity.     

Hypoplasia and hypodontia in Van der Woude syndrome.

OBJECTIVE: The purpose of this study was (1) to assess maxillary development in cleft individuals with Van der Woude syndrome (VWS) and (2) to compare hypodontia in VWS and nonsyndromic cleft matched controls. DESIGN AND SETTING: Retrospective case-control study from the Center for Craniofacial Anomalies, University of California, San Francisco, California. PATIENTS AND PARTICIPANTS: The sample consisted of 15 individuals with Van der Woude syndrome and 15 nonsyndromic cleft lip and/or palate controls paired for age, gender, and cleft type in the age range of 5 to 13 years. MAIN OUTCOME MEASURES: Cephalograms were digitized, and 31 linear and angular measurements were made. Serial panoramic radiographs were used to assess the presence or absence of permanent teeth. RESULTS: The maxillary sagittal position represented by midface length (Co-A) was significantly shorter in the Van der Woude syndrome subjects than in the matched controls (p = .031), suggesting a trend towards greater maxillary hypoplasia, particularly in Van der Woude syndrome with bilateral cleft lip and/ or palate. Measurements indicating sagittal jaw relationship (ANB angle and the Wits) were significantly smaller in the children with Van der Woude syndrome than in matched controls (p = .008 and p = .006). A significantly larger number of individuals with Van der Woude syndrome than matched controls had missing teeth (p = .014). The mandibular second premolar was missing more frequently in children with Van der Woude syndrome than in the matched controls (p = .031). The differences concerning both maxillary hypoplasia and hypodontia were most marked in the more severe cleft type, represented by bilateral cleft lip and/or palate. CONCLUSIONS: Based on these findings, the expectation is that there will be maxillary hypoplasia and hypodontia of greater severity in Van der Woude syndrome than in nonsyndromic clefts.     

Morphologic and management characteristics of individuals with unilateral cleft lip and palate who required maxillary advancement.

OBJECTIVE: To delineate factors that may contribute to maxillary hypoplasia requiring maxillary advancement surgery in individuals with nonsyndromic unilateral cleft lip and palate (UCLP). METHODS: This retrospective, longitudinal study used lateral cephalometric radiographs and chart reviews of 16 nonsyndromic UCLP individuals who underwent Le Fort I maxillary advancement and 16 controls matched for cleft type, age, and gender. Cephalometric measurements were made at three time points (T1, T2, and T3): mean ages of 10.7, 13.3, and 15.8 years for the Le Fort group and 10.11, 12.9, and 15.7 years, respectively, for the control group. Information regarding team care, timing and number of surgical procedures, and number of congenitally missing teeth were determined from clinical records. RESULTS: The Le Fort group had significant maxillary hypoplasia at all time points compared to the UCLP controls, indicated by midface length measurements, ANB and Wit's analysis (p < .001). The Le Fort group had twice the number of palatal surgical procedures and number of missing teeth in the maxillary arch as compared with the cleft controls. Most of the control group had consistent team care, while most of the surgical group did not. CONCLUSIONS: Maxillary hypoplasia that will require a Le Fort I advancement can be determined as early as age 10. Multiple missing maxillary teeth, secondary palate procedures including pharyngeal flaps, and inconsistent team care with delayed orthodontic intervention are contributing factors to maxillary underdevelopment.     

A PNA-transportan conjugate targeted to the TAR region of the HIV-1 genome exhibits both antiviral and virucidal properties

We have earlier reported that anti-TAR PNA conjugated with the membrane-transducing peptide transportan inhibits transactivation of the HIV-1 LTR resulting in decreased production of HIV-1 virions by chronically infected H9 cells (N., Kaushik, A., Basu, P., Palumbo, R.L., Myers, V.N., Pandey, 2002. Anti-TAR polyamide nucleotide analog conjugated with a membrane permeating peptide inhibits HIV-1 production. J. Virol. 76, 3881-3891). In this study, we have found that the PNA(TAR)-transportan conjugate is efficiently internalized by cells and kinetics analysis reveals a sigmoidal curve with a cooperativity index of 6, indicating very rapid cellular uptake. Additionally, analysis of uptake at varying temperatures or in the presence of phenylarsine oxide revealed that the mechanism of uptake is neither receptor-dependent nor occurs via endocytosis. We also found that the PNA(TAR)-transportan conjugate exhibits potent virucidal activity as HIV-1 virions pretreated with the conjugate were rendered noninfectious, suggesting that the conjugate may also permeate the virus envelope. The anti-HIV-1 virucidal activity of the conjugate may be useful either in topical formulations designed to block HIV-1 infection or as a prophylactic agent for inactivation of HIV-1 in the circulating plasma prior to attachment and entry.     

Case reports of oculofaciocardiodental syndrome with unusual dental findings

We report on two new cases of oculofaciocardiodental (OFCD) syndrome characterized by cataracts, microphthalmia, facial anomalies, cleft palate, cardiac septal defects, and canine radiculomegaly. We also review previous patients. The syndrome is caused by mutations in the BCOR gene, which maps to Xp11.4. Mutational analysis in one of our patients showed a deletion of a single nucleotide, c.2613delC, predicting a novel frameshift mutation with a premature stop codon, p.F871Lfs8X.